Advertisement

  • Superoxide anion radicals induce IGF‐1 resistance through concomitant activation of PTP1B and PTEN
    1. Karmveer Singh1,2,,
    2. Pallab Maity1,2,,
    3. Linda Krug1,2,
    4. Patrick Meyer1,2,
    5. Nicolai Treiber1,
    6. Tanja Lucas3,
    7. Abhijit Basu1,
    8. Stefan Kochanek3,
    9. Meinhard Wlaschek1,2,
    10. Hartmut Geiger1,2,4,5 and
    11. Karin Scharffetter‐Kochanek*,1,2
    1. 1Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany
    2. 2Aging Research Center (ARC), Ulm, Germany
    3. 3Department of Gene Therapy, University of Ulm, Ulm, Germany
    4. 4Institute of Molecular Medicine and Stem Cell Aging, University of Ulm, Ulm, Germany
    5. 5Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH, USA
    1. *Corresponding author. Tel: +49 731 50057501; Fax: +49 73150057502; E‐mail: karin.scharffetter-kochanek{at}uniklinik-ulm.de
    1. These authors contributed equally to this work

    New insight into a previously unreported mitochondrial superoxide anion (Formula)‐dependent activation of PTP1B and PTEN with subsequent repression of IGF‐1 signalling, and its implications for skin ageing and other pathologies with aberrant IGF‐1 signalling.

    Synopsis

    New insight into a previously unreported mitochondrial superoxide anion (Formula)‐dependent activation of PTP1B and PTEN with subsequent repression of IGF‐1 signalling, and its implications for skin ageing and other pathologies with aberrant IGF‐1 signalling.

    • Novel suppressive role of superoxide anions (Formula) on IGF‐1 signalling.

    • Accumulation of mitochondrial Formula activates and induces membrane translocation of ER‐bound PTP1B and cytosolic PTEN.

    • Inhibition of PTP1B and PTEN rescue IGF‐1 signalling even in the presence of high mitochondrial Formula.

    • ageing
    • IGF‐1
    • phosphatase
    • reactive oxygen species
    • superoxide anions
    • Received March 17, 2014.
    • Revision received November 6, 2014.
    • Accepted November 13, 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.

    Karmveer Singh, Pallab Maity, Linda Krug, Patrick Meyer, Nicolai Treiber, Tanja Lucas, Abhijit Basu, Stefan Kochanek, Meinhard Wlaschek, Hartmut Geiger, Karin Scharffetter‐Kochanek
  • HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin‐1 knock‐in mice
    1. Hikaru Ito1,,
    2. Kyota Fujita1,,
    3. Kazuhiko Tagawa1,,
    4. Xigui Chen1,,
    5. Hidenori Homma1,,
    6. Toshikazu Sasabe1,
    7. Jun Shimizu2,
    8. Shigeomi Shimizu3,
    9. Takuya Tamura1,
    10. Shin‐ichi Muramatsu4 and
    11. Hitoshi Okazawa*,1,5
    1. 1Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo‐ku Tokyo, Japan
    2. 2Department of Neurology, The University of Tokyo, Bunkyo‐ku Tokyo, Japan
    3. 3Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo‐ku Tokyo, Japan
    4. 4Department of Neurology, Jichi Medical University, Shimotsuke Tochigi, Japan
    5. 5Center for Brain Integration Research, Tokyo Medical and Dental University, Bunkyo‐ku Tokyo, Japan
    1. *Corresponding author. Tel: +81 3 5803 5847; E‐mail: okazawa-tky{at}umin.ac.jp
    1. These authors contributed equally to this work

    2. These authors contributed equally to this work

    Spinocerebellar ataxia type 1 (SCA1) is an intractable neurodegenerative disease. A gene therapy approach targeting HMGB1 against the SCA1 pathology in a mutant Atxn1 knock‐in mouse model prolonged lifespan and correct DNA damage defects in the mitochondrial genome.

    Synopsis

    Spinocerebellar ataxia type 1 (SCA1) is an intractable neurodegenerative disease. A gene therapy approach targeting HMGB1 against the SCA1 pathology in a mutant Atxn1 knock‐in mouse model prolonged lifespan and correct DNA damage defects in the mitochondrial genome.

    • Mitochondrial genome DNA damage is repaired by HMGB1.

    • The abnormal gene expression profile of Purkinje cells is partially corrected by HMGB1.

    • The mean and maximum lifespan of Atxn1‐KI mice are substantially prolonged (by 60–70%) by means of the gene therapy of HMGB1.

