- Research ArticleCholesterol metabolism promotes B‐cell positioning during immune pathogenesis of chronic obstructive pulmonary disease
- Jie Jia1,2,†,
- Thomas M Conlon1,2,†,
- Rim SJ Sarker1,2,
- Demet Taşdemir3,
- Natalia F Smirnova1,2,
- Barkha Srivastava1,2,
- Stijn E Verleden4,
- Gizem Güneş1,2,
- Xiao Wu5,
- Cornelia Prehn6,7,
- Jiaqi Gao1,2,
- Katharina Heinzelmann1,2,
- Jutta Lintelmann5,
- Martin Irmler8,
- Stefan Pfeiffer9,
- Michael Schloter9,
- Ralf Zimmermann5,10,
- Martin Hrabé de Angelis7,8,11,
- Johannes Beckers7,8,11,
- Jerzy Adamski6,7,11,
- Hasan Bayram3,12,
- Oliver Eickelberg (oliver.eickelberg{at}ucdenver.edu)*,1,2,13 and
- Ali Önder Yildirim (oender.yildirim{at}helmholtz-muenchen.de)*,1,2
- 1Comprehensive Pneumology Center (CPC), Institute of Lung Biology and Disease, Helmholtz Zentrum München, Munich, Germany
- 2Member of the German Center for Lung Research (DZL), Munich, Germany
- 3Department of Chest Diseases, School of Medicine, University of Gaziantep, Gaziantep, Turkey
- 4Division of Pneumology, KU Leuven, Leuven, Belgium
- 5Joint Mass Spectrometry Centre, Comprehensive Molecular Analytics, Helmholtz Zentrum München, Munich, Germany
- 6Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Munich, Germany
- 7German Center for Diabetes Research (DZD), Munich, Germany
- 8Institute of Experimental Genetics, Helmholtz Zentrum München, Munich, Germany
- 9Research Unit Comparative Microbiome Analysis, Helmholtz Zentrum München, Munich, Germany
- 10University of Rostock, Rostock, Germany
- 11Chair of Experimental Genetics, Technische Universität München, Freising‐Weihenstephan, Germany
- 12School of Medicine, Koç University, Istanbul, Turkey
- 13Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, CO, USA
- ↵*
Corresponding author. Tel: +1 303 724 4075; E‐mail: oliver.eickelberg{at}ucdenver.edu
Corresponding author. Tel: +49 89 3187 4037; E‐mail: oender.yildirim{at}helmholtz-muenchen.de
↵† These authors contributed equally to this work
COPD is the third leading cause of death worldwide with limited therapy. iBALT is a crucial contributor to COPD pathogenesis. Local airway production of oxysterols is crucial for iBALT formation without affecting B and T cell activation, whose inhibition offers new therapeutic potential.
Synopsis
COPD is the third leading cause of death worldwide with limited therapy. iBALT is a crucial contributor to COPD pathogenesis. Local airway production of oxysterols is crucial for iBALT formation without affecting B and T cell activation, whose inhibition offers new therapeutic potential.
Oxysterol metabolizing enzymes CH25H and CYP7B1 are upregulated in airway epithelial cells of COPD patients and cigarette smoke‐exposed mice.
Mice deficient in CH25H or the oxysterol receptor EBI2 failed to generate iBALT in their lungs and critically were protected against emphysema development following chronic cigarette smoke exposure.
B cells failed to migrate ex vivo towards CS‐stimulated airways from Ch25h−/− mice or mice in which oxysterol synthesis genetically and pharmacologically had been blocked.
Therapeutically, the CYP7B1 inhibitor clotrimazole resolved iBALT formation and attenuated cigarette smoke‐induced COPD in a murine model suggesting a novel therapeutic option for COPD patients.
EMBO Mol Med (2018) e8349
- Received July 31, 2017.
- Revision received March 8, 2018.
- Accepted March 14, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
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.
- Research ArticleIdentification of circadian clock modulators from existing drugs
- T Katherine Tamai1,
- Yusuke Nakane1,2,
- Wataru Ota1,2,
- Akane Kobayashi1,2,
- Masateru Ishiguro1,2,
- Naoya Kadofusa1,
- Keisuke Ikegami3,
- Kazuhiro Yagita4,
- Yasufumi Shigeyoshi3,
- Masaki Sudo1,
- Taeko Nishiwaki‐Ohkawa1,2,
- Ayato Sato1 and
- Takashi Yoshimura (takashiy{at}agr.nagoya-u.ac.jp)*,1,2,5,6
- 1Institute of Transformative Bio‐Molecules (WPI‐ITbM), Nagoya University, Nagoya, Japan
- 2Laboratory of Animal Physiology, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan
- 3Department of Anatomy and Neurobiology, Kindai University Faculty of Medicine, Osaka, Japan
- 4Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto, Japan
- 5Avian Bioscience Research Center, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan
- 6Division of Seasonal Biology, National Institute for Basic Biology, Okazaki, Japan
- ↵*Corresponding author. Tel: +81 52 789 4056; E‐mail: takashiy{at}agr.nagoya-u.ac.jp
Chronic circadian misalignment has long term consequences on our health and leads to increased risk of developing diabetes, cardiovascular disease and cancer. Using a drug repurposing approach, dehydroepiandrosterone (DHEA) was identified as an important circadian clock modulator.
