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BIOTECHNOLOGY (236 journals)                  1 2 | Last

Showing 1 - 200 of 237 Journals sorted alphabetically
3 Biotech     Open Access   (Followers: 8)
Advanced Biomedical Research     Open Access  
Advances in Bioscience and Biotechnology     Open Access   (Followers: 14)
Advances in Genetic Engineering & Biotechnology     Hybrid Journal   (Followers: 8)
African Journal of Biotechnology     Open Access   (Followers: 6)
Algal Research     Partially Free   (Followers: 10)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 64)
American Journal of Bioinformatics Research     Open Access   (Followers: 7)
American Journal of Polymer Science     Open Access   (Followers: 31)
Anadolu University Journal of Science and Technology : C Life Sciences and Biotechnology     Open Access  
Animal Biotechnology     Hybrid Journal   (Followers: 8)
Annales des Sciences Agronomiques     Full-text available via subscription  
Applied Biochemistry and Biotechnology     Hybrid Journal   (Followers: 43)
Applied Bioenergy     Open Access  
Applied Biosafety     Hybrid Journal  
Applied Food Biotechnology     Open Access   (Followers: 3)
Applied Microbiology and Biotechnology     Hybrid Journal   (Followers: 63)
Applied Mycology and Biotechnology     Full-text available via subscription   (Followers: 4)
Arthroplasty Today     Open Access   (Followers: 1)
Artificial Cells, Nanomedicine and Biotechnology     Hybrid Journal   (Followers: 1)
Asia Pacific Biotech News     Hybrid Journal   (Followers: 2)
Asian Journal of Biotechnology     Open Access   (Followers: 8)
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: 5)
Bio-Algorithms and Med-Systems     Hybrid Journal   (Followers: 2)
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: 4)
Biological Cybernetics     Hybrid Journal   (Followers: 10)
Biomarkers and Genomic Medicine     Open Access   (Followers: 3)
Biomarkers in Drug Development     Partially Free   (Followers: 1)
Biomaterials Research     Open Access   (Followers: 4)
BioMed Research International     Open Access   (Followers: 4)
Biomédica     Open Access  
Biomedical and Biotechnology Research Journal     Open Access  
Biomedical Engineering Research     Open Access   (Followers: 6)
Biomedical glasses     Open Access  
Biomedical Reports     Full-text available via subscription  
BioMedicine     Open Access  
Biomedika     Open Access  
Bioprinting     Hybrid Journal   (Followers: 1)
Bioresource Technology Reports     Hybrid Journal   (Followers: 1)
Bioscience, Biotechnology, and Biochemistry     Hybrid Journal   (Followers: 21)
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: 5)
Biotechnology & Biotechnological Equipment     Open Access   (Followers: 4)
Biotechnology Advances     Hybrid Journal   (Followers: 33)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 44)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 155)
Biotechnology and Bioprocess Engineering     Hybrid Journal   (Followers: 5)
Biotechnology and Genetic Engineering Reviews     Hybrid Journal   (Followers: 13)
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: 5)
Biotechnology for Biofuels     Open Access   (Followers: 10)
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: 1)
Biotechnology Techniques     Hybrid Journal   (Followers: 10)
Biotecnología Aplicada     Open Access  
Bioteknologi (Biotechnological Studies)     Open Access  
Biotribology     Hybrid Journal   (Followers: 1)
BMC Biotechnology     Open Access   (Followers: 16)
Cell Biology and Development     Open Access  
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: 2)
Copernican Letters     Open Access   (Followers: 1)
Critical Reviews in Biotechnology     Hybrid Journal   (Followers: 20)
Crop Breeding and Applied Biotechnology     Open Access   (Followers: 3)
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: 56)
Current Pharmaceutical Biotechnology     Hybrid Journal   (Followers: 9)
Current Research in Bioinformatics     Open Access   (Followers: 12)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 3)
Current trends in Biotechnology and Pharmacy     Open Access   (Followers: 8)
EBioMedicine     Open Access  
Electronic Journal of Biotechnology     Open Access  
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: 9)
Food Science and Biotechnology     Hybrid Journal   (Followers: 8)
Frontiers in Bioengineering and Biotechnology     Open Access   (Followers: 6)
Frontiers in Systems Biology     Open Access   (Followers: 2)
Fungal Biology and Biotechnology     Open Access   (Followers: 2)
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: 2)
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: 13)
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: 1)
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: 4)
Journal of Applied Biomedicine     Open Access   (Followers: 2)
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 Biotechnology and Strategic Health Research     Open Access  
Journal of Chemical and Biological Interfaces     Full-text available via subscription   (Followers: 1)
Journal of Chemical Technology & Biotechnology     Hybrid Journal   (Followers: 9)
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: 3)
Journal of Essential Oil Research     Hybrid Journal   (Followers: 2)
Journal of Experimental Biology     Full-text available via subscription   (Followers: 24)
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 Biology and Biotechnology     Open Access  
Journal of Molecular Microbiology and Biotechnology     Full-text available via subscription   (Followers: 11)
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: 1)
Journal of Organic and Biomolecular Simulations     Open Access  
Journal of Plant Biochemistry and Biotechnology     Hybrid Journal   (Followers: 4)
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: 4)
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: 13)
Molecular Genetics and Metabolism Reports     Open Access   (Followers: 3)
Nanobiomedicine     Open Access  
Nanobiotechnology     Hybrid Journal   (Followers: 2)
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: 535)

        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  [3162 journals]
  • The Tumor Microenvironment: A Druggable Target for Metastatic Disease'

    • Authors: EBioMedicine
      Pages: 1 - 2
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): EBioMedicine

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.005
      Issue No: Vol. 31 (2018)
  • Activation of AMPK for a Break in Hepatic Lipid Accumulation and
           Circulating Cholesterol

    • Authors: Marc Foretz; Benoit Viollet
      Pages: 15 - 16
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Marc Foretz, Benoit Viollet

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.009
      Issue No: Vol. 31 (2018)
  • 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
      Pages: 25 - 35
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      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: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.02.025
      Issue No: Vol. 31 (2018)
  • A Validated Clinical Risk Prediction Model for Lung Cancer in Smokers of
           All Ages and Exposure Types: A HUNT Study

    • Authors: Maria Markaki; Ioannis Tsamardinos; Arnulf Langhammer; Vincenzo Lagani; Kristian Hveem; Oluf Dimitri Røe
      Pages: 36 - 46
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Maria Markaki, Ioannis Tsamardinos, Arnulf Langhammer, Vincenzo Lagani, Kristian Hveem, Oluf Dimitri Røe
      Lung cancer causes >1·6 million deaths annually, with early diagnosis being paramount to effective treatment. Here we present a validated risk assessment model for lung cancer screening. The prospective HUNT2 population study in Norway examined 65,237 people aged >20years in 1995–97. After a median of 15·2years, 583 lung cancer cases had been diagnosed; 552 (94·7%) ever-smokers and 31 (5·3%) never-smokers. We performed multivariable analyses of 36 candidate risk predictors, using multiple imputation of missing data and backwards feature selection with Cox regression. The resulting model was validated in an independent Norwegian prospective dataset of 45,341 ever-smokers, in which 675 lung cancers had been diagnosed after a median follow-up of 11·6years. Our final HUNT Lung Cancer Model included age, pack-years, smoking intensity, years since smoking cessation, body mass index, daily cough, and hours of daily indoors exposure to smoke. External validation showed a 0·879 concordance index (95% CI [0·866–0·891]) with an area under the curve of 0·87 (95% CI [0·85–0·89]) within 6years. Only 22% of ever-smokers would need screening to identify 81·85% of all lung cancers within 6years. Our model of seven variables is simple, accurate, and useful for screening selection.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.03.027
      Issue No: Vol. 31 (2018)
  • Effect of Trinucleotide Repeats in the Huntington's Gene on Intelligence

    • Authors: Jessica K. Lee; Amy Conrad; Eric Epping; Kathy Mathews; Vincent Magnotta; Jeffrey D. Dawson; Peg Nopoulos
      Pages: 47 - 53
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Jessica K. Lee, Amy Conrad, Eric Epping, Kathy Mathews, Vincent Magnotta, Jeffrey D. Dawson, Peg Nopoulos
      Background Huntington's Disease (HD) is caused by an abnormality in the HTT gene. This gene includes trinucleotide repeats ranging from 10 to 35, and when expanded beyond 39, causes HD. We previously reported that CAG repeats in the normal range had a direct and beneficial effect on brain development with higher repeats being associated with higher cognitive function. The current study now expands this line of inquiry to evaluate the effects of CAG repeat throughout the entire spectrum of repeats from 15 to 58. Methods We evaluated brain function in children ages 6–18 years old. DNA samples were processed to quantify the number of CAG repeats within HTT. Linear regression was used to determine if number of CAG repeats predicted measures of brain function. Findings The number of repeats in HTT, had a non-linear effect on a measure of general intelligence with an inverted U shape pattern. Increasing repeat length was associated with higher GAI scores up until roughly 40–41 repeats. After this peak, increasing repeat length was associated with declining GAI scores. Interpretation HTT may confer an advantage or a disadvantage depending upon the repeat length, playing a key role in the determination of intelligence, or causing a uniquely human brain disease.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.03.031
      Issue No: Vol. 31 (2018)
  • A Genomic-clinicopathologic Nomogram for the Preoperative Prediction of
           Lymph Node Metastasis in Bladder Cancer

