EMBO Molecular Medicine

Cover image for Vol. 7 Issue 4

Early View (Online Version of Record published before inclusion in an issue)

Edited By: Stefanie Dimmeler (Chief Editor), Roberto Buccione and Céline Carret (EMBO Editors)

Online ISSN: 1757-4684

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  1. 1 - 28
  1. Research Articles

    1. You have full text access to this OnlineOpen article
      Cellular and molecular determinants of all-trans retinoic acid sensitivity in breast cancer: Luminal phenotype and RARα expression

      Floriana Centritto, Gabriela Paroni, Marco Bolis, Silvio Ken Garattini, Mami Kurosaki, Maria Monica Barzago, Adriana Zanetti, James Neil Fisher, Mark Francis Scott, Linda Pattini, Monica Lupi, Paolo Ubezio, Francesca Piccotti, Alberto Zambelli, Paola Rizzo, Maurizio Gianni', Maddalena Fratelli, Mineko Terao and Enrico Garattini

      Article first published online: 17 APR 2015 | DOI: 10.15252/emmm.201404670

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      This study provides fundamental information for the development of retinoid-based therapies for breast cancer and suggests that therapeutic strategies based on the use of RARα-specific retinoids may overcome toxicity due to use of pan-RAR agonists.

    2. You have full text access to this OnlineOpen article
      Antigen delivery by filamentous bacteriophage fd displaying an anti-DEC-205 single-chain variable fragment confers adjuvanticity by triggering a TLR9-mediated immune response

      Rossella Sartorius, Luciana D'Apice, Maria Trovato, Fausta Cuccaro, Valerio Costa, Maria Giovanna De Leo, Vincenzo Manuel Marzullo, Carmelo Biondo, Sabato D'Auria, Maria Antonietta De Matteis, Alfredo Ciccodicola and Piergiuseppe De Berardinis

      Article first published online: 17 APR 2015 | DOI: 10.15252/emmm.201404525

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      Filamentous fd bacteriophages engineered to display antigens and targeted to dendritic cells via DEC-205 activate both innate and adaptive immune responses and are an attractive immunization system avoiding administration of exogenous adjuvants.

    3. You have full text access to this OnlineOpen article
      Lack of kinase-independent activity of PI3Kγ in locus coeruleus induces ADHD symptoms through increased CREB signaling

      Ivana D'Andrea, Valentina Fardella, Stefania Fardella, Fabio Pallante, Alessandra Ghigo, Roberta Iacobucci, Angelo Maffei, Emilio Hirsch, Giuseppe Lembo and Daniela Carnevale

      Article first published online: 16 APR 2015 | DOI: 10.15252/emmm.201404697

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      PI3K regulates synaptic plasticity and behavioral flexibility via a kinase-independent but CREB-dependent mechanism in noradrenergic neurons of the locus coeruleus. PI3Kγ-deficient mice model main features of attention-deficit/hyperactivity disorders (ADHD).

    4. You have full text access to this OnlineOpen article
      ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat

      Simone Meidhof, Simone Brabletz, Waltraut Lehmann, Bogdan-Tiberius Preca, Kerstin Mock, Manuel Ruh, Julia Schüler, Maria Berthold, Anika Weber, Ulrike Burk, Michael Lübbert, Martin Puhr, Zoran Culig, Ulrich Wellner, Tobias Keck, Peter Bronsert, Simon Küsters, Ulrich T Hopt, Marc P Stemmler and Thomas Brabletz

      Article first published online: 14 APR 2015 | DOI: 10.15252/emmm.201404396

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      Therapy resistance is a major problem in cancer medicine. Based on the identification of novel mediators of ZEB1-associated therapy resistance, the HDAC inhibitor mocetinostat is found to efficiently restore drug sensitivity in aggressive cancer cells.

    5. You have full text access to this OnlineOpen article
      A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy

      Leonardo Bee, Alessia Nasca, Alice Zanolini, Filippo Cendron, Pio d'Adamo, Rodolfo Costa, Costanza Lamperti, Lucia Celotti, Daniele Ghezzi and Massimo Zeviani

      Article first published online: 14 APR 2015 | DOI: 10.15252/emmm.201404803

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      A homozygous nonsense XRCC4 mutation was identified in two identical twins with an adult-onset encephalocardiomyopathy but without immunodeficiency. XRCC4 is a partner of LIG4 and functions in non-homologous end-joining repair of double-strand DNA breaks.