Synopsis
Chronic circadian misalignment has long term consequences on our health and leads to increased risk of developing diabetes, cardiovascular disease and cancer. Using a drug repurposing approach, dehydroepiandrosterone (DHEA) was identified as an important circadian clock modulator.
Approximately 5% of the screened drugs altered circadian period.
DHEA shortened circadian period in cells and tissues.
When fed to mice, DHEA shortened circadian period and significantly reduced jet‐lag.
ABL1/2 tyrosine kinases and BCR serine/threonine kinase are involved in regulating circadian period.
Drug repurposing is a useful approach to identify new circadian clock modulators.
EMBO Mol Med (2018) e8724
- Received November 26, 2017.
- Revision received March 19, 2018.
- Accepted March 22, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
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.
- Research ArticleMyeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity
- Dayanira Alsina‐Beauchamp1,
- Alejandra Escós1,
- Pilar Fajardo1,
- Diego González‐Romero1,
- Ester Díaz‐Mora1,
- Ana Risco1,
- Miguel A Martín‐Serrano1,
- Carlos del Fresno2,
- Jorge Dominguez‐Andrés1,
- Noelia Aparicio1,
- Rafal Zur1,
- Natalia Shpiro3,
- Gordon D Brown4,
- Carlos Ardavín1,
- Mihai G Netea5,
- Susana Alemany6,
- Juan J Sanz‐Ezquerro7 and
- Ana Cuenda (acuenda{at}cnb.csic.es)*,1
- 1Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
- 2Immunobiology of Inflammation Laboratory Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
- 3Medical Research Council Protein Phosphorylation Unit, Sir James Black Building, School of Life Sciences, University of Dundee, Dundee, UK
- 4Aberdeen Fungal Group, Institute of Medical Sciences, Medical Research Council Centre for Medical Mycology at the University of Aberdeen, Aberdeen, UK
- 5Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- 6Instituto de Investigaciones Biomédicas Alberto Sols, CSIC‐UAM, Madrid, Spain
- 7Department of Cellular and Molecular Biology, CNB/CSIC, Madrid, Spain
- ↵*Corresponding author. Tel: +34‐915855451; E‐mail: acuenda{at}cnb.csic.es
Candida albicans infections cause high mortality in immunocompromised patients. This study shows that p38γ/p38δ are essential for the immune response to C. albicans by regulating host antifungal activity. p38γ/p38δ inhibition reduces mice fungal burden, establishing p38γ/p38δ as therapeutic targets.
Synopsis
Candida albicans infections cause high mortality in immunocompromised patients. This study shows that p38γ/p38δ are essential for the immune response to C. albicans by regulating host antifungal activity. p38γ/p38δ inhibition reduces mice fungal burden, establishing p38γ/p38δ as therapeutic targets.
Deletion of p38γ/p38δ protects mice from C. albicans infection.
p38γ/p38δ control fungicidal capacity through ROS and iNOS production.
p38γ/p38δ regulate the inflammatory response to C. albicans through a new Dectin‐1 pathway in macrophages.
Chemical inhibition of p38γ/p38δ reduces fungal burden in a candidiasis mouse model.
EMBO Mol Med (2018) e8485
- Received September 14, 2017.
- Revision received March 12, 2018.
- Accepted March 19, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
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.