    • Authors: Shao-Xu Wu; Jian Huang; Zhuo-Wei Liu; Hai-Ge Chen; Pi Guo; Qing-Qing Cai; Jun-Jiong Zheng; Hai-De Qin; Zao-Song Zheng; Xin Chen; Rui-Yun Zhang; Si-Liang Chen; Tian-Xin Lin
      Pages: 54 - 65
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Shao-Xu Wu, Jian Huang, Zhuo-Wei Liu, Hai-Ge Chen, Pi Guo, Qing-Qing Cai, Jun-Jiong Zheng, Hai-De Qin, Zao-Song Zheng, Xin Chen, Rui-Yun Zhang, Si-Liang Chen, Tian-Xin Lin
      Preoperative lymph node (LN) status is important for the treatment of bladder cancer (BCa). Here, we report a genomic-clinicopathologic nomogram for preoperatively predicting LN metastasis in BCa. In the discovery stage, 325 BCa patients from TCGA were involved and LN-status-related mRNAs were selected. In the training stage, multivariate logistic regression analysis was used to developed a genomic-clinicopathologic nomogram for preoperative LN metastasis prediction in the training set (SYSMH set, n =178). In the validation stage, we validated the nomogram using two independent sample sets (SYSUCC set, n =142; RJH set, n =104) with respect to its discrimination, calibration and clinical usefulness. As results, we identified five LN-status-related mRNAs, including ADRA1D, COL10A1, DKK2, HIST2H3D and MMP11. Then, a genomic classifier was developed to classify patients into high- and low-risk groups in the training set. Furthermore, a nomogram incorporating the five-mRNA-based classifier, image-based LN status, transurethral resection (TUR) T stage, and TUR lymphovascular invasion (LVI) was constructed in the training set, which performed well in the training and validation sets. Decision curve analysis demonstrated the clinical value of our nomogram. Thus, our genomic-clinicopathologic nomogram shows favorable discriminatory ability and may aid in clinical decision-making, especially for cN-patients.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.03.034
      Issue No: Vol. 31 (2018)
  • Predominant Asymmetrical Stem Cell Fate Outcome Limits the Rate of Niche
           Succession in Human Colonic Crypts

    • Authors: Craig Stamp; Anze Zupanic; Ashwin Sachdeva; Elizabeth A. Stoll; Daryl P. Shanley; John C. Mathers; Thomas B.L. Kirkwood; Rakesh Heer; Benjamin D. Simons; Doug M. Turnbull; Laura C. Greaves
      Pages: 166 - 173
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Craig Stamp, Anze Zupanic, Ashwin Sachdeva, Elizabeth A. Stoll, Daryl P. Shanley, John C. Mathers, Thomas B.L. Kirkwood, Rakesh Heer, Benjamin D. Simons, Doug M. Turnbull, Laura C. Greaves
      Stem cell (SC) dynamics within the human colorectal crypt SC niche remain poorly understood, with previous studies proposing divergent hypotheses on the predominant mode of SC self-renewal and the rate of SC replacement. Here we use age-related mitochondrial oxidative phosphorylation (OXPHOS) defects to trace clonal lineages within human colorectal crypts across the adult life-course. By resolving the frequency and size distribution of OXPHOS-deficient clones, quantitative analysis shows that, in common with mouse, long-term maintenance of the colonic epithelial crypt relies on stochastic SC loss and replacement mediated by competition for limited niche access. We find that the colonic crypt is maintained by ~5 effective SCs. However, with a SC loss/replacement rate estimated to be slower than once per year, our results indicate that the vast majority of individual SC divisions result in asymmetric fate outcome. These findings provide a quantitative platform to detect and study deviations from human colorectal crypt SC niche homeostasis during the process of colorectal carcinogenesis.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.04.017
      Issue No: Vol. 31 (2018)
  • Prognostic Role of Gene Mutations in Chronic Myelomonocytic Leukemia
           Patients Treated With Hypomethylating Agents

    • Authors: Matthieu Duchmann; Fevzi F. Yalniz; Alessandro Sanna; David Sallman; Catherine C. Coombs; Aline Renneville; Olivier Kosmider; Thorsten Braun; Uwe Platzbecker; Lise Willems; Lionel Adès; Michaela Fontenay; Raajit Rampal; Eric Padron; Nathalie Droin; Claude Preudhomme; Valeria Santini; Mrinal M. Patnaik; Pierre Fenaux; Eric Solary; Raphael Itzykson
      Pages: 174 - 181
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Matthieu Duchmann, Fevzi F. Yalniz, Alessandro Sanna, David Sallman, Catherine C. Coombs, Aline Renneville, Olivier Kosmider, Thorsten Braun, Uwe Platzbecker, Lise Willems, Lionel Adès, Michaela Fontenay, Raajit Rampal, Eric Padron, Nathalie Droin, Claude Preudhomme, Valeria Santini, Mrinal M. Patnaik, Pierre Fenaux, Eric Solary, Raphael Itzykson
      Somatic mutations contribute to the heterogeneous prognosis of chronic myelomonocytic leukemia (CMML). Hypomethylating agents (HMAs) are active in CMML, but analyses of small series failed to identify mutations predicting response or survival. We analyzed a retrospective multi-center cohort of 174 CMML patients treated with a median of 7 cycles of azacitidine (n = 68) or decitabine (n = 106). Sequencing data before treatment initiation were available for all patients, from Sanger (n = 68) or next generation (n = 106) sequencing. Overall response rate (ORR) was 52%, including complete response (CR) in 28 patients (17%). In multivariate analysis, ASXL1 mutations predicted a lower ORR (Odds Ratio [OR] = 0.85, p = 0.037), whereas TET2 mut /ASXL1 wt genotype predicted a higher CR rate (OR = 1.18, p = 0.011) independently of clinical parameters. With a median follow-up of 36.7 months, overall survival (OS) was 23.0 months. In multivariate analysis, RUNX1 mut (Hazard Ratio [HR] = 2.00, p = .011), CBL mut (HR = 1.90, p = 0.03) genotypes and higher WBC (log10(WBC) HR = 2.30, p = .005) independently predicted worse OS while the TET2 mut /ASXL1 wt predicted better OS (HR = 0.60, p = 0.05). CMML-specific scores CPSS and GFM had limited predictive power. Our results stress the need for robust biomarkers of HMA activity in CMML and for novel treatment strategies in patients with myeloproliferative features and RUNX1 mutations.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.04.018
      Issue No: Vol. 31 (2018)
  • The Novel Pathogenesis of Retinopathy Mediated by Multiple RTK Signals is
           Uncovered in Newly Developed Mouse Model

    • Authors: Hideyuki Kitahara; Sayaka Kajikawa; Yoko Ishii; Seiji Yamamoto; Takeru Hamashima; Erika Azuma; Hikari Sato; Takako Matsushima; Masabumi Shibuya; Yutaka Shimada; Masakiyo Sasahara
      Pages: 190 - 201
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Hideyuki Kitahara, Sayaka Kajikawa, Yoko Ishii, Seiji Yamamoto, Takeru Hamashima, Erika Azuma, Hikari Sato, Takako Matsushima, Masabumi Shibuya, Yutaka Shimada, Masakiyo Sasahara
      Pericyte desorption from retinal blood vessels and subsequent vascular abnormalities are the pathogenesis of diabetic retinopathy (DR). Although the involvement of abnormal signals including platelet-derived growth factor receptor-β (PDGFRβ) and vascular endothelial growth factor-A (VEGF-A) have been hypothesized in DR, the mechanisms that underlie this processes are largely unknown. Here, novel retinopathy mouse model (N-PRβ-KO) was developed with conditional Pdgfrb gene deletion by Nestin promoter-driven Cre recombinase (Nestin-Cre) that consistently reproduced through early non-proliferative to late proliferative DR pathologies. Depletion of Nestin-Cre-sensitive PDGFRβ+NG2+αSMA− pericytes suppressed pericyte-coverages and induced severe vascular lesion and hemorrhage. Nestin-Cre-insensitive PDGFRβ+NG2+αSMA+ pericytes detached from the vascular wall, and subsequently changed into myofibroblasts in proliferative membrane to cause retinal traction. PDGFRα+ astrogliosis was seen in degenerated retina. Expressions of placental growth factor (PlGF), VEGF-A and PDGF-BB were significantly increased in the retina of N-PRβ-KO. PDGF-BB may contribute to the pericyte-fibroblast transition and glial scar formation. Since VEGFR1 signal blockade significantly ameliorated the vascular phenotype in N-PRβ-KO mice, the augmented VEGFR1 signal by PlGF and VEGF-A was indicated to mediate vascular lesions. In addition to PDGF-BB, PlGF and VEGF-A with their intracellular signals may be the relevant therapeutic targets to protect eyes from DR.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.04.021
      Issue No: Vol. 31 (2018)
  • Adipocyte-derived Lysophosphatidylcholine Activates Adipocyte and Adipose
           Tissue Macrophage Nod-Like Receptor Protein 3 Inflammasomes Mediating
           Homocysteine-Induced Insulin Resistance

    • Authors: Song-Yang Zhang; Yong-Qiang Dong; Pengcheng Wang; Xingzhong Zhang; Yu Yan; Lulu Sun; Bo Liu; Dafang Zhang; Heng Zhang; Huiying Liu; Wei Kong; Gang Hu; Yatrik M. Shah; Frank J. Gonzalez; Xian Wang; Changtao Jiang
      Pages: 202 - 216
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Song-Yang Zhang, Yong-Qiang Dong, Pengcheng Wang, Xingzhong Zhang, Yu Yan, Lulu Sun, Bo Liu, Dafang Zhang, Heng Zhang, Huiying Liu, Wei Kong, Gang Hu, Yatrik M. Shah, Frank J. Gonzalez, Xian Wang, Changtao Jiang
      The adipose Nod-like receptor protein 3 (NLRP3) inflammasome senses danger-associated molecular patterns (DAMPs) and initiates insulin resistance, but the mechanisms of adipose inflammasome activation remains elusive. In this study, Homocysteine (Hcy) is revealed to be a DAMP that activates adipocyte NLRP3 inflammasomes, participating in insulin resistance. Hcy-induced activation of NLRP3 inflammasomes were observed in both adipocytes and adipose tissue macrophages (ATMs) and mediated insulin resistance. Lysophosphatidylcholine (lyso-PC) acted as a second signal activator, mediating Hcy-induced adipocyte NLRP3 inflammasome activation. Hcy elevated adipocyte lyso-PC generation in a hypoxia-inducible factor 1 (HIF1)-phospholipase A2 group 16 (PLA2G16) axis-dependent manner. Lyso-PC derived from the Hcy-induced adipocyte also activated ATM NLRP3 inflammasomes in a paracrine manner. This study demonstrated that Hcy activates adipose NLRP3 inflammasomes in an adipocyte lyso-PC-dependent manner and highlights the importance of the adipocyte NLRP3 inflammasome in insulin resistance.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.04.022
      Issue No: Vol. 31 (2018)
  • Runt-Related Transcription Factor 1 (RUNX1) Promotes TGF-β-Induced Renal
           Tubular Epithelial-to-Mesenchymal Transition (EMT) and Renal Fibrosis
           through the PI3K Subunit p110δ

