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  • Targeting DDX3 with a small molecule inhibitor for lung cancer therapy
    Targeting DDX3 with a small molecule inhibitor for lung cancer therapy
    1. Guus M Bol1,2,
    2. Farhad Vesuna1,
    3. Min Xie1,
    4. Jing Zeng3,
    5. Khaled Aziz3,
    6. Nishant Gandhi3,
    7. Anne Levine1,
    8. Ashley Irving1,
    9. Dorian Korz1,
    10. Saritha Tantravedi1,
    11. Marise R Heerma van Voss1,2,
    12. Kathleen Gabrielson4,
    13. Evan A Bordt5,
    14. Brian M Polster5,
    15. Leslie Cope6,
    16. Petra van der Groep2,
    17. Atul Kondaskar7,
    18. Michelle A Rudek6,
    19. Ramachandra S Hosmane7,
    20. Elsken van der Wall8,
    21. Paul J van Diest2,6,
    22. Phuoc T Tran3,6 and
    23. Venu Raman*,1,2,6
    1. 1Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    2. 2Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
    3. 3Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    4. 4Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    5. 5Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA
    6. 6Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    7. 7Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, MD, USA
    8. 8Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
    1. *Corresponding author. Tel: +1 410 955 7492; E‐mail: vraman2{at}jhmi.edu

    The RNA helicase DDX3 is a new independent marker of lung cancer and targeted chemotherapy option. The novel inhibitor RK‐33, combined with radiation therapy, induces tumor regression in lung cancer models, with no toxicity at the therapeutic dose.

    Synopsis

    The RNA helicase DDX3 is a new independent marker of lung cancer and targeted chemotherapy option. The novel inhibitor RK‐33, combined with radiation therapy, induces tumor regression in lung cancer models, with no toxicity at the therapeutic dose.

    • The RNA helicase DDX3 is overexpressed in lung cancer and is associated with lower survival in lung cancer patients.

    • Knockdown of DDX3 in highly aggressive lung cancer cell lines (H1299 and A549) curbed their colony‐forming abilities.

    • A small molecule inhibitor of DDX3, RK‐33, designed to bind to the nucleotide‐binding site within the DDX3 protein was synthesized.

    • RK‐33 was able to induce cell cycle arrest causing apoptosis in aggressive lung cancer, but not in normal cells, and promoted sensitization to radiation in DDX3‐overexpressing cells. Mechanistically, RK‐33 inhibited non‐homologous end joining and impaired Wnt signaling by disrupting the DDX3–β‐catenin axis.

    • RK‐33 in combination with radiation, induced tumor regression in multiple mouse models of lung cancer, while showing no toxicity at the therapeutic dose.

    • DDX3
    • DNA repair
    • lung cancer
    • radiation‐sensitizing agent
    • small molecule inhibitor
    • Received June 25, 2014.
    • Revision received February 9, 2015.
    • Accepted February 12, 2015.

    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.

    Guus M Bol, Farhad Vesuna, Min Xie, Jing Zeng, Khaled Aziz, Nishant Gandhi, Anne Levine, Ashley Irving, Dorian Korz, Saritha Tantravedi, Marise R Heerma van Voss, Kathleen Gabrielson, Evan A Bordt, Brian M Polster, Leslie Cope, Petra van der Groep, Atul Kondaskar, Michelle A Rudek, Ramachandra S Hosmane, Elsken van der Wall, Paul J van Diest, Phuoc T Tran, Venu Raman
  • A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis
    A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis
    1. Lavinia Palamiuc1,2,
    2. Anna Schlagowski3,4,
    3. Shyuan T Ngo5,6,
    4. Aurelia Vernay1,2,
    5. Sylvie Dirrig‐Grosch1,2,
    6. Alexandre Henriques1,2,
    7. Anne‐Laurence Boutillier7,
    8. Joffrey Zoll3,4,
    9. Andoni Echaniz‐Laguna1,2,8,
    10. Jean‐Philippe Loeffler*,1,2 and
    11. Frédérique René*,1,2
    1. 1INSERM, U1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France
    2. 2Université de Strasbourg UMRS1118, Strasbourg, France
    3. 3Equipe d'Accueil 3072, Mitochondrie, Stress oxydant et Protection Musculaire, Fédération de Médecine Translationelle de Strasbourg, Université de Strasbourg, Strasbourg, France
    4. 4Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique Hôpitaux Universitaires, CHRU de Strasbourg, Strasbourg, France
    5. 5School of Biomedical Sciences, The University of Queensland, St Lucia, Qld, Australia
    6. 6University of Queensland Centre for Clinical Research, The University of Queensland, Herston, Qld, Australia
    7. 7UMR7364 Laboratoire de Neurosciences Cognitives et Adaptatives, Faculté de Psychologie, Université de Strasbourg‐CNRS, GDR CNRS 2905, Strasbourg, France
    8. 8Département de Neurologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
    1. * Corresponding author. Tel: +33 368 853 081; Fax: +33 368 853 065; E‐mail: loeffler{at}unistra.fr

