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  • Insulin‐like growth factor‐1 stimulates regulatory T cells and suppresses autoimmune disease
    1. Daniel Bilbao*,1,,
    2. Luisa Luciani14,
    3. Bjarki Johannesson1,
    4. Agnieszka Piszczek15 and
    5. Nadia Rosenthal1,2,3
    1. 1Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy
    2. 2National Heart and Lung Institute, Imperial College, London, UK
    3. 3Australian Regenerative Medicine Institute/EMBL Australia, Monash University, Clayton, Vic., Australia
    4. 4Sylvester Comprehensive Cancer Center, Miller School of Medicine University of Miami, Miami, FL, USA
    5. 5Institute of Molecular Biotechnology (CSF), Vienna, Austria
    1. *Corresponding author. Tel: +39 069 0091 340; Fax: +39 069 0091 406; E‐mail: bilbao{at}embl.it
    1. These authors contributed equally to this work

    In this study, chronic recombinant human insulin‐like growth factor‐I (rhIGF‐1) delivery is shown to mediate autoimmune suppression in three mouse models of autoimmune disease by stimulating Treg cells expansion, activation and migration into affected tissues.

    Synopsis

    In this study, chronic recombinant human insulin‐like growth factor‐I (rhIGF‐1) delivery is shown to mediate autoimmune suppression in three mouse models of autoimmune disease by stimulating Treg cells expansion, activation and migration into affected tissues.

    • rhIGF‐1 stimulates proliferation of both human and mouse Treg cells in vitro.

    • rhIGF‐1 administered systemically via continuous minipump delivery halts autoimmune disease progression in mouse models of Type 1 diabetes and multiple sclerosis.

    • rhIGF‐1 directly activates Treg cell proliferation by increasing Treg cell concentration in affected tissues as shown in a mouse model where the IGF‐1 receptor was specifically ablated on Treg cells.

    • autoimmunity
    • diabetes
    • IGF‐1
    • multiple sclerosis
    • T regulatory cells
    • Received August 9, 2013.
    • Revision received September 23, 2014.
    • Accepted September 26, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Daniel Bilbao, Luisa Luciani, Bjarki Johannesson, Agnieszka Piszczek, Nadia Rosenthal
  • Combined deletion of Pten and p53 in mammary epithelium accelerates triple‐negative breast cancer with dependency on eEF2K
    1. Jeff C Liu1,
    2. Veronique Voisin2,
    3. Sharon Wang1,3,
    4. Dong‐Yu Wang4,5,
    5. Robert A Jones1,
    6. Alessandro Datti6,7,
    7. David Uehling8,
    8. Rima Al‐awar8,
    9. Sean E Egan9,10,
    10. Gary D Bader2,10,
    11. Ming Tsao4,11,
    12. Tak W Mak5,6,11 and
    13. Eldad Zacksenhaus*,1,3,11
    1. 1Division of Advanced Diagnostics, Toronto General Research Institute – University Health Network, Toronto, ON, Canada
    2. 2The Donnelly Centre, University of Toronto, Toronto, ON, Canada
    3. 3Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada
    4. 4Princess Margaret Cancer Center, Toronto, ON, Canada
    5. 5Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, ON, Canada
    6. 6SMART Laboratory for High‐Throughput Screening Programs, Lunenfeld‐Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON, Canada
    7. 7Department of Agricultural, Food and Environmental Sciences, University of Perugia, Perugia, Italy
    8. 8Drug Discovery Program, Department of Pharmacology and Toxicology, Ontario Institute for Cancer Research, University of Toronto, Toronto, ON, Canada
    9. 9Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
    10. 10Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
    11. 11Department of Medical Biophysics, University Health Network, Toronto, ON, Canada
    1. *Corresponding author. Tel: +1 416 340 4800 5106; E‐mail: eldad.zacksenhaus{at}utoronto.ca

    The tumor suppressors Pten and p53 are frequently lost in triple‐negative breast cancer (TNBC). In double mouse KO, tumors identity changed to a sarcomatoid/mesenchymal subtype; molecular and bioinformatics analyses revealed eEF2K as a potential therapeutic target.