    • Authors: Tong Zhou; Maocai Luo; Wei Cai; Siyuan Zhou; Danying Feng; Chundi Xu; Hongyan Wang
      Pages: 217 - 225
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Tong Zhou, Maocai Luo, Wei Cai, Siyuan Zhou, Danying Feng, Chundi Xu, Hongyan Wang
      Renal fibrosis is widely considered a common mechanism leading to end-stage renal failure. Epithelial-to-mesenchymal transition (EMT) plays important roles in the pathogenesis of renal fibrosis. Runt-related transcription factor 1(RUNX1) plays a vital role in hematopoiesis via Endothelial-to-Hematopoietic Transition (EHT), a process that is conceptually similar to EMT, but its role in EMT and renal fibrosis is unclear. Here, we demonstrate that RUNX1 is overexpressed in the processes of TGF-β-induced partial EMT and renal fibrosis and that the expression level of RUNX1 is SMAD3-dependent. Knockdown of RUNX1 attenuated both TGF-β-induced phenotypic changes and the expression levels of EMT marker genes in renal tubular epithelial cells (RTECs). In addition, overexpression of RUNX1 promoted the expression of EMT marker genes in renal tubular epithelial cells. Moreover, RUNX1 promoted TGF-β-induced partial EMT by increasing transcription of the PI3K subunit p110δ, which mediated Akt activation. Specific deletion of Runx1 in mouse RTECs attenuated renal fibrosis, which was induced by both unilateral ureteral obstruction (UUO) and folic acid (FA) treatment. These findings suggest that RUNX1 is a potential target for preventing renal fibrosis.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.04.023
      Issue No: Vol. 31 (2018)
  • Interventions Targeting Glucocorticoid-Krüppel-like Factor
           15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in
           Spinal Muscular Atrophy Mice

    • Authors: Lisa M. Walter; Marc-Olivier Deguise; Katharina E. Meijboom; Corinne A. Betts; Nina Ahlskog; Tirsa L.E. van Westering; Gareth Hazell; Emily McFall; Anna Kordala; Suzan M. Hammond; Frank Abendroth; Lyndsay M. Murray; Hannah K. Shorrock; Domenick A. Prosdocimo; Saptarsi M. Haldar; Mukesh K. Jain; Thomas H. Gillingwater; Peter Claus; Rashmi Kothary; Matthew J.A. Wood; Melissa Bowerman
      Pages: 226 - 242
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Lisa M. Walter, Marc-Olivier Deguise, Katharina E. Meijboom, Corinne A. Betts, Nina Ahlskog, Tirsa L.E. van Westering, Gareth Hazell, Emily McFall, Anna Kordala, Suzan M. Hammond, Frank Abendroth, Lyndsay M. Murray, Hannah K. Shorrock, Domenick A. Prosdocimo, Saptarsi M. Haldar, Mukesh K. Jain, Thomas H. Gillingwater, Peter Claus, Rashmi Kothary, Matthew J.A. Wood, Melissa Bowerman
      The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn −/− ;SMN2 and Smn 2B/− mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone), genetic (muscle-specific Klf15 overexpression) and dietary (BCAA supplementation) interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.04.024
      Issue No: Vol. 31 (2018)
  • DNA Methylation Patterns in Normal Tissue Correlate more Strongly with
           Breast Cancer Status than Copy-Number Variants

    • Authors: Yang Gao; Martin Widschwendter; Andrew E. Teschendorff
      Pages: 243 - 252
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Yang Gao, Martin Widschwendter, Andrew E. Teschendorff
      Normal tissue at risk of neoplastic transformation is characterized by somatic mutations, copy-number variation and DNA methylation changes. It is unclear however, which type of alteration may be more informative of cancer risk. We analyzed genome-wide DNA methylation and copy-number calls from the same DNA assay in a cohort of healthy breast samples and age-matched normal samples collected adjacent to breast cancer. Using statistical methods to adjust for cell type heterogeneity, we show that DNA methylation changes can discriminate normal-adjacent from normal samples better than somatic copy-number variants. We validate this important finding in an independent dataset. These results suggest that DNA methylation alterations in the normal cell of origin may offer better cancer risk prediction and early detection markers than copy-number changes.
      Graphical abstract image

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.04.025
      Issue No: Vol. 31 (2018)
  • SOX30 Inhibits Tumor Metastasis through Attenuating Wnt-Signaling via
           Transcriptional and Posttranslational Regulation of β-Catenin in Lung

    • Authors: Fei Han; Wen-bin Liu; Xiao-yan Shi; Jun-tang Yang; Xi Zhang; Zhi-ming Li; Xiao Jiang; Li Yin; Jian-jun Li; Chuan-shu Huang; Jia Cao; Jin-yi Liu
      Pages: 253 - 266
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Fei Han, Wen-bin Liu, Xiao-yan Shi, Jun-tang Yang, Xi Zhang, Zhi-ming Li, Xiao Jiang, Li Yin, Jian-jun Li, Chuan-shu Huang, Jia Cao, Jin-yi Liu
      Although high mortality of lung cancer is greatly due to distant metastasis, the mechanism of this metastasis remains unclear. Here, we investigate in lung cancer that SOX30 is sharply under-expressed in metastatic tumors compared with non-metastatic tumors, and suppresses plenty of metastasis related processes or pathways. SOX30 strongly inhibits tumor cell metastasis in vitro and in vivo. Sox30 deficiency promotes lung metastasis in Sox30−/− mice and this uncontrollable lung-metastasis is re-inhibited upon Sox30 re-expression. Mechanistically, SOX30 diminishes Wnt-signaling via directly transcriptional repressing β-catenin or interacting with β-catenin to compete with TCF for binding to β-catenin. The carboxyl-terminus of SOX30 is required for attenuating β-catenin transcriptional activity, whereas the amino-terminus of SOX30 is required for its interaction with β-catenin protein. Enhance of β-catenin attenuates the anti-metastatic role of SOX30. Moreover, Sox30 deficiency promotes tumor metastasis and reduces survival of mice. In addition, nuclear SOX30 expression is closely associated with metastasis and represents a favorable independent prognostic biomarker of lung cancer patients. Altogether, these results highlight an important role and mechanism of SOX30 in lung cancer metastasis, providing a potential therapeutic target for anti-metastasis.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.04.026
      Issue No: Vol. 31 (2018)
  • Roles of Alternative RNA Splicing of the Bif-1 Gene by SRRM4 During the
           Development of Treatment-induced Neuroendocrine Prostate Cancer

    • Authors: Yu Gan; Yinan Li; Zhi Long; Ahn R. Lee; Ning Xie; Jessica M. Lovnicki; Yuxin Tang; Xiang Chen; Jiaoti Huang; Xuesen Dong
      Pages: 267 - 275
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Yu Gan, Yinan Li, Zhi Long, Ahn R. Lee, Ning Xie, Jessica M. Lovnicki, Yuxin Tang, Xiang Chen, Jiaoti Huang, Xuesen Dong
      Treatment-induced neuroendocrine prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer (PCa) that becomes more prevalent when hormonal therapy, chemotherapy, or radiation therapy is applied to patients with metastatic prostate adenocarcinoma (AdPC). How AdPC cells survive these anti-cancer therapies and progress into t-NEPC remains unclear. By comparing the whole transcriptomes between AdPC and t-NEPC, we identified Bif-1, an apoptosis-associated gene, which undergoes alternative RNA splicing in t-NEPC. We found that while Bif-1a is the predominant variant of the Bif-1 gene in AdPC, two neural-specific variants, Bif-1b and Bif-1c, are highly expressed in t-NEPC patients, patient derived xenografts, and cell models. The neural-specific RNA splicing factor, SRRM4, promotes Bif-1b and Bif-1c splicing, and the expression of SRRM4 in tumors is strongly associated with Bif-1b/-1c levels. Furthermore, we showed that Bif-1a is pro-apoptotic, while Bif-1b and Bif-1c are anti-apoptotic in PCa cells under camptothecin and UV light irritation treatments. Taken together, our data indicate that SRRM4 regulates alternative RNA splicing of the Bif-1 gene that enables PCa cells resistant to apoptotic stimuli under anti-cancer therapies, and may contribute to AdPC progression into t-NEPC.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.002
      Issue No: Vol. 31 (2018)
  • Inhibition of HDACs-EphA2 Signaling Axis with WW437 Demonstrates Promising
           Preclinical Antitumor Activity in Breast Cancer

    • Authors: Tao Zhang; Jingjie Li; Xiaojun Ma; Yang Yang; Wei Sun; Wangrui Jin; Lei Wang; Yuan He; Feifei Yang; Zhengfang Yi; Yingqi Hua; Mingyao Liu; Yihua Chen; Zhengdong Cai
      Pages: 276 - 286
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Tao Zhang, Jingjie Li, Xiaojun Ma, Yang Yang, Wei Sun, Wangrui Jin, Lei Wang, Yuan He, Feifei Yang, Zhengfang Yi, Yingqi Hua, Mingyao Liu, Yihua Chen, Zhengdong Cai
      Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for hematologic neoplasms, which have also demonstrated clinical activities in solid tumors. In our present study, we screened our internal compound library and discovered a novel HDACi, WW437, with potent anti-breast cancer ability in vitro and in vivo. WW437 significantly inhibited phosphorylated EphA2 and EphA2 expression. Further study demonstrated WW437 blocked HDACs-EphA2 signaling axis in breast cancer. In parallel, we found that EphA2 expression positively correlates with breast cancer progression; and combined use of WW437 and an EphA2 inhibitor (ALW-II-41-27) exerted more remarkable effect on breast cancer growth than either drug alone. Our findings suggested inhibition of HDACs-EphA2 signaling axis with WW437 alone or in combination with other agents may be a promising therapeutic strategy for advanced breast cancer.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.003
      Issue No: Vol. 31 (2018)
  • Hydroxylase Activity of ASPH Promotes Hepatocellular Carcinoma Metastasis
           Through Epithelial-to-Mesenchymal Transition Pathway

