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  • MicroRNA mimicry blocks pulmonary fibrosis
    1. Rusty L Montgomery1,,
    2. Guoying Yu2,,
    3. Paul A Latimer1,
    4. Christianna Stack1,
    5. Kathryn Robinson1,
    6. Christina M Dalby1,
    7. Naftali Kaminski*,2 and
    8. Eva van Rooij*,1,3
    1. 1miRagen Therapeutics, Inc, Boulder, CO, USA
    2. 2Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA
    3. 3Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
    1. * Corresponding author. Tel: +1 203 7853508; E‐mail: naftali.kaminski{at}yale.edu

      Corresponding author. Tel: +31 30 2121800; E‐mail: e.vanrooij{at}hubrecht.eu

    1. Both authors contributed equally

    Therapeutic delivery of miR‐29 mimics during bleomycin‐induced pulmonary fibrosis in mice restores endogenous miR‐29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis.

    Synopsis

    Therapeutic delivery of miR‐29 mimics during bleomycin‐induced pulmonary fibrosis in mice restores endogenous miR‐29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis.

    • MicroRNA mimics can be used to increase levels of miRNAs in vivo in a time and dose‐dependent manner.

    • miR‐29 mimic does not affect target gene expression under basal conditions.

    • miR‐29 mimic can block and reverse aspects of bleomycin‐induced pulmonary fibrosis.

    • microRNA
    • mimic
    • miR‐29
    • pulmonary fibrosis
    • therapeutics
    • Received October 25, 2013.
    • Revision received August 13, 2014.
    • Accepted August 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.

    Rusty L Montgomery, Guoying Yu, Paul A Latimer, Christianna Stack, Kathryn Robinson, Christina M Dalby, Naftali Kaminski, Eva van Rooij
  • TLR8 signaling enhances tumor immunity by preventing tumor‐induced T‐cell senescence
    1. Jian Ye1,
    2. Chunling Ma1,2,
    3. Eddy C Hsueh3,
    4. Jie Dou1,
    5. Wei Mo1,
    6. Shuai Liu1,
    7. Bing Han1,
    8. Yi Huang1,
    9. Yanping Zhang3,
    10. Mark A Varvares4,
    11. Daniel F Hoft1 and
    12. Guangyong Peng*,1
    1. 1Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA
    2. 2Department of Laboratory Medicine, Women & Children's Health Care Hospital of Linyi, Linyi, China
    3. 3Department of Surgery, Division of General Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA
    4. 4Department of Otolaryngology‐Head and Neck Surgery, Saint Louis University School of Medicine, Saint Louis, MO, USA
    1. *Corresponding author. Tel: +1 314 977 9064; Fax: +1 314 771 3816; E‐mail: gpeng{at}slu.edu

    This study identifies the induction of T‐cell senescence as a novel mechanism utilized by human tumor cells to induce immune suppression, and provides a new strategy using TLR8 ligands to reverse tumor immunosuppressive effects for tumor immunotherapy.

    Synopsis

    This study identifies the induction of T‐cell senescence as a novel mechanism utilized by human tumor cells to induce immune suppression, and provides a new strategy using TLR8 ligands to reverse tumor immunosuppressive effects for tumor immunotherapy.

    • Tumor cells convert naïve/effector T cells into senescent T cells with potent suppressive function.

    • Tumor‐derived cAMP is responsible for the tumor cell‐induced T‐cell senescence.

    • cAMP is directly transferred from tumor cells to targeted T cells through gap junctions inducing PKA‐LCK inhibitory signaling and senescence in T cells.

    • TLR8 signaling reverses tumor‐induced T‐cell senescence via down‐regulation of cAMP in tumor cells.

    • Activation of TLR8 signaling in tumor cells prevents tumor‐specific T‐cell senescence and enhances anti‐tumor immunity.

    • immunosenescence
    • regulatory T cells
    • toll‐like receptor
    • tumor immunity
    • tumor microenvironment
    • Received January 29, 2014.
    • Revision received August 12, 2014.
    • Accepted August 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.

