- Research ArticleREST suppression mediates neural conversion of adult human fibroblasts via microRNA‐dependent and ‐independent pathways
- Janelle Drouin‐Ouellet1,†,
- Shong Lau1,†,
- Per Ludvik Brattås1,
- Daniella Rylander Ottosson1,
- Karolina Pircs1,
- Daniela A Grassi1,
- Lucy M Collins2,
- Romina Vuono2,
- Annika Andersson Sjöland3,
- Gunilla Westergren‐Thorsson3,
- Caroline Graff4,5,
- Lennart Minthon6,
- Håkan Toresson6,
- Roger A Barker1,2,
- Johan Jakobsson1 and
- Malin Parmar (malin.parmar{at}med.lu.se)*,1
- 1Division of Neurobiology and Lund Stem Cell Center, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden
- 2John van Geest Centre for Brain Repair & Department of Neurology, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge, UK
- 3Department of Experimental Medical Science, Unit of Lung Biology BMC, C12 Lund University, Lund, Sweden
- 4Division for Neurogeriatrics, Department of NVS, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden
- 5Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden
- 6Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
- ↵*Corresponding author. Tel: +46 46 222 06 20; E‐mail: malin.parmar{at}med.lu.se
↵† These authors contributed equally to this work
REST inhibition removes neuronal reprogramming barrier in adult dermal fibroblasts. The resulting high number of induced neurons from elderly patients allows for large scale biomedical applications such as disease modeling, drug screening and early and/or differential diagnostics.
Synopsis
REST inhibition removes neuronal reprogramming barrier in adult dermal fibroblasts. The resulting high number of induced neurons from elderly patients allows for large scale biomedical applications such as disease modeling, drug screening and early and/or differential diagnostics.
The most commonly used neural conversion genes Ascl1 and Brn2 elicit largely distinct transcriptional responses between fetal and adult fibroblasts.
REST inhibition removes reprogramming barrier of adult fibroblasts.
The effect of RESTi is only partially mediated via the neuron specific microRNAs miR‐9 and miR‐124 up‐regulation.
In addition to activate a similar subset of neuronal genes as miR‐9 and miR‐124 overexpression, RESTi activates a distinct set of neuronal genes.
An all‐in‐one conversion vector overexpressing Ascl1 and Brn2 and knocking down REST improves the reprogramming process and renders it suitable for biomedical applications.
- Received December 16, 2016.
- Revision received May 12, 2017.
- Accepted May 18, 2017.
- © 2017 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 ArticleOncolytic adenovirus expressing bispecific antibody targets T‐cell cytotoxicity in cancer biopsies
- Joshua D Freedman1,
- Joachim Hagel1,
- Eleanor M Scott1,
- Ioannis Psallidas2,
- Avinash Gupta3,
- Laura Spiers3,
- Paul Miller3,
- Nikolaos Kanellakis2,
- Rebecca Ashfield4,
- Kerry D Fisher1,
- Margaret R Duffy1 and
- Leonard W Seymour (len.seymour{at}oncology.ox.ac.uk)*,1
- 1Department of Oncology, University of Oxford, Oxford, UK
- 2Oxford Centre for Respiratory Medicine, Oxford University Hospitals NHS Trust, Oxford, UK
- 3Churchill Hospital, Oxford University Hospital NHS Trust, Oxford, UK
- 4Jenner Institute, University of Oxford, Oxford, UK
- ↵*Corresponding author. Tel: +44 1865 617020; E‐mail: len.seymour{at}oncology.ox.ac.uk
Oncolytic adenovirus “EnAdenotucirev” was armed to express a bispecific T‐cell engager (BiTE) targeting T cells to EpCAM+ cancer cells. This strategy mediated rapid cytotoxicity to cancer cells by tumour‐associated T cells and could overcome immune suppressive effects of malignant tumour exudates.
Synopsis
Oncolytic adenovirus “EnAdenotucirev” was armed to express a bispecific T‐cell engager (BiTE) targeting T cells to EpCAM+ cancer cells. This strategy mediated rapid cytotoxicity to cancer cells by tumour‐associated T cells and could overcome immune suppressive effects of malignant tumour exudates.
Viruses can be “armed” without losing oncolytic potency to express and secrete BiTEs only in cells supporting virus replication.
BiTE‐expressing virus can mediate targeted killing of tumour cells in clinical cancer biopsies by exogenous PBMC or endogenous T cells.
BiTE‐mediated cytotoxicity in primary malignant exudates is independent of tumour‐associated immune suppression.
- Received January 11, 2017.
- Revision received May 15, 2017.
- Accepted May 18, 2017.
