- ReviewOne level up: abnormal proteolytic regulation of IGF activity plays a role in human pathophysiology
- Jesús Argente (jesus.argente{at}uam.es)*,1,2,3,4,
- Julie A Chowen1,3,
- Luis A Pérez‐Jurado5,6,7,
- Jan Frystyk8 and
- Claus Oxvig9
- 1Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- 2Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
- 3Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- 4IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain
- 5Genetics Unit, Universitat Pompeu Fabra, Barcelona, Spain
- 6Hospital del Mar Research Institute (IMIM), Barcelona, Spain
- 7Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
- 8Medical Research Laboratory, Department of Clinical Medicine, Health, Aarhus University, Aarhus C, Denmark
- 9Department of Molecular Biology & Genetics, Aarhus University, Aarhus C, Denmark
- ↵*Corresponding author. Tel: +34 915035912; Fax: +34 915035939; E‐mail: jesus.argente{at}uam.es
This review discusses how identifying patients’ mutations in new proteins can advance our understanding of the underlying pathophysiology, i.e. delayed growth failure, but also more widely, highlight new pathways of clinical relevance like the GH/IGF‐1 axis that offer real therapeutic opportunities.
- Received April 25, 2017.
- Revision received July 15, 2017.
- Accepted July 18, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
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.
- Research ArticlemRNA mediates passive vaccination against infectious agents, toxins, and tumors
- Moritz Thran1,
- Jean Mukherjee2,
- Marion Pönisch1,
- Katja Fiedler1,
- Andreas Thess1,
- Barbara L Mui3,
- Michael J Hope3,
- Ying K Tam3,
- Nigel Horscroft1,
- Regina Heidenreich1,
- Mariola Fotin‐Mleczek1,
- Charles B Shoemaker2 and
- Thomas Schlake (thomas.schlake{at}curevac.com)*,1
- 1CureVac AG, Tübingen, Germany
- 2Department of Infectious Disease and Global Health, Tufts Cummings School of Veterinary Medicine, North Grafton, MA, USA
- 3Acuitas Therapeutics, Vancouver, BC, Canada
- ↵*Corresponding author. Tel: +49 7071 9883 1607; E‐mail: thomas.schlake{at}curevac.com
As a transient carrier of information, exogenous mRNA is considered a possibly powerful tool to instruct a body to produce its own therapeutics. Antibody‐encoding, sequence‐optimized but otherwise unmodified mRNA in LNPs empowered mice to successfully fight various biological threats.
Synopsis
As a transient carrier of information, exogenous mRNA is considered a possibly powerful tool to instruct a body to produce its own therapeutics. Antibody‐encoding, sequence‐optimized but otherwise unmodified mRNA in LNPs empowered mice to successfully fight various biological threats.
Sequence‐optimization enables efficient antibody expression from in vitro transcribed mRNA.
Exogenous mRNA can instruct cells to produce various types of antibodies.
Optimized mRNA in lipid nanoparticles provides efficient antibody expression in hepatocytes upon intravenous administration.
mRNA‐mediated antibody expression can protect mice against toxins, viruses, and tumors.
- Received February 15, 2017.
- Revision received July 12, 2017.
- Accepted July 13, 2017.
- © 2017 CureVac AG. Published under the terms of the CC BY 4.0 license
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.
- Research ArticleCDK6 protects epithelial ovarian cancer from platinum‐induced death via FOXO3 regulation
- Alessandra Dall'Acqua1,
- Maura Sonego1,
- Ilenia Pellizzari1,
- Ilenia Pellarin1,
- Vincenzo Canzonieri2,
- Sara D'Andrea1,
- Sara Benevol1,
- Roberto Sorio3,
- Giorgio Giorda4,
- Daniela Califano5,
- Marina Bagnoli6,
- Loredana Militello3,
- Delia Mezzanzanica6,
- Gennaro Chiappetta5,
- Joshua Armenia1,
- Barbara Belletti1,
- Monica Schiappacassi (mschiappacassi{at}cro.it)*,1 and
- Gustavo Baldassarre (gbaldassarre{at}cro.it)*,1
- 1Division of Molecular Oncology, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Italy
- 2Division of Pathology, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Italy
- 3Division of Medical Oncology C, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Italy
- 4Division of Gynecology‐Oncology, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Italy
- 5Genomica Funzionale, Istituto Nazionale Tumori ‐IRCCS‐ Fondazione G Pascale, Naples, Italy
- 6Molecular Therapies Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori Milan, Milan, Italy
- ↵*
Corresponding author. Tel: +39 0434 659 759/661; Fax: +39 0434 659 428; E‐mail: mschiappacassi{at}cro.it
Corresponding author. Tel: +39 0434 659 759/661; Fax: +39 0434 659 428; E‐mail: gbaldassarre{at}cro.it
In epithelial ovarian cancer cells, platinum favours binding and phosphorylation of FOXO3 by the CDK6/cyclin D3 complex. FOXO3 is thus stabilized and binds the ATR promoter thereby inducing its transcription and preventing platinum‐induced cell death.