    Synopsis

    The tumor suppressors Pten and p53 are frequently lost in triple‐negative breast cancer (TNBC). In double mouse KO, tumors identity changed to a sarcomatoid/mesenchymal subtype; molecular and bioinformatics analyses revealed eEF2K as a potential therapeutic target.

    • Disruption of Pten and p53 via MMTV‐Cre or WAP‐Cre accelerated formation of claudin‐low‐like TNBC.

    • A 24‐gene set that discriminates Pten/p53‐deficient tumors driven by MMTV‐Cre versus WAP‐Cre transgenes could predict clinical outcome for claudin‐low TNBC patients.

    • Kinome screen identified eEF2K inhibitors as most potent growth suppressors for both mouse and human Pten/p53‐deficient TNBC.

    • eEF2K inhibitors might represent a novel therapy for Pten/p53‐deficient TNBC with high AKT signaling.

    • eEF2K
    • p53
    • prognosis
    • Pten
    • triple‐negative breast cancer
    • Received July 4, 2014.
    • Revision received September 23, 2014.
    • Accepted September 25, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Jeff C Liu, Veronique Voisin, Sharon Wang, Dong‐Yu Wang, Robert A Jones, Alessandro Datti, David Uehling, Rima Al‐awar, Sean E Egan, Gary D Bader, Ming Tsao, Tak W Mak, Eldad Zacksenhaus
  • Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain‐mediated cardiotoxicity
    1. Jian Guan1,,
    2. Shikha Mishra1,,
    3. Yiling Qiu1,
    4. Jianru Shi15,
    5. Kyle Trudeau2,
    6. Guy Las2,
    7. Marc Liesa2,
    8. Orian S Shirihai2,
    9. Lawreen H Connors3,
    10. David C Seldin3,
    11. Rodney H Falk4,
    12. Calum A MacRae1 and
    13. Ronglih Liao*,1,4
    1. 1Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
    2. 2Department of Medicine, Boston University School of Medicine, Boston, MA, USA
    3. 3Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA
    4. 4Cardiac Amyloidosis Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
    5. 5Division of Cardiovascular Medicine, The Heart Institute, Good Samaritan Hospital, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    1. *Corresponding author. Tel: +1 617 525 4864; Fax: +1 617 525 4868; E‐mail: rliao{at}rics.bwh.harvard.edu
    1. These authors contributed equally to this work

    Cardiomyocyte dysfunction associated with immunoglobulin abnormal light chain protein (AL‐LC) proteotoxicity is found to be caused by a dysregulation in autophagy. Genetic or pharmacological restoration of autophagy protects against AL‐LC proteotoxicity and the development of AL amyloid cardiomyopathy.

    Synopsis

    Cardiomyocyte dysfunction associated with immunoglobulin abnormal light chain protein (AL‐LC) proteotoxicity is found to be caused by a dysregulation in autophagy. Genetic or pharmacological restoration of autophagy protects against AL‐ LC proteotoxicity and the development of AL amyloid cardiomyopathy.

    • Impaired lysosomal function and autophagic flux are early and critical steps in amyloidogenic light chain‐induced proteotoxicity.

    • Downregulation of the transcription factor TFEB underlies lysosomal dysfunction with light chain proteotoxicity.

    • Treatment with the small molecule rapamycin restored autophagic flux and protected against amyloidogenic light chain‐induced proteotoxicity.

    • Rapamycin may hold therapeutic promise for the treatment of AL amyloid cardiomyopathy.

    • amyloidosis
    • autophagy
    • cardiac toxicity
    • lysosome
    • mitochondria
    • Received April 21, 2014.
    • Revision received September 19, 2014.
    • Accepted September 19, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Jian Guan, Shikha Mishra, Yiling Qiu, Jianru Shi, Kyle Trudeau, Guy Las, Marc Liesa, Orian S Shirihai, Lawreen H Connors, David C Seldin, Rodney H Falk, Calum A MacRae, Ronglih Liao
  • 5‐azacytidine inhibits nonsense‐mediated decay in a MYC‐dependent fashion
    1. Madhuri Bhuvanagiri1,2,3,
    2. Joe Lewis3,
    3. Kerstin Putzker3,
    4. Jonas P Becker1,2,
    5. Stefan Leicht3,
    6. Jeroen Krijgsveld3,
    7. Richa Batra4,
    8. Brad Turnwald1,2,
    9. Bogdan Jovanovic5,
    10. Christian Hauer1,2,3,
    11. Jana Sieber1,2,
    12. Matthias W Hentze*,1,3 and
    13. Andreas E Kulozik*,1,2
    1. 1Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany
    2. 2Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany
    3. 3European Molecular Biology Laboratory, Heidelberg, Germany
    4. 4Department of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark
    5. 5Centre for Molecular Biology of the University of HeidelbergUniversity of Heidelberg, Heidelberg, Germany
    1. * Corresponding author. Tel: +49 6221 387501; E‐mail: hentze{at}embl.de

