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  • Haemophilus influenzae responds to glucocorticoids used in asthma therapy by modulation of biofilm formation and antibiotic resistance
    <div xmlns="http://www.w3.org/1999/xhtml"><em>Haemophilus influenzae</em> responds to glucocorticoids used in asthma therapy by modulation of biofilm formation and antibiotic resistance</div>
    1. Chris S Earl1,
    2. Teh Wooi Keong2,
    3. Shi‐qi An1,
    4. Sarah Murdoch1,
    5. Yvonne McCarthy3,
    6. Junkal Garmendia4,5,
    7. Joseph Ward6,
    8. J Maxwell Dow3,
    9. Liang Yang2,
    10. George A O'Toole7 and
    11. Robert P Ryan*,1
    1. 1Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee, UK
    2. 2Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore
    3. 3School of Microbiology, Biosciences Institute, University College Cork, Cork, Ireland
    4. 4Instituto de Agrobiotecnología, CSIC‐Universidad Pública Navarra‐Gobierno Navarra, Mutilva, Spain
    5. 5Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
    6. 6Division of Molecular Medicine, College of Life Sciences, University of Dundee, Dundee, UK
    7. 7Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
    1. *Corresponding author. Tel: +44 1382 384272; E‐mail: rpryan{at}dundee.ac.uk

    Transcriptional and phenotypic analyses show a direct effect of glucocorticosteroids on the behavior of Haemophilus influenzae increasing bacterial persistence and antimicrobial resistance during respiratory infection.

    Synopsis

    Transcriptional and phenotypic analyses show a direct effect of glucocorticosteroids on the behavior of Haemophilus influenzae increasing bacterial persistence and antimicrobial resistance during respiratory infection.

    • The glucocorticosteroid beclomethasone promotes H. influenzae persistence without influencing the host inflammatory response in a mouse model of acute infection.

    • Beclomethasone induces specific alteration in the expression of H. influenzae genes implicated in biofilm formation, host colonization and survival in vivo.

    • Examination of sputum samples from asthma patients undertaking steroid treatment showed many of the same alterations in H. influenzae gene expression as those induced by beclomethasone.

    • Mutation analysis and transcriptome profiling identified the alternate sigma factor RpoE as an element in the glucocortico‐steroid response.

    • Mutation of rpoE or addition of glucocorticosteroid to H. influenzae led to alteration in biofilm formation and enhanced resistance to antibiotics in models of respiratory infection.

    • antibiotic resistance
    • asthma
    • biofilm
    • Haemophilus influenzae
    • steroids
    • Received January 28, 2015.
    • Revision received April 26, 2015.
    • Accepted April 27, 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.

    Chris S Earl, Teh Wooi Keong, Shi‐qi An, Sarah Murdoch, Yvonne McCarthy, Junkal Garmendia, Joseph Ward, J Maxwell Dow, Liang Yang, George A O'Toole, Robert P Ryan
  • Glucocorticoid‐induced microRNA‐511 protects against TNF by down‐regulating TNFR1
    Glucocorticoid‐induced microRNA‐511 protects against TNF by down‐regulating TNFR1
    1. Leen Puimège1,2,
    2. Filip Van Hauwermeiren1,2,
    3. Sophie Steeland1,2,
    4. Sara Van Ryckeghem1,2,
    5. Jolien Vandewalle1,2,
    6. Sofie Lodens1,2,
    7. Lien Dejager1,2,
    8. Sofie Vandevyver1,2,
    9. Jan Staelens1,23,
    10. Steven Timmermans1,2,
    11. Roosmarijn E Vandenbroucke1,2, and
    12. Claude Libert*,1,2,
    1. 1VIB Inflammation Research Center, Ghent, Belgium
    2. 2Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
    3. 3VIB Headquarters VIB, Ghent, Belgium
    1. *Corresponding author. Tel: +3293313700; Fax: +3293313609; E‐mail: claude.libert{at}irc.vib-ugent.be
    1. These authors share last co‐authorship

    Focusing on TNRF1, the major TNF receptor, resistance of SPRET/Ei mice to TNF‐induced lethal inflammation results from miR‐511 down‐regulation of TNRF1 expression. miR‐511 treatment or glucocorticoid induction of miR‐511 in vivo protects mice against TNF‐induced sepsis.

    Synopsis

    Focusing on TNRF1, the major TNF receptor, resistance of SPRET/Ei mice to TNF‐induced lethal inflammation results from miR‐511 down‐regulation of TNRF1 expression. miR‐511 treatment or glucocorticoid induction of miR‐511 in vivo protects mice against TNF‐induced sepsis.