    Jian Ye, Chunling Ma, Eddy C Hsueh, Jie Dou, Wei Mo, Shuai Liu, Bing Han, Yi Huang, Yanping Zhang, Mark A Varvares, Daniel F Hoft, Guangyong Peng
  • Specific roles for dendritic cell subsets during initiation and progression of psoriasis
    1. Elisabeth Glitzner1,
    2. Ana Korosec1,
    3. Patrick M Brunner2,
    4. Barbara Drobits1,
    5. Nicole Amberg1,
    6. Helia B Schonthaler3,
    7. Tamara Kopp2,
    8. Erwin F Wagner3,
    9. Georg Stingl2,
    10. Martin Holcmann1 and
    11. Maria Sibilia*,1
    1. 1Department of Medicine I, Comprehensive Cancer Center Institute of Cancer Research Medical University of Vienna, Vienna, Austria
    2. 2Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, Vienna, Austria
    3. 3BBVA Foundation–CNIO Cancer Cell Biology Programme Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    1. *Corresponding author. Tel: +43 140160 57502; Fax: +43 140160 957502; E‐mail: maria.sibilia{at}meduniwien.ac.at

    Resident epidermal LCs, which are gradually lost from the epidermis in active disease phase psoriasis, are responsible for maintaining a suppressive skin environment by balancing the anti‐inflammatory IL‐10 and pro‐inflammatory IL‐23 axis.

    Synopsis

    Resident epidermal LCs, which are gradually lost from the epidermis in active disease phase psoriasis, are responsible for maintaining a suppressive skin environment by balancing the anti‐inflammatory IL‐10 and pro‐inflammatory IL‐23 axis.

    • Langerhans cells (LCs) are severely reduced and plasmacytoid DCs (pDCs) are increased in human psoriasis as well as in mouse models of psoriasis

    • Depletion of pDCs in mice prior to psoriasis induction results in disease amelioration whereas depletion during active disease has no effect

    • Depletion of LCs during active psoriasis results in disease aggravation whereas depletion before disease initiation has no effect

    • The anti‐inflammatory role of LCs is mediated by direct release of the immunosuppressive cytokine IL‐10 and by preventing excessive IL‐23 accumulation in the skin

    • pDC depletion results in reduced IL‐23 levels and therapeutic inhibition of IL‐23 receptor ameliorates disease symptoms

    • AP‐1
    • IL‐23
    • Langerhans cells
    • plasmacytoid dendritic cells
    • psoriasis
    • Received March 27, 2014.
    • Revision received August 12, 2014.
    • Accepted August 15, 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.

    Elisabeth Glitzner, Ana Korosec, Patrick M Brunner, Barbara Drobits, Nicole Amberg, Helia B Schonthaler, Tamara Kopp, Erwin F Wagner, Georg Stingl, Martin Holcmann, Maria Sibilia
  • The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation
    1. Anne Abot1,,
    2. Coralie Fontaine1,,
    3. Mélissa Buscato1,
    4. Romain Solinhac1,
    5. Gilles Flouriot2,
    6. Aurélie Fabre1,
    7. Anne Drougard1,
    8. Shyamala Rajan3,
    9. Muriel Laine3,
    10. Alain Milon4,
    11. Isabelle Muller4,
    12. Daniel Henrion5,
    13. Marine Adlanmerini1,
    14. Marie‐Cécile Valéra1,
    15. Anne Gompel6,
    16. Céline Gerard7,
    17. Christel Péqueux7,
    18. Mélanie Mestdagt7,
    19. Isabelle Raymond‐Letron8,
    20. Claude Knauf1,
    21. François Ferriere2,
    22. Philippe Valet1,
    23. Pierre Gourdy1,
    24. Benita S Katzenellenbogen9,
    25. John A Katzenellenbogen9,
    26. Françoise Lenfant1,
    27. Geoffrey L Greene3,
    28. Jean‐Michel Foidart7 and
    29. Jean‐François Arnal*,1
    1. 1INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse – UPS, Toulouse, France
    2. 2Institut de Recherche en Santé Environnement et Travail, IRSET, INSERM U1085, Team TREC, Biosit, Université de Rennes I, Rennes, France
    3. 3Department for Cancer Research, University of Chicago, Chicago, IL, USA
    4. 4CNRS and Université de Toulouse, IPBS, Toulouse, France
    5. 5INSERM U1083, CNRS UMR 6214, Université d'Angers, Angers, France
    6. 6APHP, Unité de Gynécologie Endocrinienne, Université Paris Descartes, Paris, France
    7. 7Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA‐cancer), Université de Liège, Liège, Belgique
    8. 8INP, ENVT, Université de Toulouse, Toulouse, France
    9. 9Departments of Molecular and Integrative Biology and Chemistry, University of Illinois at Urbana‐Champaign, Urbana, IL, USA
    1. *Corresponding author. Tel: +33 561 32 36 83; Fax: +33 561 32 20 84; E‐mail: Jean-Francois.Arnal{at}inserm.fr
    1. The authors equally contributed to this work