  2. Reports

    1. You have full text access to this OnlineOpen article
      Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early-onset arteriopathy and cavitating leukoencephalopathy

      Tommaso Pippucci, Alessandra Maresca, Pamela Magini, Giovanna Cenacchi, Vincenzo Donadio, Flavia Palombo, Valentina Papa, Alex Incensi, Giuseppe Gasparre, Maria Lucia Valentino, Carmela Preziuso, Annalinda Pisano, Michele Ragno, Rocco Liguori, Carla Giordano, Caterina Tonon, Raffaele Lodi, Antonia Parmeggiani, Valerio Carelli and Marco Seri

      Article first published online: 13 APR 2015 | DOI: 10.15252/emmm.201404399

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      A recessive homozygous protein-truncating NOTCH3 mutation is found in a patient with devastating childhood-onset, vascular leukoencephalopathy, suggesting that this could be the underlying mechanism in other patients with similar severe pathology.

  3. Research Articles

    1. You have full text access to this OnlineOpen article
      Fusion protein of retinol-binding protein and albumin domain III reduces liver fibrosis

      Hongsik Lee, Hyeyeun Jeong, Sangeun Park, Wonbaek Yoo, Soyoung Choi, Kyungmin Choi, Min-Goo Lee, Mihwa Lee, DaeRyong Cha, Young-Sik Kim, Jeeyoung Han, Wonkon Kim, Sun-Hwa Park and Junseo Oh

      Article first published online: 11 APR 2015 | DOI: 10.15252/emmm.201404527

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      Hepatic stellate cell (HSC)-targeted albumin fusion protein (R-III) downregulates retinoic acid (RA) signaling and HSC activation. Intravenous R-III localizes to HSCs and reduces liver fibrosis.

    2. You have full text access to this OnlineOpen article
      Divergent androgen regulation of unfolded protein response pathways drives prostate cancer

      Xia Sheng, Yke Jildouw Arnoldussen, Margrethe Storm, Martina Tesikova, Hatice Zeynep Nenseth, Sen Zhao, Ladan Fazli, Paul Rennie, Bjørn Risberg, Håkon Wæhre, Håvard Danielsen, Ian G Mills, Yang Jin, Gökhan Hotamisligil and Fahri Saatcioglu

      Article first published online: 11 APR 2015 | DOI: 10.15252/emmm.201404509

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      Androgens generate a divergent UPR response whereby the IRE1α arm is activated, and the PERK one inhibited. Genetic depletion or small molecule inhibition of IRE1α inhibited prostate cancer cell growth in vitro and tumor.

  4. Reviews

    1. You have full text access to this OnlineOpen article
      Mitochondrial dynamism and heart disease: changing shape and shaping change

      Gerald W Dorn II

      Article first published online: 10 APR 2015 | DOI: 10.15252/emmm.201404575

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      A comprehensive overview of the clinical and experimental evidence for and against a meaningful role for the mitochondrial dynamics and quality control in normal and diseased hearts.

  5. Closeup

    1. You have full text access to this OnlineOpen article
      A new twist to the emerging functions of ceramides in cancer: novel role for platelet acid sphingomyelinase in cancer metastasis

      Yusuf A Hannun and Benjamin Newcomb

      Article first published online: 9 APR 2015 | DOI: 10.15252/emmm.201505161

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      Hannun and Newcomb comment on the paper published in this issue providing evidence of cross talk between platelets and tumor cells via acid sphingomyelinase-mediated trans-cellular signaling, required for lung seeding of melanoma cells.

  6. Research Articles

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      Vasculotide reduces endothelial permeability and tumor cell extravasation in the absence of binding to or agonistic activation of Tie2

      Florence T H Wu, Christina R Lee, Elena Bogdanovic, Aaron Prodeus, Jean Gariépy and Robert S Kerbel

      Article first published online: 7 APR 2015 | DOI: 10.15252/emmm.201404193

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      Vasculotide (VT) reduced trans-endothelial permeability and tumor cell migration in vitro and, in vivo, delayed metastasis to the lungs while not affecting primary breast cancer growth. The effect of VT appeared to be independent of Tie2.

    2. You have full text access to this OnlineOpen article
      Regulation of hematogenous tumor metastasis by acid sphingomyelinase

      Alexander Carpinteiro, Katrin Anne Becker, Lukasz Japtok, Gabriele Hessler, Simone Keitsch, Miroslava Požgajovà, Kurt W Schmid, Constantin Adams, Stefan Müller, Burkhard Kleuser, Michael J Edwards, Heike Grassmé, Iris Helfrich and Erich Gulbins

      Article first published online: 7 APR 2015 | DOI: 10.15252/emmm.201404571

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      Melanoma cells induce acid sphingomyelinase (Asm) release from platelets, which in turn induces ceramide in melanoma cells, clustering of α5β1 integrin, and tumor cell trapping. Asm loss or inhibition protects mice from hematogenous tumor metastasis.

