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  • Maternally inherited genetic variants of CADPS2 are present in Autism Spectrum Disorders and Intellectual Disability patients
    1. Elena Bonora1,,
    2. Claudio Graziano1,,
    3. Fiorella Minopoli1,2,
    4. Elena Bacchelli2,
    5. Pamela Magini1,
    6. Chiara Diquigiovanni1,
    7. Silvia Lomartire2,
    8. Francesca Bianco1,
    9. Manuela Vargiolu1,
    10. Piero Parchi3,
    11. Elena Marasco4,
    12. Vilma Mantovani1,4,
    13. Luca Rampoldi5,
    14. Matteo Trudu5,
    15. Antonia Parmeggiani3,
    16. Agatino Battaglia6,
    17. Luigi Mazzone7,
    18. Giada Tortora1,
    19. IMGSAC8,,
    20. Elena Maestrini2,
    21. Marco Seri*,1 and
    22. Giovanni Romeo1
    1. 1Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola‐Malpighi Hospital University of Bologna, Bologna, Italy
    2. 2Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
    3. 3Department of Neurology, University of Bologna, Bologna, Italy
    4. 4CRBA, S. Orsola‐Malpighi Hospital, Bologna, Italy
    5. 5Molecular Genetics of Renal Disorders Unit, Division of Genetics and Cell Biology San Raffaele Scientific Institute, Milan, Italy
    6. 6Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Calambrone (Pisa), Italy
    7. 7Unit of Child Neuropsychiatry, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy
    8. 8IMGSAC Institute of Neuroscience and Health and Society,, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
    1. *Corresponding author. Tel: +39 51 2088421; Fax: +39 51 2088416; E‐mail: marco.seri{at}unibo.it.

    Monoallelic and tissue‐specific expression of novel CADPS2 gene variants was identified in two siblings with borderline cognitive decline and epilepsy, suggesting a role for CADPS2 in intellectual disability and autism spectrum disorders.

    Synopsis

    Monoallelic and tissue‐specific expression of novel CADPS2 gene variants was identified in two siblings with borderline cognitive decline and epilepsy, suggesting a role for CADPS2 in intellectual disability and autism spectrum disorders.

    • Two rare variants of maternal origin (an intragenic deletion and a missense change) were identified in CADPS2 in a cohort of patients with neurodevelopmental abnormalities; the p. Asp1113Asn variant was shown to disrupt the interaction with dopamine receptor type 2 (D2DR).

    • Differentially methylated sites were identified in CADPS2 first intron, in blood and amygdala, but they did not show a parent‐of‐origin methylation pattern typical of an imprinted gene.

    • Tissue‐specific, monoallelic maternal expression of CADPS2 in blood and in the amygdala plays a key role in regulating social interactions and supports the importance of a fine modulation of CADPS2 for human behavior.

    • CADPS2 variants may contribute to intellectual disability and autism susceptibility, and their role should be interpreted in light of possible parent‐of‐origin effect.

    • autism spectrum disorders
    • CADPS2
    • intellectual disability
    • monoallelic expression
    • mutation screening
    • Received June 27, 2013.
    • Revision received March 8, 2014.
    • Accepted March 11, 2014.