- Research ArticlePATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice
- Marie Christou‐Kent1,
- Zine‐Eddine Kherraf1,
- Amir Amiri‐Yekta1,2,3,
- Emilie Le Blévec1,
- Thomas Karaouzène1,
- Béatrice Conne4,
- Jessica Escoffier1,
- Said Assou5,
- Audrey Guttin6,
- Emeline Lambert1,
- Guillaume Martinez1,2,7,
- Magalie Boguenet1,
- Selima Fourati Ben Mustapha8,
- Isabelle Cedrin Durnerin9,
- Lazhar Halouani8,
- Ouafi Marrakchi8,
- Mounir Makni8,
- Habib Latrous8,
- Mahmoud Kharouf8,
- Charles Coutton1,2,7,
- Nicolas Thierry‐Mieg10,
- Serge Nef4,
- Serge P Bottari1,
- Raoudha Zouari8,
- Jean Paul Issartel6,
- Pierre F Ray1,2,† and
- Christophe Arnoult (christophe.arnoult{at}univ-grenoble-alpes.fr)*,1,†
- 1Genetics, Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
- 2UM GI‐DPI, CHU de Grenoble, Grenoble, France
- 3Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
- 4Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
- 5IRMB, INSERM U1183, CHRU Montpellier, Université Montpellier, Montpellier, France
- 6Grenoble Neuroscience Institute, INSERM 1216, Université Grenoble Alpes, Grenoble, France
- 7UM de Génétique Chromosomique, CHU de Grenoble, Grenoble, France
- 8Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, Tunis, Tunisia
- 9Service de Médecine de la Reproduction, Centre Hospitalier Universitaire Jean Verdier, Assistance Publique ‐ Hôpitaux de Paris, Bondy, France
- 10Univ. Grenoble Alpes/CNRS, TIMC‐IMAG CNRS UMR 5525, Grenoble, France
- ↵*Corresponding author. Tel: +33 476 637 408; E‐mail: christophe.arnoult{at}univ-grenoble-alpes.fr
↵† These authors contributed equally to this work as senior authors
A novel mutation in the gene PATL2 causes oocyte maturation arrest at the germinal vesicle (GV) stage. In mice, Patl2 deficiency during oocyte growth modifies the global transcriptional landscape of GV oocytes, causing dramatic defects and hampering normal maturation.
Synopsis
A novel mutation in the gene PATL2 causes oocyte maturation arrest at the germinal vesicle (GV) stage. In mice, Patl2 deficiency during oocyte growth modifies the global transcriptional landscape of GV oocytes, causing dramatic defects and hampering normal maturation.
In a cohort of 23 infertile women from North Africa with oocyte meiotic deficiency (OMD), a truncating mutation in the gene PATL2, encoding an RNA‐binding protein, was identified in 26% of patients.
Patl2 knockout female mice presented severe subfertility, confirming the human diagnostic. Patl2 knockout mouse oocytes could progress to the MII stage, however with numerous morphological defects hampering normal fertilisation and development.
Patl2 is not detectable in primordial follicle oocytes, but is strongly expressed during oocyte growth and remains detectable at least until the MII stage.
Patl2 has a unique expression pattern from primordial follicle‐stage to MII‐stage oocytes and did not colocalise with Cpeb1, Msy2 or Ddx6 known to stabilise mRNA during oocyte growth.
Patl2 deficiency leads to a down or up‐regulation of a subset of mRNAs encoding proteins which are crucial for oocyte meiotic progression and early embryonic development, with no effect on the GV‐MII transition.
EMBO Mol Med (2018) e8515
- Received September 21, 2017.
- Revision received March 12, 2018.
- Accepted March 19, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
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.
- News & ViewsA novel combination treatment against melanoma with NRAS mutation and therapy resistance
- Yanlin Yu (yuy{at}mail.nih.gov)1
Targeted cancer therapies have shown some progress in treating BRAF‐mutant melanoma, but not against NRAS‐mutant and treatment‐resistant melanoma. In this issue of EMBO Molecular Medicine, Echevarría‐Vargas et al (2018) report that cotargeting BET and MEK pathways efficiently kills immune therapy‐resistant and NRAS‐mutant melanoma tumor cells.
See also: IM Echevarría-Vargas et al
Targeting NRAS‐mutant and treatment‐resistant melanoma remains problematic. In this issue of EMBO Molecular Medicine, Yanlin Yu discusses the Echevarría‐Vargas et al report that co‐targeting BET and MEK pathways efficiently kills immune therapy‐resistant and NRAS mutant melanoma tumor cells.
EMBO Mol Med (2018) e8573
- Published 2018. This article is a U.S. Government work and is in the public domain in the USA
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.