    • Authors: Qifei Zou; Ying Hou; Haibo Wang; Kui Wang; Xianglei Xing; Yong Xia; Xuying Wan; Jun Li; Binghua Jiao; Jingfeng Liu; Aimin Huang; Dong Wu; Hongjun Xiang; Timothy M. Pawlik; Hongyang Wang; Wan Yee Lau; Yizheng Wang; Feng Shen
      Pages: 287 - 298
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Qifei Zou, Ying Hou, Haibo Wang, Kui Wang, Xianglei Xing, Yong Xia, Xuying Wan, Jun Li, Binghua Jiao, Jingfeng Liu, Aimin Huang, Dong Wu, Hongjun Xiang, Timothy M. Pawlik, Hongyang Wang, Wan Yee Lau, Yizheng Wang, Feng Shen
      Over-expression of aspartyl (asparagynal)-β-hydroxylase (ASPH) contributes to hepatocellular carcinoma (HCC) invasiveness, but the role of ASPH hydroxylase activity in this process remains to be defined. As such, the current study investigated the role of ASPH hydroxylase activity in downstream signalling of HCC tumorgenesis and, specifically, metastasis development. Over-expression of wild-type ASPH, but not a hydroxylase mutant, promoted HCC cell migration in vitro, as well as intrahepatic and distant metastases in vivo. The enhanced migration and epithelial to mesenchymal transition (EMT) activation was notably absent in response to hydroxylase activity blockade. Vimentin, a regulator of EMT, interacted with ASPH and likely mediated the effect of ASPH hydroxylase activity with cell migration. The enhanced hydroxylase activity in tumor tissues predicted worse prognoses of HCC patients. Collectively, the hydroxylase activity of ASPH affected HCC metastasis through interacting with vimentin and regulating EMT. As such, ASPH might be a promising therapeutic target of HCC.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.004
      Issue No: Vol. 31 (2018)
  • Circulating Salivary miRNA hsa-miR-221 as Clinically Validated Diagnostic
           Marker for Hand, Foot, and Mouth Disease in Pediatric Patients

    • Authors: Nyo Min; Previtha Dawn Sakthi Vale; Anng Anng Wong; Natalie Woon Hui Tan; Chia Yin Chong; Chih-Jung Chen; Robert Y.L. Wang; Justin Jang Hann Chu
      Pages: 299 - 306
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Nyo Min, Previtha Dawn Sakthi Vale, Anng Anng Wong, Natalie Woon Hui Tan, Chia Yin Chong, Chih-Jung Chen, Robert Y.L. Wang, Justin Jang Hann Chu
      Enhancements in the diagnostic capabilities using host biomarkers are currently much needed where sensitivity and specificity issues plague the diagnosis of Hand, Foot and Mouth Disease (HFMD) in pediatrics clinical samples. We investigated miRNome profiles of HFMD saliva samples against healthy children and developed miRNA-based diagnosis models. Our 6-miRNA scoring model predicted HFMD with an overall accuracy of 85.11% in the training set and 92.86% in the blinded test set of Singapore cohort. Blinded evaluation of the model in Taiwan HFMD cases resulted in 77.08% accuracy with the 6-miRNA model and 68.75% with the 4-miRNA model. The strongest predictor of HFMD in all of the panels, hsa-miR-221 was found to be consistently and significantly downregulated in all of our HFMD cohorts. This is the first study to prove that HFMD infection could be diagnosed by circulating miRNAs in patient's saliva. Moreover, this study also serves as a stepping stone towards the future development of other infectious disease diagnosis workflows using novel biomarkers.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.006
      Issue No: Vol. 31 (2018)
  • Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and
           Immunity in α-Synuclein Aggregation Disorders

    • Authors: Scott Ugras; Malcolm J. Daniels; Hossein Fazelinia; Neal S. Gould; Anastasia K. Yocum; Kelvin C. Luk; Esteban Luna; Hua Ding; Chris McKennan; Steven Seeholzer; Dan Martinez; Perry Evans; Daniel Brown; John E. Duda; Harry Ischiropoulos
      Pages: 307 - 319
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      Author(s): Scott Ugras, Malcolm J. Daniels, Hossein Fazelinia, Neal S. Gould, Anastasia K. Yocum, Kelvin C. Luk, Esteban Luna, Hua Ding, Chris McKennan, Steven Seeholzer, Dan Martinez, Perry Evans, Daniel Brown, John E. Duda, Harry Ischiropoulos
      Accumulation of aggregated α-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson's disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how α-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of α-synuclein aggregation, 6% of 6215 proteins and 1.6% of 8183 phosphopeptides changed in abundance, indicating conservation of proteostasis and phosphorylation signaling. The proteomic analysis confirmed changes in abundance of proteins that regulate dopamine synthesis and transport, synaptic activity and integrity, and unearthed changes in mRNA binding, processing and protein translation. Phosphorylation signaling changes centered on axonal and synaptic cytoskeletal organization and structural integrity. Proteostatic responses included a significant increase in the levels of Lmp7, a component of the immunoproteasome. Increased Lmp7 levels and activity were also quantified in postmortem human brains with PD and dementia with Lewy bodies. Functionally, the immunoproteasome degrades α-synuclein aggregates and generates potentially antigenic peptides. Expression and activity of the immunoproteasome may represent testable targets to induce adaptive responses that maintain proteome integrity and modulate immune responses in protein aggregation disorders.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.007
      Issue No: Vol. 31 (2018)
  • 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
      First page: 320
      Abstract: Publication date: May 2018
      Source:EBioMedicine, Volume 31
      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: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.02.014
      Issue No: Vol. 31 (2018)
  • Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated
           with Lung Adenocarcinoma

    • Authors: Zhaoxi Wang; Yongyue Wei; Ruyang Zhang; Li Su; Stephanie M. Gogarten; Geoffrey Liu; Paul Brennan; John K. Field; James D. McKay; Jolanta Lissowska; Beata Swiatkowska; Vladimir Janout; Ciprian Bolca; Milica Kontic; Ghislaine Scelo; David Zaridze; Cathy C. Laurie; Kimberly F. Doheny; Elizabeth K. Pugh; Beth A. Marosy; Kurt N. Hetrick; Xiangjun Xiao; Claudio Pikielny; Rayjean J. Hung; Christopher I. Amos; Xihong Lin; David C. Christiani
      Abstract: Publication date: Available online 31 May 2018
      Author(s): Zhaoxi Wang, Yongyue Wei, Ruyang Zhang, Li Su, Stephanie M. Gogarten, Geoffrey Liu, Paul Brennan, John K. Field, James D. McKay, Jolanta Lissowska, Beata Swiatkowska, Vladimir Janout, Ciprian Bolca, Milica Kontic, Ghislaine Scelo, David Zaridze, Cathy C. Laurie, Kimberly F. Doheny, Elizabeth K. Pugh, Beth A. Marosy, Kurt N. Hetrick, Xiangjun Xiao, Claudio Pikielny, Rayjean J. Hung, Christopher I. Amos, Xihong Lin, David C. Christiani
      Recent technological advancements have permitted high-throughput measurement of the human genome, epigenome, metabolome, transcriptome, and proteome at the population level. We hypothesized that subsets of genes identified from omic studies might have closely related biological functions and thus might interact directly at the network level. Therefore, we conducted an integrative analysis of multi-omic datasets of non-small cell lung cancer (NSCLC) to search for association patterns beyond the genome and transcriptome. A large, complex, and robust gene network containing well-known lung cancer-related genes, including EGFR and TERT, was identified from combined gene lists for lung adenocarcinoma. Members of the hypoxia-inducible factor (HIF) gene family were at the center of this network. Subsequent sequencing of network hub genes within a subset of samples from the Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO) consortium revealed a SNP (rs12614710) in EPAS1 associated with NSCLC that reached genome-wide significance (OR = 1.50; 95% CI: 1.31–1.72; p = 7.75 × 10−9). Using imputed data, we found that this SNP remained significant in the entire TRICL-ILCCO consortium (p = .03). Additional functional studies are warranted to better understand interrelationships among genetic polymorphisms, DNA methylation status, and EPAS1 expression.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.024
  • Research Paper By Targeting Atg7 MicroRNA-143 Mediates Oxidative
           Stress-Induced Autophagy of c-Kit+ Mouse Cardiac Progenitor Cells

    • Authors: Wenya Fengzhi; Ding Xiuxiu Wang Huang Lai Zhang Chongwei Bingjie
      Abstract: Publication date: Available online 30 May 2018
      Author(s): Wenya Ma, Fengzhi Ding, Xiuxiu Wang, Qi Huang, Lai Zhang, Chongwei Bi, Bingjie Hua, Ye Yuan, Zhenbo Han, Mengyu Jin, Tianyi Liu, Ying Yu, Benzhi Cai, Zhimin Du
      Therapeutic efficiency of cardiac progenitor cells (CPCs) transplantation is limited by its low survival and retention in infarcted myocardium. Autophagy plays a critical role in regulating cell death and apoptosis, but the role of microRNAs (miRNAs) in oxidative stress-induced autophagy of CPCs remains unclear. This study aimed to explore if miRNAs mediate autophagy of c-kit+ CPCs. We found that the silencing of miR-143 promoted the autophagy of c-kit+ CPCs in response to H2O2, and the protective effect of miR-143 inhibitor was abrogated by autophagy inhibitor 3-methyladenine (3-MA). Furthermore, autophagy-related gene 7 (Atg7) was identified as the target gene of miR-143 by dual luciferase reporter assays. In vivo, after transfection with miR-143 inhibitor, c-kit+ CPCs from green fluorescent protein transgenic mice were more observed in infarcted mouse hearts. Moreover, transplantation of c-kit+ CPCs with miR-143 inhibitor improved cardiac function after myocardial infarction. Take together, our study demonstrated that miR-143 mediates oxidative stress-induced autophagy to enhance the survival of c-kit+ CPCs by targeting Atg7, which will provide a complementary approach for improving CPC-based heart repair.

