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  • Targeting the adaptive molecular landscape of castration‐resistant prostate cancer
    Targeting the adaptive molecular landscape of castration‐resistant prostate cancer
    1. Alexander W Wyatt*,1 and
    2. Martin E Gleave*,1
    1. 1Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
    1. * Corresponding author. Tel: +1 604 875 4818; E‐mail: awyatt{at}prostatecentre.com

      Corresponding author. Tel: +1 604 875 4818; E‐mail: m.gleave{at}ubc.ca

    State‐of‐the‐art overview of the landscape of castration‐resistant prostate cancer and in‐depth analysis of the recent successes and failures of therapeutic strategies designed to target AR reactivation and adaptive survival pathways.

    • androgen receptor
    • castration‐resistant prostate cancer
    • stress response
    • survival pathways
    • tumour heterogeneity
    • Received January 17, 2015.
    • Revision received March 12, 2015.
    • Accepted March 26, 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 W Wyatt, Martin E Gleave
  • Cellular and molecular determinants of all‐trans retinoic acid sensitivity in breast cancer: Luminal phenotype and RARα expression
    <div xmlns="http://www.w3.org/1999/xhtml">Cellular and molecular determinants of all‐<em>trans</em> retinoic acid sensitivity in breast cancer: <em>Luminal</em> phenotype and RARα expression</div>
    1. Floriana Centritto1,,
    2. Gabriela Paroni1,,
    3. Marco Bolis1,,
    4. Silvio Ken Garattini1,
    5. Mami Kurosaki1,
    6. Maria Monica Barzago1,
    7. Adriana Zanetti1,
    8. James Neil Fisher1,
    9. Mark Francis Scott1,
    10. Linda Pattini2,
    11. Monica Lupi3,
    12. Paolo Ubezio3,
    13. Francesca Piccotti4,
    14. Alberto Zambelli5,
    15. Paola Rizzo6,
    16. Maurizio Gianni'1,
    17. Maddalena Fratelli1,
    18. Mineko Terao1 and
    19. Enrico Garattini*,1
    1. 1Laboratory of Molecular Biology, IRCCS‐Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, Italy
    2. 2Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
    3. 3Department of Oncology, IRCCS‐Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, Italy
    4. 4IRCCS‐Fondazione “Salvatore Maugeri”, Pavia, Italy
    5. 5Oncologia Medica, Ospedale Papa Giovanni XXIII, Bergamo, Italy
    6. 6Gene Therapy and Cellular Reprogramming, IRCCS‐ Istituto di Ricerche Farmacologiche “Mario Negri”, Bergamo, Italy
    1. *Corresponding author. Tel: +39 02 39014533; E‐mail: enrico.garattini{at}marionegri.it
    1. These authors contributed equally to this work

    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.

    Synopsis

    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.

    • Profiling of 42 breast cancer cell lines for ATRA sensitivity demonstrates that Luminal and ER+ (estrogen receptor‐positive) cells are generally responsive, while Basal and HER2+ cells are generally refractory to the retinoid.

    • The results obtained with cell‐lines were confirmed in short‐term cultures of breast tumor samples, which indicate that a large fraction of Luminal/ER+ carcinomas are ATRA sensitive.

    • Using biological and pharmacological approaches, RARα is shown to be the major mediator of ATRA anti‐proliferative responses in retinoid‐sensitive cells.

    • Gene‐sets associated with ATRA‐sensitivity are identified in breast cancer cell lines and validated with whole‐genome gene‐expression microarrays in short‐term tissue cultures.

    • breast cancer
    • luminal phenotype
    • nuclear receptor
    • RARalpha
    • retinoic acid
    • Received September 19, 2014.
    • Revision received March 23, 2015.
    • Accepted March 25, 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.

