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  • Compassionate use of experimental therapies: who should decide?
    Compassionate use of experimental therapies: who should decide?
    1. Patricia J Zettler (pzettler{at}gsu.edu)1
    1. 1Center for Law, Health & Society, Georgia State University College of Law, Atlanta, GA, USA

    In addition to being an example of unsubstantiated hype about regenerative medicine, the controversy around the Italy‐based Stamina Foundation's unproven stem cell therapy represents another chapter in a continuing debate about how to balance patients' requests for early access to experimental medicines with requirements for demonstrating safety and effectiveness. Compassionate use of the Stamina therapy arguably should not have been permitted under Italy's laws, but public pressure was intense and judges ultimately granted access. One lesson from these events is that expert regulatory agencies may be the institutions most competent to make compassionate use decisions and that policies should include more specific criteria for authorizing compassionate use. But even where regulatory agencies make decisions based on clear rules, difficult questions will arise.

    In the aftermath of the Stamina case, Patti Zettler discusses the difficult balance between the need to demonstrate safety and effectiveness of new medicines and requests from seriously ill patients for early access to experimental treatments.

    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.

    Patricia J Zettler
  • Folate levels modulate oncogene‐induced replication stress and tumorigenicity
    Folate levels modulate oncogene‐induced replication stress and tumorigenicity
    1. Noa Lamm1,
    2. Karin Maoz1,
    3. Assaf C Bester1,
    4. Michael M Im2,
    5. Donna S Shewach2,
    6. Rotem Karni3 and
    7. Batsheva Kerem*,1
    1. 1Department of Genetics, The Alexander Silberman Institute of Life Sciences Edmond J. Safra Campus The Hebrew University of Jerusalem, Jerusalem, Israel
    2. 2Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, MI, USA
    3. 3Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel‐Canada The Hebrew University‐Hadassah Medical School, Jerusalem, Israel
    1. *Corresponding author. Tel: +972 2 6585689; E‐mail: kerem{at}cc.huji.ac.il

    Oncogene‐induced replication stress is shown here as a quantitative trait enhanced by non‐genetic factors such as the essential dietary nutrient folate. The combination of oncogene expression and folate deficiency enhances replication‐induced genomic instability and cancer development in vivo.

    Synopsis

    Oncogene‐induced replication stress is shown here as a quantitative trait enhanced by non‐genetic factors such as the essential dietary nutrient folate. The combination of oncogene expression and folate deficiency enhances replication‐induced genomic instability and cancer development in vivo.

    • Folate deficiency by itself leads to replication stress in a concentration‐dependent manner that can be rescued by nucleoside supplementation.

    • The extent of oncogene‐induced replication stress can be enhanced by an additional source of stress, resulting in enhanced DNA damage.

    • Activation of the DNA damage response pathways by ATM and ATR is enhanced by the combination of oncogene expression and folate deficiency.

    • Tumorigenicity potential in vitro and tumor development in vivo caused by oncogene expression are significantly enhanced by folate deficiency.

    • cancer development
    • chromosomal instability
    • folate deficiency
    • oncogene expression
    • replication stress
    • Received November 5, 2014.
    • Revision received June 26, 2015.
    • Accepted June 29, 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.

    Noa Lamm, Karin Maoz, Assaf C Bester, Michael M Im, Donna S Shewach, Rotem Karni, Batsheva Kerem
  • Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches
    Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches
    1. Ivano Di Meo1,
    2. Costanza Lamperti1 and
    3. Valeria Tiranti*,1
    1. 1Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy
    1. *Corresponding author. Tel: +39 022 394 2633; Fax: +39 022 394 2619; E‐mail: tiranti{at}istituto-besta.it

    A comprehensive discussion of mitochondrial diseases caused by the accumulation of compounds normally present in traces, leading to toxic and inhibitory effects on the OXPHOS system.

    • mitochondrial diseases
    • OXPHOS
    • sulfide catabolism
    • therapeutic approaches
    • thymidine/deoxyuridine catabolism
    • Received April 14, 2015.
    • Revision received May 29, 2015.
    • Accepted June 16, 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.