      PubDate: 2018-05-31T15:37:00Z
  • Takeda G Protein-Coupled Receptor 5-Mechanistic Target of Rapamycin
           Complex 1 Signaling Contributes to the Increment of Glucagon-Like
           Peptide-1 Production after Roux-en-Y Gastric Bypass

    • Authors: Hening Zhai; Zhi Li; Miao Peng; Zhaoqi Huang; Tingfeng Qin; Linxi Chen; Hanbing Li; Heng Zhang; Weizhen Zhang; Geyang Xu
      Abstract: Publication date: Available online 30 May 2018
      Author(s): Hening Zhai, Zhi Li, Miao Peng, Zhaoqi Huang, Tingfeng Qin, Linxi Chen, Hanbing Li, Heng Zhang, Weizhen Zhang, Geyang Xu
      Background The mechanism by which Roux-en-Y Gastric Bypass (RYGB) increases the secretion of glucagon-like peptide-1 (GLP-1) remains incompletely defined. Here we investigated whether TGR5-mTORC1 signaling mediates the RYGB-induced alteration in GLP-1 production in mice and human beings. Methods Circulating bile acids, TGR5-mTORC1 signaling, GLP-1 synthesis and secretion were determined in lean or obese male C57BL/6 mice with or without RYGB operation, as well as in normal glycemic subjects, obese patients with type 2 diabetes before and after RYGB. Results Positive relationships were observed among circulating bile acids, ileal mechanistic target of rapamycin complex 1 (mTORC1) signaling and GLP-1 during changes in energy status in the present study. RYGB increased circulating bile acids, ileal Takeda G protein-coupled receptor 5 (TGR5) and mTORC1 signaling activity, as well as GLP-1 production in both mice and human subjects. Inhibition of ileal mTORC1 signaling by rapamycin significantly attenuated the stimulation of bile acid secretion, TGR5 expression and GLP-1 synthesis induced by RYGB in lean and diet-induced obese mice. GLP-1 production and ileal TGR5-mTORC1 signaling were positively correlated with plasma deoxycholic acid (DCA) in mice. Treatment of STC-1 cells with DCA stimulated the production of GLP-1. This effect was associated with a significant enhancement of TGR5-mTORC1 signaling. siRNA knockdown of mTORC1 or TGR5 abolished the enhancement of GLP-1 synthesis induced by DCA. DCA increased interaction between mTOR-regulatory-associated protein of mechanistic target of rapamycin (Raptor) and TGR5 in STC-1 cells. Interpretation Deoxycholic acid-TGR5-mTORC1 signaling contributes to the up-regulation of GLP-1 production after RYGB.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.026
  • Identifying Circulating Tumor DNA Mutation Profiles in Metastatic Breast
           Cancer Patients with Multiline Resistance

    • Authors: Zhe-Yu Hu; Ning Xie; Can Tian; Xiaohong Yang; Liping Liu; Jing Li; Huawu Xiao; Hui Wu; Jun Lu; Jianxiang Gao; Xuming Hu; Min Cao; Zhengrong Shui; Mengjia Xiao; Yu Tang; Qiongzhi He; Lianpeng Chang; Xuefeng Xia; Xin Yi; Qianjin Liao; Quchang Ouyang
      Abstract: Publication date: Available online 26 May 2018
      Author(s): Zhe-Yu Hu, Ning Xie, Can Tian, Xiaohong Yang, Liping Liu, Jing Li, Huawu Xiao, Hui Wu, Jun Lu, Jianxiang Gao, Xuming Hu, Min Cao, Zhengrong Shui, Mengjia Xiao, Yu Tang, Qiongzhi He, Lianpeng Chang, Xuefeng Xia, Xin Yi, Qianjin Liao, Quchang Ouyang
      Purpose In cancer patients, tumor gene mutations contribute to drug resistance and treatment failure. In patients with metastatic breast cancer (MBC), these mutations increase after multiline treatment, thereby decreasing treatment efficiency. The aim of this study was to evaluate gene mutation patterns in MBC patients to predict drug resistance and disease progression. Method A total of 68 MBC patients who had received multiline treatment were recruited. Circulating tumor DNA (ctDNA) mutations were evaluated and compared among hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) subgroups. Results The baseline gene mutation pattern (at the time of recruitment) varied among HR/HER2 subtypes. BRCA1 and MED12 were frequently mutated in triple negative breast cancer (TNBC) patients, PIK3CA and FAT1 mutations were frequent in HR+ patients, and PIK3CA and ERBB2 mutations were frequent in HER2+ patients. Gene mutation patterns also varied in patients who progressed within either 3 months or 3–6 months of chemotherapy treatment. For example, in HR+ patients who progressed within 3 months of treatment, the frequency of TERT mutations significantly increased. Other related mutations included FAT1 and NOTCH4. In HR+ patients who progressed within 3–6 months, PIK3CA, TP53, MLL3, ERBB2, NOTCH2, and ERS1 were the candidate mutations. This suggests that different mechanisms underlie disease progression at different times after treatment initiation. In the COX model, the ctDNA TP53 + PIK3CA gene mutation pattern successfully predicted progression within 6 months. Conclusion ctDNA gene mutation profiles differed among HR/HER2 subtypes of MBC patients. By identifying mutations associated with treatment resistance, we hope to improve therapy selection for MBC patients who received multiline treatment.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.015
  • Mesenchymal Stromal Cells Directly Promote Inflammation by Canonical NLRP3
           and Non-canonical Caspase-11 Inflammasomes

    • Authors: Yaozhen Chen; Xiangyang Qin; Qunxing An; Jing Yi; Fan Feng; Dandan Yin; Ning An; Zheng Liu; Lihong Weng; Shouwen Chen; Xingbin Hu; Wen Yin
      Abstract: Publication date: Available online 26 May 2018
      Author(s): Yaozhen Chen, Xiangyang Qin, Qunxing An, Jing Yi, Fan Feng, Dandan Yin, Ning An, Zheng Liu, Lihong Weng, Shouwen Chen, Xingbin Hu, Wen Yin
      Mesenchymal stromal cells (MSCs) based therapy is a promising approach to treat inflammatory disorders. However, therapeutic effect is not always achieved. Thus the mechanism involved in inflammation requires further elucidation. To explore the mechanisms by which MSCs respond to inflammatory stimuli, we investigated whether MSCs employed inflammasomes to participate in inflammation. Using in vitro and in vivo models, we found that canonical NLRP3 and non-canonical caspase-11 inflammasomes were activated in bone-associated MSCs (BA-MSCs) to promote the inflammatory response. The NLRP3 inflammasome was activated to mainly elicit IL-1β/18 release, whereas the caspase-11 inflammasome managed pyroptosis. Furthermore, we sought a small molecule component (66PR) to inhibit the activation of inflammasomes in BA-MSCs, which consequently improved their survival and therapeutic potential in inflammation bowel diseases. These current findings indicated that MSCs themselves could directly promote the inflammatory response by an inflammasome-dependent pathway. Our observations suggested that inhibition of the proinflammatory property may improve MSCs utilization in inflammatory disorders.
      Graphical abstract image

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.023
  • Inhibition of Microsomal Prostaglandin E Synthase-1 in Cancer-Associated
           Fibroblasts Suppresses Neuroblastoma Tumor Growth

    • Authors: Anna Kock; Karin Larsson; Filip Bergqvist; Nina Eissler; Lotta H.M. Elfman; Joan Raouf; Marina Korotkova; John Inge Johnsen; Per-Johan Jakobsson; Per Kogner
      Abstract: Publication date: Available online 24 May 2018
      Author(s): Anna Kock, Karin Larsson, Filip Bergqvist, Nina Eissler, Lotta H.M. Elfman, Joan Raouf, Marina Korotkova, John Inge Johnsen, Per-Johan Jakobsson, Per Kogner
      Despite recent progress in diagnosis and treatment, survival for children with high-risk metastatic neuroblastoma is still poor. Prostaglandin E2 (PGE2)-driven inflammation promotes tumor growth, immune suppression, angiogenesis and resistance to established cancer therapies. In neuroblastoma, cancer-associated fibroblasts (CAFs) residing in the tumor microenvironment are the primary source of PGE2. However, clinical targeting of PGE2 with current non-steroidal anti-inflammatory drugs or cyclooxygenase inhibitors has been limited due to risk of adverse side effects. By specifically targeting microsomal prostaglandin E synthase-1 (mPGES-1) activity with a small molecule inhibitor we could block CAF-derived PGE2 production leading to reduced tumor growth, impaired angiogenesis, inhibited CAF migration and infiltration, reduced tumor cell proliferation and a favorable shift in the M1/M2 macrophage ratio. In this study, we provide proof-of-principle of the benefits of targeting mPGES-1 in neuroblastoma, applicable to a wide variety of tumors. This non-toxic single drug treatment targeting infiltrating stromal cells opens up for combination treatment options with established cancer therapies.
      Graphical abstract image

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.008
  • TP53 Mutation as Potential Negative Predictor for Response of Anti-CTLA-4
           Therapy in Metastatic Melanoma

    • Authors: Wenjing Xiao; Nan Du; Taoyuan Huang; Jinan Guo; Xingkui Mo; Tao Yuan; Yong Chen; Ting Ye; Chunwei Xu; Wenxian Wang; Guoqiang Wang; Shangli Cai; Jing Chen
      Abstract: Publication date: Available online 22 May 2018
      Author(s): Wenjing Xiao, Nan Du, Taoyuan Huang, Jinan Guo, Xingkui Mo, Tao Yuan, Yong Chen, Ting Ye, Chunwei Xu, Wenxian Wang, Guoqiang Wang, Shangli Cai, Jing Chen
      TP53 has been proved to be associated with cytotoxic T-cell induced apoptosis, however, the association between TP53 and the benefit of immunotherapy in melanoma has not been studied. In the present study, we examined the relationship between TP53 mutation and response to CTLA-4 blockade in metastatic melanoma by analyzing the data from one public cohort consisting of 110 patients with metastatic melanoma. The sequencing, mRNA and survival data of 368 patients with skin melanoma from The Cancer Genome Atlas (TCGA) was used to explore the underlying mechanism. TP53 mutation was associated with significant poorer progression-free survival (HR, 2.25; 95% CI, 1.15–4.37; P = 0.014), poorer overall survival (HR, 2.05; 95% CI, 1.02–4.13; P = 0.040) and trend of poorer response (OR, 0.20; 95% CI, 0.02–1.62; P = 0.131). The correlations were significant in multivariate analysis including lactate dehydrogenase, tumor mutational burden and tumor stage (P < 0.05). In TCGA, no association was observed between TP53 mutation and survival (P = 0.55). The mRNA expression of FAS was lower in patients with TP53 mutation than TP53 wild-type. Our findings suggest that TP53 mutation is a potential negative predictor of metastatic melanoma treated with CTLA-4 blockade.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.019
  • Model Animal Mimicking Human Virus-induced Diabetes

    • Authors: Keiichiro Mine; Hirokazu Takahashi; Seiho Nagafuchi
      Abstract: Publication date: Available online 19 May 2018
      Author(s): Keiichiro Mine, Hirokazu Takahashi, Seiho Nagafuchi

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.018
  • Liver Imaging in Precision Medicine

    • Authors: Jiahong Dong; Xiaolong Qi
      Abstract: Publication date: Available online 18 May 2018
      Author(s): Jiahong Dong, Xiaolong Qi

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.017
  • Plasma Circulating Extracellular RNAs in Left Ventricular Remodeling
           Post-Myocardial Infarction