    • Mouse strain SPRET/Ei resists TNF‐induced lethal shock, a model of sepsis, because of low TNFR1 expression.

    • This low TNFR1 expression is due to high miR‐511 expression in these mice.

    • MiR‐511 was validated as a true TNFR1 regulator, also in vivo.

    • MiR‐511 is induced by glucocorticoids.

    • glucocorticoids
    • miRs
    • receptor regulation
    • sepsis
    • TNF
    • Received December 31, 2014.
    • Revision received April 27, 2015.
    • Accepted April 28, 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.

    Leen Puimège, Filip Van Hauwermeiren, Sophie Steeland, Sara Van Ryckeghem, Jolien Vandewalle, Sofie Lodens, Lien Dejager, Sofie Vandevyver, Jan Staelens, Steven Timmermans, Roosmarijn E Vandenbroucke, Claude Libert
  • Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease
    Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease
    1. Eleonor Olsson1,2,[Link],
    2. Christof Winter1,2,[Link],
    3. Anthony George1,2,
    4. Yilun Chen1,2,
    5. Jillian Howlin1,2,
    6. Man‐Hung Eric Tang1,2,
    7. Malin Dahlgren1,2,
    8. Ralph Schulz1,2,3,
    9. Dorthe Grabau4,
    10. Danielle van Westen5,
    11. Mårten Fernö1,2,
    12. Christian Ingvar6,
    13. Carsten Rose2,7,8,
    14. Pär‐Ola Bendahl1,2,
    15. Lisa Rydén2,6,
    16. Åke Borg1,2,3,8,
    17. Sofia K Gruvberger‐Saal1,2,
    18. Helena Jernström1,2 and
    19. Lao H Saal*,1,2,8
    1. 1Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
    2. 2Lund University Cancer Center, Lund, Sweden
    3. 3SCIBLU Genomics, Department of Clinical Sciences, Lund University, Lund, Sweden
    4. 4Department of Pathology, Skåne University Hospital, Lund, Sweden
    5. 5Department of Radiology, Skåne University Hospital, Lund, Sweden
    6. 6Department of Surgery, Lund University and Skåne University Hospital, Lund, Sweden
    7. 7Department of Immunotechnology, Lund University, Lund, Sweden
    8. 8CREATE Health Strategic Centre for Translational Cancer Research, Lund University, Lund, Sweden
    1. *Corresponding author. Tel: +46 46 2220365; Fax: +46 46 147327; E‐mail: lao.saal{at}med.lu.se; Twitter: @LaoSaal
    1. These authors contributed equally to this article and are listed alphabetically

    Serial measurement of circulating tumor DNA (ctDNA) is shown to be a robust and accurate occult metastatic disease biomarker in patients diagnosed with primary breast cancer. Measured ctDNA levels are a quantitative risk factor for poor outcomes.

    Synopsis

    Serial measurement of circulating tumor DNA (ctDNA) is shown to be a robust and accurate occult metastatic disease biomarker in patients diagnosed with primary breast cancer. Measured ctDNA levels are a quantitative risk factor for poor outcomes.

    • A combination of low‐coverage whole‐genome sequencing with personalized droplet digital PCR, analytical methods, and a bioinformatics pipeline was developed for quantification of ctDNA in blood plasma samples collected during clinical follow‐up of patients with primary (non‐metastatic) breast cancer.

    • ctDNA analysis can discriminate patients with eventual metastasis from those with long‐term disease‐free survival with 93% sensitivity and 100% specificity (ROC area 0.98, P = 0.001).

    • ctDNA‐based detection of occult metastatic disease preceded clinical detection for 86% of patients by an average 11 months and in some cases by 3 years.

    • No ctDNA could be detected at any time‐point after surgery for patients with long‐term disease‐free survival.

    • The level of ctDNA was a quantitative risk factor for clinical metastatic disease (logistic regression odds ratio 2.1 for each doubling of ctDNA levels, P = 0.02) and death (odds ratio 1.3 per ctDNA doubling, P = 0.04).

    • breast carcinoma
    • circulating tumor DNA
    • early detection
    • liquid biopsy
    • metastasis
    • Received December 1, 2014.
    • Revision received April 14, 2015.
    • Accepted April 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.