    Ivano Di Meo, Costanza Lamperti, Valeria Tiranti
  • Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms
    Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms
    1. Alexander Nyström1,
    2. Kerstin Thriene1,2,3,,
    3. Venugopal Mittapalli1,,
    4. Johannes S Kern1,
    5. Dimitra Kiritsi1,
    6. Jörn Dengjel1,2,3,4 and
    7. Leena Bruckner‐Tuderman*,1,3
    1. 1Department of Dermatology, Medical Center ‐ University of Freiburg, Freiburg, Germany
    2. 2ZBSA Center for Biological Systems Analysis, Freiburg, Germany
    3. 3FRIAS Freiburg Institute for Advanced Studies, Freiburg, Germany
    4. 4BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
    1. *Corresponding author. Tel: +49 761 270 67160; Fax: +49 761 270 69360; E‐mail: bruckner-tuderman{at}uniklinik-freiburg.de
    1. These authors contributed equally to this work

    Targeting the secondary consequences of collagen VII loss with FDA‐approved drug losartan ameliorates recessive dystrophic epidermolysis bullosa (RDEB) in a mouse model.

    Synopsis

    Targeting the secondary consequences of collagen VII loss with FDA‐approved drug losartan ameliorates recessive dystrophic epidermolysis bullosa (RDEB) in a mouse model.

    • Modulation of disease mechanisms by repurposing approved drugs is an attractive approach to manage connective tissue disorders.

    • In RDEB, disease progression is driven by repeated cycles of tissue damage, inflammation, and TGF‐β‐mediated matrix remodeling.

    • Reduction of TGF‐β activity by targeting the angiotensin–renin system with losartan effectively slows down disease progression in a preclinical setting.

    • Treatment of RDEB mice with 0.6 g/l losartan in drinking water reduced digit fusion and prolonged functionality of forepaws for up to 30 weeks.

    • RDEB can be significantly ameliorated without correcting the underlying genetic defect.

    • collagen VII
    • dystrophic epidermolysis bullosa
    • fibrosis
    • losartan
    • TGF‐β
    • Received January 23, 2015.
    • Revision received June 12, 2015.
    • Accepted June 18, 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.

    Alexander Nyström, Kerstin Thriene, Venugopal Mittapalli, Johannes S Kern, Dimitra Kiritsi, Jörn Dengjel, Leena Bruckner‐Tuderman
  • Mitochondrial roles in disease: a box full of surprises
    Mitochondrial roles in disease: a box full of surprises
    1. Anu Suomalainen (anu.wartiovaara{at}helsinki.fi)1,2,3
    1. 1Research Programs Unit, Molecular Neurology, Helsinki, Finland
    2. 2Neuroscience Center, University of Helsinki, Helsinki, Finland
    3. 3Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland

    This commentary inaugurates a new review series in EMBO Molecular Medicine focused on mitochondrial diseases. This area of medicine, which actually encompasses most disease areas, has long since come of age and is now positioned for the next leap toward the development of effective therapies. The aims of the review series are to offer a comprehensive overview of this exciting area of medicine and research and to provide timely discussions for clinicians and investigators on the new discoveries elucidating how mitochondrial metabolism contributes to an expanding group of complex, heterogeneous, and difficult‐to‐tackle diseases.

    Anu Suomalainen offers a compact, authoritative overview of the burgeoning field of mitochondrial medicine and presents the upcoming EMBO Molecular Medicine “Mitochondrial Diseases” review series by many of the leaders in the field.

    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.

    Anu Suomalainen
  • Semaphorin‐3C signals through Neuropilin‐1 and PlexinD1 receptors to inhibit pathological angiogenesis
    Semaphorin‐3C signals through Neuropilin‐1 and PlexinD1 receptors to inhibit pathological angiogenesis
    1. Wan‐Jen Yang1,2,,
    2. Junhao Hu3,,
    3. Akiyoshi Uemura4,
    4. Fabian Tetzlaff1,
    5. Hellmut G Augustin2,3 and
    6. Andreas Fischer*,1,2,5
    1. 1Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ‐ZMBH Alliance), Heidelberg, Germany
    2. 2Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim (CBTM) Heidelberg University, Mannheim, Germany
    3. 3Vascular Oncology and Metastasis (A190), German Cancer Research Center (DKFZ‐ZMBH Alliance), Heidelberg, Germany
    4. 4Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
    5. 5Department of Medicine I and Clinical Chemistry, Heidelberg University, Heidelberg, Germany
    1. *Corresponding author. Tel: +49 06221424150; Fax: +49 6221424159; Email: a.fischer{at}dkfz-heidelberg.de
    1. These authors contributed equally to this work

