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  Subjects -> BIOLOGY (Total: 3126 journals)
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BIOTECHNOLOGY (236 journals)                  1 2 | Last

Showing 1 - 200 of 239 Journals sorted alphabetically
3 Biotech     Open Access   (Followers: 8)
Advanced Biomedical Research     Open Access  
Advances in Bioscience and Biotechnology     Open Access   (Followers: 16)
Advances in Genetic Engineering & Biotechnology     Hybrid Journal   (Followers: 7)
Advances in Regenerative Medicine     Open Access   (Followers: 2)
African Journal of Biotechnology     Open Access   (Followers: 6)
Algal Research     Partially Free   (Followers: 11)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 67)
American Journal of Bioinformatics Research     Open Access   (Followers: 7)
American Journal of Polymer Science     Open Access   (Followers: 32)
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 Biosafety     Hybrid Journal  
Applied Food Biotechnology     Open Access   (Followers: 3)
Applied Microbiology and Biotechnology     Hybrid Journal   (Followers: 64)
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: 9)
Asian Pacific Journal of Tropical Biomedicine     Open Access   (Followers: 2)
Australasian Biotechnology     Full-text available via subscription   (Followers: 1)
Banat's Journal of Biotechnology     Open Access  
BBR : Biochemistry and Biotechnology Reports     Open Access   (Followers: 5)
Beitr?ge zur Tabakforschung International/Contributions to Tobacco Research     Open Access   (Followers: 2)
Bio-Algorithms and Med-Systems     Hybrid Journal   (Followers: 2)
Bio-Research     Full-text available via subscription   (Followers: 3)
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   (Followers: 1)
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)
Biosensors Journal     Open Access  
Biosimilars     Open Access   (Followers: 1)
Biosurface and Biotribology     Open Access  
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
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: 6)
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: 153)
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: 2)
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: 40)
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  
BIOTIK : Jurnal Ilmiah Biologi Teknologi dan Kependidikan     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)
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)
Indonesian Journal of Medicine     Open Access  
Industrial Biotechnology     Hybrid Journal   (Followers: 17)
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: 3)
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)
JMIR Biomedical Engineering     Open Access  
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: 64)
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   (Followers: 1)
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: 25)
Journal of Genetic Engineering and Biotechnology     Open Access   (Followers: 5)
Journal of Ginseng Research     Open Access  
Journal of Industrial Microbiology and Biotechnology     Hybrid Journal   (Followers: 17)
Journal of Integrative Bioinformatics     Open Access  
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: 12)
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)
Meat Technology     Open Access  
Messenger     Full-text available via subscription  
Metabolic Engineering Communications     Open Access   (Followers: 4)
Metalloproteinases In Medicine     Open Access  
Microbial Biotechnology     Open Access   (Followers: 9)
MicroMedicine     Open Access   (Followers: 3)
Molecular and Cellular Biomedical Sciences     Open Access   (Followers: 1)
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  
Nanomedicine and Nanobiology     Full-text available via subscription  
Nanomedicine Research Journal     Open Access  

        1 2 | Last

Journal Cover
EBioMedicine
Journal Prestige (SJR): 2.895
Citation Impact (citeScore): 3
Number of Followers: 0  

  This is an Open Access Journal Open Access journal
ISSN (Print) 2352-3964
Published by Elsevier Homepage  [3161 journals]
  • IL-33-HIF1α Axis in Hypoxic Pulmonary Hypertension

    • Abstract: Publication date: Available online 7 July 2018Source: EBioMedicineAuthor(s): Rahul Kumar, Brian Graham
       
  • The Chromosomal Conformation Signature: A New Kid on the Block in ALS
           Biomarker Research'

    • Abstract: Publication date: Available online 7 July 2018Source: EBioMedicineAuthor(s): Koen Poesen
       
  • A Nucleolar Stress–Specific p53–miR-101 Molecular Circuit Functions as
           an Intrinsic Tumor-Suppressor Network

    • Abstract: Publication date: Available online 7 July 2018Source: EBioMedicineAuthor(s): Yuko Fujiwara, Motonobu Saito, Ana I. Robles, Momoyo Nishida, Fumitaka Takeshita, Masatoshi Watanabe, Takahiro Ochiya, Jun Yokota, Takashi Kohno, Curtis C. Harris, Naoto Tsuchiya BackgroundActivation of intrinsic p53 tumor-suppressor (TS) pathways is an important principle underlying cancer chemotherapy. It is necessary to elucidate the precise regulatory mechanisms of these networks to create new treatment strategies.MethodsComprehensive analyses were carried out by microarray. Expression of miR-101 was analyzed by clinical samples of lung adenocarcinomas.FindingsWe discovered a functional link between p53 and miR-101, which form a molecular circuit in response to nucleolar stress. Inhibition of RNA polymerase I (Pol I) transcription resulted in the post-transcriptional activation of miR-101 in a p53-dependent manner. miR-101 induced G2 phase–specific feedback regulation of p53 through direct repression of its target, EG5, resulting in elevated phosphorylation of ATM. In lung cancer patients, low expression of miR-101 was associated with significantly poorer prognosis exclusively in p53 WT cases. miR-101 sensitized cancer cells to Pol I transcription inhibitors and strongly repressed xenograft growth in mice. Interestingly, the most downstream targets of this circuit included the inhibitor of apoptosis proteins (IAPs). Repression of cIAP1 by a selective inhibitor, birinapant, promoted activation of the apoptosis induced by Pol I transcription inhibitor in p53 WT cancer cells.InterpretationOur findings indicate that the p53–miR-101 circuit is a component of an intrinsic TS network formed by nucleolar stress, and that mimicking activation of this circuit represents a promising strategy for cancer therapy.FundNational Institute of Biomedical Innovation, Ministry of Education, Culture, Sports & Technology of Japan, Japan Agency for Medical Research and Development.
       