    Eleonor Olsson, Christof Winter, Anthony George, Yilun Chen, Jillian Howlin, Man‐Hung Eric Tang, Malin Dahlgren, Ralph Schulz, Dorthe Grabau, Danielle van Westen, Mårten Fernö, Christian Ingvar, Carsten Rose, Pär‐Ola Bendahl, Lisa Rydén, Åke Borg, Sofia K Gruvberger‐Saal, Helena Jernström, Lao H Saal
  • Increased CSF Aβ during the very early phase of cerebral Aβ deposition in mouse models
    Increased CSF Aβ during the very early phase of cerebral Aβ deposition in mouse models
    1. Luis F Maia*,1,2,3,
    2. Stephan A Kaeser1,2,
    3. Julia Reichwald4,
    4. Marius Lambert1,2,
    5. Ulrike Obermüller1,2,
    6. Juliane Schelle1,2,
    7. Jörg Odenthal1,2,
    8. Peter Martus5,
    9. Matthias Staufenbiel1,2,4 and
    10. Mathias Jucker*,1,2
    1. 1Department of Cellular Neurology, Hertie Institute for Clinical Brain Research University of Tübingen, Tübingen, Germany
    2. 2DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany
    3. 3Department of Neurology, Hospital de Santo António‐CHP, Porto, Portugal
    4. 4Novartis Institutes for Biomedical Research Neuroscience Discovery Basel, Basel, Switzerland
    5. 5Institute of Clinical Epidemiology and applied Biostatistics University of Tübingen, Tübingen, Germany
    1. * Corresponding author. Tel: +49 7071 29 86863; Fax: +49 7071 29 4521; E‐mail: luis.maia{at}medizin.uni-tuebingen.de

      Corresponding author. Tel: +49 7071 29 86863; Fax: +49 7071 29 4521; E‐mail: mathias.jucker{at}uni-tuebingen.de

    Cerebrospinal fluid (CSF) Amyloid‐β (Aβ) exhibits a biphasic profile in three amyloid precursor protein (APP) transgenic mouse models, with the peak coinciding with the first amyloid plaques in the mouse cortex, further stressing the need for longitudinal biomarker studies in clinical settings.

    Synopsis

    Cerebrospinal fluid (CSF) Amyloid‐β (Aβ) exhibits a biphasic profile in three amyloid precursor protein (APP) transgenic mouse models, with the peak coinciding with the first amyloid plaques in the mouse cortex, further stressing the need for longitudinal biomarker studies in clinical settings.

    • CSF Aβ increase may constitute the earliest biomarker of Aβ deposition.

    • The CSF Aβ biphasic changes seem to be governed distinctively: first, by the increase in Aβ generation and second, by Aβ sequestration in the brain deposits.

    • Mouse models of Alzheimer's disease are relevant translational tools.

    • Alzheimer's disease
    • biomarker
    • CSF
    • preclinical
    • Received January 8, 2015.
    • Revision received April 20, 2015.
    • Accepted April 21, 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.

    Luis F Maia, Stephan A Kaeser, Julia Reichwald, Marius Lambert, Ulrike Obermüller, Juliane Schelle, Jörg Odenthal, Peter Martus, Matthias Staufenbiel, Mathias Jucker
  • Therapeutic inhibition of TRF1 impairs the growth of p53‐deficient K‐RasG12Vinduced lung cancer by induction of telomeric DNA damage
    <div xmlns="http://www.w3.org/1999/xhtml">Therapeutic inhibition of TRF1 impairs the growth of <em>p53</em>‐deficient <em>K‐Ras</em><sup><em>G12V</em></sup><em>‐</em>induced lung cancer by induction of telomeric DNA damage</div>
    1. María García‐Beccaria1,,
    2. Paula Martínez1,,
    3. Marinela Méndez‐Pertuz1,,
    4. Sonia Martínez2,
    5. Carmen Blanco‐Aparicio2,
    6. Marta Cañamero3,
    7. Francisca Mulero4,
    8. Chiara Ambrogio5,
    9. Juana M Flores6,
    10. Diego Megias7,
    11. Mariano Barbacid4,
    12. Joaquín Pastor2 and
    13. Maria A Blasco*,1
    1. 1Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    2. 2Experimental Therapeutics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    3. 3Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    4. 4Molecular Imaging Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    5. 5Experimental Oncology, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    6. 6Animal Surgery and Medicine Department, Faculty of Veterinary Science, Complutense University of Madrid, Madrid, Spain
    7. 7Microscopy Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    1. *Corresponding author. Tel: +34 91 732 8031; Fax: +34 91 732 8028; E‐mail: mblasco{at}cnio.es
    1. These authors contributed equally to this work

    Activation of rapid telomere uncapping by inhibition of TRF1 can block growth of already established K‐Ras‐induced lung cancers independently of telomere length, and without seriously affecting mouse survival or tissue function.