    • AAV
    • DNA damage repair
    • HMGB1
    • mitochondria
    • SCA1
    • Received July 2, 2014.
    • Revision received November 11, 2014.
    • Accepted November 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.

    Hikaru Ito, Kyota Fujita, Kazuhiko Tagawa, Xigui Chen, Hidenori Homma, Toshikazu Sasabe, Jun Shimizu, Shigeomi Shimizu, Takuya Tamura, Shin‐ichi Muramatsu, Hitoshi Okazawa
  • REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids
    1. Gleb Baida1,
    2. Pankaj Bhalla1,
    3. Kirill Kirsanov2,
    4. Ekaterina Lesovaya2,
    5. Marianna Yakubovskaya2,
    6. Kit Yuen1,
    7. Shuchi Guo1,
    8. Robert M Lavker1,
    9. Ben Readhead3,
    10. Joel T Dudley3 and
    11. Irina Budunova*,1
    1. 1Department of Dermatology, Northwestern University, Chicago, IL, USA
    2. 2N. Blokhin Cancer Research Center, RAMS, Moscow, Russia
    3. 3Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    1. *Corresponding author. Tel: +1 312 503 4669; Fax: +1 312 503 4325; E‐mail: i-budunova{at}northwestern.edu

    Cutaneous atrophy is the major adverse effect of topical glucocorticoids (GC). In a preclinical setting, knockdown of the stress‐inducible mTOR inhibitor REDD1 preserves the anti‐inflammatory effect of GC while protecting from atrophy.

    Synopsis

    Cutaneous atrophy is the major adverse effect of topical glucocorticoids (GC). In a preclinical setting, knockdown of the stress‐inducible mTOR inhibitor REDD1 preserves the anti‐inflammatory effect of GC while protecting from atrophy.

    • REDD1, a stress‐inducible inhibitor of mTOR, is up‐regulated in human and mouse skin in response to glucocorticoids used at atrophogenic doses.

    • REDD1 KO animals preserve sensitivity to the anti‐inflammatory effect of glucocorticoids, but are more resistant to steroid‐induced skin atrophy.

    • In a REDD1 KO cell context, gene activation by glucocorticoids (including genes involved in catabolism and degradation of lipids and proteins) is altered. However, the negative regulation of pro‐inflammatory genes, which underlies the therapeutic effects of glucocorticoids, was preserved.

    • The findings suggest the development of safer GR‐targeted therapy based on the combination of topical glucocorticoids combined with REDD1 inhibitors to prevent/attenuate skin atrophy.

    • glucocorticoid
    • glucocorticoid receptor
    • mTOR
    • REDD1
    • skin atrophy
    • Received September 3, 2014.
    • Revision received October 29, 2014.
    • Accepted October 30, 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.

    Gleb Baida, Pankaj Bhalla, Kirill Kirsanov, Ekaterina Lesovaya, Marianna Yakubovskaya, Kit Yuen, Shuchi Guo, Robert M Lavker, Ben Readhead, Joel T Dudley, Irina Budunova
  • Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus‐specific neutralizing antibody response
    1. Zhisheng Her1,2,,
    2. Terk‐Shin Teng1,,
    3. Jeslin JL Tan1,,
    4. Teck‐Hui Teo1,3,
    5. Yiu‐Wing Kam1,
    6. Fok‐Moon Lum1,2,
    7. Wendy WL Lee1,3,
    8. Christelle Gabriel111,
    9. Rossella Melchiotti1,4,
    10. Anand K Andiappan1,
    11. Valeria Lulla5,
    12. Aleksei Lulla5,
    13. Mar K Win6,
    14. Angela Chow6,
    15. Subhra K Biswas1,
    16. Yee‐Sin Leo6,
    17. Marc Lecuit7,8,9,
    18. Andres Merits5,
    19. Laurent Rénia1 and
    20. Lisa FP Ng*,1,2,1012
    1. 1Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore
    2. 2Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
    3. 3NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
    4. 4Doctoral School in Translational and Molecular Medicine (DIMET), University of Milano‐Bicocca, Milan, Italy
    5. 5Institute of Technology, University of Tartu, Tartu, Estonia
    6. 6Institute of Infectious Disease and Epidemiology (IIDE), Tan Tock Seng Hospital, Singapore, Singapore
    7. 7Institut Pasteur, Biology of Infection Unit, Paris, France
    8. 8Inserm U1117, Paris, France
    9. 9Paris Descartes University Sorbonne Paris Cité, Necker‐Enfants Malades University Hospital, Institut Imagine, Paris, France
    10. 10Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
    11. 11INSERM, U1016 Institut Cochin, 22 Rue Mechain, 75014, Paris, France
    12. 12 Laboratory of Microbial Immunity, Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Biopolis, Immunos, 8A Biomedical Grove, #04‐06, Singapore, 138648, Singapore
    1. *Corresponding author. Tel: +65 6407 0028; Fax: +65 6464 2057; E‐mail: lisa_ng{at}immunol.a-star.edu.sg
    1. These authors contributed equally to this work