Synopsis
In epithelial ovarian cancer cells, platinum favours binding and phosphorylation of FOXO3 by the CDK6/cyclin D3 complex. FOXO3 is thus stabilized and binds the ATR promoter thereby inducing its transcription and preventing platinum‐induced cell death.
CDK6 in complex with cyclin D3 participates in the control of DNA damage response.
CDK6 binds and phosphorylates FOXO3 on serine 325 to control ATR expression.
High CDK6 expression predicts poor survival of EOC patients.
A combination of platinum‐based chemotherapy with pharmacological CDK6 inhibition might be a new therapeutic option for EOC patients.
- Received August 30, 2016.
- Revision received July 10, 2017.
- Accepted July 11, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
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.
- News & Viewsβ‐Klotho sustains postnatal GnRH biology and spins the thread of puberty
- Micheline Misrahi (micheline.misrahi{at}aphp.fr)1
This article highlights the newly discovered role of β‐Klotho in postnatal GnRH biology through the identification of a patient congenital hypogonadotropic hypogonadism‐associated FGFR1 mutation that results in decreased FGF21 metabolic signaling.
- © 2017 The Author. Published under the terms of the CC BY 4.0 license
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.
- Research ArticleThe cardiac microenvironment uses non‐canonical WNT signaling to activate monocytes after myocardial infarction
- Ingmar Sören Meyer1,2,
- Andreas Jungmann1,
- Christoph Dieterich1,2,
- Min Zhang1,
- Felix Lasitschka3,4,
- Susann Werkmeister1,
- Jan Haas1,2,
- Oliver J Müller1,2,
- Michael Boutros2,5,
- Matthias Nahrendorf6,
- Hugo A Katus1,2,
- Stefan E Hardt1 and
- Florian Leuschner (florian.leuschner{at}med.uni-heidelberg.de)*,1,2
- 1Department of Medicine III, University of Heidelberg, Heidelberg, Germany
- 2DZHK (German Centre for Cardiovascular Research), Partnersite, Heidelberg/Mannheim, Germany
- 3Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- 4Tissue Bank of the National Center for Tumor Diseases (NCT), Heidelberg, Germany
- 5Division Signaling and Functional Genomics, German Cancer Research Center (DKFZ) and Heidelberg University, Heidelberg, Germany
- 6Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- ↵*Corresponding author. Tel: +49 6221 56 8676; E‐mail: florian.leuschner{at}med.uni-heidelberg.de
Non‐canonical WNT signaling is shown to be re‐activated in the heart upon injury. Locally secreted Wnt proteins drive accumulating myeloid cells toward a proinflammatory state and impact healing after myocardial infarction.
Synopsis
Non‐canonical WNT signaling is shown to be re‐activated in the heart upon injury. Locally secreted Wnt proteins drive accumulating myeloid cells toward a proinflammatory state and impact healing after myocardial infarction.
Non‐canonical WNT signaling is activated in accumulating inflammatory monocytes in the heart following myocardial infarction.
WNT Inhibitory Factor 1 (WIF1), an inhibitor of WNT signaling, is secreted from cardiomyocytes during hypoxia and following myocardial infarction in mice and humans.
Knockout of WIF1 leads to an exaggerated monocyte response and aggravates infarct healing.
Cardiomyocyte‐specific overexpression of WIF1 reduces non‐canonical WNT signaling in accumulating monocytes, limits inflammation and ameliorates left ventricular function after myocardial infarction.
- Received January 10, 2017.
- Revision received June 7, 2017.
- Accepted June 20, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
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.
- ReviewClinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts
- Jessica Hartmann (jessica.hartmann{at}pei.de)*,1,
- Martina Schüßler‐Lenz2,3,
- Attilio Bondanza4 and
- Christian J Buchholz (christian.buchholz{at}pei.de)*,1,3
- 1Molecular Biotechnology and Gene Therapy, Paul‐Ehrlich‐Institut, Langen, Germany
- 2Division of Medical Biotechnology, Paul‐Ehrlich‐Institut, Langen, Germany
- 3German Cancer Consortium (DKTK), Heidelberg, Germany
- 4Innovative immunotherapies, Ospedale San Raffaele, Milano, Italy
- ↵*
Corresponding author. Tel: +49 6103774026; E‐mail: jessica.hartmann{at}pei.de
Corresponding author. Tel: +49 6103774011; E‐mail: christian.buchholz{at}pei.de
Authoritative, insightful overview of the problems and general hurdles preventing efficient clinical development of chimeric antigen receptor (CAR) T cell therapy for cancer as well as future opportunities.
- Received December 19, 2016.
- Revision received July 3, 2017.
- Accepted July 11, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
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.
- Research ArticleKLB, encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism
- Cheng Xu1,
- Andrea Messina1,
- Emmanuel Somm1,
- Hichem Miraoui1,18,
- Tarja Kinnunen2,
- James Acierno Jr1,
- Nicolas J Niederländer1,
- Justine Bouilly1,
- Andrew A Dwyer1,3,
- Yisrael Sidis1,
- Daniele Cassatella1,
- Gerasimos P Sykiotis1,
- Richard Quinton4,
- Christian De Geyter5,
- Mirjam Dirlewanger6,
- Valérie Schwitzgebel6,
- Trevor R Cole7,
- Andrew A Toogood8,
- Jeremy MW Kirk9,
- Lacey Plummer10,
- Urs Albrecht11,
- William F Crowley Jr10,
- Moosa Mohammadi12,
- Manuel Tena‐Sempere13,14,15,
- Vincent Prevot16,17 and
- Nelly Pitteloud (nelly.pitteloud{at}chuv.ch)*,1
- 1Service of Endocrinology, Diabetology & Metabolism, Lausanne University Hospital, Lausanne, Switzerland
- 2Department of Biology, School of Applied Sciences, University of Huddersfield, Huddersfield, UK
- 3University of Lausanne Institute of Higher Education and Research in Healthcare, Lausanne, Switzerland
- 4Institute for Genetic Medicine, University of Newcastle‐on‐Tyne, Newcastle‐on Tyne, UK
- 5Clinic of Gynecological Endocrinology and Reproductive Medicine, University Hospital, University of Basel, Basel, Switzerland
- 6Pediatric Endocrine and Diabetes Unit, Children's Hospital, University Hospitals and Faculty of Medicine, Geneva, Switzerland
- 7Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham, UK
- 8Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, UK
- 9Department of Endocrinology, Birmingham Children's Hospital, Birmingham, UK
- 10National Center for Translational Research in Reproduction and Infertility, Harvard Reproductive Endocrine Sciences Center of the Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- 11Department of Biology, Biochemistry, Faculty of Science, University of Fribourg, Fribourg, Switzerland
- 12Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, USA
- 13Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain
- 14Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC/HURS), Cordoba, Spain
- 15CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba, Spain
- 16Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, JPARC, Lille, France
- 17FHU 1000 Days for Health, School of Medicine, University of Lille, Lille, France
- 18Present Address: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- ↵*Corresponding author. Tel: +41 021 314 87 96; E‐mail: nelly.pitteloud{at}chuv.ch
Defects in FGF21/KLB/FGFR1 signaling contribute to GnRH deficiency in both humans and mice. This signaling pathway is a novel link between metabolism and reproduction.
Synopsis
Defects in FGF21/KLB/FGFR1 signaling contribute to GnRH deficiency in both humans and mice. This signaling pathway is a novel link between metabolism and reproduction.
Heterozygous loss‐of‐function mutations in KLB are found in patients with congenital hypogonadotropic hypogonadism.
Klb‐deficient mice delayed sexual maturation and impaired fertility with decreased gonadotropins due to a hypothalamic defect.
Klb is expressed in the postnatal hypothalamus including GnRH neurons.
FGF21 reaches GnRH neurons via fenestrated capillaries in the hypothalamus in vivo and enhances GnRH release in median eminence explants in vitro.
- Received December 1, 2016.
- Revision received June 23, 2017.
- Accepted June 27, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
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.