    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, Enrico Garattini
  • Antigen delivery by filamentous bacteriophage fd displaying an anti‐DEC‐205 single‐chain variable fragment confers adjuvanticity by triggering a TLR9‐mediated immune response
    Antigen delivery by filamentous bacteriophage fd displaying an anti‐DEC‐205 single‐chain variable fragment confers adjuvanticity by triggering a TLR9‐mediated immune response
    1. Rossella Sartorius1,
    2. Luciana D'Apice1,
    3. Maria Trovato1,
    4. Fausta Cuccaro1,
    5. Valerio Costa2,
    6. Maria Giovanna De Leo3,
    7. Vincenzo Manuel Marzullo1,3,
    8. Carmelo Biondo4,
    9. Sabato D'Auria1,5,
    10. Maria Antonietta De Matteis3,
    11. Alfredo Ciccodicola2,6 and
    12. Piergiuseppe De Berardinis*,1
    1. 1Institute of Protein Biochemistry, National Council of Research, Naples, Italy
    2. 2Institute of Genetics and Biophysics A. Buzzati‐Traverso, National Council of Research, Naples, Italy
    3. 3Telethon Institute of Genetics and Medicine, Pozzuoli (NA), Italy
    4. 4Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, University of Messina, Messina, Italy
    5. 5Institute of Food Science, National Council of Research, Avellino, Italy
    6. 6Department of Science and Technology, University Parthenope of Naples, Naples, Italy
    1. *Corresponding author. Tel.: +39 0816132566; E‐mail: p.deberardinis{at}ibp.cnr.it

    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.

    Synopsis

    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.

    • Antigens displayed on anti‐DEC‐205‐targeted bacteriophages are efficiently cross‐presented by DCs.

    • fd virions targeted to DCs via DEC‐205 are delivered to endolysosomal compartments where they co‐localize with active TLR9.

    • Transcriptome analysis using RNA‐Seq of bacteriophage‐pulsed DCs elucidates the signature induced by fd anti‐DEC‐205‐based vaccine and showed the up‐regulation of gene pathways involved in the innate and adaptive immune responses.

    • Production of pro‐inflammatory cytokines and type I interferon is induced in DC‐targeted bacteriophage fd particles displaying anti‐DEC‐205 scFv and abolished in MyD88−/− and Tlr9−/− mice.

    • fdsc‐αDEC bacteriophages combine adjuvanticity and ability to activate specific immune responses, and may thus represent a relevant option in vaccinology.

    • antigen delivery
    • DEC‐205
    • dendritic cells
    • filamentous bacteriophage
    • TLR9
    • Received August 8, 2014.
    • Revision received March 19, 2015.
    • Accepted March 24, 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.

    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, Piergiuseppe De Berardinis
  • Lack of kinase‐independent activity of PI3Kγ in locus coeruleus induces ADHD symptoms through increased CREB signaling
    Lack of kinase‐independent activity of PI3Kγ in locus coeruleus induces ADHD symptoms through increased CREB signaling
    1. Ivana D'Andrea1,,
    2. Valentina Fardella1,,
    3. Stefania Fardella1,
    4. Fabio Pallante1,
    5. Alessandra Ghigo2,
    6. Roberta Iacobucci1,
    7. Angelo Maffei1,
    8. Emilio Hirsch2,
    9. Giuseppe Lembo*,1,3 and
    10. Daniela Carnevale*,1,3
    1. 1Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli (IS), Italy
    2. 2Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
    3. 3Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
    1. * Corresponding author. Tel: +39 0865 929644; Fax: +39 0865 927575; E‐mail: lembo{at}neuromed.it

      Corresponding author. Tel: +39 0865 929614; Fax: +39 0865 927575; E‐mail: daniela.carnevale{at}neuromed.it

    1. These authors contributed equally to this work

    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).

    Synopsis

    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).

    • PI3Kγ KO mice exhibit symptomatic traits of the attention‐deficit/hyperactivity disorder (ADHD), displaying deficits in the attentive and mnemonic domains, coupled with typical hyperactivity, as well as social dysfunctions.

    • PI3Kγ controls locus coeruleus (LC) functions in the modulations of these behavioral domains by kinase‐independent mechanisms; the PI3Kγ KD (kinase‐defective) mice are not affected.

    • PI3Kγ physically interacts with phosphodiesterase 4D (PDE4D) in the LC and controls cAMP–CREB signaling, which is constitutively increased in PI3Kγ KO mice.

    • Selective genetic targeting of increased CREB signaling in the LC by stereotactic approach rescues the ADHD phenotype of PI3Kγ KO mice.

    • catecholamine
    • CREB
    • mouse model
    • phosphodiesterases (PDEs)
    • stereotactic surgery
    • Received September 30, 2014.
    • Revision received March 16, 2015.
    • Accepted March 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.