    • Authors: Kirsty M. Danielson; Ravi Shah; Ashish Yeri; Xiaojun Liu; Fernando Camacho Garcia; Michael Silverman; Kahraman Tanriverdi; Avash Das; Chunyang Xiao; Michael Jerosch-Herold; Bobak Heydari; Siddique Abbasi; Kendall Van Keuren-Jensen; Jane E. Freedman; Yaoyu E. Wang; Anthony Rosenzweig; Raymond Y. Kwong; Saumya Das
      Abstract: Publication date: Available online 18 May 2018
      Author(s): Kirsty M. Danielson, Ravi Shah, Ashish Yeri, Xiaojun Liu, Fernando Camacho Garcia, Michael Silverman, Kahraman Tanriverdi, Avash Das, Chunyang Xiao, Michael Jerosch-Herold, Bobak Heydari, Siddique Abbasi, Kendall Van Keuren-Jensen, Jane E. Freedman, Yaoyu E. Wang, Anthony Rosenzweig, Raymond Y. Kwong, Saumya Das
      Despite substantial declines in mortality following myocardial infarction (MI), subsequent left ventricular remodeling (LVRm) remains a significant long-term complication. Extracellular small non-coding RNAs (exRNAs) have been associated with cardiac inflammation and fibrosis and we hypothesized that they are associated with post-MI LVRm phenotypes. RNA sequencing of exRNAs was performed on plasma samples from patients with “beneficial” (decrease LVESVI ≥ 20%, n = 11) and “adverse” (increase LVESVI ≥ 15%, n = 11) LVRm. Selected differentially expressed exRNAs were validated by RT-qPCR (n = 331) and analyzed for their association with LVRm determined by cardiac MRI. Principal components of exRNAs were associated with LVRm phenotypes post-MI; specifically, LV mass, LV ejection fraction, LV end systolic volume index, and fibrosis. We then investigated the temporal regulation and cellular origin of exRNAs in murine and cell models and found that: 1) plasma and tissue miRNA expression was temporally regulated; 2) the majority of the miRNAs were increased acutely in tissue and at sub-acute or chronic time-points in plasma; 3) miRNA expression was cell-specific; and 4) cardiomyocytes release a subset of the identified miRNAs packaged in exosomes into culture media in response to hypoxia/reoxygenation. In conclusion, we find that plasma exRNAs are temporally regulated and are associated with measures of post-MI LVRm.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.013
  • Recellularization of Decellularized Venous Grafts Using Peripheral Blood:
           A Critical Evaluation

    • Authors: Mia H. Rambøl; Jonny Hisdal; Jon O. Sundhagen; Jan E. Brinchmann; Antonio Rosales
      Abstract: Publication date: Available online 17 May 2018
      Author(s): Mia H. Rambøl, Jonny Hisdal, Jon O. Sundhagen, Jan E. Brinchmann, Antonio Rosales
      Vascular disease is a major cause of death worldwide, and the growing need for replacement vessels is not fully met by autologous grafts or completely synthetic alternatives. Tissue engineering has emerged as a compelling strategy for the creation of blood vessels for reconstructive surgeries. One promising method to obtain a suitable vessel scaffold is decellularization of donor vascular tissue followed by recellularization with autologous cells. To prevent thrombosis of vascular grafts, a confluent and functional autologous endothelium is required, and researchers are still looking for the optimal cell source and recellularization procedure. Recellularization of a decellularized scaffold with only a small volume of whole blood was recently put forward as a feasible option. Here we show that, in contrast to the published results, this method fails to re-endothelialize decellularized veins. Only occasional nucleated cells were seen on the luminal surface of the scaffolds. Instead, we saw fibrin threads, platelets and scattered erythrocytes. Molecular remnants of the endothelial cells were still attached to the scaffold, which explains in part why earlier results were misinterpreted. Decellularized vascular tissues may still be the best scaffolds available for vascular tissue engineering. However, for the establishment of an adequate autologous endothelial lining, methods other than exposure to autologous whole blood need to be developed.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.012
  • Patients with Concurrent Tuberculosis and Diabetes Have a Pro-Atherogenic
           Plasma Lipid Profile

    • Authors: Frank Vrieling; Katharina Ronacher; Léanie Kleynhans; Erik van den Akker; Gerhard Walzl; Tom H.M. Ottenhoff; Simone A. Joosten
      Abstract: Publication date: Available online 17 May 2018
      Author(s): Frank Vrieling, Katharina Ronacher, Léanie Kleynhans, Erik van den Akker, Gerhard Walzl, Tom H.M. Ottenhoff, Simone A. Joosten
      Background Type 2 diabetes mellitus (DM) is a major risk factor for development of tuberculosis (TB), however the underlying molecular foundations are unclear. Since lipids play a central role in the development of both DM and TB, lipid metabolism may be important for TB-DM pathophysiology. Methods A 1H NMR spectroscopy-based platform was used to determine 225 lipid and other metabolic intermediates in plasma samples of healthy controls (n = 50) and patients with TB (n = 50), DM (n = 50) or TB-DM (n = 27). Results TB patients presented with wasting disease, represented by decreased amino acid levels including histidine and alanine. Conversely, DM patients were dyslipidemic as evidenced by high levels of very low-density lipoprotein triglycerides and low high-density lipoprotein cholesterol. TB-DM patients displayed metabolic characteristics of both wasting and dyslipidemia combined with disease interaction-specific increases in phospholipid metabolites (e.g. sphingomyelins) and atherogenic remnant-like lipoprotein particles. Biomarker analysis identified the ratios of phenylalanine/histidine and esterified cholesterol/sphingomyelin as markers for TB classification regardless of DM-status. Conclusions TB-DM patients possess a distinctive plasma lipid profile with pro-atherogenic properties. These findings support further research on the benefits of improved blood lipid control in the treatment of TB-DM.

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.011
  • The Promising Role of New Generation HDACis in Anti-Cancer Therapies

    • Authors: Eric Hervouet
      Abstract: Publication date: Available online 11 May 2018
      Author(s): Eric Hervouet

      PubDate: 2018-05-31T15:37:00Z
      DOI: 10.1016/j.ebiom.2018.05.014
  • Development and Validation of a 28-gene Hypoxia-related Prognostic
           Signature for Localized Prostate Cancer

    • Authors: Lingjian Yang; Darren Roberts Mandeep Takhar Nicholas Erho Becky A.S.
      Abstract: Publication date: Available online 23 April 2018
      Author(s): Lingjian Yang, Darren Roberts, Mandeep Takhar, Nicholas Erho, Becky A.S. Bibby, Niluja Thiruthaneeswaran, Vinayak Bhandari, Wei-Chen Cheng, Syed Haider, Amy M.B. McCorry, Darragh McArt, Suneil Jain, Mohammed Alshalalfa, Ashley Ross, Edward Schaffer, Robert B. Den, R. Jeffrey Karnes, Eric Klein, Peter J. Hoskin, Stephen J. Freedland, Alastair D. Lamb, David E. Neal, Francesca M. Buffa, Robert G. Bristow, Paul C. Boutros, Elai Davicioni, Ananya Choudhury, Catharine M.L. West
      Background Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer. Method Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). Results A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P < .05), with borderline significances achieved in the other two (P < .1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P = .007) or definitive radiotherapy alone (n = 248, P = .035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P = .002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P = .0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours. Conclusion A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.

      PubDate: 2018-04-25T09:27:06Z
  • Lighting a Fire in the Tumor Microenvironment Using Oncolytic

    • Authors: Carole Achard; Abera Surendran; Marie-Eve Wedge; Guy Ungerechts; John Bell; Carolina S. Ilkow
      Abstract: Publication date: Available online 23 April 2018
      Author(s): Carole Achard, Abera Surendran, Marie-Eve Wedge, Guy Ungerechts, John Bell, Carolina S. Ilkow
      Oncolytic virus (OV) therapy is potentially a game-changing cancer treatment that has garnered significant interest due to its versatility and multi-modal approaches towards tumor eradication. In the field of cancer immunotherapy, the immunological phenotype of the tumor microenvironment (TME) is an important determinant of disease prognosis and therapeutic success. There is accumulating data that OVs are capable of dramatically altering the TME immune landscape, leading to improved antitumor activity alone or in combination with assorted immune modulators. Herein, we review how OVs disrupt the immunosuppressive TME and can be used strategically to create a “pro-immune” microenvironment that enables and promotes potent, long-lasting host antitumor immune responses.

      PubDate: 2018-04-25T09:27:06Z
      DOI: 10.1016/j.ebiom.2018.04.020
  • Mass Spectrometric Identification of Urinary Biomarkers of Pulmonary

    • Authors: Flonza Isa; Sean Collins; Myung Hee Lee; Diessy Decome; Nancy Dorvil; Patrice Joseph; Lauren Smith; Stephen Salerno; Martin T. Wells; Steven Fischer; James M. Bean; Jean W. Pape; Warren D. Johnson; Daniel W. Fitzgerald; Kyu Y. Rhee
      Abstract: Publication date: Available online 22 April 2018
      Author(s): Flonza Isa, Sean Collins, Myung Hee Lee, Diessy Decome, Nancy Dorvil, Patrice Joseph, Lauren Smith, Stephen Salerno, Martin T. Wells, Steven Fischer, James M. Bean, Jean W. Pape, Warren D. Johnson, Daniel W. Fitzgerald, Kyu Y. Rhee
      Background Tuberculosis (TB) is the leading infectious cause of death worldwide. A major barrier to control of the pandemic is a lack of clinical biomarkers with the ability to distinguish active TB from healthy and sick controls and potential for development into point-of-care diagnostics. Methods We conducted a prospective case control study to identify candidate urine-based diagnostic biomarkers of active pulmonary TB (discovery cohort) and obtained a separate blinded “validation” cohort of confirmed cases of active pulmonary TB and controls with non-tuberculous pulmonary disease for validation. Clean-catch urine samples were collected and analyzed using high performance liquid chromatography-coupled time-of-flight mass spectrometry. Results We discovered ten molecules from the discovery cohort with receiver-operator characteristic (ROC) area-under-the-curve (AUC) values >85%. These 10 molecules also significantly decreased after 60 days of treatment in a subset of 20 participants followed over time. Of these, a specific combination of diacetylspermine, neopterin, sialic acid, and, N-acetylhexosamine exhibited ROC AUCs >80% in a blinded validation cohort of participants with active TB and non-tuberculous pulmonary disease. Conclusion Urinary levels of diacetylspermine, neopterin, sialic acid and, N-acetylhexosamine distinguished patients with tuberculosis from healthy controls and patients with non-tuberculous pulmonary diseases, providing a potential noninvasive biosignature of active TB. Funding sources This study was funded by Weill Cornell Medicine, the Weill Medical College T32 training grant, the Clinical and Translational Science Center at Weill Cornell, the NIH Fogarty International Center grants and, the NIH Tuberculosis Research Unit (Tri-I TBRU).