    Semaphorin‐3C is a potent and selective inhibitor of pathological retinal angiogenesis that acts by signaling through Nrp‐1 and PlexinD1 receptors.

    Synopsis

    Semaphorin‐3C is a potent and selective inhibitor of pathological retinal angiogenesis that acts by signaling through Nrp‐1 and PlexinD1 receptors.

    • The neural guidance molecule Semaphorin‐3C impairs the integrity of endothelial cell junctions and cell survival by signaling through the Nrp‐1 and PlexinD1 receptors.

    • Nrp‐1 and PlexinD1 are highly expressed in growing blood vessels and these immature vessels are specifically targeted by Semaphorin‐3C.

    • Pathological angiogenesis in a model of retinopathy of prematurity is curbed by local administration of recombinant Semaphorin‐3C protein.

    • angiogenesis
    • semaphorin
    • retinopathy of prematurity
    • Sema3C
    • Received December 3, 2014.
    • Revision received June 17, 2015.
    • Accepted June 19, 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.

    Wan‐Jen Yang, Junhao Hu, Akiyoshi Uemura, Fabian Tetzlaff, Hellmut G Augustin, Andreas Fischer
  • The cholesterol‐binding protein NPC2 restrains recruitment of stromal macrophage‐lineage cells to early‐stage lung tumours
    The cholesterol‐binding protein NPC2 restrains recruitment of stromal macrophage‐lineage cells to early‐stage lung tumours
    1. Tamihiro Kamata*,1,,
    2. Hong Jin1,,
    3. Susan Giblett1,
    4. Bipin Patel1,
    5. Falguni Patel1,
    6. Charles Foster1 and
    7. Catrin Pritchard*,1
    1. 1Department of Biochemistry, University of Leicester, Leicester, UK
    1. * Corresponding author. Tel: +44 116 7029; Fax: +44 116 7018; E‐mail: tk83{at}le.ac.uk

      Corresponding author. Tel: +44 116 7029; Fax: +44 116 7018; E‐mail: cap8{at}le.ac.uk

    1. These authors contributed equally to this work

    M2‐polarised immature macrophage‐lineage cells (IMCs) found in the early lung adenoma microenvironment and recruited via CCR1 signalling. Adenoma‐secreted Niemann‐Pick type C2 protein suppresses IMC recruitment to the tumour microenvironment.

    Synopsis

    M2‐polarised immature macrophage‐lineage cells (IMCs) found in the early lung adenoma microenvironment and recruited via CCR1 signalling. Adenoma‐secreted Niemann‐Pick type C2 protein suppresses IMC recruitment to the tumour microenvironment.

    • Characterisation of the V600EBRAF‐driven early lung adenoma microenvironment identifies IMCs.

    • IMCs secrete CCR1 chemokines, and CCR1 inhibition prevents IMC recruitment in vivo.

    • IMCs are required for adenoma maintenance since CCR1 inhibition suppresses adenoma burden.

    • Niemann‐Pick type C2 (NPC2) protein is secreted by adenoma cells and suppresses IMC recruitment to the microenvironment.

    • Exogenous NPC2 is incorporated by IMCs wherein it suppresses CCR1 chemokine secretion.

    • CCR1
    • lung adenoma
    • NPC2
    • tumour‐associated macrophage‐lineage cells
    • V600 EBRAF
    • Received November 11, 2014.
    • Revision received June 16, 2015.
    • Accepted June 18, 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.

    Tamihiro Kamata, Hong Jin, Susan Giblett, Bipin Patel, Falguni Patel, Charles Foster, Catrin Pritchard