- © 2017 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 ArticleA normal genetic variation modulates synaptic MMP‐9 protein levels and the severity of schizophrenia symptoms
- Katarzyna Lepeta1,
- Katarzyna J Purzycka2,†,
- Katarzyna Pachulska‐Wieczorek2,†,
- Marina Mitjans3,
- Martin Begemann3,
- Behnam Vafadari1,
- Krystian Bijata4,
- Ryszard W Adamiak2,
- Hannelore Ehrenreich (ehrenreich{at}em.mpg.de)*,3,
- Magdalena Dziembowska (m.dziembowska{at}cent.uw.edu.pl)*,1,5 and
- Leszek Kaczmarek (l.kaczmarek{at}nencki.gov.pl)*,1
- 1Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
- 2Department of RNA Structure and Function, Institute of Bioorganic Chemistry, Poznan, Poland
- 3Clinical Neuroscience, Max Planck Institute of Experimental Medicine, DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
- 4Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Laboratory of RNA Biology and Functional Genomics, Warsaw, Poland
- 5Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland
- ↵*
Corresponding author. Tel: +49 551 3899 628; E‐mail: ehrenreich{at}em.mpg.de
Corresponding author. Tel: +48 22 5543 721; E‐mail: m.dziembowska{at}cent.uw.edu.pl
Corresponding author. Tel: +48 22 659 3001; E‐mail: l.kaczmarek{at}nencki.gov.pl
↵† These authors contributed equally to this work
A single‐nucleotide polymorphism rs20544 located in the 3′ untranslated region of the MMP‐9 gene modulates synaptic MMP‐9 protein levels and contributes significantly to the chronic delusional syndrome in schizophrenia patients.
Synopsis
A single‐nucleotide polymorphism rs20544 located in the 3′ untranslated region of the MMP‐9 gene modulates synaptic MMP‐9 protein levels and contributes significantly to the chronic delusional syndrome in schizophrenia patients.
rs20544 MMP‐9 gene polymorphism markedly affects delusional symptoms in schizophrenic patients, without influencing overall susceptibility to the disease.
rs20544 polymorphism influences synaptic MMP‐9 activity and the morphology of dendritic spines.
rs20544 polymorphism affects MMP‐9 mRNA structure and the affinity of FMRP binding to MMP‐9 mRNA.
lower levels of MMP‐9 in the brain in Mmp‐9 heterozygous mice resulted in greater sensitivity to psychosis‐related locomotor hyperactivity.
- Received February 21, 2017.
- Revision received May 12, 2017.
- Accepted May 15, 2017.
- © 2017 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.
- ReviewCalcineurin–NFAT signalling in myeloid leucocytes: new prospects and pitfalls in immunosuppressive therapy
- 1Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne's University Hospital Brno, Brno, Czech Republic
- ↵*Corresponding author. Tel: +420 511 158 279; E‐mail: jan.fric{at}fnusa.cz
This review summarises our current knowledge on calcineurin‐NFAT in innate immune responses and discusses the use of calcineurin inhibitors known in transplantation medicine for autoimmune pathologies and inflammatory disorders.
- Received February 19, 2017.
- Revision received May 22, 2017.
- Accepted May 23, 2017.
- © 2017 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 ArticleSynergistic antibacterial effect of silver and ebselen against multidrug‐resistant Gram‐negative bacterial infections
- Lili Zou1,
- Jun Lu (jun.lu{at}ki.se) (junlu{at}swu.edu.cn)*,1,2,
- Jun Wang3,
- Xiaoyuan Ren1,
- Lanlan Zhang1,
- Yu Gao4,
- Martin E Rottenberg4 and
- Arne Holmgren (arne.holmgren{at}ki.se)*,1
- 1Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
- 2School of Pharmaceutical Sciences, Southwest University, Chongqing, China
- 3Translational Neuroscience & Neural Regeneration and Repair Institute/Institute of Cell Therapy, The First Hospital of Yichang, Three Gorges University, Yichang, China
- 4Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- ↵*
Corresponding author. Tel: +86 13594206128; E‐mails: jun.lu{at}ki.se; junlu{at}swu.edu.cn
Corresponding author. Tel: +46 70 6467686; Fax: +46 8 7284716; E‐mail: arne.holmgren{at}ki.se
Silver acts synergistically with the selenazol drug ebselen to combat five clinically most difficult‐to‐treat multidrug‐resistant Gram‐negative bacteria, by targeting thiol‐dependent antioxidant systems.
Synopsis
Silver acts synergistically with the selenazol drug ebselen to combat five clinically most difficult‐to‐treat multidrug‐resistant Gram‐negative bacteria, by targeting thiol‐dependent antioxidant systems.
Five most clinically difficult‐to‐treat MDR Gram‐negative bacteria are highly sensitive to a synergistic combination of silver and ebselen. In contrast, silver has no synergistic toxicity with ebselen on mammalian cells.
Silver and ebselen can directly inhibit E. coli thioredoxin reductase, and rapidly deplete GSH, which results in elevation of ROS production and stop in DNA synthesis to induce cell death.
The bactericidal efficacy of silver and ebselen was further confirmed in the treatment of mild and acute MDR E. coli peritonitis in mice.
The silver and ebselen combination offers a proof of concept in targeting essential bacterial systems to be developed for novel efficient treatments against MDR Gram‐negative bacterial infections.
- Received February 6, 2017.
- Revision received May 11, 2017.
- Accepted May 11, 2017.