      PubDate: 2018-04-25T09:27:06Z
      DOI: 10.1016/j.ebiom.2018.04.014
  • Therapeutic Injury and Tumor Regrowth: Tumor Resection and Radiation
           Establish the Recurrent Glioblastoma Microenvironment

    • Authors: Daniel J. Silver; Justin D. Lathia
      Abstract: Publication date: Available online 20 April 2018
      Author(s): Daniel J. Silver, Justin D. Lathia

      PubDate: 2018-04-25T09:27:06Z
      DOI: 10.1016/j.ebiom.2018.04.016
  • Vitamin D as a Potential Therapeutic Target and Prognostic Marker for
           Colorectal Cancer

    • Authors: Vasile V. Bintintan
      Abstract: Publication date: Available online 19 April 2018
      Author(s): Vasile V. Bintintan

      PubDate: 2018-04-25T09:27:06Z
      DOI: 10.1016/j.ebiom.2018.04.015
  • The Engagement Between Vitamin D and the Immune System: Is Consolidation
           by a Marriage to Be Expected'

    • Authors: Jan Damoiseaux; Joost Smolders
      Abstract: Publication date: Available online 18 April 2018
      Author(s): Jan Damoiseaux, Joost Smolders

      PubDate: 2018-04-25T09:27:06Z
      DOI: 10.1016/j.ebiom.2018.04.013
  • Replication of a Gene-Diet Interaction at CD36, NOS3 and PPARG in Response
           to Omega-3 Fatty Acid Supplements on Blood Lipids: A Double-Blind
           Randomized Controlled Trial

    • Authors: Ju-Sheng Zheng; Jiewen Chen; Ling Wang; Hong Yang; Ling Fang; Ying Yu; Liping Yuan; Jueping Feng; Kelei Li; Jun Tang; Mei Lin; Chao-Qiang Lai; Duo Li
      Abstract: Publication date: Available online 17 April 2018
      Author(s): Ju-Sheng Zheng, Jiewen Chen, Ling Wang, Hong Yang, Ling Fang, Ying Yu, Liping Yuan, Jueping Feng, Kelei Li, Jun Tang, Mei Lin, Chao-Qiang Lai, Duo Li
      Background Modulation of genetic variants on the effect of omega-3 fatty acid supplements on blood lipids is still unclear. Methods In a double-blind randomized controlled trial, 150 patients with type 2 diabetes (T2D) were randomized into omega-3 fatty acid group (n = 56 for fish oil and 44 for flaxseed oil) and control group (n = 50) for 180 days. All patients were genotyped for genetic variants at CD36 (rs1527483), NOS3 (rs1799983) and PPARG (rs1801282). Linear regression was used to examine the interaction between omega-3 fatty acid intervention and CD36, NOS3 or PPARG variants for blood lipids. Findings Significant interaction with omega-3 fatty acid supplements was observed for CD36 on triglycerides (p-interaction = 0.042) and PPAGR on low-density lipoprotein-cholesterol (p-interaction = 0.02). We also found a significant interaction between change in erythrocyte phospholipid omega-3 fatty acid composition and NOS3 genotype on triglycerides (p-interaction = 0.042), total cholesterol (p-interaction = 0.013) and ratio of total cholesterol to high-density lipoprotein cholesterol (p-interaction = 0.015). The T2D patients of CD36-G allele, PPARG-G allele and NOS3-A allele tended to respond better to omega-3 fatty acids in improving lipid profiles. The interaction results of the omega-3 fatty acid group were mainly attributed to the fish oil supplements. Interpretation This study suggests that T2D patients with different genotypes at CD36, NOS3 and PPARG respond differentially to intervention of omega-3 supplements in blood lipid profiles.

      PubDate: 2018-04-25T09:27:06Z
      DOI: 10.1016/j.ebiom.2018.04.012
  • Tandem Repeats and Repeatomes: Delving Deeper into the ‘Dark
           Matter’ of Genomes

    • Authors: Anthony J. Hannan
      Abstract: Publication date: Available online 14 April 2018
      Author(s): Anthony J. Hannan

      PubDate: 2018-04-15T15:21:08Z
      DOI: 10.1016/j.ebiom.2018.04.004
  • Integrative (epi) Genomic Analysis to Predict Response to
           Androgen-Deprivation Therapy in Prostate Cancer

    • Authors: Sukanya Panja; Sheida Hayati; Nusrat J. Epsi; James Scott Parrott; Antonina Mitrofanova
      Abstract: Publication date: Available online 12 April 2018
      Author(s): Sukanya Panja, Sheida Hayati, Nusrat J. Epsi, James Scott Parrott, Antonina Mitrofanova
      Therapeutic resistance is a central problem in clinical oncology. We have developed a systematic genome-wide computational methodology to allow prioritization of patients with favorable and poor therapeutic response. Our method, which integrates DNA methylation and mRNA expression data, uncovered a panel of 5 differentially methylated sites, which explain expression changes in their site-harboring genes, and demonstrated their ability to predict primary resistance to androgen-deprivation therapy (ADT) in the TCGA prostate cancer patient cohort (hazard ratio = 4.37). Furthermore, this panel was able to accurately predict response to ADT across independent prostate cancer cohorts and demonstrated that it was not affected by Gleason, age, or therapy subtypes. We propose that this panel could be utilized to prioritize patients who would benefit from ADT and patients at risk of resistance that should be offered an alternative regimen. Such approach holds a long-term objective to build an adaptable accurate platform for precision therapeutics.

      PubDate: 2018-04-15T15:21:08Z
      DOI: 10.1016/j.ebiom.2018.04.007
  • Salmonella Typhi Colonization Provokes Extensive Transcriptional Changes
           Aimed at Evading Host Mucosal Immune Defense During Early Infection of
           Human Intestinal Tissue

    • Authors: K.P. Nickerson; S. Senger; Y. Zhang; R. Lima; S. Patel; L. Ingano; W.A. Flavahan; D.K.V. Kumar; C.M. Fraser; C.S. Faherty; M.B. Sztein; M. Fiorentino; A. Fasano
      Abstract: Publication date: Available online 12 April 2018
      Author(s): K.P. Nickerson, S. Senger, Y. Zhang, R. Lima, S. Patel, L. Ingano, W.A. Flavahan, D.K.V. Kumar, C.M. Fraser, C.S. Faherty, M.B. Sztein, M. Fiorentino, A. Fasano
      Commensal microorganisms influence a variety of host functions in the gut, including immune response, glucose homeostasis, metabolic pathways and oxidative stress, among others. This study describes how Salmonella Typhi, the pathogen responsible for typhoid fever, uses similar strategies to escape immune defense responses and survive within its human host. To elucidate the early mechanisms of typhoid fever, we performed studies using healthy human intestinal tissue samples and “mini-guts,” organoids grown from intestinal tissue taken from biopsy specimens. We analyzed gene expression changes in human intestinal specimens and bacterial cells both separately and after colonization. Our results showed mechanistic strategies that S. Typhi uses to rearrange the cellular machinery of the host cytoskeleton to successfully invade the intestinal epithelium, promote polarized cytokine release and evade immune system activation by downregulating genes involved in antigen sampling and presentation during infection. This work adds novel information regarding S. Typhi infection pathogenesis in humans, by replicating work shown in traditional cell models, and providing new data that can be applied to future vaccine development strategies.

      PubDate: 2018-04-15T15:21:08Z
      DOI: 10.1016/j.ebiom.2018.04.005
  • Reduced Cortical Excitability, Neuroplasticity, and Salivary Cortisol in
           11–13-Year-Old Children Born to Women with Gestational Diabetes Mellitus

    • Authors: Jago M. Van Dam; Amy J. Garrett; Luke A. Schneider; Nicolette A. Hodyl; Mitchell R. Goldsworthy; Suzette Coat; Janet A. Rowan; William M. Hague; Julia B. Pitcher
      Abstract: Publication date: Available online 10 April 2018
      Author(s): Jago M. Van Dam, Amy J. Garrett, Luke A. Schneider, Nicolette A. Hodyl, Mitchell R. Goldsworthy, Suzette Coat, Janet A. Rowan, William M. Hague, Julia B. Pitcher
      Background Children exposed to gestational diabetes mellitus (GDM) in utero are at increased risk of neurodevelopmental difficulties, including autism and impaired motor control. However, the underlying neurophysiology is unknown. Methods Using transcranial magnetic stimulation, we assessed cortical excitability, long-term depression (LTD)-like neuroplasticity in 45 GDM-exposed and 12 control children aged 11–13 years. Data were analysed against salivary cortisol and maternal diabetes severity and treatment (insulin [N = 22] or metformin [N = 23]) during pregnancy. Findings GDM-exposed children had reduced cortical excitability (p = .003), LTD-like neuroplasticity (p = .005), and salivary cortisol (p < .001) when compared with control children. Higher maternal insulin resistance (IR) before and during GDM treatment was associated with a blunted neuroplastic response in children (p = .014) and this was not accounted for by maternal BMI. Additional maternal and neonatal measures, including fasting plasma glucose and inflammatory markers, predicted neurophysiological outcomes. The metformin and insulin treatment groups had similar outcomes. Interpretation These results suggest that GDM can contribute to subtle differences in child neurophysiology, and possibly cortisol secretion, persisting into early adolescence. Importantly, these effects appear to occur during second trimester, before pharmacologic treatment typically commences, and can be predicted by maternal insulin resistance. Therefore, earlier detection and treatment of GDM may be warranted. Metformin appears to be safe for these aspects of neurodevelopment.