      Corresponding author. Tel: +33 368 853 086; Fax: +33 368 853 065; E‐mail: frederique.rene{at}unistra.fr

    Altered metabolic homeostasis is an early event in amyotrophic lateral sclerosis (ALS) manifestation. This study reveals that skeletal muscles stop using glucose as a source of energy but use lipids instead and this chronic pathologic alteration in muscles is exacerbated with disease progression.

    Synopsis

    Altered metabolic homeostasis is an early event in amyotrophic lateral sclerosis (ALS) manifestation. This study reveals that skeletal muscles stop using glucose as a source of energy but use lipids instead and this chronic pathologic alteration in muscles is exacerbated with disease progression.

    • The early alteration of muscle metabolic equilibrium between glucose and lipid use impacts on the capacity for muscle to efficiently adapt to increased energetic demands in the SOD1G86R ALS mouse model.

    • PDK4 is central to these metabolic changes, being upregulated at early asymptomatic stages and increasing throughout disease progression in the SOD1G86R model, as well as in ALS patients.

    • The metabolic alterations described are specific to glycolytic muscle (TA) in the SOD1G86R model.

    • Regulation of the glycolytic pathway presents as a potential therapeutic strategy as a drug targeting of PDK4 improves muscle function and overall metabolic status in the SOD1G86R model.

    • amyotrophic lateral sclerosis
    • exercise
    • glucose
    • lipids
    • muscle
    • Received July 14, 2014.
    • Revision received February 17, 2015.
    • Accepted February 20, 2015.

    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.

    Lavinia Palamiuc, Anna Schlagowski, Shyuan T Ngo, Aurelia Vernay, Sylvie Dirrig‐Grosch, Alexandre Henriques, Anne‐Laurence Boutillier, Joffrey Zoll, Andoni Echaniz‐Laguna, Jean‐Philippe Loeffler, Frédérique René
  • Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine
    Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine
    1. Joan Castellsagué1,2,,
    2. Bernat Gel3,,
    3. Juana Fernández‐Rodríguez1,2,,
    4. Roger Llatjós4,
    5. Ignacio Blanco1,
    6. Yolanda Benavente5,
    7. Diana Pérez‐Sidelnikova6,
    8. Javier García‐del Muro7,
    9. Joan Maria Viñals6,
    10. August Vidal4,
    11. Rafael Valdés‐Mas8,
    12. Ernest Terribas3,
    13. Adriana López‐Doriga1,2,
    14. Miguel Angel Pujana2,
    15. Gabriel Capellá1,2,
    16. Xose S Puente8,
    17. Eduard Serra*,3,
    18. Alberto Villanueva*,2 and
    19. Conxi Lázaro*,1,2
    1. 1Hereditary Cancer Program, Catalan Institute of Oncology (ICO‐IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
    2. 2Translational Research Laboratory ICO‐IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
    3. 3Institut de Medicina Predictiva i Personalitzada del Càncer (IMPPC), Badalona, Barcelona, Spain
    4. 4Pathology Service, HUB‐IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
    5. 5Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Program ICO‐IDIBELL and CIBER Epidemiología y Salud Pública (CIBERESP), L'Hospitalet de Llobregat, Barcelona, Spain
    6. 6Plastic Surgery Service HUB‐IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
    7. 7Medical Oncology Service ICO‐IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
    8. 8Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain
    1. * Corresponding author. Tel: +34 93 2607342; Fax: +34 93 2607466; E‐mail: clazaro{at}iconcologia.net