    This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Elena Bonora, Claudio Graziano, Fiorella Minopoli, Elena Bacchelli, Pamela Magini, Chiara Diquigiovanni, Silvia Lomartire, Francesca Bianco, Manuela Vargiolu, Piero Parchi, Elena Marasco, Vilma Mantovani, Luca Rampoldi, Matteo Trudu, Antonia Parmeggiani, Agatino Battaglia, Luigi Mazzone, Giada Tortora, , Elena Maestrini, Marco Seri, Giovanni Romeo
  • HES6 drives a critical AR transcriptional programme to induce castration‐resistant prostate cancer through activation of an E2F1‐mediated cell cycle network
    1. Antonio Ramos‐Montoya1,,
    2. Alastair D Lamb*,1,2,,
    3. Roslin Russell3,
    4. Thomas Carroll4,
    5. Sarah Jurmeister1,
    6. Nuria Galeano‐Dalmau1,
    7. Charlie E Massie1,
    8. Joan Boren3,
    9. Helene Bon1,
    10. Vasiliki Theodorou311,
    11. Maria Vias3,
    12. Greg L Shaw1,2,
    13. Naomi L Sharma1,213,
    14. Helen Ross‐Adams1,
    15. Helen E Scott1,
    16. Sarah L Vowler4,
    17. William J Howat5,
    18. Anne Y Warren1,6,
    19. Richard F Wooster712,
    20. Ian G Mills1,8,9, and
    21. David E Neal*,1,2,10,
    1. 1Uro‐Oncology Research Group Cancer Research UK Cambridge Institute University of Cambridge Li Ka Shing Centre, Cambridge, UK
    2. 2Department of Urology, Addenbrooke's Hospital, Cambridge, UK
    3. 3Cancer Research UK Cambridge Institute University of Cambridge Li Ka Shing Centre, Cambridge, UK
    4. 4Bioinformatics Core Facility, Cancer Research UK Cambridge Institute University of Cambridge Li Ka Shing Centre, Cambridge, UK
    5. 5Histopathology/ISH Core Facility, Cancer Research UK Cambridge Institute University of Cambridge Li Ka Shing Centre, Cambridge, UK
    6. 6Department of Pathology, Addenbrooke's Hospital, Cambridge, UK
    7. 7Cancer Metabolism Drug Discovery, Oncology R&D, Collegeville, PA, USA
    8. 8Prostate Cancer Research Group Nordic EMBL Partnership Centre for Molecular Medicine Norway (NCMM) University of Oslo, Oslo, Norway
    9. 9Departments of Cancer Prevention and Urology, Institute of Cancer Research and Oslo University Hospitals, Oslo, Norway
    10. 10Department of Oncology, University of Cambridge, Cambridge, UK
    11. 11 Institute of Molecular Biology and Biotechnology (IMBB) Foundation for Research and Technology‐Hellas (IMBB‐FORTH), Heraklion Crete, Greece
    12. 12 Blend Therapeutics, Watertown, MA, USA
    13. 13 Nuffield Department of Surgical Sciences, University of Oxford Roosevelt Drive, Oxford, UK
    1. * Corresponding author. Tel: +44 1223 331940; Fax: +44 1223 769007; E‐mail: alastair.lamb{at}cruk.cam.ac.uk

      Corresponding author. Tel: +44 1223 331940; Fax: +44 1223 769007; E‐mail: den22{at}cam.ac.uk

    1. These authors contributed equally to this work.

    2. These senior authors contributed equally to this work.

    HES6 promotes castration resistance, maintains AR chromatin binding at a subset of sites in the absence of hormone stimulation and predicts poor outcome after prostatectomy. Inhibition of HES6‐responsive gene PLK1 enhances anti‐androgen sensitivity.

    Synopsis

    HES6 promotes castration resistance, maintains AR chromatin binding at a subset of sites in the absence of hormone stimulation and predicts poor outcome after prostatectomy. Inhibition of HES6‐responsive gene PLK1 enhances anti‐androgen sensitivity.

    • HES6 promotes castration resistance in prostate cancer cells.

    • HES6 maintains AR chromatin binding at a subset of sites in the absence of hormone stimulation.

    • HES6‐associated genes predict poor clinical outcome after radical prostatectomy.

    • HES6‐responsive gene PLK1 is highly expressed in a new hormone relapse TMA. Inhibition of PLK1 enhances sensitivity to anti‐androgens.

    • androgen receptor
    • castrate‐resistant prostate cancer
    • gene expression signature
    • HES6
    • PLK1
    • Received October 16, 2013.
    • Revision received March 6, 2014.
    • Accepted March 10, 2014.

    This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Antonio Ramos‐Montoya, Alastair D Lamb, Roslin Russell, Thomas Carroll, Sarah Jurmeister, Nuria Galeano‐Dalmau, Charlie E Massie, Joan Boren, Helene Bon, Vasiliki Theodorou, Maria Vias, Greg L Shaw, Naomi L Sharma, Helen Ross‐Adams, Helen E Scott, Sarah L Vowler, William J Howat, Anne Y Warren, Richard F Wooster, Ian G Mills, David E Neal
  • Monocyte‐derived dendritic cells promote T follicular helper cell differentiation
    1. Svetoslav Chakarov1,2,3,4 and
    2. Nicolas Fazilleau*,1,2,3,4
    1. 1Centre de Physiopathologie de Toulouse Purpan, Toulouse, France
    2. 2INSERM U1043, Toulouse, France
    3. 3CNRS UMR5282, Toulouse, France
    4. 4Université Toulouse III Paul‐Sabatier, Toulouse, France
    1. *Corresponding author. Tel: +33 5 62 74 45 19; Fax: +33 5 62 74 45 58; E‐mail: nicolas.fazilleau{at}inserm.fr

    Adding CpG‐B oligonucleotides to vaccine adjuvants is shown to increase T‐cell‐dependent B‐cell response via IL‐6 secretion. Conventional and monocyte‐derived dendritic cells activate CD4+ T cells towards the Tfh lineage resulting in a more efficient vaccine.