      Corresponding author. Tel: +49 6221 564555; E‐mail: andreas.kulozik{at}med.uni-heidelberg.de

    The clinically approved drug 5‐azacytidine inhibits nonsense‐mediated decay (NMD) through a MYC‐dependent mechanism. This supports its repurposing to treat Mendelian or acquired genetic diseases that may benefit from NMD inhibition.

    Synopsis

    The clinically approved drug 5‐azacytidine inhibits nonsense‐mediated decay (NMD) through a MYC‐dependent mechanism. This supports its repurposing to treat Mendelian or acquired genetic diseases that may benefit from NMD inhibition.

    • 5‐azacytidine is medically licensed and has been used for the treatment of some forms of leukemia for many years.

    • Nonsense‐mediated decay (NMD) can be inhibited by 5‐azacytidine via a MYC‐dependent mechanism at concentrations that correspond to drug levels in patients.

    • 5‐azacytidine might thus be repurposed for the treatment of Mendelian or acquired genetic diseases that may benefit from an inhibition of NMD.

    • 5‐azacytidine
    • MYC
    • nonsense‐mediated decay
    • premature termination codons
    • Received July 22, 2014.
    • Revision received September 2, 2014.
    • Accepted September 3, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Madhuri Bhuvanagiri, Joe Lewis, Kerstin Putzker, Jonas P Becker, Stefan Leicht, Jeroen Krijgsveld, Richa Batra, Brad Turnwald, Bogdan Jovanovic, Christian Hauer, Jana Sieber, Matthias W Hentze, Andreas E Kulozik
  • Emerging treatment strategies for glioblastoma multiforme
    1. Steven K Carlsson1,
    2. Shaun P Brothers1 and
    3. Claes Wahlestedt*,1
    1. 1Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation University of Miami Miller School of Medicine, Miami, FL, USA
    1. *Corresponding author. Tel: +1 305 243 7694; Fax: +1 305 243 2523; E‐mail: cwahlestedt{at}med.miami.edu

    A comprehensive overview and discussion of our current understanding of glioblastoma multiforme (GBM) pathophysiology and heterogeneity, diagnostic techniques and treatment options, including novel therapies such as monoclonal antibodies and small‐molecule inhibitors.

    • biomarkers
    • brain imaging
    • cancer stem cells
    • epigenetics
    • glioblastoma multiforme (GBM)
    • Received April 14, 2014.
    • Revision received August 27, 2014.
    • Accepted September 10, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Steven K Carlsson, Shaun P Brothers, Claes Wahlestedt
  • Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2
    1. Kamalika Mojumdar1,,
    2. Feng Liang1,,
    3. Christian Giordano1,
    4. Christian Lemaire1,
    5. Gawiyou Danialou1,
    6. Tatsuma Okazaki1,
    7. Johanne Bourdon1,
    8. Moutih Rafei2,
    9. Jacques Galipeau3,4,
    10. Maziar Divangahi1 and
    11. Basil J Petrof*,1
    1. 1Meakins‐Christie Laboratories and Respiratory Division, McGill University Health Centre and Research Institute, Montreal, QC, Canada
    2. 2Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada
    3. 3Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
    4. 4Department of Pediatrics, Emory University, Atlanta, GA, USA
    1. *Corresponding author. Tel: +1 514 934 1934, ext. 35946; Fax: +1 514 843 1695; E‐mail: basil.petrof{at}mcgill.ca
    1. These authors contributed equally

    Inflammatory macrophages are shown here to play a central role in the mdx‐mouse pathology, a model for Duchenne muscular dystrophy. Genetic ablation or pharmacologic inhibition of CCR2 confers therapeutic benefits in animals, improving muscle structure and function.