    3. You have full text access to this OnlineOpen article
      ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8+ cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy

      Chunyang Li, Weiyun Li, Jun Xiao, Shaozhuo Jiao, Fei Teng, Shengjie Xue, Chi Zhang, Chun Sheng, Qibin Leng, Christopher E Rudd, Bin Wei and Hongyan Wang

      Article first published online: 7 APR 2015 | DOI: 10.15252/emmm.201404578

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      ADAP and SKAP55 can enhance PD-1 expression via the transcription factor NFATc1 in CD8+ CTLs. Targeting this pathway in CTLs enhances cytotoxic responses against tumor cells in vitro and in vivo.

  7. Closeup

    1. You have full text access to this OnlineOpen article
      New insights into the pathology of pulmonary hypertension: implication of the miR-210/ISCU1/2/Fe-S Axis

      Haiyang Tang, Ramon J Ayon and Jason X-J Yuan

      Article first published online: 7 APR 2015 | DOI: 10.15252/emmm.201505160

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      Yuan and colleagues discuss on the paper published in this issue showing that hypoxia-inducible miR-210 down-regulates its targets ISCU1/2 to regulate pulmonary vascular and endothelial levels of Fe-S clusters upon acquired injury or mutations.

  8. Research Articles

    1. You have full text access to this OnlineOpen article
      Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumour chemoresistance

      Camille Duluc, Siham Moatassim-Billah, Mounira Chalabi-Dchar, Aurélie Perraud, Rémi Samain, Florence Breibach, Marion Gayral, Pierre Cordelier, Marie-Bernadette Delisle, Marie-Pierre Bousquet-Dubouch, Richard Tomasini, Herbert Schmid, Muriel Mathonnet, Stéphane Pyronnet, Yvan Martineau and Corinne Bousquet

      Article first published online: 1 APR 2015 | DOI: 10.15252/emmm.201404346

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      A novel drug association combining current chemotherapies with pharmacological inhibition of the Cancer-Associated Fibroblast secretome with the somatostatin analogue SOM230 (Pasireotide), effectively reverses chemoresistance in pancreatic cancer.

    2. You have full text access to this OnlineOpen article
      Defects in mitophagy promote redox-driven metabolic syndrome in the absence of TP53INP1

      Marion Seillier, Laurent Pouyet, Prudence N'Guessan, Marie Nollet, Florence Capo, Fabienne Guillaumond, Laure Peyta, Jean-François Dumas, Annie Varrault, Gyslaine Bertrand, Stéphanie Bonnafous, Albert Tran, Gargi Meur, Piero Marchetti, Magalie A Ravier, Stéphane Dalle, Philippe Gual, Dany Muller, Guy A Rutter, Stéphane Servais, Juan L Iovanna and Alice Carrier

      Article first published online: 31 MAR 2015 | DOI: 10.15252/emmm.201404318

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      TP53INP1, a p53-regulated protein with antioxidant and tumor suppressive functions, is shown to prevent redox-driven obesity, which leads to insulin resistance and type 2 diabetes, likely by impacting on mitochondria homeostasis and mitophagy.

    3. You have full text access to this OnlineOpen article
      Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension

      Kevin White, Yu Lu, Sofia Annis, Andrew E Hale, B Nelson Chau, James E Dahlman, Craig Hemann, Alexander R Opotowsky, Sara O Vargas, Ivan Rosas, Mark A Perrella, Juan C Osorio, Kathleen J Haley, Brian B Graham, Rahul Kumar, Rajan Saggar, Rajeev Saggar, W Dean Wallace, David J Ross, Omar F Khan, Andrew Bader, Bernadette R Gochuico, Majed Matar, Kevin Polach, Nicolai M Johannessen, Haydn M Prosser, Daniel G Anderson, Robert Langer, Jay L Zweier, Laurence A Bindoff, David Systrom, Aaron B Waxman, Richard C Jin and Stephen Y Chan

      Article first published online: 30 MAR 2015 | DOI: 10.15252/emmm.201404511

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      Hypoxia-inducible miR-210 down-regulates its targets ISCU1/2 to regulate pulmonary vascular and endothelial levels of Fe-S clusters upon acquired injury or mutations. A patient with ISCU loss-of-function mutation presents with pulmonary vasculopathy.

    4. You have full text access to this OnlineOpen article
      Targeting DDX3 with a small molecule inhibitor for lung cancer therapy

      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 and Venu Raman

      Article first published online: 27 MAR 2015 | DOI: 10.15252/emmm.201404368

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      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.

    5. You have full text access to this OnlineOpen article
      A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis

      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 and Frédérique René

      Article first published online: 27 MAR 2015 | DOI: 10.15252/emmm.201404433

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      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.