    Ivana D'Andrea, Valentina Fardella, Stefania Fardella, Fabio Pallante, Alessandra Ghigo, Roberta Iacobucci, Angelo Maffei, Emilio Hirsch, Giuseppe Lembo, Daniela Carnevale
  • A nonsense mutation of human XRCC4 is associated with adult‐onset progressive encephalocardiomyopathy
    A nonsense mutation of human XRCC4 is associated with adult‐onset progressive encephalocardiomyopathy
    1. Leonardo Bee15,
    2. Alessia Nasca2,
    3. Alice Zanolini2,
    4. Filippo Cendron1,
    5. Pio d'Adamo3,
    6. Rodolfo Costa1,
    7. Costanza Lamperti2,
    8. Lucia Celotti1,
    9. Daniele Ghezzi*,2 and
    10. Massimo Zeviani*,2,4
    1. 1Department of Biology, University of Padua, Padua, Italy
    2. 2Molecular Neurogenetics Unit, Foundation IRCCS Institute of Neurology “Carlo Besta”, Milan, Italy
    3. 3Department of Medical Sciences, University of Trieste, Trieste, Italy
    4. 4MRC Mitochondrial Biology Unit, CB2 0XY, Cambridge, UK
    5. 5Center for Epigenetics and Metabolism, Department of Biological Chemistry, University of California, Irvine, CA, USA
    1. * Corresponding author. Tel: +39 0223942627; Fax: +39 0223942619; E‐mail: dghezzi{at}istituto-besta.it

      Corresponding author. Tel: +44 1223 252702; Fax: +44 1223 252705; E‐mail: mdz21{at}mrc-mbu.cam.ac.uk

    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.

    Synopsis

    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.

    • Patients have no sign of immunodeficiency or malignancy.

    • XRCC4 transcript was strongly reduced, and the protein was undetectable in patients' tissues/cells.

    • In contrast to previous reports, in our patients LIG4 was only slightly reduced.

    • Functional assays on mutant cells demonstrated reduction, but not abolition of the ability to repair double‐strand DNA breaks.

    • DNA repair
    • encephalocardiomyopathy
    • NHEJ
    • XRCC4
    • Received October 31, 2014.
    • Revision received March 23, 2015.
    • Accepted March 24, 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.

    Leonardo Bee, Alessia Nasca, Alice Zanolini, Filippo Cendron, Pio d'Adamo, Rodolfo Costa, Costanza Lamperti, Lucia Celotti, Daniele Ghezzi, Massimo Zeviani
  • ZEB1‐associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat
    ZEB1‐associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat
    1. Simone Meidhof1,2,3,,
    2. Simone Brabletz4,,
    3. Waltraut Lehmann1,3,
    4. Bogdan‐Tiberius Preca1,3,
    5. Kerstin Mock1,3,
    6. Manuel Ruh4,
    7. Julia Schüler5,
    8. Maria Berthold1,
    9. Anika Weber1,
    10. Ulrike Burk1,
    11. Michael Lübbert6,7,
    12. Martin Puhr8,
    13. Zoran Culig8,
    14. Ulrich Wellner9,
    15. Tobias Keck9,
    16. Peter Bronsert10,
    17. Simon Küsters1,
    18. Ulrich T Hopt1,
    19. Marc P Stemmler4 and
    20. Thomas Brabletz*,4,711
    1. 1Department of General and Visceral Surgery, University of Freiburg Medical Center, Freiburg, Germany
    2. 2 Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany
    3. 3 Faculty of Biology, Albert Ludwigs University Freiburg, Freiburg, Germany
    4. 4Experimental Medicine I, Nikolaus‐Fiebiger‐Center for Molecular Medicine, FAU University Erlangen‐Nürnberg, Erlangen, Germany
    5. 5Oncotest GmbH, Institute for Experimental Oncology, Freiburg, Germany
    6. 6Department of Hematology and Oncology, University of Freiburg Medical Center, Freiburg, Germany
    7. 7German Cancer Consortium (DKTK), Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
    8. 8Division of Experimental Urology, Innsbruck Medical University, Innsbruck, Austria
    9. 9Department of Surgery, University Medical Center Schleswig‐Holstein, Campus Lübeck, Germany
    10. 10Tumorbank Comprehensive Cancer Center Freiburg and Institute of Surgical Pathology, University Medical Center Freiburg, Freiburg, Germany
    11. 11Chair Experimental Medicine I, Nikolaus‐Fiebiger‐Center for Molecular Medicine, University Erlangen‐Nürnberg, Erlangen, Germany
    1. *Corresponding author. Tel: +49 9131 8529104; E‐mail: thomas.brabletz{at}fau.de
    1. These authors contributed equally to this work

    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.