- © 2017 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 ArticleTargeting endothelin receptor signalling overcomes heterogeneity driven therapy failure
- Michael P Smith1,
- Emily J Rowling1,
- Zsofia Miskolczi1,
- Jennifer Ferguson1,
- Loredana Spoerri2,
- Nikolas K Haass2,3,
- Olivia Sloss1,
- Sophie McEntegart1,
- Imanol Arozarena1,4,
- Alex von Kriegsheim5,
- Javier Rodriguez5,
- Holly Brunton1,
- Jivko Kmarashev6,
- Mitchell P Levesque6,
- Reinhard Dummer6,
- Dennie T Frederick7,
- Miles C Andrews8,
- Zachary A Cooper8,
- Keith T Flaherty7,
- Jennifer A Wargo8 and
- Claudia Wellbrock (claudia.wellbrock{at}manchester.ac.uk)*,1
- 1Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- 2Translational Research Institute, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia
- 3Discipline of Dermatology, University of Sydney, Sydney, NSW, Australia
- 4Navarrabiomed‐Fundación Miguel Servet‐Idisna, Pamplona, Spain
- 5Systems Biology Ireland, School of Medicine, UCD, Dublin 4, Ireland
- 6Department of Dermatology, Universitätsspital Zürich, University of Zurich, Zurich, Switzerland
- 7Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA
- 8Division of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- ↵*Corresponding author. Tel: +44 161 2755189; E‐mail: claudia.wellbrock{at}manchester.ac.uk
Melanoma heterogeneity challenges durable responses to BRAF targeting. During BRAF‐inhibitor treatment endothelin‐1 (EDN1) supports phenotype heterogeneity thereby allowing outgrowth of resistant cells. Blocking EDN1 signalling can overcome this support.
Synopsis
Melanoma heterogeneity challenges durable responses to BRAF targeting. During BRAF‐inhibitor treatment endothelin‐1 (EDN1) supports phenotype heterogeneity thereby allowing outgrowth of resistant cells. Blocking EDN1 signalling can overcome this support.
Phenotype heterogeneity in melanoma is characterised by MITF‐high and AXL‐high subpopulations.
Tumours enriched in AXL‐high subpopulations are resistant to BRAF‐inhibitor treatment.
BRAF inhibitor‐responding tumours contain a small population of AXL‐high cells.
Treatment with BRAF inhibitor induces upregulation of EDN1, and paracrine acting EDN1 supports the outgrowth of AXL‐high subpopulations.
Treatment with EDN receptor (EDNR) antagonists overcomes paracrine EDN1 signalling and prolongs BRAF‐inhibitor responses.
- Received October 5, 2016.
- Revision received May 4, 2017.
- Accepted May 5, 2017.
- © 2017 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 ArticleHPV/E7 induces chemotherapy‐mediated tumor suppression by ceramide‐dependent mitophagy
- Raquela J Thomas1,2,
- Natalia Oleinik1,2,
- Shanmugam Panneer Selvam1,2,
- Silvia G Vaena1,2,
- Mohammed Dany1,2,
- Rose N Nganga1,2,
- Ryan Depalma1,2,
- Kyla D Baron1,2,
- Jisun Kim1,2,
- Zdzislaw M Szulc1 and
- Besim Ogretmen (ogretmen{at}musc.edu)*,1,2
- 1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
- 2Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
- ↵*Corresponding author. Tel: +1 843 792 0940; Fax: +1 843 792 2556; E‐mail: ogretmen{at}musc.edu
HPV infection increases the risk of head and neck squamous cell carcinoma (HNSCC), but also improves sensitivity to therapy. Here, HPV infection is shown to enhance HNSCC cell death by inducing ceramide‐dependent lethal mitophagy.
Synopsis
HPV infection increases the risk of head and neck squamous cell carcinoma (HNSCC), but also improves sensitivity to therapy. Here, HPV infection is shown to enhance HNSCC cell death by inducing ceramide‐dependent lethal mitophagy.
HPV16‐E7 selectively mediates HNSCC cell death via activation of cytoplasmic E2F5 function, liberated by targeting retinoblastoma protein.
Activated E2F5 binds and stabilizes Drp1 oligomers as a scaffolding molecule, inducing mitochondrial translocation of Drp1 and mitochondrial fission.
E2F5‐Drp1‐mediated mitochondrial fission enhances CerS1/ceramide‐dependent mitophagy and HNSCC cell death.
Inhibition of E2F5‐Drp1 complex by site‐directed mutagenesis of E2F5 attenuates HPV‐E7/ceramide‐mediated lethal mitophagy in response to cisplatin in HPV(+) HNSCC cells.
Restoring Drp1 activation using an E2F5‐peptide mimetic increases mitochondrial Drp1 localization, enhancing ceramide‐dependent mitophagy and cisplatin‐mediated tumor suppression in HPV(−) HNSCC in situ and in vivo without pathologic HPV infection.
- Received September 19, 2016.
- Revision received May 1, 2017.
- Accepted May 4, 2017.
- © 2017 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.