    TLR3‐mediated innate response against CHIKV infection modulates the adaptive immune response and TLR3 deficiency results in enhanced viremia and more severe pathology in mice; in CHIKV‐infected patients, TLR3 expression is high and a TLR3 SNP associates with disease severity.

    Synopsis

    TLR3‐mediated innate response against CHIKV infection modulates the adaptive immune response and TLR3 deficiency results in enhanced viremia and more severe pathology in mice; in CHIKV‐infected patients, TLR3 expression is high and a TLR3 SNP associates with disease severity.

    • TLR3 regulates host immunity in CHIKV infection and pathology in humans and mice.

    • A loss of TLR3 was demonstrated to markedly increase virus replication and dissemination that led to more severe joint pathology.

    • Bone marrow chimeric experiments indicated that TLR3‐expressing hematopoietic cells play a role CHIKV clearance.

    • The loss of TLR3 impaired neutralizing capacity due to altered virus‐neutralizing epitope specificity.

    • SNP genotyping analysis on TLR from patients identified SNP rs6552950 as associated with disease severity.

    • Chikungunya virus
    • innate immunity
    • joint inflammation
    • neutralizing antibodies
    • TLR3
    • Received July 22, 2014.
    • Revision received October 31, 2014.
    • Accepted November 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.

    Zhisheng Her, Terk‐Shin Teng, Jeslin JL Tan, Teck‐Hui Teo, Yiu‐Wing Kam, Fok‐Moon Lum, Wendy WL Lee, Christelle Gabriel, Rossella Melchiotti, Anand K Andiappan, Valeria Lulla, Aleksei Lulla, Mar K Win, Angela Chow, Subhra K Biswas, Yee‐Sin Leo, Marc Lecuit, Andres Merits, Laurent Rénia, Lisa FP Ng
  • Key drivers of biomedical innovation in cancer drug discovery
    1. Margit A Huber*,1 and
    2. Norbert Kraut*,2
    1. 1Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
    2. 2Oncology Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
    1. * Corresponding author. Tel: +49 731 500 57647; E‐mail: margit.huber{at}uniklinik-ulm.de

      Corresponding author. E‐mail: norbert.kraut{at}boehringer-ingelheim.com

    Discovery and translational research has led to the identification of a series of “cancer drivers”—genes that, when mutated or otherwise misregulated, can drive malignancy. An increasing number of drugs that directly target such drivers have demonstrated activity in clinical trials and are shaping a new landscape for molecularly targeted cancer therapies. Such therapies rely on molecular and genetic diagnostic tests to detect the presence of a biomarker that predicts response. Here, we highlight some of the key discoveries bringing precision oncology to cancer patients. Large‐scale “omics” approaches as well as modern, hypothesis‐driven science in both academic and industry settings have significantly contributed to the field. Based on these insights, we discuss current challenges and how to foster future biomedical innovation in cancer drug discovery and development.

    Huber and Kraut discuss the current challenges in drug discovery including drug resistance and the need for improved preclinical models, and how to accelerate biomedical innovation through enhanced collaboration between academia and industry.

    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.

    Margit A Huber, Norbert Kraut
  • Biology, detection, and clinical implications of circulating tumor cells
    1. Simon A Joosse1,,
    2. Tobias M Gorges1, and
    3. Klaus Pantel*,1
    1. 1Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany
    1. *Corresponding author. Tel: +49 40 7410 53503; E‐mail: pantel{at}uke.de
    1. Contributed equally.

    An overview of the biology of tumor cell dissemination, including an in depth discussion of the current advances and limitations in the detection/isolation of circulating tumor cells and their potential prognostic and diagnostic value.

    • Disseminating tumor cells (DTC)
    • EMT
    • metastasis
    • tumor cell dormancy
    • tumor cell plasticity
    • Received July 15, 2014.
    • Revision received October 2, 2014.
    • Accepted October 20, 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.

    Simon A Joosse, Tobias M Gorges, Klaus Pantel