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  • Cyclic‐di‐GMP signalling and biofilm‐related properties of the Shiga toxin‐producing 2011 German outbreak Escherichia coli O104:H4
    1. Anja M Richter1,,
    2. Tatyana L Povolotsky1,,
    3. Lothar H Wieler2 and
    4. Regine Hengge*,1
    1. 1Institute of Biology / Microbiology Humboldt‐Universität zu Berlin, Berlin, Germany
    2. 2Institute of Microbiology and Epizootics Freie Universität Berlin, Berlin, Germany
    1. *Corresponding author. Tel: +49 2093 8101; Fax: +49 2093 8102; E‐mail: Regine.hengge{at}hu-berlin.de
    1. These authors contributed equally to this work

    The detailed genomic and experimental characterization of cyclic‐di‐GMP signaling and production of biofilm and curli fibres, but not cellulose, reveals a unique combination of features that may provide clues to the high virulence of the 2011 German outbreak Escherichia coli O104:H4 strain.

    Synopsis

    The detailed genomic and experimental characterization of cyclic‐di‐GMP signaling and production of biofilm and curli fibres, but not cellulose, reveals a unique combination of features that may provide clues to the high virulence of the 2011 German outbreak Escherichia coli O104:H4 strain.

    • The outbreak strain has a novel c‐di‐GMP‐producing diguanylate cyclase (DgcX) with the highest expression observed to date for such an enzyme in E. coli.

    • Several other c‐di‐GMP‐related enzymes also show altered expression that can contribute to high c‐di‐GMP accumulation potential.

    • High levels of the c‐di‐GMP‐regulated biofilm regulator CsgD and amyloid curli fibres are produced at human body temperature, combined with an inability to generate cellulose.

    • Since curli fibres were previously shown to be highly inflammatory with cellulose counteracting this effect, this high production of ‘naked’, i.e. non‐cellulose‐associated curli fibres by the outbreak strain may enhance inflammation, thereby facilitating efficient transition of Stx into the blood stream and progression to HUS.

    • amyloid
    • curli
    • EAEC
    • EHEC
    • haemolytic uraemic syndrome
    • Received June 1, 2014.
    • Revision received October 2, 2014.
    • Accepted October 6, 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.

    Anja M Richter, Tatyana L Povolotsky, Lothar H Wieler, Regine Hengge
  • Molecular profiling of single circulating tumor cells with diagnostic intention
    1. Bernhard Polzer1,,
    2. Gianni Medoro2,,
    3. Sophie Pasch3,
    4. Francesca Fontana2,
    5. Laura Zorzino4,
    6. Aurelia Pestka5,
    7. Ulrich Andergassen5,
    8. Franziska Meier‐Stiegen6,
    9. Zbigniew T Czyz1,3,
    10. Barbara Alberter1,
    11. Steffi Treitschke1,
    12. Thomas Schamberger3,
    13. Maximilian Sergio2,
    14. Giulia Bregola2,
    15. Anna Doffini2,
    16. Stefano Gianni2,
    17. Alex Calanca2,
    18. Giulio Signorini2,
    19. Chiara Bolognesi2,
    20. Arndt Hartmann7,
    21. Peter A Fasching8,
    22. Maria T Sandri4,
    23. Brigitte Rack5,
    24. Tanja Fehm6,
    25. Giuseppe Giorgini2,
    26. Nicolò Manaresi2, and
    27. Christoph A Klein*,1,3,
    1. 1Project Group “Personalized Tumor Therapy”, Fraunhofer Institute for Toxicology und Experimental Medicine, Regensburg, Germany
    2. 2Silicon Biosystems S.p.A., Bologna, Italy
    3. 3Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany
    4. 4Division of Laboratory Medicine, European Institute of Oncology, Milan, Italy
    5. 5Department of Gynecology and Obstetrics, University Munich, Munich, Germany
    6. 6Department of Gynecology and Obstetrics, University of Düsseldorf, Düsseldorf, Germany
    7. 7Department of Pathology, University Erlangen, Erlangen, Germany
    8. 8Department of Gynecology and Obstetrics, University Erlangen, Erlangen, Germany
    1. *Corresponding author. Tel: +49 941 9446720; Fax: +49 941 9446719; E‐mail: christoph.klein{at}klinik.uni-regensburg.de
    1. These authors contributed equally and share first authorship

    2. These authors contributed equally and share senior authorship

    A novel workflow enabling detection, isolation and characterization of single circulating tumors cells (CTCs) from blood suggests that CTCs may harbor genetic alterations undetectable in the primary tumor and associated with therapy resistance.

    Synopsis

    A novel workflow enabling detection, isolation and characterization of single circulating tumors cells (CTCs) from blood suggests that CTCs may harbor genetic alterations undetectable in the primary tumor and associated with therapy resistance.

    • Single circulating tumor cells (CTCs) are analyzed by a semi‐automated workflow combining CellSearch® enrichment, DEPArrayTM isolation and Ampli1TM whole genome amplification (WGA).

    • The WGA quality of single CTCs is assessed by a genome integrity index (GII).

    • The GII predicts outcome of downstream sequence‐based molecular assays.

    • Single cell analysis reveals the existence of rare potential therapy escape variants.

    • The diagnostic precision of the workflow enables molecular monitoring of CTCs under iatrogenic selection.

    • breast cancer
    • circulating tumor cells
    • metastasis
    • single cell analysis
    • Received March 5, 2014.
    • Revision received September 25, 2014.
    • Accepted September 29, 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.

    Bernhard Polzer, Gianni Medoro, Sophie Pasch, Francesca Fontana, Laura Zorzino, Aurelia Pestka, Ulrich Andergassen, Franziska Meier‐Stiegen, Zbigniew T Czyz, Barbara Alberter, Steffi Treitschke, Thomas Schamberger, Maximilian Sergio, Giulia Bregola, Anna Doffini, Stefano Gianni, Alex Calanca, Giulio Signorini, Chiara Bolognesi, Arndt Hartmann, Peter A Fasching, Maria T Sandri, Brigitte Rack, Tanja Fehm, Giuseppe Giorgini, Nicolò Manaresi, Christoph A Klein
  • 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