    Estetrol (E4) is shown to be a less potent estrogen than E2 but with the features of a natural Selective ER Modulator suggesting its application as a safe oral contraceptive or for the hormonal treatment of menopause.

    Synopsis

    Estetrol (E4) is shown to be a less potent estrogen than E2 but with the features of a natural Selective ER Modulator suggesting its application as a safe oral contraceptive or for the hormonal treatment of menopause.

    • The nuclear transcriptional activity of ERα in the mouse uterus leading to the proliferation of the endometrial epithelium is modulated by E4.

    • The prevention of atheroma, another process recognized to be nuclear ERα‐dependent, is promoted by E4 in hypercholesterolemic mice.

    • At variance with E2, neither acceleration of endothelial healing nor activation of endothelial NO synthase, two ERα membrane‐dependent effects, are affected by E4.

    • The ERα membrane‐dependent effects of E2 are antagonized by E4, not only in the endothelium, but also in MCF‐7 breast cancer cells.

    • E4 acts as a natural Selective Estrogen Receptor Modulator (SERM) uncoupling nuclear and membrane activation, and its medical potential should now be fully explored.

    • endothelium
    • estetrol
    • estrogen receptor
    • uterus
    • Received April 2, 2014.
    • Revision received August 6, 2014.
    • Accepted August 8, 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.

    Anne Abot, Coralie Fontaine, Mélissa Buscato, Romain Solinhac, Gilles Flouriot, Aurélie Fabre, Anne Drougard, Shyamala Rajan, Muriel Laine, Alain Milon, Isabelle Muller, Daniel Henrion, Marine Adlanmerini, Marie‐Cécile Valéra, Anne Gompel, Céline Gerard, Christel Péqueux, Mélanie Mestdagt, Isabelle Raymond‐Letron, Claude Knauf, François Ferriere, Philippe Valet, Pierre Gourdy, Benita S Katzenellenbogen, John A Katzenellenbogen, Françoise Lenfant, Geoffrey L Greene, Jean‐Michel Foidart, Jean‐François Arnal
  • Epithelial‐mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients
    1. Tuan Zea Tan1,
    2. Qing Hao Miow2,
    3. Yoshio Miki3,
    4. Tetsuo Noda3,
    5. Seiichi Mori3,
    6. Ruby Yun‐Ju Huang1,4, and
    7. Jean Paul Thiery*,1,2,5,
    1. 1Cancer Science Institute of Singapore, National University of Singapore, Singapore
    2. 2Institute of Molecular and Cell Biology, A*STAR, Singapore
    3. 3Cancer Institute of Japanese Foundation for Cancer Research, Kyoto, Japan
    4. 4Department of Obstetrics and Gynaecology, National University Health System, Singapore
    5. 5Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
    1. *Corresponding author. Tel: +65 6516 3242; Fax: +65 6516 1453; E‐mail: jpthiery{at}imcb.a-star.edu.sg
    1. Co‐senior authors.

    A novel EMT scoring method reveals that EMT status does not unanimously correlate with poorer overall and disease‐free survival. Different EMTed tumours show distinct responses to certain chemotherapeutics, with the potential to stratify patients by EMT status.

    Synopsis

    A novel EMT scoring method reveals that EMT status does not unanimously correlate with poorer overall and disease‐free survival. Different EMTed tumours show distinct responses to certain chemotherapeutics, with the potential to stratify patients by EMT status.

    • A novel scoring method was developed based on transcriptomics to universally estimate and compare the Epithelial‐Mesenchymal Transition (EMT) phenotype across cancer types.

    • A spectrum of EMT was established across more than 15 cancers using this EMT scoring method.

    • Correlations of EMT status with poorer overall‐ and disease‐free survival were not unanimously observed in all cancers.