      Corresponding author. Tel: +34 93 2607952; Fax: +34 93 2607466; E‐mail: avillanueva{at}iconcologia.net

      Corresponding author. Tel: +34 93 5543067; Fax: +34 93 4651472; E‐mail: eserra{at}imppc.org

    1. These authors contributed equally to this work

    The first patient‐derived MPNST orthoxenograft models are presented together with a preclinical proof‐of‐concept experimentation that supports the use of sorafenib‐based combination therapy to curb MPNST growth.

    Synopsis

    The first patient‐derived MPNST orthoxenograft models are presented together with a preclinical proof‐of‐concept experimentation that supports the use of sorafenib‐based combination therapy to curb MPNST growth.

    • Five malignant peripheral nerve sheath tumor (MPNST) orthoxenograft models—both sporadic and NF1‐associated—are presented.

    • A comprehensive histological, genomic and transcriptomic characterization shows that the models reliably mimic the respective primary tumors, validating these models for pre‐clinical personalized treatments.

    • A first preclinical drug experimentation performed as a proof of concept shows that combined therapy with sorafenib is the most effective in reducing MPNST growth.

    • MPNST
    • NF1
    • patient‐derived tumor xenograft
    • preclinical mouse models
    • sorafenib
    • Received August 13, 2014.
    • Revision received February 24, 2015.
    • Accepted February 25, 2015.

    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.

    Joan Castellsagué, Bernat Gel, Juana Fernández‐Rodríguez, Roger Llatjós, Ignacio Blanco, Yolanda Benavente, Diana Pérez‐Sidelnikova, Javier García‐del Muro, Joan Maria Viñals, August Vidal, Rafael Valdés‐Mas, Ernest Terribas, Adriana López‐Doriga, Miguel Angel Pujana, Gabriel Capellá, Xose S Puente, Eduard Serra, Alberto Villanueva, Conxi Lázaro
  • The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene
    <div xmlns="http://www.w3.org/1999/xhtml">The clinical heterogeneity of coenzyme Q<sub>10</sub> deficiency results from genotypic differences in the <em>Coq9</em> gene</div>
    1. Marta Luna‐Sánchez1,2,
    2. Elena Díaz‐Casado1,2,
    3. Emanuele Barca3,
    4. Miguel Ángel Tejada4,5,
    5. Ángeles Montilla‐García4,5,
    6. Enrique Javier Cobos4,5,
    7. Germaine Escames1,2,
    8. Dario Acuña‐Castroviejo1,2,
    9. Catarina M Quinzii3 and
    10. Luis Carlos López*,1,2
    1. 1Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain
    2. 2Centro de Investigación Biomédica, Instituto de Biotecnología, Parque Tecnológico de Ciencias de la Salud, Granada, Spain
    3. 3Department of Neurology, Columbia University Medical Center, New York, NY, USA
    4. 4Departamento de Farmacología, Facultad de Medicina, Universidad de Granada, Granada, Spain
    5. 5Centro de Investigación Biomédica, Instituto de Neurociencias, Parque Tecnológico de Ciencias de la Salud, Granada, Spain
    1. *Corresponding author. Tel: +34 9582 41000, ext 20197; E‐mail: luisca{at}ugr.es

    Two different premature terminations in the COQ9 protein uniquely affect the expression levels of components of the multiprotein complex for CoQ biosynthesis, establishing for the first time a genotype/clinical phenotype relationship with therapeutic consequences.

    Synopsis

    Two different premature terminations in the COQ9 protein uniquely affect the expression levels of components of the multiprotein complex for CoQ biosynthesis, establishing for the first time a genotype/clinical phenotype relationship with therapeutic consequences.

