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BIOTECHNOLOGY (227 journals)                  1 2 | Last

Showing 1 - 200 of 227 Journals sorted alphabetically
3 Biotech     Open Access   (Followers: 7)
Advances in Bioscience and Biotechnology     Open Access   (Followers: 15)
Advances in Genetic Engineering & Biotechnology     Hybrid Journal   (Followers: 8)
African Journal of Biotechnology     Open Access   (Followers: 6)
Algal Research     Partially Free   (Followers: 9)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 69)
American Journal of Bioinformatics Research     Open Access   (Followers: 8)
American Journal of Polymer Science     Open Access   (Followers: 30)
Animal Biotechnology     Hybrid Journal   (Followers: 10)
Annales des Sciences Agronomiques     Full-text available via subscription  
Applied Biochemistry and Biotechnology     Hybrid Journal   (Followers: 42)
Applied Bioenergy     Open Access  
Applied Biosafety     Hybrid Journal  
Applied Microbiology and Biotechnology     Hybrid Journal   (Followers: 62)
Applied Mycology and Biotechnology     Full-text available via subscription   (Followers: 5)
Arthroplasty Today     Open Access   (Followers: 1)
Artificial Cells, Nanomedicine and Biotechnology     Hybrid Journal   (Followers: 2)
Asia Pacific Biotech News     Hybrid Journal   (Followers: 2)
Asian Journal of Biotechnology     Open Access   (Followers: 9)
Asian Pacific Journal of Tropical Biomedicine     Open Access   (Followers: 2)
Australasian Biotechnology     Full-text available via subscription   (Followers: 1)
Banat's Journal of Biotechnology     Open Access  
BBR : Biochemistry and Biotechnology Reports     Open Access   (Followers: 4)
Bio-Algorithms and Med-Systems     Hybrid Journal   (Followers: 1)
Bio-Research     Full-text available via subscription   (Followers: 2)
Bioactive Materials     Open Access   (Followers: 1)
Biocatalysis and Agricultural Biotechnology     Hybrid Journal   (Followers: 4)
Biocybernetics and Biological Engineering     Full-text available via subscription   (Followers: 5)
Bioethics UPdate     Hybrid Journal  
Biofuels     Hybrid Journal   (Followers: 11)
Biofuels Engineering     Open Access   (Followers: 1)
Biological & Pharmaceutical Bulletin     Full-text available via subscription   (Followers: 5)
Biological Cybernetics     Hybrid Journal   (Followers: 10)
Biomarkers and Genomic Medicine     Open Access   (Followers: 5)
Biomarkers in Drug Development     Partially Free   (Followers: 1)
Biomaterials Research     Open Access   (Followers: 4)
BioMed Research International     Open Access   (Followers: 6)
Biomédica     Open Access  
Biomedical Engineering Research     Open Access   (Followers: 7)
Biomedical glasses     Open Access  
Biomedical Reports     Full-text available via subscription  
BioMedicine     Open Access  
Bioprinting     Hybrid Journal  
Bioresource Technology Reports     Hybrid Journal  
Bioscience, Biotechnology, and Biochemistry     Hybrid Journal   (Followers: 22)
Biosimilars     Open Access   (Followers: 1)
Biosurface and Biotribology     Open Access  
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 2)
BioTechniques : The International Journal of Life Science Methods     Full-text available via subscription   (Followers: 28)
Biotechnologia Acta     Open Access   (Followers: 1)
Biotechnologie, Agronomie, Société et Environnement     Open Access   (Followers: 2)
Biotechnology     Open Access   (Followers: 7)
Biotechnology & Biotechnological Equipment     Open Access   (Followers: 5)
Biotechnology Advances     Hybrid Journal   (Followers: 33)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 44)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 160)
Biotechnology and Bioprocess Engineering     Hybrid Journal   (Followers: 6)
Biotechnology and Genetic Engineering Reviews     Hybrid Journal   (Followers: 14)
Biotechnology and Health Sciences     Open Access   (Followers: 1)
Biotechnology and Molecular Biology Reviews     Open Access   (Followers: 1)
Biotechnology Annual Review     Full-text available via subscription   (Followers: 7)
Biotechnology for Biofuels     Open Access   (Followers: 11)
Biotechnology Frontier     Open Access   (Followers: 2)
Biotechnology Journal     Hybrid Journal   (Followers: 16)
Biotechnology Law Report     Hybrid Journal   (Followers: 4)
Biotechnology Letters     Hybrid Journal   (Followers: 34)
Biotechnology Progress     Hybrid Journal   (Followers: 39)
Biotechnology Reports     Open Access  
Biotechnology Research International     Open Access   (Followers: 2)
Biotechnology Techniques     Hybrid Journal   (Followers: 10)
Biotecnología Aplicada     Open Access  
Biotribology     Hybrid Journal  
BMC Biotechnology     Open Access   (Followers: 16)
Chinese Journal of Agricultural Biotechnology     Full-text available via subscription   (Followers: 4)
Communications in Mathematical Biology and Neuroscience     Open Access  
Computational and Structural Biotechnology Journal     Open Access   (Followers: 2)
Computer Methods and Programs in Biomedicine     Hybrid Journal   (Followers: 8)
Contributions to Tobacco Research     Open Access   (Followers: 3)
Copernican Letters     Open Access   (Followers: 1)
Critical Reviews in Biotechnology     Hybrid Journal   (Followers: 20)
Crop Breeding and Applied Biotechnology     Open Access   (Followers: 4)
Current Bionanotechnology     Hybrid Journal  
Current Biotechnology     Hybrid Journal   (Followers: 4)
Current Opinion in Biomedical Engineering     Hybrid Journal   (Followers: 1)
Current Opinion in Biotechnology     Hybrid Journal   (Followers: 55)
Current Pharmaceutical Biotechnology     Hybrid Journal   (Followers: 9)
Current Research in Bioinformatics     Open Access   (Followers: 14)
Current trends in Biotechnology and Pharmacy     Open Access   (Followers: 9)
EBioMedicine     Open Access  
Electronic Journal of Biotechnology     Open Access   (Followers: 1)
Entomologia Generalis     Full-text available via subscription  
Environmental Science : Processes & Impacts     Full-text available via subscription   (Followers: 4)
Experimental Biology and Medicine     Hybrid Journal   (Followers: 3)
Folia Medica Indonesiana     Open Access  
Food Bioscience     Hybrid Journal  
Food Biotechnology     Hybrid Journal   (Followers: 13)
Food Science and Biotechnology     Hybrid Journal   (Followers: 9)
Frontiers in Bioengineering and Biotechnology     Open Access   (Followers: 6)
Frontiers in Systems Biology     Open Access   (Followers: 2)
Fungal Biology and Biotechnology     Open Access   (Followers: 1)
GM Crops and Food: Biotechnology in Agriculture and the Food Chain     Full-text available via subscription   (Followers: 1)
GSTF Journal of BioSciences     Open Access  
HAYATI Journal of Biosciences     Open Access  
Horticulture, Environment, and Biotechnology     Hybrid Journal   (Followers: 11)
IEEE Transactions on Molecular, Biological and Multi-Scale Communications     Hybrid Journal   (Followers: 1)
IET Nanobiotechnology     Hybrid Journal   (Followers: 2)
IIOAB Letters     Open Access  
IN VIVO     Full-text available via subscription   (Followers: 4)
Indian Journal of Biotechnology (IJBT)     Open Access   (Followers: 2)
Indonesia Journal of Biomedical Science     Open Access   (Followers: 1)
Indonesian Journal of Biotechnology     Open Access   (Followers: 1)
Industrial Biotechnology     Hybrid Journal   (Followers: 18)
International Biomechanics     Open Access  
International Journal of Bioinformatics Research and Applications     Hybrid Journal   (Followers: 15)
International Journal of Biomechatronics and Biomedical Robotics     Hybrid Journal   (Followers: 4)
International Journal of Biomedical Research     Open Access   (Followers: 2)
International Journal of Biotechnology     Hybrid Journal   (Followers: 5)
International Journal of Biotechnology and Molecular Biology Research     Open Access   (Followers: 2)
International Journal of Biotechnology for Wellness Industries     Partially Free   (Followers: 1)
International Journal of Environment, Agriculture and Biotechnology     Open Access   (Followers: 5)
International Journal of Functional Informatics and Personalised Medicine     Hybrid Journal   (Followers: 4)
International Journal of Medicine and Biomedical Research     Open Access   (Followers: 1)
International Journal of Nanotechnology and Molecular Computation     Full-text available via subscription   (Followers: 3)
International Journal of Radiation Biology     Hybrid Journal   (Followers: 4)
Iranian Journal of Biotechnology     Open Access  
ISABB Journal of Biotechnology and Bioinformatics     Open Access  
Italian Journal of Food Science     Open Access   (Followers: 1)
Journal of Biometrics & Biostatistics     Open Access   (Followers: 3)
Journal of Bioterrorism & Biodefense     Open Access   (Followers: 6)
Journal of Petroleum & Environmental Biotechnology     Open Access   (Followers: 2)
Journal of Advanced Therapies and Medical Innovation Sciences     Open Access  
Journal of Advances in Biotechnology     Open Access   (Followers: 5)
Journal Of Agrobiotechnology     Open Access  
Journal of Analytical & Bioanalytical Techniques     Open Access   (Followers: 7)
Journal of Animal Science and Biotechnology     Open Access   (Followers: 6)
Journal of Applied Biomedicine     Open Access   (Followers: 3)
Journal of Applied Biotechnology     Open Access   (Followers: 2)
Journal of Applied Biotechnology Reports     Open Access   (Followers: 2)
Journal of Applied Mathematics & Bioinformatics     Open Access   (Followers: 5)
Journal of Biologically Active Products from Nature     Hybrid Journal   (Followers: 1)
Journal of Biomaterials and Nanobiotechnology     Open Access   (Followers: 6)
Journal of Biomedical Photonics & Engineering     Open Access  
Journal of Biomedical Practitioners     Open Access  
Journal of Bioprocess Engineering and Biorefinery     Full-text available via subscription  
Journal of Bioprocessing & Biotechniques     Open Access  
Journal of Biosecurity, Biosafety and Biodefense Law     Hybrid Journal   (Followers: 3)
Journal of Biotechnology     Hybrid Journal   (Followers: 68)
Journal of Chemical and Biological Interfaces     Full-text available via subscription   (Followers: 1)
Journal of Chemical Technology & Biotechnology     Hybrid Journal   (Followers: 10)
Journal of Chitin and Chitosan Science     Full-text available via subscription  
Journal of Colloid Science and Biotechnology     Full-text available via subscription  
Journal of Commercial Biotechnology     Full-text available via subscription   (Followers: 6)
Journal of Crop Science and Biotechnology     Hybrid Journal   (Followers: 7)
Journal of Essential Oil Research     Hybrid Journal   (Followers: 3)
Journal of Experimental Biology     Full-text available via subscription   (Followers: 25)
Journal of Genetic Engineering and Biotechnology     Open Access   (Followers: 5)
Journal of Ginseng Research     Open Access  
Journal of Industrial Microbiology and Biotechnology     Hybrid Journal   (Followers: 16)
Journal of Integrative Bioinformatics     Open Access  
Journal of International Biotechnology Law     Hybrid Journal   (Followers: 3)
Journal of Medical Imaging and Health Informatics     Full-text available via subscription  
Journal of Molecular Microbiology and Biotechnology     Full-text available via subscription   (Followers: 14)
Journal of Nano Education     Full-text available via subscription  
Journal of Nanobiotechnology     Open Access   (Followers: 4)
Journal of Nanofluids     Full-text available via subscription   (Followers: 2)
Journal of Organic and Biomolecular Simulations     Open Access  
Journal of Plant Biochemistry and Biotechnology     Hybrid Journal   (Followers: 6)
Journal of Science and Applications : Biomedicine     Open Access  
Journal of the Mechanical Behavior of Biomedical Materials     Hybrid Journal   (Followers: 11)
Journal of Trace Elements in Medicine and Biology     Hybrid Journal   (Followers: 1)
Journal of Tropical Microbiology and Biotechnology     Full-text available via subscription  
Journal of Yeast and Fungal Research     Open Access   (Followers: 1)
Marine Biotechnology     Hybrid Journal   (Followers: 5)
Messenger     Full-text available via subscription  
Metabolic Engineering Communications     Open Access   (Followers: 4)
Metalloproteinases In Medicine     Open Access  
Microalgae Biotechnology     Open Access   (Followers: 2)
Microbial Biotechnology     Open Access   (Followers: 9)
MicroMedicine     Open Access   (Followers: 3)
Molecular and Cellular Biomedical Sciences     Open Access  
Molecular Biotechnology     Hybrid Journal   (Followers: 16)
Molecular Genetics and Metabolism Reports     Open Access   (Followers: 3)
Nanobiomedicine     Open Access  
Nanobiotechnology     Hybrid Journal   (Followers: 3)
Nanomaterials and Nanotechnology     Open Access  
Nanomaterials and Tissue Regeneration     Open Access  
Nanomedicine and Nanobiology     Full-text available via subscription  
Nanomedicine Research Journal     Open Access  
Nanotechnology Reviews     Hybrid Journal   (Followers: 5)
Nature Biotechnology     Full-text available via subscription   (Followers: 521)
Network Modeling and Analysis in Health Informatics and Bioinformatics     Hybrid Journal   (Followers: 3)
New Biotechnology     Hybrid Journal   (Followers: 4)
Nigerian Journal of Biotechnology     Open Access  
Nova Biotechnologica et Chimica     Open Access  
NPG Asia Materials     Open Access  
npj Biofilms and Microbiomes     Open Access  
OA Biotechnology     Open Access  
Plant Biotechnology Journal     Open Access   (Followers: 10)
Plant Biotechnology Reports     Hybrid Journal   (Followers: 4)
Preparative Biochemistry and Biotechnology     Hybrid Journal   (Followers: 4)