    Synopsis

    Activation of rapid telomere uncapping by inhibition of TRF1 can block growth of already established K‐Ras‐induced lung cancers independently of telomere length, and without seriously affecting mouse survival or tissue function.

    • Genetic Trf1 ablation impairs the growth of p53‐null K‐RasG12V‐induced lung carcinomas and increases mouse survival independently of telomere length.

    • Inhibition of TRF1 binding to telomeres can be achieved in vivo by small molecules and blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function.

    • Ubiquitous TRF1 downregulation allows tissue function with limited side effects.

    • cancer
    • drug development
    • shelterin
    • telomeres
    • TRF1
    • Received July 31, 2014.
    • Revision received March 30, 2015.
    • Accepted April 2, 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.

    María García‐Beccaria, Paula Martínez, Marinela Méndez‐Pertuz, Sonia Martínez, Carmen Blanco‐Aparicio, Marta Cañamero, Francisca Mulero, Chiara Ambrogio, Juana M Flores, Diego Megias, Mariano Barbacid, Joaquín Pastor, Maria A Blasco
  • When natural mutants do not fit our expectations: the intriguing case of patients with XRCC4 mutations revealed by whole‐exome sequencing
    <div xmlns="http://www.w3.org/1999/xhtml">When natural mutants do not fit our expectations: the intriguing case of patients with <em>XRCC4</em> mutations revealed by whole‐exome sequencing</div>
    1. Jean‐Pierre de Villartay (devillartay{at}gmail.com) 1,2
    1. 1INSERM UMR1163 Laboratory of Genome Dynamics in the Immune System (DGSI), Paris, France
    2. 2Paris Descartes University‐Sorbonne Paris Cité Imagine Institute, Paris, France

    Mutations in the XRCC4 gene have been recently identified through whole‐exome sequencing (WES). While the overall clinical presentation of the patients (severe short stature, microcephaly, gonadal failure) generally conforms with what is expected for the defect of a critical non‐homologous end‐joining (NHEJ) DNA repair factor, the absence of consequence on the proper development of the immune system is rather surprising, given the role of NHEJ in V(D)J recombination. Several hypotheses can be envisioned to explain this discrepancy. Overall, these findings highlight the power of WES in identifying new molecular causes for human diseases while providing with new exciting scientific question to address.

    See also: L Bee et al

    Mutations in the XRCC4 gene have been recently identified in several patients revealing common expected phenotypic traits but also unexpected surprising findings such as absence of consequence on the proper development of the immune system.

    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.

    Jean‐Pierre de Villartay
  • PI3K signaling in the locus coeruleus: a new molecular pathway for ADHD research
    PI3K signaling in the locus coeruleus: a new molecular pathway for ADHD research
    1. Emmanuel Darcq1 and
    2. Brigitte L Kieffer (brigitte.kieffer{at}douglas.mcgill.ca) 1
    1. 1Department of Psychiatry, Faculty of Medicine, Douglas Hospital Research Center, McGill University, Montreal, QC, Canada

    Attention‐deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by hyperactivity, inattention, and impulsive behaviors and has significant societal impact. ADHD is recognized as a heterogeneous disease, and genetic and/or environmental factors underlying pathogenesis remain largely unknown. There is an obvious need to increase knowledge on molecular signaling and brain pathways underlying disease development, and genetic mouse models are key to this goal. In this issue of EMBO Molecular Medicine, D'Andrea et al (2015) combine state‐of‐the‐art genetic and behavioral approaches in the mouse to demonstrate an essential role for PI3Kγ and cAMP homeostasis in ADHD‐related behaviors, through signaling mechanisms operating at the level of the locus coeruleus, the main source of noradrenaline in the brain. Furthermore, the study posits PI3Kγ knockout mice as a novel tool of high interest for modeling ADHD endophenotypes.

    See also: I D'Andrea et al

    In this issue of EMBO Molecular Medicine, D'Andrea et al generate a novel mouse model to model Attention Deficit/Hyperactivity Disorder (ADHD) phenotype and show an essential role for PI3Kγ and cAMP homeostasis in ADHD‐related behaviours.

    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.

    Emmanuel Darcq, Brigitte L Kieffer