    • The first mouse model of mild mitochondrial myopathy due to CoQ deficiency was generated and characterized (Coq9Q95X).

    • The clinical phenotypes of CoQ deficiency observed in two mouse models (Coq9Q95X and Coq9R239X) are caused by genotypic difference in the Coq9 gene and were influenced by the efficiency of nonsense‐mediated mRNA decay.

    • CoQ multiprotein complex for CoQ biosynthesis was destabilized by the presence of a truncated protein in Coq9R239X mice, leading to a severe CoQ deficiency and clinical phenotype.

    • Whether a bypass therapy aimed at increasing CoQ biosynthesis is successful depends on CoQ biosynthetic proteins levels.

    • CoQ multiprotein complex
    • Coq9
    • mitochondrial myopathy
    • mouse model
    • nonsense‐mediated mRNA decay
    • Received October 31, 2014.
    • Revision received February 24, 2015.
    • Accepted February 26, 2015.

    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.

    Marta Luna‐Sánchez, Elena Díaz‐Casado, Emanuele Barca, Miguel Ángel Tejada, Ángeles Montilla‐García, Enrique Javier Cobos, Germaine Escames, Dario Acuña‐Castroviejo, Catarina M Quinzii, Luis Carlos López
  • CRISPR‐Cas9: how research on a bacterial RNA‐guided mechanism opened new perspectives in biotechnology and biomedicine
    CRISPR‐Cas9: how research on a bacterial RNA‐guided mechanism opened new perspectives in biotechnology and biomedicine
    1. Emmanuelle Charpentier (emmanuelle.charpentier{at}mims.umu.se) 1,2,3
    1. 1Department of Regulation in Infection Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
    2. 2Department of Molecular Biology, The Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden
    3. 3Hannover Medical School, Hannover, Germany

    The 2015 Louis‐Jeantet Prize for Medicine winner Emmanuelle Charpentier describes the CRISPR‐Cas9 unique mechanism. The system was harnessed into a new tool that makes genome editing within the cell a simple and straightforward system.

    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.

    Emmanuelle Charpentier
  • Consequence of the tumor‐associated conversion to cyclin D1b
    Consequence of the tumor‐associated conversion to cyclin D1b
    1. Michael A Augello1,2,
    2. Lisa D Berman‐Booty1,2,
    3. Richard Carr 3rd2,3,
    4. Akihiro Yoshida4,5,
    5. Jeffry L Dean1,2,
    6. Matthew J Schiewer1,2,
    7. Felix Y Feng6,7,8,
    8. Scott A Tomlins6,8,9,
    9. Erhe Gao10,
    10. Walter J Koch10,11,
    11. Jeffrey L Benovic2,3,
    12. John Alan Diehl4,5 and
    13. Karen E Knudsen*,1,2,12,13
    1. 1Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
    2. 2Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
    3. 3Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
    4. 4Medical University of South Carolina, Charleston, SC, USA
    5. 5Hollings Cancer Center, Charleston, SC, USA
    6. 6Michigan Center for Translational Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA
    7. 7Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI, USA
    8. 8Comprehensive Cancer Center University of Michigan Medical Center, Ann Arbor, MI, USA
    9. 9Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, USA
    10. 10Pharmacology & Center for Translational Medicine, Philadelphia, PA, USA
    11. 11Temple University School of Medicine, Philadelphia, PA, USA
    12. 12Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA
    13. 13Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA
    1. *Corresponding author. Tel: +1 215 503 8574 (office); +1 215 503 8573 (lab); Fax: +1 215 923 4498; E‐mail: karen.knudsen{at}jefferson.edu

    Novel murine models were generated that mimic tumour‐associated conversion to cyclin D1b and novel links uncovered between cyclin D1b expression and high PARP activity and genome instability markers, which could be exploited to inhibit tumour growth.

    Synopsis

    Novel murine models were generated that mimic tumour‐associated conversion to cyclin D1b and novel links uncovered between cyclin D1b expression and high PARP activity and genome instability markers, which could be exploited to inhibit tumour growth.