        1 2 | Last

Journal Cover EBioMedicine
  [SJR: 1.304]   [H-I: 5]   [0 followers]  Follow
  This is an Open Access Journal Open Access journal
   ISSN (Print) 2352-3964
   Published by Elsevier Homepage  [3177 journals]
  • Losmapimod: A Novel Clinical Drug to Overcome Gefitinib-Resistance

    • Authors: Yukio Nishimura
      Pages: 2 - 3
      Abstract: Publication date: February 2018
      Source:EBioMedicine, Volume 28
      Author(s): Yukio Nishimura

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.019
      Issue No: Vol. 28 (2018)
  • Can We Find Breast Cancer via Salivary Fluid Glycosylation Analyses'

    • Authors: Udo Jeschke
      First page: 4
      Abstract: Publication date: February 2018
      Source:EBioMedicine, Volume 28
      Author(s): Udo Jeschke

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.034
      Issue No: Vol. 28 (2018)
  • Targetable Metabolic Vulnerability in Diffuse Large B-Cell Lymphoma

    • Authors: Jie Xiong; Wei-Li Zhao
      Pages: 5 - 6
      Abstract: Publication date: February 2018
      Source:EBioMedicine, Volume 28
      Author(s): Jie Xiong, Wei-Li Zhao

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.036
      Issue No: Vol. 28 (2018)
  • The Comeback of Scarlet Fever

    • Authors: Samson S.Y. Wong; Kwok-Yung Yuen
      Pages: 7 - 8
      Abstract: Publication date: February 2018
      Source:EBioMedicine, Volume 28
      Author(s): Samson S.Y. Wong, Kwok-Yung Yuen

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.030
      Issue No: Vol. 28 (2018)
  • Protein-Rich or Amino-Acid Only Diets Entrain the Liver Clock: Time to
           Scrap Insulin'

    • Authors: Andrea Maugeri; Jude A. Oben; Manlio Vinciguerra
      Pages: 9 - 10
      Abstract: Publication date: February 2018
      Source:EBioMedicine, Volume 28
      Author(s): Andrea Maugeri, Jude A. Oben, Manlio Vinciguerra

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.020
      Issue No: Vol. 28 (2018)
  • From Tissue Engineering to Regenerative Surgery

    • Authors: I. Martin; M. Jakob; D.J. Schaefer
      Pages: 11 - 12
      Abstract: Publication date: February 2018
      Source:EBioMedicine, Volume 28
      Author(s): I. Martin, M. Jakob, D.J. Schaefer

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.029
      Issue No: Vol. 28 (2018)
  • Emphysema and Interstitial Pneumonia in Rheumatoid Arthritis

    • Authors: Fumikazu Sakai
      Pages: 13 - 14
      Abstract: Publication date: February 2018
      Source:EBioMedicine, Volume 28
      Author(s): Fumikazu Sakai

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.040
      Issue No: Vol. 28 (2018)
  • Long-term Persistent Elite HIV-controllers: The Right Model of Functional

    • Authors: Laura Tarancon-Diez; Beatriz Dominguez-Molina; Pompeyo Viciana; Luis Lopez-Cortes; Ezequiel Ruiz-Mateos
      Pages: 15 - 16
      Abstract: Publication date: February 2018
      Source:EBioMedicine, Volume 28
      Author(s): Laura Tarancon-Diez, Beatriz Dominguez-Molina, Pompeyo Viciana, Luis Lopez-Cortes, Ezequiel Ruiz-Mateos

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.013
      Issue No: Vol. 28 (2018)
  • LDL Receptor Gene-Ablated Hamsters: A Rodent Model of Familial
           Hypercholesterolemia with Dominant Inheritance and Diet-Induced Coronary

    • Authors: Simon Hoffman; Khosrow Adeli
      Pages: 17 - 18
      Abstract: Publication date: February 2018
      Source:EBioMedicine, Volume 28
      Author(s): Simon Hoffman, Khosrow Adeli

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.037
      Issue No: Vol. 28 (2018)
  • Long Non-Coding RNAs Associated with Metabolic Traits in Human White
           Adipose Tissue

    • Authors: Hui Gao; Alastair Kerr; Hong Jiao; Chung-Chau Hon; Mikael Rydén; Ingrid Dahlman; Peter Arner
      Abstract: Publication date: Available online 15 March 2018
      Author(s): Hui Gao, Alastair Kerr, Hong Jiao, Chung-Chau Hon, Mikael Rydén, Ingrid Dahlman, Peter Arner
      Long non-coding RNAs (lncRNAs) belong to a recently discovered class of molecules proposed to regulate various cellular processes. Here, we systematically analyzed their expression in human subcutaneous white adipose tissue (WAT) and found that a limited set was differentially expressed in obesity and/or the insulin resistant state. Two lncRNAs herein termed adipocyte-specific metabolic related lncRNAs, ASMER-1 and ASMER-2 were enriched in adipocytes and regulated by both obesity and insulin resistance. Knockdown of either ASMER-1 or ASMER-2 by antisense oligonucleotides in in vitro differentiated human adipocytes revealed that both genes regulated adipogenesis, lipid mobilization and adiponectin secretion. The observed effects could be attributed to crosstalk between ASMERs and genes within the master regulatory pathways for adipocyte function including PPARG and INSR. Altogether, our data demonstrate that lncRNAs are modulators of the metabolic and secretory functions in human fat cells and provide an emerging link between WAT and common metabolic conditions.

      PubDate: 2018-03-16T08:15:34Z
      DOI: 10.1016/j.ebiom.2018.03.010
  • Plectin-1 Targeted Dual-modality Nanoparticles for Pancreatic Cancer

    • Authors: Xiao Chen; Hao Zhou; Xiaoshuang Li; Na Duan; Shouyou Hu; Yongkang Liu; Yali Yue; Lina Song; Yifen Zhang; Donghui Li; Zhongqiu Wang
      Abstract: Publication date: Available online 15 March 2018
      Author(s): Xiao Chen, Hao Zhou, Xiaoshuang Li, Na Duan, Shouyou Hu, Yongkang Liu, Yali Yue, Lina Song, Yifen Zhang, Donghui Li, Zhongqiu Wang
      Background Biomarker-targeted molecular imaging holds promise for early detection of pancreatic cancer. The aim of this study was to design and evaluate a plectin-1 targeted multi-functional nanoparticle probe for pancreatic cancer imaging. Methods 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-amino(polyethylene glycol) (DSPE-PEG-NH2)-modified superparamagnetic iron oxide (Fe3O4) nanoparticles (SPION) were conjugated with plectin-1 antibody and/or Cy7 to create the multi-functional targeted nanoparticle targeted probe (Plectin-SPION-Cy7) or non-targeted probe (SPION-Cy7). Pancreatic carcinoma cell lines expressing plectin-1 were cultured with the targeted or control probes and then were imaged using confocal laser scanning microscopy and magnetic resonance imaging (MRI). Accumulations of the nanoparticles in pancreatic tumor xenografted mice were determined by MRI and fluorescence imaging. Results In vitro optical imaging and MRI showed that the targeted nanoparticles were highly accumulated in MIAPaCa2 and XPA-1 carcinoma cells but not in non-carcinoma MIN6 cells, which was further confirmed by Prussian blue staining. In vivo MRI showed a significant T2 signal reduction. Prussian blue staining further confirmed that the plectin-1 targeted nanoparticles were highly accumulated in the tumor mass but not in normal pancreatic tissues, or in the liver and kidney, and few nanoparticles were observed in the tumors of mice injected with SPION-Cy7. Conclusions Our data demonstrate that plectin-1 targeted fluorescence and MR dual-functional nanoparticle can visualize pancreatic cancer, and it has great potential to be used with various imaging devices for pancreatic cancer detection.