    Synopsis

    Adding CpG‐B oligonucleotides to vaccine adjuvants is shown to increase T‐cell‐dependent B‐cell response via IL‐6 secretion. Conventional and monocyte‐derived dendritic cells activate CD4+ T cells towards the Tfh lineage resulting in a more efficient vaccine.

    • Addition of type B CpG to other vaccine adjuvants promotes B‐cell immunity.

    • Increase in humoral response in response to CpG results from an enhancement of the Tfh lineage.

    • Monocyte‐derived dendritic cells orchestrate the increase in the Tfh pool in response to CpG.

    • IL‐6 produced by CpG‐sensitised monocyte‐derived dendritic cells promotes Tfh‐cell development.

    • adjuvant
    • antibody
    • dendritic cell
    • T lymphocyte
    • Toll‐like receptor
    • Received January 24, 2014.
    • Revision received March 7, 2014.
    • Accepted March 11, 2014.

    This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Svetoslav Chakarov, Nicolas Fazilleau
  • HIF factors cooperate with PML‐RARα to promote acute promyelocytic leukemia progression and relapse
    1. Nadia Coltella1,
    2. Stefano Percio2,
    3. Roberta Valsecchi1,
    4. Roberto Cuttano16,
    5. Jlenia Guarnerio1,
    6. Maurilio Ponzoni3,
    7. Pier Paolo Pandolfi4,
    8. Giovanni Melillo57,
    9. Linda Pattini2 and
    10. Rosa Bernardi*,1
    1. 1Division of Molecular Oncology, Leukemia Unit, San Raffaele Scientific Institute, Milan, Italy
    2. 2Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
    3. 3Pathology Unit, Leukemia Unit, San Raffaele Scientific Institute, Milan, Italy
    4. 4Department of Medicine and Pathology, Cancer Research Institute Beth Israel Deaconess Cancer Center Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA, USA
    5. 5Science Applications International Corporation‐Frederick, Inc. Frederick National Laboratory for Cancer Research, Frederick, MD, USA
    6. 6IFOM Fondazione FIRC Institute of Molecular Oncology, Milan, Italy
    7. 7Global Medicines Development, AstraZeneca Oncology, Gaithersburg, MD, USA
    1. *Corresponding author. Tel: +39 2 26435606; Fax: +39 2 26435602; E‐mail: bernardi.rosa{at}hsr.it

    PML‐RARα cooperates with HIF‐1α to activate a pro‐leukemogenic program. Consequently, HIF‐1α inhibition curbs leukemia progression and, in synergy with retinoic acid, eliminates leukemia‐initiating cells.

    Synopsis

    PML‐RARα cooperates with HIF‐1α to activate a pro‐leukemogenic program. Consequently, HIF‐1α inhibition curbs leukemia progression and, in synergy with retinoic acid, eliminates leukemia‐initiating cells.

    • PML‐RARα is a HIF‐α transcriptional co‐activator.

    • HIF‐dependent gene signatures are upregulated in APL leukemic promyelocytes.

    • HIF‐1α regulates cell migration, chemotaxis, neo‐angiogenesis and self‐renewal of leukemic blasts in acute promyelocytic leukemia.

    • HIF‐1α levels increase upon treatment of acute promyelocytic leukemia cells with all‐trans retinoic acid.

    • HIF‐1α inhibition synergizes with all‐trans retinoic acid to eliminate leukemia‐initiating cells in acute promyelocytic leukemia.

    • acute promyelocytic leukemia
    • hypoxia‐inducible transcription factor
    • leukemia‐initiating cells
    • mouse models
    • PML‐RARα
    • Received May 21, 2013.
    • Revision received February 28, 2014.
    • Accepted February 28, 2014.