    • Novel murine models were generated that mimic the tumor‐associated conversion to cyclin D1b.

    • Induction of cyclin D1b phenocopies some but not all phenotypes observed upon cyclin D1 loss.

    • Unlike cells expressing full‐length cyclin D1, cells expressing endogenous cyclin D1b undergo transformation, thus demonstrating the unique transforming capacity of this cyclin D1 variant.

    • Cyclin D1b induces evidence of DNA damage and promotes PARP1 activity, linking the DNA damage pathway to cyclin D1b‐mediated oncogenic events.

    • Novel means to suppress growth of cyclin D1b‐positive tumor cells were identified, providing the first preclinical insight into means by which to target tumors reliant on cyclin D1b expression.

    • cell cycle
    • cyclin
    • cyclin D1b
    • PARP
    • Received May 10, 2014.
    • Revision received February 12, 2015.
    • Accepted February 13, 2015.

    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.

    Michael A Augello, Lisa D Berman‐Booty, Richard Carr, Akihiro Yoshida, Jeffry L Dean, Matthew J Schiewer, Felix Y Feng, Scott A Tomlins, Erhe Gao, Walter J Koch, Jeffrey L Benovic, John Alan Diehl, Karen E Knudsen
  • Low‐dose TNF augments fracture healing in normal and osteoporotic bone by up‐regulating the innate immune response
    Low‐dose TNF augments fracture healing in normal and osteoporotic bone by up‐regulating the innate immune response
    1. James K Chan1,
    2. Graeme E Glass1,
    3. Adel Ersek1,
    4. Andrew Freidin1,
    5. Garry A Williams14,
    6. Kate Gowers2,
    7. Ana I Espirito Santo1,
    8. Rosemary Jeffery35,
    9. William R Otto3,
    10. Richard Poulsom35,
    11. Marc Feldmann1,
    12. Sara M Rankin2,
    13. Nicole J Horwood1 and
    14. Jagdeep Nanchahal*,1
    1. 1Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
    2. 2National Heart and Lung Institute, Imperial College London, London, UK
    3. 3Histopathology Laboratory and In Situ Hybridisation Service, Cancer Research UK – London Research Institute, London, UK
    4. 4Department of Basic Science and Craniofacial Biology, New York University, New York, NY, USA
    5. 5Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
    1. *Corresponding author. Tel: +44 1865 612633; Fax: +44 1865 612601; E‐mail: jagdeep.nanchahal{at}kennedy.ox.ac.uk

    Delayed fracture healing is associated with excessive morbidity and mortality, particularly in osteoporotic patients. This study demonstrates that acceleration of fracture healing may be achieved by targeting the early inflammatory response.

    Synopsis

    Delayed fracture healing is associated with excessive morbidity and mortality, particularly in osteoporotic patients. This study demonstrates that acceleration of fracture healing may be achieved by targeting the early inflammatory response.

    • Low‐dose TNF local addition during the early inflammatory phase augments fracture repair in mice with normal and osteoporotic bone, while administration of either anti‐TNF or IL‐10 impairs it.

    • TNF is expressed during the early inflammatory response by neutrophils and monocytes/macrophages at the fracture site in mice.

    • Depletion of neutrophils using Ly6G‐blocking antibody impairs monocyte/macrophage recruitment and fracture repair in vivo.

    • Addition of rhTNF promotes recruitment of neutrophils, monocytes, and CCL2 expression.

    • CCR2 inhibition impairs fracture repair in vivo.

    • bone
    • CCL2
    • fracture
    • inflammation
    • TNF
    • Received August 17, 2014.
    • Revision received February 1, 2015.
    • Accepted February 13, 2015.

    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.

    James K Chan, Graeme E Glass, Adel Ersek, Andrew Freidin, Garry A Williams, Kate Gowers, Ana I Espirito Santo, Rosemary Jeffery, William R Otto, Richard Poulsom, Marc Feldmann, Sara M Rankin, Nicole J Horwood, Jagdeep Nanchahal