      PubDate: 2018-03-16T08:15:34Z
      DOI: 10.1016/j.ebiom.2018.03.008
  • Large-Scale Urinary Proteome Dataset Across Tumor Types Reveals Candidate
           Biomarkers for Lung Cancer

    • Authors: Irene V. Bijnsdorp; Connie R. Jimenez
      Abstract: Publication date: Available online 14 March 2018
      Author(s): Irene V. Bijnsdorp, Connie R. Jimenez

      PubDate: 2018-03-16T08:15:34Z
      DOI: 10.1016/j.ebiom.2018.03.012
  • A Nanomedicine Approach to Manage Cancer – Imaging Pancreatic Cancer
           Using Targeted Iron Oxide Nanoparticles

    • Authors: Liron L. Israel
      Abstract: Publication date: Available online 12 March 2018
      Author(s): Liron L. Israel

      PubDate: 2018-03-16T08:15:34Z
      DOI: 10.1016/j.ebiom.2018.03.011
  • HIV-1 Promotes the Degradation of Components of the Type 1 IFN JAK/STAT
           Pathway and Blocks Anti-viral ISG Induction

    • Authors: Siobhan Gargan; Suaad Ahmed; Rebecca Mahony; Ciaran Bannan; Silvia Napoletano; Cliona O'farrelly; Persephone Borrow; Colm Bergin; Nigel J. Stevenson
      Abstract: Publication date: Available online 9 March 2018
      Author(s): Siobhan Gargan, Suaad Ahmed, Rebecca Mahony, Ciaran Bannan, Silvia Napoletano, Cliona O'farrelly, Persephone Borrow, Colm Bergin, Nigel J. Stevenson
      Anti-retroviral therapy successfully suppresses HIV-1 infection, but fails to provide a cure. During infection Type 1 IFNs normally play an essential role in viral clearance, but in vivo IFN-α only has a modest impact on HIV-1 infection, suggesting its possible targeting by HIV. Here, we report that the HIV protein, Vif, inhibits effective IFN-α signalling via degradation of essential JAK/STAT pathway components. We found that STAT1 and STAT3 are specifically reduced in HEK293T cells expressing Vif and that full length, infectious HIV-1 IIIB strain promotes their degradation in a Vif-dependent manner. HIV-1 IIIB infection of myeloid ThP1 cells also reduced the IFN-α-mediated induction of the anti-viral gene, ISG15, but not MxA, revealing a functional consequence of this HIV-1-mediated immune evasion strategy. Interestingly, while total STAT levels were not reduced upon in vitro IIIB infection of primary human PBMCs, IFN-α-mediated phosphorylation of STAT1 and STAT3 and ISG induction were starkly reduced, with removal of Vif (IIIBΔVif), partially restoring pSTATs, ISG15 and MxB induction. Similarly, pSTAT1 and pSTAT3 expression and IFN-α-induced ISG15 were reduced in PBMCs from HIV-infected patients, compared to healthy controls. Furthermore, IFN-α pre-treatment of a CEM T lymphoblast cells significantly inhibited HIV infection/replication (measured by cellular p24), only in the absence of Vif (IIIBΔVif), but was unable to suppress full length IIIB infection. When analysing the mechanism by which Vif might target the JAK/STAT pathway, we found Vif interacts with both STAT1 and STAT3, (but not STAT2), and its expression promotes ubiquitination and MG132-sensitive, proteosomal degradation of both proteins. Vif's Elongin-Cullin-SOCS-box binding motif enables the formation of an active E3 ligase complex, which, via mutational analysis, we found to be required for Vif's degradation of STAT1 and STAT3. In fact, the E3 ligase scaffold proteins, Cul5 and Rbx2, were also found to be essential for Vif-mediated proteasomal degradation of STAT1 and STAT3. These results reveal a target for HIV-1-Vif and demonstrate how HIV-1 impairs the anti-viral activity of Type 1 IFNs, possibly explaining why both endogenous and therapeutic IFN-α fail to activate more effective control over HIV infection.

      PubDate: 2018-03-16T08:15:34Z
      DOI: 10.1016/j.ebiom.2018.03.006
  • Low Bioavailability and High Immunogenicity of a New Brand of E. coli
           l-Asparaginase with Active Host Contaminating Proteins

    • Authors: Priscila Pini Zenatti; Natacha Azussa Migita; Nathália Moreno Cury; Rosângela Aparecida Mendes-Silva; Fabio Cesar Gozzo; Pedro Otavio de Campos-Lima; José Andrés Yunes; Silvia Regina Brandalise
      Abstract: Publication date: Available online 9 March 2018
      Author(s): Priscila Pini Zenatti, Natacha Azussa Migita, Nathália Moreno Cury, Rosângela Aparecida Mendes-Silva, Fabio Cesar Gozzo, Pedro Otavio de Campos-Lima, José Andrés Yunes, Silvia Regina Brandalise
      The drug l-asparaginase is a cornerstone in the treatment of acute lymphoblastic leukemia (ALL). The native E. coli l-asparaginase used in Brazil until recently has been manufactured by Medac/Kyowa. Then a decision was taken by the Ministry of Health in 2017 to supply the National Health System with a cheaper alternative l-asparaginase manufactured by Beijing SL Pharmaceutical, called Leuginase®. As opposed to Medac, the asparaginase that has been in use in Brazil under the trade name of Aginasa®, it was not possible to find a single entry with the terms Leuginase in the Pubmed repository. The apparent lack of clinical studies and the scarcity of safety information provided to the hospitals by the drug distributor created a debate among Brazilian pediatric oncologists about issues of safety and efficacy that culminated eventually in a court decision to halt the distribution of the new drug all over the country. Boldrini Children's Center, a non-profit pediatric oncohematology hospital, has conducted its own evaluation of Leuginase®. Mass spectrometry analyses found at least 12 different contaminating host-cell proteins (HCP) in Leuginase®. The presence of two HCP (beta-lactamase and malate dehydrogenase) was confirmed by orthogonal methodologies. The relative number of HCP peptides ranged from 19 to 37% of the total peptides identified by mass spectrometry. In vivo studies in mice injected with Leuginase® revealed a 3 times lower plasma bioavailability and the development of higher antibody titres against l-asparaginase in comparison to Aginasa®-injected animals. The decision to buy a new drug based on its price alone is not safe. Developing countries are especially vulnerable to cheaper alternatives that lack solid quality assurance.

      PubDate: 2018-03-16T08:15:34Z
      DOI: 10.1016/j.ebiom.2018.03.005
  • Revealing the Complexity of Mitochondrial DNA-Related Disorders

    • Authors: Daniele Orsucci; Gabriele Siciliano; Michelangelo Mancuso
      Abstract: Publication date: Available online 9 March 2018
      Author(s): Daniele Orsucci, Gabriele Siciliano, Michelangelo Mancuso

      PubDate: 2018-03-16T08:15:34Z
      DOI: 10.1016/j.ebiom.2018.03.007
  • Inflammatory Cytokine Profiles in Visceral and Subcutaneous Adipose
           Tissues of Obese Patients Undergoing Bariatric Surgery Reveal Lack of
           Correlation With Obesity or Diabetes

    • Authors: Volatiana Rakotoarivelo; Gregory Lacraz; Marian Mayhue; Christine Brown; Diane Rottembourg; Julie Fradette; Subburaj Ilangumaran; Alfredo Menendez; Marie-France Langlois; Sheela Ramanathan
      Abstract: Publication date: Available online 8 March 2018
      Author(s): Volatiana Rakotoarivelo, Gregory Lacraz, Marian Mayhue, Christine Brown, Diane Rottembourg, Julie Fradette, Subburaj Ilangumaran, Alfredo Menendez, Marie-France Langlois, Sheela Ramanathan
      Population studies have linked insulin resistance to systemic low-grade chronic inflammation and have reported elevated levels of inflammatory cytokines such as TNFα, IL-1β and IL-6, individually or in certain combinations, in adipose tissues or in the serum. We undertook this comprehensive study to simultaneously evaluate the expression of several pro-inflammatory and anti-inflammatory cytokines in serum and in the visceral and subcutaneous adipose tissues from obese patients undergoing bariatric surgery. We observed that several inflammatory cytokines implicated in obesity-associated inflammation showed no significant difference in protein or gene expression between obese patients with or without diabetes and control groups. IL1B gene expression was significantly elevated in the visceral adipose tissues of obese patients, but did not correlate with their diabetes status. Despite the significant increase in IL1B expression in the obese group, a significant proportion of obese patients did not express TNFA, IL1B or IL6 in visceral adipose tissues. Certain inflammatory cytokines showed correlation with the chemokine CCL2 and VEGF-A in visceral adipose tissues. Our findings suggest that the inflammatory cytokine profile in metabolic syndrome is more complex than what is currently perceived and that chronic inflammation in obese patients likely results from incremental contribution from different cytokines and possibly other inflammatory mediators from within and outside the adipose tissues. It is possible that this obesity associated chronic inflammation is not predicted by a single mediator, but rather includes a large spectrum of possible profiles.