    Synopsis

    Inflammatory macrophages are shown here to play a central role in the mdx‐mouse pathology, a model for Duchenne muscular dystrophy. Genetic ablation or pharmacologic inhibition of CCR2 confers therapeutic benefits in animals, improving muscle structure and function.

    • CD11b(high) macrophages (MP) derived from Ly6C(high) inflammatory monocytes are key pathogenesis mediators in the mdx mouse model of Duchenne muscular dystrophy.

    • Loss of CCR2 preferentially reduces CD11b(high) MP accumulation in the mdx diaphragm and mitigates proinflammatory polarization of intramuscular MP.

    • Genetic as well as pharmacological blockade of CCR2 in mdx mice ameliorates dystrophic histopathologic features and improves mdx diaphragm muscle force production.

    • CCR2 blockade may serve as a useful therapeutic modulator of the immune response in muscular dystrophy.

    • CCR2
    • chemokines
    • inflammatory monocytes
    • macrophage polarization
    • muscular dystrophy
    • Received February 17, 2014.
    • Revision received September 16, 2014.
    • Accepted September 18, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Kamalika Mojumdar, Feng Liang, Christian Giordano, Christian Lemaire, Gawiyou Danialou, Tatsuma Okazaki, Johanne Bourdon, Moutih Rafei, Jacques Galipeau, Maziar Divangahi, Basil J Petrof
  • Protection and mechanism of action of a novel human respiratory syncytial virus vaccine candidate based on the extracellular domain of small hydrophobic protein
    1. Bert Schepens*,1,2,
    2. Koen Sedeyn1,2,
    3. Liesbeth Vande Ginste1,2,
    4. Sarah De Baets1,2,
    5. Michael Schotsaert1,2,
    6. Kenny Roose1,2,
    7. Lieselot Houspie3,
    8. Marc Van Ranst3,
    9. Brian Gilbert4,
    10. Nico van Rooijen5,
    11. Walter Fiers1,2,
    12. Pedro Piedra4,6 and
    13. Xavier Saelens*,1,2
    1. 1VIB Inflammation Research Center, Ghent, Belgium
    2. 2Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
    3. 3Laboratory of Clinical Virology, Rega Institute for Medical Research KU Leuven, Leuven, Belgium
    4. 4Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
    5. 5Department of Molecular Cell Biology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
    6. 6Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
    1. * Corresponding author. Tel: +32 9 33 13 624; Fax: +32 9 221 76 73; E‐mail: bert.schepens{at}irc.vib-ugent.be

      Corresponding author. Tel: +32 9 33 13 620; Fax: +32 9 221 76 73; E‐mail: xavier.saelens{at}irc.vib-ugent.be

    Vaccination with the ectodomain of the Small Hydrophobic Protein (SHe) controls pulmonary replication of Human Respiratory Syncytial Virus (HRSV). Combining SHe‐based antigens to vaccines that aim at inducing neutralizing antibodies could further improve immunoprotection against HRSV.

    Synopsis

    Vaccination with the ectodomain of the small hydrophobic protein (SHe) controls pulmonary replication of human respiratory syncytial virus (HRSV). Combining SHe‐based antigens to vaccines that aim at inducing neutralizing antibodies could further improve immunoprotection against HRSV.

    • SHe‐based vaccination induces SHe‐specific non‐neutralizing antibodies that reduce viral replication in two animal models.

    • Pulmonary HRSV replication and associated morbidity are reduced by SHe‐specific immune serum.

    • The reduction of viral replication by SHe‐specific antibodies strongly depends on Fcγ receptor I and/or III and at least partially on alveolar macrophages.

    • HRSV‐infected cells, but not virions, are readily recognized by SHe‐specific antibodies.

    • alveolar macrophages
    • Fcγ receptor
    • human respiratory syncytial virus
    • small hydrophobic protein
    • vaccine
    • Received February 24, 2014.
    • Revision received September 8, 2014.
    • Accepted September 9, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Bert Schepens, Koen Sedeyn, Liesbeth Vande Ginste, Sarah De Baets, Michael Schotsaert, Kenny Roose, Lieselot Houspie, Marc Van Ranst, Brian Gilbert, Nico van Rooijen, Walter Fiers, Pedro Piedra, Xavier Saelens