    • Differential and preferential responses of EMTed tumours to certain chemotherapeutics were observed, suggesting the potential to stratify patients by EMT status.

    • drug response
    • epithelial‐mesenchymal transition
    • gene expression signature
    • microarray
    • prognosis
    • Received April 28, 2014.
    • Revision received August 7, 2014.
    • Accepted August 8, 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.

    Tuan Zea Tan, Qing Hao Miow, Yoshio Miki, Tetsuo Noda, Seiichi Mori, Ruby Yun‐Ju Huang, Jean Paul Thiery
  • CaM Kinase II mediates maladaptive post‐infarct remodeling and pro‐inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury
    1. Martin Weinreuter1,2,,
    2. Michael M Kreusser1,2,,
    3. Jan Beckendorf1,2,
    4. Friederike C Schreiter1,2,
    5. Florian Leuschner2,3,
    6. Lorenz H Lehmann1,2,
    7. Kai P Hofmann1,2,
    8. Julia S Rostosky1,2,
    9. Nathalie Diemert1,2,
    10. Chang Xu1,2,
    11. Hans Christian Volz2,3,
    12. Andreas Jungmann2,3,
    13. Alexander Nickel4,
    14. Carsten Sticht5,
    15. Norbert Gretz5,
    16. Christoph Maack4,
    17. Michael D Schneider6,
    18. Hermann‐Josef Gröne7,
    19. Oliver J Müller2,3,
    20. Hugo A Katus2,3 and
    21. Johannes Backs*,1,2
    1. 1Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany
    2. 2DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
    3. 3Department of Cardiology, University of Heidelberg, Heidelberg, Germany
    4. 4Department of Cardiology, Saarland University, Homburg, Germany
    5. 5Medical Research Center, University of Heidelberg Medical Faculty Mannheim, Mannheim, Germany
    6. 6British Heart Foundation Centre of Research Excellence, Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK
    7. 7Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
    1. *Corresponding author. Tel: +49 6221 56 37714; Fax: +49 6221 56 5515; E‐mail: johannes.backs{at}med.uni-heidelberg.de
    1. These authors contributed equally to the work.

    CaMKII is critically involved in post‐infarct remodelling via the activation of inflammatory pathways. At variance with previous reports, however, CaMKII does not appear to be relevant in acute damage after ischemia/reperfusion injury.

    Synopsis

    CaMKII is critically involved in post‐infarct remodelling via the activation of inflammatory pathways. At variance with previous reports, however, CaMKII does not appear to be relevant in acute damage after ischemia/reperfusion (I/R) injury.

    • Acute myocardial I/R‐induced damage is not mediated by CaMKII whereas post‐I/R remodelling and inflammatory processes are.

    • Leukocyte infiltration and expression of members of the chemokine (C‐C motif) ligand family, in particular CCL3 (macrophage inflammatory protein‐1a, MIP‐1a), are reduced in mice lacking the two cardiac CaMKII isoforms delta and gamma upon I/R injury.

    • CaMKII is sufficient and required for CCL3 expression in cardiomyocytes.

    • apoptosis
    • Ca2+/calmodulin‐dependent protein kinase II
    • cardiac remodeling
    • gene replacement
    • ischemia/reperfusion injury
    • Received January 10, 2014.
    • Revision received July 30, 2014.
    • Accepted August 1, 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.

    Martin Weinreuter, Michael M Kreusser, Jan Beckendorf, Friederike C Schreiter, Florian Leuschner, Lorenz H Lehmann, Kai P Hofmann, Julia S Rostosky, Nathalie Diemert, Chang Xu, Hans Christian Volz, Andreas Jungmann, Alexander Nickel, Carsten Sticht, Norbert Gretz, Christoph Maack, Michael D Schneider, Hermann‐Josef Gröne, Oliver J Müller, Hugo A Katus, Johannes Backs
  • A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis
    Giorgia Zadra, Cornelia Photopoulos, Svitlana Tyekucheva, Pedram Heidari, Qing Ping Weng, Giuseppe Fedele, Hong Liu, Natalia Scaglia, Carmen Priolo, Ewa Sicinska, Umar Mahmood, Sabina Signoretti, Neal Birnberg, Massimo Loda