      PubDate: 2018-03-16T08:15:34Z
      DOI: 10.1016/j.ebiom.2018.03.004
  • Visual Restoration after Cataract Surgery Promotes Functional and
           Structural Brain Recovery

    • Authors: Haotian Lin; Li Zhang; Duoru Lin; Wan Chen; Yi Zhu; Chuan Chen; Kevin C. Chan; Yizhi Liu; Weirong Chen
      Abstract: Publication date: Available online 7 March 2018
      Author(s): Haotian Lin, Li Zhang, Duoru Lin, Wan Chen, Yi Zhu, Chuan Chen, Kevin C. Chan, Yizhi Liu, Weirong Chen
      Background Visual function and brain function decline concurrently with aging. Notably, cataract patients often present with accelerated age-related decreases in brain function, but the underlying mechanisms are still unclear. Optical structures of the anterior segment of the eyes, such as the lens and cornea, can be readily reconstructed to improve refraction and vision quality. However, the effects of visual restoration on human brain function and structure remain largely unexplored. Methods A prospective, controlled clinical trial was conducted. Twenty-six patients with bilateral age-related cataracts (ARCs) who underwent phacoemulsification and intraocular lens implantation and 26 healthy controls without ARC, matched for age, sex, and education, were recruited. Visual functions (including visual acuity, visual evoke potential, and contrast sensitivity), the Mini-Mental State Examination and functional magnetic resonance imaging (including the fractional amplitude of low-frequency fluctuations and grey matter volume variation) were assessed for all the participants and reexamined for ARC patients after cataract surgery. This trial was registered with (NCT02644720). Findings Compared with the healthy controls, the ARC patients presented decreased brain functionality as well as structural alterations in visual and cognitive-related brain areas preoperatively. Three months postoperatively, significant functional improvements were observed in the visual and cognitive-related brain areas of the patients. Six months postoperatively, the patients' grey matter volumes in these areas were significantly increased. Notably, both the function and structure in the visual and cognitive-related brain areas of the patients improved significantly and became comparable to those of the healthy controls 6months postoperatively. Interpretation We demonstrated that ocular reconstruction can functionally and structurally reverse cataract-induced brain changes. The integrity of the eye is essential for maintaining the structure and function of the brain within and beyond the primary visual pathway.

      PubDate: 2018-03-16T08:15:34Z
      DOI: 10.1016/j.ebiom.2018.03.002
  • Functional Polymorphisms at ERCC1/XPF Genes Confer Neuroblastoma Risk in
           Chinese Children

    • Authors: Zhen-Jian Zhuo; Wei Liu; Jiao Zhang; Jinhong Zhu; Ruizhong Zhang; Jue Tang; Tianyou Yang; Yan Zou; Jing He; Huimin Xia
      Abstract: Publication date: Available online 7 March 2018
      Author(s): Zhen-Jian Zhuo, Wei Liu, Jiao Zhang, Jinhong Zhu, Ruizhong Zhang, Jue Tang, Tianyou Yang, Yan Zou, Jing He, Huimin Xia
      Variations in nucleotide excision repair pathway genes may predispose to initiation of cancers. However, polymorphisms of ERCC1/XPF genes and neuroblastoma risk have not been investigated before. To evaluate the relevance of polymorphisms of ERCC1/XPF genes in influencing neuroblastoma susceptibility, we genotyped four polymorphisms in ERCC1/XPF genes using a Chinese population of 393 cases and 812 controls. The results showed that ERCC1 rs2298881 and rs11615 predisposed to enhanced neuroblastoma risk [CA vs. AA: adjusted odds ratio (OR)=1.94, 95% confidence interval (CI)=1.30–2.89, P =0.0012; CC vs. AA: adjusted OR=2.18, 95% CI=1.45–3.26, P =0.0002 for rs2298881, and AG vs. GG: adjusted OR=1.31, 95% CI=1.02–1.69, P =0.038 for rs11615]. Moreover, XPF rs2276466 was also associated with increased neuroblastoma risk (GG vs. CC: adjusted OR=1.66, 95% CI=1.02–2.71, P =0.043). In the combined analysis of ERCC1, we found that carriers with 2–3 risk genotypes were more likely to get risk of neuroblastoma, when compared to those with 0–1 risk genotype (adjusted OR=1.75; 95% CI=1.25–2.45, P =0.0012). Our study indicates that common genetic variations in ERCC1/XPF genes predispose to neuroblastoma risk, which needs to be further validated by ongoing efforts.

      PubDate: 2018-03-16T08:15:34Z
      DOI: 10.1016/j.ebiom.2018.03.003
  • Bedaquiline Phenotypic and Genotypic Susceptibility Testing, Work in

    • Authors: Simon Tiberi; Andrea Maurizio Cabibbe; Jennifer Tomlins; Daniela Maria Cirillo; Giovanni Battista Migliori
      Abstract: Publication date: Available online 8 February 2018
      Author(s): Simon Tiberi, Andrea Maurizio Cabibbe, Jennifer Tomlins, Daniela Maria Cirillo, Giovanni Battista Migliori

      PubDate: 2018-03-16T08:15:34Z
      DOI: 10.1016/j.ebiom.2018.02.006
  • The Janus-like Face of IL-4Rα in Macrophages during Liver Fibrosis

    • Authors: Thomas Ritz; Frank Tacke
      Abstract: Publication date: Available online 5 February 2018
      Author(s): Thomas Ritz, Frank Tacke

      PubDate: 2018-03-16T08:15:34Z
      DOI: 10.1016/j.ebiom.2018.02.004
  • Vaccines for Improved Cellular Immunity to Influenza

    • Authors: Graham Pawelec; Janet MacElhaney
      Abstract: Publication date: Available online 5 March 2018
      Author(s): Graham Pawelec, Janet MacElhaney

      PubDate: 2018-03-07T06:12:46Z
      DOI: 10.1016/j.ebiom.2018.03.001
  • Correlates of Protection Against SIVmac251 Infection in Rhesus Macaques
           Immunized With Chimpanzee-Derived Adenovirus Vectors

    • Authors: Steven Tuyishime; Larissa H. Haut; Raj K. Kurupati; James M. Billingsley; Diane Carnathan; Sailaja Gangahara; Tiffany M. Styles; ZhiQuan Xiang; Yan Li; Malte Zopfs; Qin Liu; XiangYang Zhou; Mark G. Lewis; Rama R. Amara; Steven Bosinger; Guido Silvestri; Hildegund C.J. Ertl
      Abstract: Publication date: Available online 4 March 2018
      Author(s): Steven Tuyishime, Larissa H. Haut, Raj K. Kurupati, James M. Billingsley, Diane Carnathan, Sailaja Gangahara, Tiffany M. Styles, ZhiQuan Xiang, Yan Li, Malte Zopfs, Qin Liu, XiangYang Zhou, Mark G. Lewis, Rama R. Amara, Steven Bosinger, Guido Silvestri, Hildegund C.J. Ertl
      We report on prime-boost vaccine regimens with two simian adenovirus (Ad) vectors (SAdV) or two human serotype Ad vectors (HAdV) expressing Gag and gp160 of simian immunodeficiency virus (SIV)mac239 tested in HAdV-seropositive rhesus macaques (RMs) repeatedly challenged rectally with low doses of SIVmac251. Both vaccine regimens reduced set point and peak viral loads (PVL) and accelerated viral clearance. In SAdV-vaccinated controller genotype RMs resistance against infection correlated with levels of envelope (Env)-specific antibody (Ab) titers. In both vaccine groups CD8+T cells controlled viral loads (VL) upon infection. Circulating CD4+ and CD8+ T cells showed significant changes in their transcriptome over time following vaccination, which differed between the vaccine groups. T cells from SIV-resistant RMs had unique transcriptional profiles indicating that both follicular T helper (TFH) cell responses and highly activated CD8+ T cells may play a role in protection.

      PubDate: 2018-03-07T06:12:46Z
      DOI: 10.1016/j.ebiom.2018.02.025
  • Oligodendrocyte Progenitor Cells and Macrophages/Microglia Produce Glioma
           Stem Cell Niches at the Tumor Border

    • Authors: Takuichiro Hide; Yoshihiro Komohara; Yuko Miyasato; Hideo Nakamura; Keishi Makino; Motohiro Takeya; Jun-ichi Kuratsu; Akitake Mukasa; Shigetoshi Yano
      Abstract: Publication date: Available online 1 March 2018
      Author(s): Takuichiro Hide, Yoshihiro Komohara, Yuko Miyasato, Hideo Nakamura, Keishi Makino, Motohiro Takeya, Jun-ichi Kuratsu, Akitake Mukasa, Shigetoshi Yano
      Glioblastoma (GBM) usually develops in adult brain white matter. Even after complete resection, GBM recurs around the tumor removal cavity, where GBM cells acquire chemo-radioresistance. Characterization of the tumor border microenvironment is critical for improving prognosis in patients with GBM. Here, we compared microRNA (miRNA) expression in samples from the tumor, tumor border, and periphery by miRNA microarray. The top three of miRNAs showing higher expression in the tumor border were related to oligodendrocyte differentiation, and pathologically oligodendrocyte lineage cells were increased in the border, where macrophages and microglia also colocalized. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, similar to that produced by FGF1, EGF and HB-EGF, IL-1β, corresponding to OPCs and macrophages, respectively. Thus, OPCs and macrophages/microglia may form a glioma stem cell niche at the tumor border, representing a novel promising target for prevention of recurrence.

      PubDate: 2018-03-07T06:12:46Z
      DOI: 10.1016/j.ebiom.2018.02.024
  • Endogenous Mobilization of Bone-Marrow Cells Into the Murine Retina
           Induces Fusion-Mediated Reprogramming of Müller Glia Cells

    • Authors: Martina Pesaresi; Sergi Bonilla-Pons; Giacoma Simonte; Daniela Sanges; Umberto Di Vicino; Maria Pia Cosma
      Abstract: Publication date: Available online 28 February 2018
      Author(s): Martina Pesaresi, Sergi Bonilla-Pons, Giacoma Simonte, Daniela Sanges, Umberto Di Vicino, Maria Pia Cosma
      Müller glial cells (MGCs) represent the most plastic cell type found in the retina. Following injury, zebrafish and avian MGCs can efficiently re-enter the cell cycle, proliferate and generate new functional neurons. The regenerative potential of mammalian MGCs, however, is very limited. Here, we showed that N-methyl-d-aspartate (NMDA) damage stimulates murine MGCs to re-enter the cell cycle and de-differentiate back to a progenitor-like stage. These events are dependent on the recruitment of endogenous bone marrow cells (BMCs), which, in turn, is regulated by the stromal cell-derived factor 1 (SDF1)-C-X-C motif chemokine receptor type 4 (CXCR4) pathway. BMCs mobilized into the damaged retina can fuse with resident MGCs, and the resulting hybrids undergo reprogramming followed by re-differentiation into cells expressing markers of ganglion and amacrine neurons. Our findings constitute an important proof-of-principle that mammalian MGCs retain their regenerative potential, and that such potential can be activated via cell fusion with recruited BMCs. In this perspective, our study could contribute to the development of therapeutic strategies based on the enhancement of mammalian endogenous repair capabilities.