    Synopsis

    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.

    • Strategy to counteract the well‐known cancer‐promoting functions of the EMT inducer ZEB1.

    • Identification of the stemness‐inhibiting microRNA miR‐203 as major ZEB1 target inducing drug sensitivity.

    • Identification of the class I HDAC inhibitor mocetinostat as drug to interfere with ZEB1 function and overcome ZEB1‐associated drug resistance.

    • Mocetinostat has better effects in combination with chemotherapeutics compared to other HDACis, such as SAHA.

    • Blueprint for further drug screens with reduction in ZEB1 function as major readout.

    • cancer stem cells
    • drug resistance
    • HDAC inhibitor
    • miR‐203
    • ZEB1
    • Received July 3, 2014.
    • Revision received March 16, 2015.
    • Accepted March 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.

    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, Thomas Brabletz
  • Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early‐onset arteriopathy and cavitating leukoencephalopathy
    Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early‐onset arteriopathy and cavitating leukoencephalopathy
    1. Tommaso Pippucci1,2,,
    2. Alessandra Maresca3,4,,
    3. Pamela Magini2,
    4. Giovanna Cenacchi4,
    5. Vincenzo Donadio3,
    6. Flavia Palombo2,
    7. Valentina Papa4,
    8. Alex Incensi3,
    9. Giuseppe Gasparre2,
    10. Maria Lucia Valentino3,4,
    11. Carmela Preziuso5,
    12. Annalinda Pisano5,
    13. Michele Ragno6,
    14. Rocco Liguori3,4,
    15. Carla Giordano5,
    16. Caterina Tonon4,7,
    17. Raffaele Lodi4,7,
    18. Antonia Parmeggiani2,8,
    19. Valerio Carelli*,3,4 and
    20. Marco Seri*,1,2
    1. 1U.O. Genetica Medica, Policlinico Sant'Orsola‐Malpighi, Bologna, Italy
    2. 2Dipartimento di Scienze Mediche Chirurgiche (DIMEC), University of Bologna, Bologna, Italy
    3. 3IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
    4. 4Unita' di Neurologia, Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, Italy
    5. 5Dipartimento di Scienze Radiologiche, Oncologiche ed Anatomopatologiche, Sapienza, University of Rome, Rome, Italy
    6. 6Divisione di Neurologia, Ospedale Mazzoni, Azienda Sanitaria Unica Regionale, Ascoli Piceno, Italy
    7. 7Unità Risonanza Magnetica Funzionale, Policlinico S.Orsola‐Malpighi, Bologna, Italy
    8. 8U.O. Neuropsichiatria Infantile, Policlinico S.Orsola‐Malpighi, Bologna, Italy
    1. * Corresponding author. Tel: +39 051 4966747; Fax: +39 051 2092751; E‐mail: valerio.carelli{at}unibo.it

      Corresponding author. Tel: +39 051 2088421/051 6363694; Fax: +39 051 2088416; E‐mail: marco.seri{at}unibo.it

    1. These authors contributed equally to this work

    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.

    Synopsis

    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.

    • For the first time, a recessive homozygous protein‐truncating mutation in NOTCH3 has been found in a patient with a devastating childhood‐onset, vascular leukoencephalopathy.

    • This mutation is shown to abolish NOTCH3 expression and signaling, with downregulation of NOTCH3 target genes.

    • In the patient, vessels were characterized by SMC degeneration, similar to that observed in CADASIL. However, GOM deposits, the CADASIL hallmark, were absent, mirroring the Notch3−/− mouse model.

    • Both the heterozygous consanguineous parents displayed similar but less dramatic trends in NOTCH3 signaling impairment and vascular damage.

    • CADASIL
    • cerebral arteriopathy
    • exome
    • leukoencephalopathy
    • NOTCH3
    • Received July 4, 2014.
    • Revision received March 9, 2015.
    • Accepted March 12, 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.

    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, Marco Seri