      PubDate: 2018-04-15T15:21:08Z
      DOI: 10.1016/j.ebiom.2018.04.011
  • Genomic Response to Vitamin D Supplementation in the Setting of a
           Randomized, Placebo-controlled Trial

    • Authors: Antonio J. Berlanga-Taylor; Katharine Plant; Andrew Dahl; Evelyn Lau; Michael Hill; David Sims; Andreas Heger; Jonathan Emberson; Jane Armitage; Robert Clarke; Julian C. Knight
      Abstract: Publication date: Available online 10 April 2018
      Author(s): Antonio J. Berlanga-Taylor, Katharine Plant, Andrew Dahl, Evelyn Lau, Michael Hill, David Sims, Andreas Heger, Jonathan Emberson, Jane Armitage, Robert Clarke, Julian C. Knight
      Background Vitamin D deficiency has been associated with multiple diseases, but the causal relevance and underlying processes are not fully understood. Elucidating the mechanisms of action of drug treatments in humans is challenging, but application of functional genomic approaches in randomized trials may afford an opportunity to systematically assess molecular responses. Methods In the Biochemical Efficacy and Safety Trial of Vitamin D (BEST-D), a double-blind, placebo-controlled, dose-finding, randomized clinical trial, 305 community-dwelling individuals aged over 65 years were randomly allocated to treatment with vitamin D3 4000 IU, 2000 IU or placebo daily for 12 months. Genome-wide genotypes at baseline, and transcriptome and plasma levels of cytokines (IFN-γ, IL-10, IL-8, IL-6 and TNF-α) at baseline and after 12 months, were measured. The trial had >90% power to detect 1.2-fold changes in gene expression. Findings Allocation to vitamin D for 12-months was associated with 2-fold higher plasma levels of 25-hydroxy-vitamin D (25[OH]D, 4000 IU regimen), but had no significant effect on whole-blood gene expression (FDR < 5%) or on plasma levels of cytokines compared with placebo. In pre-specified analysis, rs7041 (intron variant, GC) had a significant effect on circulating levels of 25(OH)D in the low dose, but not on the placebo or high dose vitamin D regimen. A gene expression quantitative trait locus analysis (eQTL) demonstrated evidence of 31,568 cis-eQTLs (unique SNP-probe pairs) among individuals at baseline and 34,254 after supplementation for 12 months (any dose). No significant associations involving vitamin D supplementation response eQTLs were found. Interpretation We performed a comprehensive functional genomics and molecular analysis of vitamin D supplementation in a randomized, placebo-controlled trial. Although this study was limited to mostly Caucasian individuals aged over 65 years, the results differ from many previous studies and do not support a strong effect of vitamin D on long-term transcriptomic changes in blood or on plasma cytokine levels. The trial demonstrates the feasibility of applying functional genomic and genetic approaches in randomized trials to assess molecular and individual level responses. Key Result Supplementation with high-dose vitamin D in older people for 12 months in a randomized, placebo-controlled trial had no significant effect on gene expression or on plasma concentrations of selected cytokines. Trial Registration SRCTN registry (Number 07034656) and the European Clinical Trials Database (EudraCT Number 2011-005763-24).

      PubDate: 2018-04-15T15:21:08Z
      DOI: 10.1016/j.ebiom.2018.04.010
  • Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers
           Cholesterol in Rodent and Primate Preclinical Models

    • Authors: Ryan M. Esquejo; Christopher T. Salatto; Jake Delmore; Bina Albuquerque; Allan Reyes; Yuji Shi; Rob Moccia; Emily Cokorinos; Matthew Peloquin; Mara Monetti; Jason Barricklow; Eliza Bollinger; Brennan K. Smith; Emily A. Day; Chuong Nguyen; Kieran F. Geoghegan; John M. Kreeger; Alan Opsahl; Jessica Ward; Amit S. Kalgutkar; David Tess; Lynne Butler; Norimitsu Shirai; Timothy F. Osborne; Gregory R. Steinberg; Morris J. Birnbaum; Kimberly O. Cameron; Russell A. Miller
      Abstract: Publication date: Available online 8 April 2018
      Author(s): Ryan M. Esquejo, Christopher T. Salatto, Jake Delmore, Bina Albuquerque, Allan Reyes, Yuji Shi, Rob Moccia, Emily Cokorinos, Matthew Peloquin, Mara Monetti, Jason Barricklow, Eliza Bollinger, Brennan K. Smith, Emily A. Day, Chuong Nguyen, Kieran F. Geoghegan, John M. Kreeger, Alan Opsahl, Jessica Ward, Amit S. Kalgutkar, David Tess, Lynne Butler, Norimitsu Shirai, Timothy F. Osborne, Gregory R. Steinberg, Morris J. Birnbaum, Kimberly O. Cameron, Russell A. Miller
      Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a treatment for metabolic diseases; we show that the AMPK β1-biased activator PF-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclinical models. PF-06409577 is able to inhibit de novo lipid and cholesterol synthesis pathways, and causes a reduction in hepatic lipids and mRNA expression of markers of hepatic fibrosis. These effects require AMPK activity in the hepatocytes. Treatment of hyperlipidemic rats or cynomolgus monkeys with PF-06409577 for 6 weeks resulted in a reduction in circulating cholesterol. Together these data suggest that activation of AMPK β1 complexes with PF-06409577 is capable of impacting multiple facets of liver disease and represents a promising strategy for the treatment of NAFLD and NASH in humans.

      PubDate: 2018-04-15T15:21:08Z
      DOI: 10.1016/j.ebiom.2018.04.009
  • Preoperative Prediction of Node Metastases in Bladder Cancer Patients
           Using Genomic and Clinicopathologic Data

    • Authors: Marco Moschini; Francesco Montorsi
      Abstract: Publication date: Available online 7 April 2018
      Author(s): Marco Moschini, Francesco Montorsi

      PubDate: 2018-04-15T15:21:08Z
      DOI: 10.1016/j.ebiom.2018.04.006
  • Microbial Effects on Immunity in HIV: Virus, Gender or Sexual Preference

    • Authors: Nichole R. Klatt; Jennifer A. Manuzak
      Abstract: Publication date: Available online 7 April 2018
      Author(s): Nichole R. Klatt, Jennifer A. Manuzak

      PubDate: 2018-04-15T15:21:08Z
      DOI: 10.1016/j.ebiom.2018.04.008
  • A Systems Approach to Refine Disease Taxonomy by Integrating Phenotypic
           and Molecular Networks

    • Authors: Xuezhong Zhou; Lei Lei; Jun Liu; Arda Halu; Yingying Zhang; Bing Li; Zhili Guo; Guangming Liu; Changkai Sun; Joseph Loscalzo; Amitabh Sharma; Zhong Wang
      Abstract: Publication date: Available online 6 April 2018
      Author(s): Xuezhong Zhou, Lei Lei, Jun Liu, Arda Halu, Yingying Zhang, Bing Li, Zhili Guo, Guangming Liu, Changkai Sun, Joseph Loscalzo, Amitabh Sharma, Zhong Wang
      The International Classification of Diseases (ICD) relies on clinical features and lags behind the current understanding of the molecular specificity of disease pathobiology, necessitating approaches that incorporate growing biomedical data for classifying diseases to meet the needs of precision medicine. Our analysis revealed that the heterogeneous molecular diversity of disease chapters and the blurred boundary between disease categories in ICD should be further investigated. Here, we propose a new classification of diseases (NCD) by developing an algorithm that predicts the additional categories of a disease by integrating multiple networks consisting of disease phenotypes and their molecular profiles. With statistical validations from phenotype-genotype associations and interactome networks, we demonstrate that NCD improves disease specificity owing to its overlapping categories and polyhierarchical structure. Furthermore, NCD captures the molecular diversity of diseases and defines clearer boundaries in terms of both phenotypic similarity and molecular associations, establishing a rational strategy to reform disease taxonomy.

      PubDate: 2018-04-15T15:21:08Z
      DOI: 10.1016/j.ebiom.2018.04.002
  • Genetic restriction of antigen-presentation dictates allergic
           sensitization and disease in humanized mice

    • Authors: Alina Neunkirchner; Bernhard Kratzer; Cordula Köhler; Ursula Smole; Lukas F. Mager; Klaus G. Schmetterer; Doris Trapin; Victoria Leb-Reichl; Edward Rosloniec; Ronald Naumann; Lukas Kenner; Beatrice Jahn-Schmid; Barbara Bohle; Rudolf Valenta; Winfried F. Pickl
      Abstract: Publication date: Available online 5 April 2018
      Author(s): Alina Neunkirchner, Bernhard Kratzer, Cordula Köhler, Ursula Smole, Lukas F. Mager, Klaus G. Schmetterer, Doris Trapin, Victoria Leb-Reichl, Edward Rosloniec, Ronald Naumann, Lukas Kenner, Beatrice Jahn-Schmid, Barbara Bohle, Rudolf Valenta, Winfried F. Pickl
      Background Immunoglobulin(Ig)E-associated allergies result from misguided immune responses against innocuous antigens. CD4+ T lymphocytes are critical for initiating and perpetuating that process, yet the crucial factors determining whether an individual becomes sensitized towards a given allergen remain largely unknown. Objective To determine the key factors for sensitization and allergy towards a given allergen. Methods We here created a novel human T cell receptor(TCR) and human leucocyte antigen (HLA)-DR1 (TCR-DR1) transgenic mouse model of asthma, based on the human-relevant major mugwort (Artemisia vulgaris) pollen allergen Art v 1 to examine the critical factors for sensitization and allergy upon natural allergen exposure via the airways in the absence of systemic priming and adjuvants. Results Acute allergen exposure led to IgE-independent airway hyperreactivity (AHR) and T helper(Th)2-prone lung inflammation in TCR-DR1, but not DR1, TCR or wildtype (WT) control mice, that was alleviated by prophylactic interleukin(IL)-2-αIL-2 mAb complex-induced expansion of Tregs. Chronic allergen exposure sensitized one third of single DR1 transgenic mice, however, without impacting on lung function. Similar treatment led to AHR and Th2-driven lung pathology in >90% of TCR-DR1 mice. Prophylactic and therapeutic expansion of Tregs with IL-2-αIL-2 mAb complexes blocked the generation and boosting of allergen-specific IgE associated with chronic allergen exposure. Conclusions We identify genetic restriction of allergen presentation as primary factor dictating allergic sensitization and disease against the major pollen allergen from the weed mugwort, which frequently causes sensitization and disease in humans. Furthermore, we demonstrate the importance of the balance between allergen-specific T effector and Treg cells for modulating allergic immune responses.

      PubDate: 2018-04-15T15:21:08Z
      DOI: 10.1016/j.ebiom.2018.04.001
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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Fax: +00 44 (0)131 4513327
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