      PubDate: 2018-03-07T06:12:46Z
      DOI: 10.1016/j.ebiom.2018.02.023
  • Obesity and Cancer: Existing and New Hypotheses for a Causal Connection

    • Authors: Trevor W. Stone; Megan McPherson; L. Gail Darlington
      Abstract: Publication date: Available online 27 February 2018
      Author(s): Trevor W. Stone, Megan McPherson, L. Gail Darlington
      Existing explanations of obesity-associated cancer emphasise direct mutagenic effects of dietary components or hormonal imbalance. Some of these hypotheses are reviewed briefly, but recent evidence suggests a major role for chronic inflammation in cancer risk, possibly involving dietary content. These ideas include the inflammation-induced activation of the kynurenine pathway and its role in feeding and metabolism by activation of the aryl hydrocarbon receptor (AHR) and by modulating synaptic transmission in the brain. Evidence for a role of the kynurenine pathway in carcinogenesis then provides a potentially major link between obesity and cancer. A second new hypothesis is based on evidence that serine proteases can deplete cells of the tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin. These enzymes include mammalian chymotryptic proteases released by pro-inflammatory neutrophils and macrophages. Blood levels of chymotrypsin itself increase in parallel with food intake. The mechanistically similar bacterial enzyme subtilisin is widespread in the environment, animal probiotics, meat processing and cleaning products. Simple public health schemes in these areas, with selective serine protease inhibitors and AHR antagonists and could prevent a range of intestinal and other cancers.

      PubDate: 2018-03-07T06:12:46Z
      DOI: 10.1016/j.ebiom.2018.02.022
  • MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at
           Low Mutant Load

    • Authors: Yi Shiau Ng; Nichola Z. Lax; Paul Maddison; Charlotte L. Alston; Emma L. Blakely; Philippa D. Hepplewhite; Gillian Riordan; Surita Meldau; Patrick F. Chinnery; Germaine Pierre; Efstathia Chronopoulou; Ailian Du; Imelda Hughes; Andrew A. Morris; Smaragda Kamakari; Georgia Chrousos; Richard J. Rodenburg; Christiaan G.J. Saris; Catherine Feeney; Steven A. Hardy; Takafumi Sakakibara; Akira Sudo; Yasushi Okazaki; Kei Murayama; Helen Mundy; Michael G. Hanna; Akira Ohtake; Andrew M. Schaefer; Mike P. Champion; Doug M. Turnbull; Robert W. Taylor; Robert D.S. Pitceathly; Robert McFarland; Gráinne S. Gorman
      Abstract: Publication date: Available online 24 February 2018
      Author(s): Yi Shiau Ng, Nichola Z. Lax, Paul Maddison, Charlotte L. Alston, Emma L. Blakely, Philippa D. Hepplewhite, Gillian Riordan, Surita Meldau, Patrick F. Chinnery, Germaine Pierre, Efstathia Chronopoulou, Ailian Du, Imelda Hughes, Andrew A. Morris, Smaragda Kamakari, Georgia Chrousos, Richard J. Rodenburg, Christiaan G.J. Saris, Catherine Feeney, Steven A. Hardy, Takafumi Sakakibara, Akira Sudo, Yasushi Okazaki, Kei Murayama, Helen Mundy, Michael G. Hanna, Akira Ohtake, Andrew M. Schaefer, Mike P. Champion, Doug M. Turnbull, Robert W. Taylor, Robert D.S. Pitceathly, Robert McFarland, Gráinne S. Gorman
      Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10 years (range: 5·4 months−37 years, IQR = 17·9 years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with LS/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094T>C.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.010
  • Mesenchymal Stem Cell-derived Neural Progenitor Cells in Progressive
           Multiple Sclerosis: Great Expectations

    • Authors: Laura E. Baldassari; Jeffrey A. Cohen
      Abstract: Publication date: Available online 23 February 2018
      Author(s): Laura E. Baldassari, Jeffrey A. Cohen

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.021
  • The Relationship Between Environmental Factors and the Profile of
           Epstein-Barr Virus Antibodies in the Lytic and Latent Infection Periods in
           Healthy Populations from Endemic and Non-Endemic Nasopharyngeal Carcinoma
           Areas in China

    • Authors: Yong-Qiao He; Wen-Qiong Xue; Feng-Hua Xu; Ya-Fei Xu; Jiang-Bo Zhang; Huan-Lin Yu; Qi-Sheng Feng; Li-Zhen Chen; Su-Mei Cao; Qing Liu; Jianbing Mu; Yi-Xin Zeng; Wei-Hua Jia
      Abstract: Publication date: Available online 23 February 2018
      Author(s): Yong-Qiao He, Wen-Qiong Xue, Feng-Hua Xu, Ya-Fei Xu, Jiang-Bo Zhang, Huan-Lin Yu, Qi-Sheng Feng, Li-Zhen Chen, Su-Mei Cao, Qing Liu, Jianbing Mu, Yi-Xin Zeng, Wei-Hua Jia
      Our previous study found that smoking was associated with an elevated level of the antibody against VCA in the Epstein-Barr virus (EBV) lytic phase, which was an important predictive marker of the risk of nasopharyngeal carcinoma (NPC). It remained unknown whether environmental factors were associated with the levels of other EBV antibodies, such as Zta-IgA, EA-IgA, EBNA1-IgA, and LMP1-IgA, in the lytic and latent infection periods. We aimed to investigate the possible environmental inducers that could affect EBV antibody levels in two independent healthy male populations from endemic NPC areas in South China (N = 1498) and non-endemic NPC areas in North China (N = 1961). We performed ELISA and immunoenzymatic assays to test the levels of antibodies specific to the EBV antigens. The seropositive rates of antibodies against the antigens expressed in both the EBV latent and lytic infection periods, namely, LMP1-IgA, EBNA1-IgA, and Zta-IgA, in endemic areas (28.65%, 5.43% and 14.49%, respectively) were significantly higher than those in non-endemic areas (14.43%, 1.07% and 6.32%, respectively). Smoking was associated with higher seropositivity for EBNA1-IgA (OR = 1.47, 95% CI = 1.12–1.93) and Zta-IgA (OR = 1.28, 95% CI = 0.99–1.66), with dose-response effects, while not associated with the levels of LMP1-IgA. In conclusion, smoking was an important environmental factor, which associated with increased levels of EBNA1-IgA, and Zta-IgA.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.019
  • Reciprocal modulation of mesenchymal stem cells and tumor cells promotes
           lung cancer metastasis

    • Authors: Giulia Fregni; Mathieu Quinodoz; Emely Möller; Joanna Vuille; Sabine Galland; Carlo Fusco; Patricia Martin; Igor Letovanec; Paolo Provero; Carlo Rivolta; Nicolo Riggi; Ivan Stamenkovic
      Abstract: Publication date: Available online 23 February 2018
      Author(s): Giulia Fregni, Mathieu Quinodoz, Emely Möller, Joanna Vuille, Sabine Galland, Carlo Fusco, Patricia Martin, Igor Letovanec, Paolo Provero, Carlo Rivolta, Nicolo Riggi, Ivan Stamenkovic
      Metastasis is a multi-step process in which direct crosstalk between cancer cells and their microenvironment plays a key role. Here, we assessed the effect of paired tumor-associated and normal lung tissue mesenchymal stem cells (MSCs) on the growth and dissemination of primary human lung carcinoma cells isolated from the same patients. We show that the tumor microenvironment modulates MSC gene expression and identify a four-gene MSC signature that is functionally implicated in promoting metastasis. We also demonstrate that tumor-associated MSCs induce the expression of genes associated with an aggressive phenotype in primary lung cancer cells and selectively promote their dissemination rather than local growth. Our observations provide insight into mechanisms by which the stroma promotes lung cancer metastasis.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.017
  • Pelvic Chlamydial Infection Predisposes to Ectopic Pregnancy by
           Upregulating Integrin β1 to Promote Embryo-tubal Attachment

    • Authors: Syed F. Ahmad; Jeremy K. Brown; Lisa L. Campbell; Magda Koscielniak; Catriona Oliver; Nick Wheelhouse; Gary Entrican; Stuart McFee; Gillian S. Wills; Myra O. McClure; Patrick J. Horner; Sevasti Gaikoumelou; Kai F. Lee; Hilary O.D. Critchley; W.C. Duncan; Andrew W. Horne
      Abstract: Publication date: Available online 23 February 2018
      Author(s): Syed F. Ahmad, Jeremy K. Brown, Lisa L. Campbell, Magda Koscielniak, Catriona Oliver, Nick Wheelhouse, Gary Entrican, Stuart McFee, Gillian S. Wills, Myra O. McClure, Patrick J. Horner, Sevasti Gaikoumelou, Kai F. Lee, Hilary O.D. Critchley, W.C. Duncan, Andrew W. Horne
      Tubal ectopic pregnancies are a leading cause of global maternal morbidity and mortality. Previous infection with Chlamydia trachomatis is a major risk factor for tubal embryo implantation but the biological mechanism behind this association is unclear. Successful intra-uterine embryo implantation is associated with increased expression of endometrial “receptivity” integrins (cell adhesion molecules). We examined integrin expression in Fallopian tubes of women with previous C. trachomatis infection, in mice experimentally infected with C. trachomatis, in immortalised human oviductal epithelial cells (OE-E6/E7) and in an in vitro model of human embryo attachment (trophoblast spheroid-OE-E6/7 cell co-culture). Previous exposure with C. trachomatis increased Fallopian tube/oviduct integrin-subunit beta-1 (ITGB1) in women and mice compared to controls. C. trachomatis increased OE-E6/E7 cell ITGB1 expression and promoted trophoblast attachment to OE-E6/E7 cells which was negated by anti-ITGB1-antibody. We demonstrate that infection with C. trachomatis increases tubal ITGB1 expression, predisposing to tubal embryo attachment and ectopic pregnancy.
      Graphical abstract image

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.020
  • Pathophysiological Characteristics Associated With Epileptogenesis in
           Human Hippocampal Sclerosis