- Research ArticleCo‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma
- Ileabett M Echevarría‐Vargas1,
- Patricia I Reyes‐Uribe1,
- Adam N Guterres1,
- Xiangfan Yin1,
- Andrew V Kossenkov1,
- Qin Liu1,
- Gao Zhang1,
- Clemens Krepler1,
- Chaoran Cheng2,
- Zhi Wei2,
- Rajasekharan Somasundaram1,
- Giorgos Karakousis3,4,
- Wei Xu3,
- Jennifer JD Morrissette5,6,
- Yiling Lu7,
- Gordon B Mills7,
- Ryan J Sullivan8,
- Miao Benchun8,
- Dennie T Frederick8,
- Genevieve Boland9,
- Keith T Flaherty8,
- Ashani T Weeraratna10,11,
- Meenhard Herlyn1,10,
- Ravi Amaravadi4,12,
- Lynn M Schuchter4,12,
- Christin E Burd13,
- Andrew E Aplin14,
- Xiaowei Xu4,7 and
- Jessie Villanueva (jvillanueva{at}wistar.org)*,1,10
- 1Molecular & Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA
- 2College of Computing Sciences, New Jersey Institute of Technology, Newark, NJ, USA
- 3Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
- 4Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- 5Center for Personalized Diagnostics, Hospital of the University of Pennsylvania University of Pennsylvania, Philadelphia, PA, USA
- 6Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- 7Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- 8Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
- 9Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- 10Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
- 11Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA
- 12Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- 13Departments of Molecular Genetics and Cancer Biology and Genetics, Ohio State University, Columbus, OH, USA
- 14Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
- ↵*Corresponding author. Tel: +1 215 495 6818; E‐mail: jvillanueva{at}wistar.org
Oncogenic NRAS has been deemed undrugabble; an alternative approach is to target NRAS effectors and non‐oncogene addictions. Co‐targeting MEK and BET synergistically downregulated TCF19 and restrained the growth of NRASMut melanoma tumors including tumors resistant to targeted and immunotherapies.
Synopsis
Oncogenic NRAS has been deemed undrugabble; an alternative approach is to target NRAS effectors and non‐oncogene addictions. Co‐targeting MEK and BET synergistically downregulated TCF19 and restrained the growth of NRASMut melanoma tumors including tumors resistant to targeted and immunotherapies.
High BRD4 levels are associated with poor outcome in NRASMut melanoma patients, suggesting that BRD4 plays a key role and hence, constitutes a vulnerability that can be therapeutically exploited.
Combining BET and MEK inhibitors restrained the growth of NRASMut melanoma and prolonged the survival of mice bearing tumors refractory to MAPK and checkpoint inhibitors with no overt toxicity.
Co‐targeting BET and MEK mitigates a MAPK‐ and checkpoint‐inhibitor resistance transcriptional signature (IPRES) and downregulates the transcription factor TCF19.
TCF19 blockade triggers apoptosis of NRASMut melanoma cells.
Downregulation of TCF19 is associated with response to targeted or immunotherapies.
EMBO Mol Med (2018) e8446
- Received September 1, 2017.
- Revision received March 7, 2018.
- Accepted March 12, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
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.
- Research ArticleAmyloid blood biomarker detects Alzheimer's disease
- Andreas Nabers1,†,
- Laura Perna2,†,
- Julia Lange1,
- Ute Mons2,
- Jonas Schartner1,
- Jörn Güldenhaupt1,
- Kai‐Uwe Saum2,
- Shorena Janelidze3,
- Bernd Holleczek4,
- Dan Rujescu5,
- Oskar Hansson3,6,
- Klaus Gerwert (gerwert{at}bph.rub.de)*,2 and
- Hermann Brenner2,7
- 1Department of Biophysics, Ruhr‐University Bochum, Bochum, Germany
- 2Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- 3Department of Clinical Sciences, Lund University, Lund, Sweden
- 4Saarland Cancer Registry, Saarbrücken, Germany
- 5Department of Psychiatry, Psychotherapy and Psychosomatics, University of Halle, Halle, Germany
- 6Memory Clinic, Skåne University Hospital, Malmö, Sweden
- 7Network Aging Research (NAR), University of Heidelberg, Heidelberg, Germany
- ↵*Corresponding author. Tel: +49 234 32 24462; E‐mail: gerwert{at}bph.rub.de
↵† These authors contributed equally to this work
Determination of the amyloid‐β secondary structure distribution in blood plasma by an immuno‐IR‐sensor correlates with PET scanning and CSF markers in Alzheimer's disease (AD) patients, with potentials to be an accurate, simple, and minimally invasive biomarker for early AD detection.
Synopsis
Determination of the amyloid‐β secondary structure distribution in blood plasma by an immuno‐IR‐sensor correlates with PET scanning and CSF markers in Alzheimer's disease (AD) patients, with potentials to be an accurate, simple, and minimally invasive biomarker for early AD detection.
The amyloid‐β (Aβ) secondary structure distribution in blood plasma can be directly determined by the secondary structure sensitive amide I band.
Prodromal AD cases (BioFINDER study) showed significant correlations between the amide I frequency shift and PET scanning results or CSF biomarker values.
Early AD identification (Esther) yielded in 71% sensitivity, 91% specificity, and a LR+ of 7.9–8 years before clinical symptoms appeared, in agreement with the BioFINDER study.
The plasma biomarker may be used as a routine minimal‐invasive, low‐cost funnel to pre‐select individuals which should undergo lumbar puncture or PET scanning.
EMBO Mol Med (2018) e8763
- Received December 7, 2017.
- Revision received March 2, 2018.
- Accepted March 6, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
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.