    6. You have full text access to this OnlineOpen article
      Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine

      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 and Conxi Lázaro

      Article first published online: 25 MAR 2015 | DOI: 10.15252/emmm.201404430

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      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.

    7. You have full text access to this OnlineOpen article
      The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene

      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 and Luis Carlos López

      Article first published online: 23 MAR 2015 | DOI: 10.15252/emmm.201404632

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      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.

    8. You have full text access to this OnlineOpen article
      Consequence of the tumor-associated conversion to cyclin D1b

      Michael A Augello, Lisa D Berman-Booty, Richard Carr 3rd, 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 and Karen E Knudsen

      Article first published online: 18 MAR 2015 | DOI: 10.15252/emmm.201404242

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      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.

    9. You have full text access to this OnlineOpen article
      Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response

      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 and Jagdeep Nanchahal

      Article first published online: 14 MAR 2015 | DOI: 10.15252/emmm.201404487

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      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.

    10. You have full text access to this OnlineOpen article
      Phospholipid oxidation generates potent anti-inflammatory lipid mediators that mimic structurally related pro-resolving eicosanoids by activating Nrf2

      Peter Bretscher, Julian Egger, Abdijapar Shamshiev, Martin Trötzmüller, Harald Köfeler, Erick M Carreira, Manfred Kopf and Stefan Freigang

      Article first published online: 13 MAR 2015 | DOI: 10.15252/emmm.201404702

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      This study characterizes the potent anti-inflammatory bioactivity of oxidized phospholipids and identifies a fatty acid epoxycyclopentenone as the active component that triggers Nrf2 signaling in myeloid cells and alleviates inflammation and endotoxin-induced lung injury in a mouse model.

    11. You have full text access to this OnlineOpen article
      Inhibition of lethal inflammatory responses through the targeting of membrane-associated Toll-like receptor 4 signaling complexes with a Smad6-derived peptide

      Youn Sook Lee, Jin Seok Park, Su Myung Jung, Sang-Doo Kim, Jun Hwan Kim, Jae Young Lee, Kyeong Cheon Jung, Mizuko Mamura, Sangho Lee, Seong-Jin Kim, Yoe-Sik Bae and Seok Hee Park

      Article first published online: 12 MAR 2015 | DOI: 10.15252/emmm.201404653

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      Smaducin-6, a synthetic membrane-tethered palmitic acid-conjugated peptide composed of 20 amino acid of Smad6, is shown here to be the first therapeutic peptide targeting Pellino-1 in the TLR4 signaling pathway for the treatment of sepsis.

    12. You have full text access to this OnlineOpen article
      Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease

      Sang-Min Oh, Mi-Yoon Chang, Jae-Jin Song, Yong-Hee Rhee, Eun-Hye Joe, Hyun-Seob Lee, Sang-Hoon Yi and Sang-Hun Lee

      Article first published online: 10 MAR 2015 | DOI: 10.15252/emmm.201404610

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      Gene therapy of Nurr1 and Foxa2 protects midbrain dopamine (mDA) neurons from degeneration in a mouse model of Parkinson's disease (PD), suggesting that exploitation of the physiological mechanisms promoting mDA neuron survival might be an option for developing treatments for PD.

    13. You have full text access to this OnlineOpen article
      Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy

      Michael Gramlich, Luna Simona Pane, Qifeng Zhou, Zhifen Chen, Marta Murgia, Sonja Schötterl, Alexander Goedel, Katja Metzger, Thomas Brade, Elvira Parrotta, Martin Schaller, Brenda Gerull, Ludwig Thierfelder, Annemieke Aartsma-Rus, Siegfried Labeit, John J Atherton, Julie McGaughran, Richard P Harvey, Daniel Sinnecker, Matthias Mann, Karl-Ludwig Laugwitz, Meinrad Paul Gawaz and Alessandra Moretti

      Article first published online: 10 MAR 2015 | DOI: 10.15252/emmm.201505047

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      Truncating mutations in the giant sarcomeric protein titin (TTN) are a major cause for inherited forms of dilated cardiomyopathy (DCM). Antisense oligonucleotides (AON)-mediated exon skipping is shown here to be a promising strategy as potential treatment option for DCM.

  9. Perspectives

    1. You have full text access to this OnlineOpen article
      From the principles of genomic data sharing to the practices of data access committees

      Mahsa Shabani, Bartha Maria Knoppers and Pascal Borry

      Article first published online: 10 MAR 2015 | DOI: 10.15252/emmm.201405002

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      Data access arrangements and data access committees (DACs) are central for implementing the policies and principles of data sharing. Their functionality is here discussed through the perspective of existing practices.

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