    • Authors: Hiroki Kitaura; Hiroshi Shirozu; Hiroshi Masuda; Masafumi Fukuda; Yukihiko Fujii; Akiyoshi Kakita
      Abstract: Publication date: Available online 21 February 2018
      Author(s): Hiroki Kitaura, Hiroshi Shirozu, Hiroshi Masuda, Masafumi Fukuda, Yukihiko Fujii, Akiyoshi Kakita
      Mesial temporal lobe epilepsy (MTLE) is the most frequent focal epileptic syndrome in adults, and the majority of seizures originate primarily from the hippocampus. The resected hippocampal tissue often shows severe neuronal loss, a condition referred to as hippocampal sclerosis (HS). In order to understand hippocampal epileptogenesis in MTLE, it seems important to clarify any discrepancies between the clinical and pathological features of affected patients. Here we investigated epileptiform activities ex vivo using living hippocampal tissue taken from patients with MTLE. Flavoprotein fluorescence imaging and local field potential recordings revealed that epileptiform activities developed from the subiculum. Moreover, physiological and morphological experiments revealed possible impairment of K+ clearance in the subiculum affected by HS. Stimulation of mossy fibers induced recurrent trans-synaptic activity in the granule cell layer of the dentate gyrus, suggesting that mossy fiber sprouting in HS also contributes to the epileptogenic mechanism. These results indicate that pathophysiological alterations involving the subiculum and dentate gyrus could be responsible for epileptogenesis in patients with MTLE.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.013
  • Methylation of PD-1 Promoter Gene as New Prognostic Marker for IDH Mutant
           Low-Grade Glioma'

    • Authors: Christine Marosi
      Abstract: Publication date: Available online 21 February 2018
      Author(s): Christine Marosi

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.018
  • Corrigendum to “Fecal Clostridium symbiosum for Noninvasive Detection of
           Early and Advanced Colorectal Cancer: Test and Validation Studies”
           [Ebiomedicine 25 (2017) 32-40]

    • Authors: Yuan-Hong Xie; Qin-Yan Gao; Guo-Xiang Cai; Xiao-Min Sun; Tian-Hui Zou; Hui-Min Chen; Si-Yi Yu; Yi-Wen Qiu; Wei-Qi Gu; Xiao-Yu Chen; Yun Cui; Danfeng Sun; Zhan-Ju Liu; San-Jun Cai; Jie Xu; Ying-Xuan Chen; Jing-Yuan Fang
      Abstract: Publication date: Available online 20 February 2018
      Author(s): Yuan-Hong Xie, Qin-Yan Gao, Guo-Xiang Cai, Xiao-Min Sun, Tian-Hui Zou, Hui-Min Chen, Si-Yi Yu, Yi-Wen Qiu, Wei-Qi Gu, Xiao-Yu Chen, Yun Cui, Danfeng Sun, Zhan-Ju Liu, San-Jun Cai, Jie Xu, Ying-Xuan Chen, Jing-Yuan Fang

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.014
  • Lighting Up Alpha-synuclein Oligomers

    • Authors: Franziska Richter
      Abstract: Publication date: Available online 19 February 2018
      Author(s): Franziska Richter

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.016
  • Therapeutic Genome Editing With CRISPR/Cas9 in a Humanized Mouse Model
           Ameliorates α1-antitrypsin Deficiency Phenotype

    • Authors: Mikael Bjursell; Michelle J. Porritt; Elke Ericson; Amir Taheri-Ghahfarokhi; Maryam Clausen; Lisa Magnusson; Therese Admyre; Roberto Nitsch; Lorenz Mayr; Leif Aasehaug; Frank Seeliger; Marcello Maresca; Mohammad Bohlooly-Y; John Wiseman
      Abstract: Publication date: Available online 19 February 2018
      Author(s): Mikael Bjursell, Michelle J. Porritt, Elke Ericson, Amir Taheri-Ghahfarokhi, Maryam Clausen, Lisa Magnusson, Therese Admyre, Roberto Nitsch, Lorenz Mayr, Leif Aasehaug, Frank Seeliger, Marcello Maresca, Mohammad Bohlooly-Y, John Wiseman
      α1-antitrypsin (AAT) is a circulating serine protease inhibitor secreted from the liver and important in preventing proteolytic neutrophil elastase associated tissue damage, primarily in lungs. In humans, AAT is encoded by the SERPINA1 (hSERPINA1) gene in which a point mutation (commonly referred to as PiZ) causes aggregation of the miss-folded protein in hepatocytes resulting in subsequent liver damage. In an attempt to rescue the pathologic liver phenotype of a mouse model of human AAT deficiency (AATD), we used adenovirus to deliver Cas9 and a guide-RNA (gRNA) molecule targeting hSERPINA1. Our single dose therapeutic gene editing approach completely reverted the phenotype associated with the PiZ mutation, including circulating transaminase and human AAT (hAAT) protein levels, liver fibrosis and protein aggregation. Furthermore, liver histology was significantly improved regarding inflammation and overall morphology in hSERPINA1 gene edited PiZ mice. Genomic analysis confirmed significant disruption to the hSERPINA1 transgene and quantitative mRNA analysis showed a reduction in hAAT, fibrosis and hepatocyte proliferation as a result of editing. Our findings indicate that therapeutic gene editing in hepatocytes is possible in an AATD mouse model.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.015
  • IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates
           Liver Fibrosis Progression and Reversal

    • Authors: Shih-Yen Weng; Xiaoyu Wang; Santosh Vijayan; Yilang Tang; Yong Ook Kim; Kornelius Padberg; Tommy Regen; Olena Molokanova; Tao Chen; Tobias Bopp; Hansjörg Schild; Frank Brombacher; Jeff R. Crosby; Michael L. McCaleb; Ari Waisman; Ernesto Bockamp; Detlef Schuppan
      Abstract: Publication date: Available online 17 February 2018
      Author(s): Shih-Yen Weng, Xiaoyu Wang, Santosh Vijayan, Yilang Tang, Yong Ook Kim, Kornelius Padberg, Tommy Regen, Olena Molokanova, Tao Chen, Tobias Bopp, Hansjörg Schild, Frank Brombacher, Jeff R. Crosby, Michael L. McCaleb, Ari Waisman, Ernesto Bockamp, Detlef Schuppan
      Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause of worldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs fibrolytic macrophage function remain ill defined. We studied the role of interleukin-4 receptor α (IL-4Rα), a potential central switch of macrophage polarization, in liver fibrosis progression and reversal. We demonstrate that inflammatory monocyte infiltration and liver fibrogenesis were suppressed in general IL-4Rα−/− as well as in macrophage-specific IL-4Rα−/− (IL-4RαΔLysM) mice. However, with deletion of IL-4RαΔLysM spontaneous fibrosis reversal was retarded. Results were replicated by pharmacological intervention using IL-4Rα-specific antisense oligonucleotides. Retarded resolution was linked to the loss of M2-type resident macrophages, which secreted MMP-12 through IL-4 and IL-13-mediated phospho-STAT6 activation. We conclude that IL-4Rα signaling regulates macrophage functional polarization in a context-dependent manner. Pharmacological targeting of macrophage polarization therefore requires disease stage specific treatment strategies. Research in Context Alternative (M2-type) macrophage activation through IL-4Rα promotes liver inflammation and fibrosis progression but speeds up fibrosis reversal. This demonstrates context dependent, opposing roles of M2-type macrophages. During reversal IL-4Rα induces fibrolytic MMPs, especially MMP-12, through STAT6. Liver specific antisense oligonucleotides efficiently block IL-4Rα expression and attenuate fibrosis progression.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.028
  • p204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling
           in Mice

    • Authors: Young-Su Yi; Jinlong Jian; Elena Gonzalez-Gugel; Yong-Xiang Shi; Qingyun Tian; Wenyu Fu; Aubryanna Hettinghouse; Wenhao Song; Ronghan Liu; Michun He; Huabing Qi; Jing Yang; Xiaolan Du; GuoZhi Xiao; Lin Chen; Chuan-ju Liu
      Abstract: Publication date: Available online 16 February 2018
      Author(s): Young-Su Yi, Jinlong Jian, Elena Gonzalez-Gugel, Yong-Xiang Shi, Qingyun Tian, Wenyu Fu, Aubryanna Hettinghouse, Wenhao Song, Ronghan Liu, Michun He, Huabing Qi, Jing Yang, Xiaolan Du, GuoZhi Xiao, Lin Chen, Chuan-ju Liu
      p204, a murine member of an interferon-inducible p200 family, was reported to recognize intracellular viral and bacterial DNAs, however, its role in the innate immunity in vivo remains unknown due to the lack of p204-deficient animal models. In this study we first generated the p204 −/− mice. Unexpectedly, p204 deficiency led to significant defect in extracellular LPS signaling in macrophages, as demonstrated by dramatic reductions of LPS-mediated IFN-β and pro-inflammatory cytokines. The serum levels of IFN-β and pro-inflammatory cytokines were also significantly reduced in p204 −/− mice following LPS challenge. In addition, p204 −/− mice were resistant to LPS-induced shock. LPS-activated NF-ĸB and IRF-3 pathways were all defective in p204-deficient macrophages. p204 binds to TLR4 through its Pyrin domain, and it is required for the dimerization of TLR4 following LPS-challenge. Collectively, p204 is a critical component of canonical LPS-TLR4 signaling pathway, and these studies also suggest that p204 could be a potential target to prevent and treat inflammatory and infectious diseases.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.012
  • Heterologous Two-Dose Vaccination with Simian Adenovirus and Poxvirus
           Vectors Elicits Long-Lasting Cellular Immunity to Influenza Virus A in
           Healthy Adults

    • Authors: L. Coughlan; S. Sridhar; R. Payne; M. Edmans; A. Milicic; N. Venkatraman; B. Lugonja; L. Clifton; C. Qi; A. McMichael; P.M. Folegatti; A.M. Lawrie; R. Roberts; H. de Graaf; P. Sukhtankar; S.N. Faust; D.J.M. Lewis; T. Lambe; Hill AVS; S.C. Gilbert
      Abstract: Publication date: Available online 15 February 2018
      Author(s): L. Coughlan, S. Sridhar, R. Payne, M. Edmans, A. Milicic, N. Venkatraman, B. Lugonja, L. Clifton, C. Qi, A. McMichael, P.M. Folegatti, A.M. Lawrie, R. Roberts, H. de Graaf, P. Sukhtankar, S.N. Faust, D.J.M. Lewis, T. Lambe, Hill AVS, S.C. Gilbert
      Background T-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP) and matrix protein-1 (M1). We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults. Methods We conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18–46 years and 24 subjects aged 50 years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18 months. Findings Both vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The fold-increase and peak immune responses after a single MVA-NP + M1 vaccination was significantly higher compared to ChAdOx1 NP + M1. In a mixed regression model, T-cell responses over 18 months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP + M1. Interpretation A two dose heterologous vaccination regimen of MVA/ChAdOx1 NP + M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly cross-reactive protection against influenza A. Funding Source Medical Research Council UK, NIHR BMRC Oxford.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.011
  • Interferon Gamma Induces Reversible Metabolic Reprogramming of M1
           Macrophages to Sustain Cell Viability and Pro-Inflammatory Activity