    This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Nadia Coltella, Stefano Percio, Roberta Valsecchi, Roberto Cuttano, Jlenia Guarnerio, Maurilio Ponzoni, Pier Paolo Pandolfi, Giovanni Melillo, Linda Pattini, Rosa Bernardi
  • Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3
    1. Nahid A Khan1,
    2. Mari Auranen1,2,,
    3. Ilse Paetau1,,
    4. Eija Pirinen3,4,
    5. Liliya Euro1,
    6. Saara Forsström1,
    7. Lotta Pasila1,
    8. Vidya Velagapudi5,
    9. Christopher J Carroll1,
    10. Johan Auwerx3 and
    11. Anu Suomalainen*,1,2,6
    1. 1Molecular Neurology, Research Programs Unit, University of Helsinki, Helsinki, Finland
    2. 2Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
    3. 3Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    4. 4Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences Biocenter Kuopio University of Eastern Finland, Kuopio, Finland
    5. 5Metabolomics Unit, Institute for Molecular Medicine Finland FIMM, Helsinki, Finland
    6. 6Neuroscience Research Centre University of Helsinki, Helsinki, Finland
    1. *Corresponding author. Tel: +358 9 4717 1965; Fax: +358 9 4717 1964; E‐mail: anu.wartiovaara{at}helsinki.fi
    1. These authors contributed equally to the manuscript.

    Nicotinamide riboside (vitamin B3) delays the progression of mitochondrial myopathy by preventing pathology‐associated mitochondrial ultrastructure, improving mitochondrial DNA stability and further stimulating mitochondrial unfolded protein response.

    Synopsis

    Nicotinamide riboside (vitamin B3) delays the progression of mitochondrial myopathy by preventing pathology‐associated mitochondrial ultrastructure, improving mitochondrial DNA stability and further stimulating mitochondrial unfolded protein response.

    • Nicotinamide riboside, vitamin B3, delays the progression of mitochondrial myopathy.

    • Nicotinamide riboside cures pathology‐associated mitochondrial ultrastructure.

    • Nicotinamide riboside improves mitochondrial DNA stability.

    • Mitochondrial disease induces mitochondrial unfolded protein response, further enhanced by nicotinamide riboside.

    • Nicotinamide riboside is a promising treatment for adult‐onset mitochondrial myopathy.

    • mitochondrial myopathy
    • NAD+
    • nicotinamide riboside
    • treatment
    • unfolded protein response
    • Received February 6, 2014.
    • Revision received March 14, 2014.
    • Accepted March 17, 2014.

    This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Nahid A Khan, Mari Auranen, Ilse Paetau, Eija Pirinen, Liliya Euro, Saara Forsström, Lotta Pasila, Vidya Velagapudi, Christopher J Carroll, Johan Auwerx, Anu Suomalainen
  • The unfolded protein response affects readthrough of premature termination codons
    1. Yifat S Oren1,
    2. Michelle L McClure2,
    3. Steven M Rowe2,
    4. Eric J Sorscher2,
    5. Assaf C Bester1,
    6. Miriam Manor1,
    7. Eitan Kerem3,
    8. Joseph Rivlin4,
    9. Fouad Zahdeh1,
    10. Matthias Mann5,
    11. Tamar Geiger6 and
    12. Batsheva Kerem*,1
    1. 1Department of Genetics, The Hebrew University, Jerusalem, Israel
    2. 2Gregory Fleming James Cystic Fibrosis Research Center University of Alabama at Birmingham, Birmingham, AL, USA
    3. 3Cystic Fibrosis Center Hadassah University Hospital, Jerusalem, Israel
    4. 4The Cystic Fibrosis Center Carmel Hospital, Haifa, Israel
    5. 5Department of Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Martinsried, Germany
    6. 6Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel
    1. *Corresponding author. Tel: +972 2 6585689; Fax: +972 2 6584810; E‐mail: batshevak{at}savion.huji.ac.il

    Activation of the unfolded protein response (UPR) governs the response to readthrough treatment by regulating the levels of transcripts with PTCs. Furthermore, a novel nonsense‐mediated mRNA decay (NMD)‐UPR feedback loop is described.

    Synopsis

    Activation of the unfolded protein response (UPR) governs the response to readthrough treatment by regulating the levels of transcripts with PTCs. Furthermore, a novel nonsense‐mediated mRNA decay (NMD)‐UPR feedback loop is described.