    • Authors: Feilong Wang; Song Zhang; Ryounghoon Jeon; Ivan Vuckovic; Xintong Jiang; Amir Lerman; Clifford D. Folmes; Petras D. Dzeja; Joerg Herrmann
      Abstract: Publication date: Available online 13 February 2018
      Author(s): Feilong Wang, Song Zhang, Ryounghoon Jeon, Ivan Vuckovic, Xintong Jiang, Amir Lerman, Clifford D. Folmes, Petras D. Dzeja, Joerg Herrmann
      Classical activation of M1 macrophages with lipopolysaccharide (LPS) is associated with a metabolic switch from oxidative phosphorylation to glycolysis. However, the generalizability of such metabolic remodeling to other modes of M1 macrophage stimulation, e.g. type II interferons (IFNs) such as IFNγ, has remained unknown as has the functional significance of aerobic glycolysis during macrophage activation. Here we demonstrate that IFNγ induces a rapid activation of aerobic glycolysis followed by a reduction in oxidative phosphorylation in M1 macrophages. Elevated glycolytic flux sustains cell viability and inflammatory activity, while limiting reliance on mitochondrial oxidative metabolism. Adenosine triphosphate (ATP) distributed by aerobic glycolysis is critical for sustaining IFN-γ triggered JAK (Janus tyrosine kinase)-STAT-1 (Signal Transducer and Activator of Transcription 1) signaling with phosphorylation of the transcription factor STAT-1 as its signature trait. Inhibition of aerobic glycolysis not only blocks the M1 phenotype and pro-inflammatory cytokine/chemokine production in murine macrophages and also human monocytes/macrophages. These findings extend on the potential functional role of immuno-metabolism from LPS- to IFNγ-linked diseases such as atherosclerosis and autoimmune disease.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.009
  • Association of Air Pollution Exposure and Interleukin-13 Haplotype with
           the Risk of Aggregate Bronchitic Symptoms in Children

    • Authors: Yungling Leo Lee; Jing-Huei Chen; Chi-Min Wang; Mei-Ling Chen; Bing-Fang Hwang
      Abstract: Publication date: Available online 12 February 2018
      Author(s): Yungling Leo Lee, Jing-Huei Chen, Chi-Min Wang, Mei-Ling Chen, Bing-Fang Hwang
      Interleukin-13(IL-13) might play an important role in driving aggregate bronchitic symptoms pathogenesis. However, none of the studies assessed the interaction between air pollutants exposure and IL-13 gene on the risk of aggregate bronchitic symptoms in non-asthma children. To assess the independent and joint effects of the exposure to air pollution and IL-13 haplotypes on the risk of aggregate bronchitic symptoms, we conducted a cross-sectional study and focused on non-asthma children. The study population consisted of 2944 children. The effect of each air pollutant on the risk of aggregate bronchitic symptoms was estimated as odds ratios per interquartile range (IQR) change. In the multiple logistic regressions, adjusted for confounding factors, the risk of chronic phlegm was associated with PM2.5 exposure (aOR, 1.59; 95% CI, 1.07–2.37 per 12.51μg/m3 change), O3 exposure (aOR, 1.54 95% CI, 1.05–2.27 per 8.28ppb change) and SO2 exposure (aOR, 1.19; 95% CI, 1.02–1.39 per 0.98ppb change). Our study further provides the evidence that gene-environment interactions between IL-13 haplotype and O3 exposure on chronic phlegm (95% CI for interaction, 1.01–1.38). Identifying children who are more sensitive to air pollution helps us to provide them an efficient prevention to avoid aggregate bronchitic symptoms.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.008
  • Protective Effect of Human Leukocyte Antigen (HLA) Allele DRB1*13:02 on
           Age-Related Brain Gray Matter Volume Reduction in Healthy Women

    • Authors: Lisa M. James; Peka Christova; Scott M. Lewis; Brian E. Engdahl; Angeliki Georgopoulos; Apostolos P. Georgopoulos
      Abstract: Publication date: Available online 8 February 2018
      Author(s): Lisa M. James, Peka Christova, Scott M. Lewis, Brian E. Engdahl, Angeliki Georgopoulos, Apostolos P. Georgopoulos
      Background Reduction of brain volume (brain atrophy) during healthy brain aging is well documented and dependent on genetic, lifestyle and environmental factors. Here we investigated the possible dependence of brain gray matter volume reduction in the absence of the Human Leukocyte Antigen (HLA) allele DRB1*13:02 which prevents brain atrophy in Gulf War Illness (James et al., 2017). Methods Seventy-one cognitively healthy women (32–69years old) underwent a structural Magnetic Resonance Imaging (sMRI) scan to measure the volumes of total gray matter, cerebrocortical gray matter, and subcortical gray matter. Participants were assigned to two groups, depending on whether they lacked the DRB1*13:02 allele (No DRB1*13:02 group, N=60) or carried the DRB1*13:02 allele (N=11). We assessed the change of brain gray matter volume with age in each group by performing a linear regression where the brain volume (adjusted for total intracranial volume) was the dependent variable and age was the independent variable. Findings In the No DRB1*13:02 group, the volumes of total gray matter, cerebrocortical gray matter, and subcortical gray matter were reduced highly significantly. In contrast, none of these volumes showed a statistically significant reduction with age in the DRB1*13:02 group. Interpretation These findings document the protective effect of DRB1*13:02 on age-dependent reduction of brain gray matter in healthy individuals. Since the role of this allele is to connect to matching epitopes of external antigens for the subsequent production of antibodies and elimination of the offending antigen, we hypothesize that its protective effect may be due to the successful elimination of such antigens to which we are exposed during the lifespan, antigens that otherwise would persist causing gradual brain atrophy. In addition, we consider a possible beneficial role of DRB1*13:02 attributed to its binding to cathepsin S, a known harmful substance in brain aging (Wendt et al., 2008). Of course, other factors covarying with the presence of DRB1*13:02 could be involved.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.005
  • Neutrophil Microvesicles from Healthy Control and Rheumatoid Arthritis
           Patients Prevent the Inflammatory Activation of Macrophages

    • Authors: Hefin I. Rhys; Francesco Dell'Accio; Costantino Pitzalis; Adrian Moore; Lucy V. Norling; Mauro Perretti
      Abstract: Publication date: Available online 7 February 2018
      Author(s): Hefin I. Rhys, Francesco Dell'Accio, Costantino Pitzalis, Adrian Moore, Lucy V. Norling, Mauro Perretti
      Microvesicles (MVs) are emerging as a novel means to enact cell-to-cell communication in inflammation. Here, we aimed to ascertain the ability of neutrophil-derived MVs to modulate target cell behaviour, the focus being the macrophage. MVs were generated in response to tumour necrosis factor-α, from healthy control neutrophils or those from rheumatoid arthritis patients. MVs were used to stimulate human monocyte-derived macrophages in vitro, or administered intra-articularly in the K/BxN mouse model of arthritis. A macrophage/fibroblast-like synoviocyte co-culture system was used to study the effects of vesicles on the crosstalk between these cells. We demonstrate a direct role for phosphatidylserine and annexin-A1 exposed by the MVs to counteract classical activation of the macrophages, and promote the release of transforming growth factor-β, respectively. Classically-activated macrophages exposed to neutrophil MVs no longer activated fibroblast-like synoviocytes in subsequent co-culture settings. Finally, intra-articular administration of neutrophil MVs from rheumatoid arthritis patients in arthritic mice affected the phenotype of joint macrophages. Altogether these data, with the identification of specific MV determinants, open new opportunities to modulate on-going inflammation in the synovia – mainly by affecting macrophage polarization and potentially also fibroblast-like synoviocytes - through the delivery of autologous or heterologous MVs produced from neutrophils.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.003
  • Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive
           Non-smallcell Lung Cancer Associated With Poor Prognosis

    • Authors: Niki Karachaliou; Imane Chaib; Andres Felipe Cardona; Jordi Berenguer; Jillian Wilhelmina Paulina Bracht; Jie Yang; Xueting Cai; Zhigang Wang; Chunping Hu; Ana Drozdowskyj; Carles Codony Servat; Jordi Codony Servat; Masaoki Ito; Ilaria Attili; Erika Aldeguer; Ana Gimenez Capitan; July Rodriguez; Leonardo Rojas; Santiago Viteri; Miguel Angel Molina-Vila; Sai-Hong Ignatius Ou; Morihito Okada; Tony S. Mok; Trever G. Bivona; Mayumi Ono; Jean Cui; Santiago Ramón y Cajal; Peng Cao; Rafael Rosell
      Abstract: Publication date: Available online 5 February 2018
      Author(s): Niki Karachaliou, Imane Chaib, Andres Felipe Cardona, Jordi Berenguer, Jillian Wilhelmina Paulina Bracht, Jie Yang, Xueting Cai, Zhigang Wang, Chunping Hu, Ana Drozdowskyj, Carles Codony Servat, Jordi Codony Servat, Masaoki Ito, Ilaria Attili, Erika Aldeguer, Ana Gimenez Capitan, July Rodriguez, Leonardo Rojas, Santiago Viteri, Miguel Angel Molina-Vila, Sai-Hong Ignatius Ou, Morihito Okada, Tony S. Mok, Trever G. Bivona, Mayumi Ono, Jean Cui, Santiago Ramón y Cajal, Peng Cao, Rafael Rosell
      Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p =0.0407) and overall survival (hazard ratio of 2.23, p =0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR-mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing.
      Graphical abstract image

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.001
  • Phase I Trial of Intrathecal Mesenchymal Stem Cell-derived Neural
           Progenitors in Progressive Multiple Sclerosis

    • Authors: Violaine K. Harris; James Stark; Tamara Vyshkina; Leslie Blackshear; Gloria Joo; Valentina Stefanova; Gabriel Sara; Saud A. Sadiq
      Abstract: Publication date: Available online 3 February 2018
      Author(s): Violaine K. Harris, James Stark, Tamara Vyshkina, Leslie Blackshear, Gloria Joo, Valentina Stefanova, Gabriel Sara, Saud A. Sadiq
      Background Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system and is one of the leading causes of disability in young adults. Cell therapy is emerging as a therapeutic strategy to promote repair and regeneration in patients with disability associated with progressive MS. Methods We conducted a phase I open-label clinical trial investigating the safety and tolerability of autologous bone marrow mesenchymal stem cell-derived neural progenitor (MSC-NP) treatment in 20 patients with progressive MS. MSC-NPs were administered intrathecally (IT) in three separate doses of up to 1 × 107 cells per dose, spaced three months apart. The primary endpoint was to assess safety and tolerability of the treatment. Expanded disability status scale (EDSS), timed 25-ft walk (T25FW), muscle strength, and urodynamic testing were used to evaluate treatment response. This trial is registered with, number NCT01933802. Findings IT MSC-NP treatment was safe and well tolerated. The 20 enrolled subjects completed all 60 planned treatments without serious adverse effects. Minor adverse events included transient fever and mild headaches usually resolving in <24 h. Post-treatment disability score analysis demonstrated improved median EDSS suggesting possible efficacy. Positive trends were more frequently observed in the subset of SPMS patients and in ambulatory subjects (EDSS ≤ 6.5). In addition, 70% and 50% of the subjects demonstrated improved muscle strength and bladder function, respectively, following IT MSC-NP treatment. Interpretation The possible reversal of disability that was observed in a subset of patients warrants a larger phase II placebo-controlled study to establish efficacy of IT MSC-NP treatment in patients with MS. Funding source The Damial Foundation.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.02.002
  • Vinorelbine Potently Induces Placental Cell Death, Does Not Harm Fertility
           and is a Potential Treatment for Ectopic Pregnancy

    • Authors: Roxanne Hastie; Elgene Lim; Pavel Sluka; Lisa Campbell; Andrew W. Horne; Lenore Ellett; Natalie J. Hannan; Fiona Brownfoot; Tu'uhevaha J. Kaitu'u-Lino; Stephen Tong
      Abstract: Publication date: Available online 2 February 2018
      Author(s): Roxanne Hastie, Elgene Lim, Pavel Sluka, Lisa Campbell, Andrew W. Horne, Lenore Ellett, Natalie J. Hannan, Fiona Brownfoot, Tu'uhevaha J. Kaitu'u-Lino, Stephen Tong
      Ectopic pregnancies complicate 1–2 pregnancies and are a leading cause of maternal death. An effective oral drug therapy that replaces surgery might make its treatment safer, cheaper, simpler and therefore more widely accessible. The only current medical treatment offered to women is intramuscular methotrexate, but this only reliably resolves smaller ectopic pregnancies. As such, many ectopic pregnancies require surgical excision. We show that vinorelbine, an orally available chemotherapeutic agent, potently induced placental cell death but did not harm fertility in mice. Vinorelbine was 100–1000 times more potent than methotrexate in inducing placental cell death in vitro, and more potent than combination methotrexate and gefitinib (another proposed treatment for ectopic pregnancy being evaluated in phase III trials). Mechanistically, it caused microtubule condensation, blocked mitosis and activated the apoptosis cascade in placental cells. Vinorelbine was more efficacious than methotrexate±gefitinib in reducing the volume of placental cell tumors xenografted subcutaneously in SCID mice. Mice exposed to vinorelbine and allowed to breed, following a four week washout period, displayed normal fertility, however long-term fertility was not assessed. Human Fallopian tubes treated with vinorelbine did not exhibit up-regulation of apoptosis molecules. Our findings show that placental cells appear sensitive to vinorelbine and it has potential as a tablet-only approach to treat ectopic pregnancy.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.041
  • Corrigendum to “A vascular endothelial growth factor-dependent sprouting
           angiogenesis assay based on an in vitro human blood vessel model for the
           study of anti-angiogenic drugs” [Ebiomedicine 27 (2018) 225–236]

    • Abstract: Publication date: Available online 2 February 2018

      PubDate: 2018-02-25T04:12:39Z
  • Memory-Focused Cognitive Therapy for Cocaine Use Disorder: Theory,
           Procedures and Preliminary Evidence From an External Pilot Randomised
           Controlled Trial

    • Authors: John Marsden; Camille Goetz; Tim Meynen; Luke Mitcheson; Garry Stillwell; Brian Eastwood; John Strang; Nick Grey
      Abstract: Publication date: Available online 2 February 2018
      Author(s): John Marsden, Camille Goetz, Tim Meynen, Luke Mitcheson, Garry Stillwell, Brian Eastwood, John Strang, Nick Grey
      Background Cocaine use disorder (CUD) is a debilitating condition with no NICE-recommended medication or specific psychosocial interventions. In the United Kingdom (UK), general counselling (treatment-as-usual; TAU) is widely delivered, but has limited effectiveness. We tested the feasibility, safety and preliminary efficacy of a novel, adjunctive psychosocial intervention for CUD, called ‘memory-focused cognitive therapy’ (MFCT). Methods We did a two-arm, external pilot randomised controlled trial at a specialist community National Health Service addictions clinic in London, UK. 30 adults (≥18years), voluntarily seeking treatment for CUD (enrolled ≥14days; all with moderate-to-severe DSM5 CUD), were individually randomised (1:1) to a control group (ongoing TAU; 3×90min CUD cognitive conceptualisation assessments; 2×30min cocaine-related cue-induction procedures; and 3×30min research follow-ups); or to an intervention group (ongoing TAU; 3×90min cognitive conceptualisation assessments; 2×30min cocaine-related cue-induction procedures; 5×120min, one-to-one, MFCT sessions [in 1week]; and 3×60min research follow-ups and MFCT-relapse prevention). The primary outcome was the total percentage score on the frequency version of the Craving Experiences Questionnaire (CEQ-F) at 1-month follow-up after the intensive intervention week (clinical endpoint; recall period past 2weeks; higher score indicating greater craving). Secondary outcomes at the 1-month follow-up were percentage days abstinent (PDA) from cocaine, and longest period (days) of continuous abstinence (LPA) in the prior 28days. Outcomes were analysed as an unadjusted group mean difference (with Hedge's g effect size [ES]) and a 95% Confidence Interval [CI] for the primary outcome and a 90% CI for the secondary outcomes. Exploratory, multivariable linear (primary outcome) and Poisson regression models (secondary outcomes), with sex, age, months of regular cocaine use, baseline outcome score, and group estimated the effectiveness of the intervention. The trial is registered with the ISCRTN (ISRCTN16462783). Findings Between July 15, 2015, and November 27, 2016, 58 patients were assessed for eligibility and 30 participants were randomised (14 to the control group and 16 to the intervention). With outcome data collected for all participants at the endpoint, the intervention group mean CEQ-F score (14·77; SD 21·47) was lower than the control group mean (51·75; SD 22·72); ES -1·62; 95% CI -2·45 to −0·80. MFCT was associated with more cocaine abstinence in the intervention group (PDA 85·94; SD 18·96) than the control group (PDA 54·59; SD 30·29); ES 1·19; 90% CI 0·54 to 1·84. There was also greater maximum abstinence in the intervention group (LPA 15·69; SD 10·10) than the control group (6·00; SD 7·36); ES 1·06; 90% CI 0·41 to 1·70. Exploratory, confounder-adjusted regression models for this preliminary effect supported the treatment association for reduced craving experiences (CEQ-F Coef. -28·25; 95% CI -45·15 to −11·35); more abstinence (PDA Incidence Rate Ratio [IRR] 1·56; 95% CI 1·31 to 1·88); and greater maximum abstinence (LPA IRR 2·56; 95% CI 1·96 to 3·35), although relative weak unmeasured confounding could overturn these model-adjusted exposure-outcome associations. There were four serious adverse events (among three participants). None were judged related to study procedures or interventions. Interpretation In this first external pilot randomised controlled trial of MFCT for CUD, we have shown that the intervention and control procedures and acceptable feasible and safe, and report preliminary evidence that MFCT is associated with reduced craving and increased abstinence. These findings support progression to a substantive trial.
      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.039
  • Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and
           Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling

    • Authors: Helle Sadam; Arno Pihlak; Anri Kivil; Susan Pihelgas; Mariliis Jaago; Priit Adler; Jaak Vilo; Olli Vapalahti; Toomas Neuman; Dan Lindholm; Markku Partinen; Antti Vaheri; Kaia Palm
      Abstract: Publication date: Available online 2 February 2018
      Author(s): Helle Sadam, Arno Pihlak, Anri Kivil, Susan Pihelgas, Mariliis Jaago, Priit Adler, Jaak Vilo, Olli Vapalahti, Toomas Neuman, Dan Lindholm, Markku Partinen, Antti Vaheri, Kaia Palm
      Background Neuropathological findings support an autoimmune etiology as an underlying factor for loss of orexin-producing neurons in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1) as well as in Pandemrix influenza vaccine-induced narcolepsy type 1 (Pdmx-NT1). The precise molecular target or antigens for the immune response have, however, remained elusive. Methods Here we have performed a comprehensive antigenic repertoire analysis of sera using the next-generation phage display method - mimotope variation analysis (MVA). Samples from 64 children and adolescents were analyzed: 10 with Pdmx-NT1, 6 with sNT1, 16 Pandemrix-vaccinated, 16 H1N1 infected, and 16 unvaccinated healthy individuals. The diagnosis of NT1 was defined by the American Academy of Sleep Medicine international criteria of sleep disorders v3. Findings Our data showed that although the immunoprofiles toward vaccination were generally similar in study groups, there were also striking differences in immunoprofiles between sNT1 and Pdmx-NT1 groups as compared with controls. Prominent immune response was observed to a peptide epitope derived from prostaglandin D2 receptor (DP1), as well as peptides homologous to B cell lymphoma 6 protein. Further validation confirmed that these can act as true antigenic targets in discriminating NT1 diseased along with a novel epitope of hemagglutinin of H1N1 to delineate exposure to H1N1. Interpretation We propose that DP1 is a novel molecular target of autoimmune response and presents a potential diagnostic biomarker for NT1. DP1 is involved in the regulation of non-rapid eye movement (NREM) sleep and thus alterations in its functions could contribute to the disturbed sleep regulation in NT1 that warrants further studies. Together our results also show that MVA is a helpful method for finding novel peptide antigens to classify human autoimmune diseases, possibly facilitating the design of better therapies.

      PubDate: 2018-02-25T04:12:39Z
      DOI: 10.1016/j.ebiom.2018.01.043
  • Influenza: Our Old Fickle Foe

    • Abstract: Publication date: February 2018
      Source:EBioMedicine, Volume 28

      PubDate: 2018-02-25T04:12:39Z
School of Mathematical and Computer Sciences
Heriot-Watt University
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