    • Proteome analyses show substantial differences in unfolded protein response (UPR) activation between patients carrying PTCs, correlated with their response to readthrough treatment.

    • UPR activation enables CFTR and XLF function following readthrough treatment.

    • Proteome analyses uncover inverse correlation between UPR and nonsense‐mediated mRNA decay (NMD), suggesting a feedback‐loop mechanism between these homeostatic pathways.

    • The NMD‐UPR feedback loop augments both UPR activation and NMD attenuation.

    • The NMD‐UPR feedback loop enhances the response to readthrough treatment, highlighting its clinical importance.

    • nonsense‐mediated mRNA decay
    • premature termination codon
    • readthrough treatment
    • unfolded protein response
    • Received August 4, 2013.
    • Revision received March 3, 2014.
    • Accepted March 6, 2014.

    This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Yifat S Oren, Michelle L McClure, Steven M Rowe, Eric J Sorscher, Assaf C Bester, Miriam Manor, Eitan Kerem, Joseph Rivlin, Fouad Zahdeh, Matthias Mann, Tamar Geiger, Batsheva Kerem
  • Local acting Sticky‐trap inhibits vascular endothelial growth factor dependent pathological angiogenesis in the eye
    1. Iacovos P Michael1,
    2. Peter D Westenskow2,
    3. Sabiha Hacibekiroglu1,3,
    4. Alissa Cohen Greenwald1,
    5. Brian G Ballios3,
    6. Toshihide Kurihara2,
    7. Zhijie Li4,
    8. Carmen M Warren5,
    9. Puzheng Zhang1,
    10. Edith Aguilar2,
    11. Laura Donaldson3,
    12. Valentina Marchetti2,
    13. Takeshi Baba1,
    14. Samer M Hussein1,
    15. Hoon‐Ki Sung1,
    16. M Luisa Iruela‐Arispe5,
    17. James M Rini4,
    18. Derek van der Kooy3,6,
    19. Martin Friedlander2 and
    20. Andras Nagy*,1,3,7
    1. 1Lunenfeld‐Tanenbaum Research Institute Mount Sinai Hospital, Toronto, ON, Canada
    2. 2Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA
    3. 3Institute of Medical Science University of Toronto, Toronto, ON, Canada
    4. 4Department of Biochemistry, University of Toronto, Toronto, ON, Canada
    5. 5Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, USA
    6. 6Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
    7. 7Department of Obstetrics & Gynaecology, University of Toronto, Toronto, ON, Canada
    1. *Corresponding author. Tel: +416 586 4800, ext.: 8455; Fax: +416 586 5130; E‐mail: nagy{at}lunenfeld.ca

    A locally delivered, bifunctional recombinant “Sticky‐trap” comprising a VEGF‐trap and a heparin‐binding domain can prevent aberrant ocular angiogenesis without affecting systemic physiological VEGF‐processes.

    Synopsis

    A locally delivered, bifunctional recombinant “Sticky‐trap” comprising a VEGF‐trap and a heparin‐binding domain (HBD) can prevent aberrant ocular angiogenesis without affecting systemic physiological VEGF‐processes.

    • Bifunctional “Sticky‐trap” is comprised of VEGF‐trap and a carboxy‐terminal HBD.

    • Treatment with recombinant Sticky‐trap can prevent the development of abnormal ocular angiogenesis.

    • Sticky‐trap remains at the site of delivery; thus, it has a local antiangiogenic activity.

    • Sticky‐trap applied in the eye does not compromise systemic physiological VEGF‐processes, such as wound healing and kidney function.

    • angiogenesis
    • diabetic retinopathy
    • retinopathy of prematurity
    • Sticky‐trap
    • VEGF
    • Received December 7, 2013.
    • Revision received March 2, 2014.
    • Accepted March 5, 2014.

    This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Iacovos P Michael, Peter D Westenskow, Sabiha Hacibekiroglu, Alissa Cohen Greenwald, Brian G Ballios, Toshihide Kurihara, Zhijie Li, Carmen M Warren, Puzheng Zhang, Edith Aguilar, Laura Donaldson, Valentina Marchetti, Takeshi Baba, Samer M Hussein, Hoon‐Ki Sung, M Luisa Iruela‐Arispe, James M Rini, Derek van der Kooy, Martin Friedlander, Andras Nagy