  • Evaluation of GWAS-Identified Genetic Variants for Gastric Cancer Survival

    • Abstract: Publication date: Available online 6 July 2018Source: EBioMedicineAuthor(s): Dongying Gu, Rui Zheng, Junyi Xin, Shuwei Li, Haiyan Chu, Weida Gong, Fulin Qiang, Zhengdong Zhang, Meilin Wang, Mulong Du, Jinfei Chen BackgroundsGenome-wide association studies (GWASs) have identified several gastric cancer (GC) susceptibility loci in Asians, but their effects on disease outcome are still unknown. This study aimed to investigate whether these GWAS-identified genetic variants could serve as robust prognostic biomarkers for GC.MethodsA multistage clinical cohort, including a total of 2432 GC patients in the Chinese population, was used to identify the association between GWAS-identified risk variants and overall survival of GC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by Cox regression analysis, and the log-rank P was calculated by the log-rank test with the Kaplan-Meier method.ResultsWe found that rs2274223 A>G in PLCE1 was associated with increased GC survival in both training set (P = .011), which was independently replicated in validation set 1 (P = .045), but not in validation set 2. The area under the curve (AUC) from receiver-operator characteristic (ROC) curve showed this clinical relevance with onset age-dependence, especially in the subgroup of early-onset cases. Moreover, a significant improvement in overall survival prediction was identified when the rs2274223 genetic effect was included in the estimation; this result was also supported by the prognostic nomogram. In addition, patients with lower expression of PLCE1 showed benefits via longer survival, potentially due to the functional effect of rs2274223.InterpretationThis preliminary study suggests that a GWAS-identified genetic variant in PLCE1 may serve as a potential biomarker for GC survival. Additional replication with larger samples size is warranted to further investigation.
       
  • Short-Term Hypoxia Dampens Inflammation in vivo via Enhanced Adenosine
           Release and Adenosine 2B Receptor Stimulation

    • Abstract: Publication date: Available online 4 July 2018Source: EBioMedicineAuthor(s): Dorien Kiers, Ben Wielockx, Esther Peters, Lucas T. van Eijk, Jelle Gerretsen, Aaron John, Emmy Janssen, Rianne Groeneveld, Mara Peters, Lars Damen, Ana M. Meneses, Anja Krüger, Jeroen D. Langereis, Aldert L. Zomer, Michael R. Blackburn, Leo A. Joosten, Mihai G. Netea, Niels P. Riksen, Johannes G. van der Hoeven, Gert-Jan Scheffer Hypoxia and inflammation are closely intertwined phenomena. Critically ill patients often suffer from systemic inflammatory conditions and concurrently experience short-lived hypoxia. We evaluated the effects of short-term hypoxia on systemic inflammation, and show that it potently attenuates pro-inflammatory cytokine responses during murine endotoxemia. These effects are independent of hypoxia-inducible factors (HIFs), but involve augmented adenosine levels, in turn resulting in an adenosine 2B receptor-mediated post-transcriptional increase of interleukin (IL)-10 production. We translated our findings to humans using the experimental endotoxemia model, where short-term hypoxia resulted in enhanced plasma concentrations of adenosine, augmentation of endotoxin-induced circulating IL-10 levels, and concurrent attenuation of the pro-inflammatory cytokine response. Again, HIFs were shown not to be involved. Taken together, we demonstrate that short-term hypoxia dampens the systemic pro-inflammatory cytokine response through enhanced purinergic signaling in mice and men. These effects may contribute to outcome and provide leads for immunomodulatory treatment strategies for critically ill patients.
       
  • Engineered Kidney Tubules for Modeling Patient-Specific Diseases and Drug
           Discovery

    • Abstract: Publication date: Available online 3 July 2018Source: EBioMedicineAuthor(s): Valentina Benedetti, Valerio Brizi, Patrizia Guida, Susanna Tomasoni, Osele Ciampi, Elena Angeli, Ugo Valbusa, Ariela Benigni, Giuseppe Remuzzi, Christodoulos Xinaris The lack of engineering systems able to faithfully reproduce complex kidney structures in vitro has made it difficult to efficiently model kidney diseases and development. Using polydimethylsiloxane (PDMS) scaffolds and a kidney-derived cell line we developed a system to rapidly engineer custom-made 3D tubules with typical renal epithelial properties. This system was successfully employed to engineer patient-specific tubules, to model polycystic kidney disease (PKD) and test drug efficacy, and to identify a potential new pharmacological treatment. By optimizing our system we constructed functional ureteric bud (UB)-like tubules from human induced pluripotent stem cells (iPSCs), and identified a combination of growth factors that induces budding morphogenesis like embryonic kidneys do. Finally, we applied this assay to investigate budding defects in UB-like tubules derived from a patient with a PAX2 mutation.Our system enables the modeling of human kidney disease and development, drug testing and discovery, and lays the groundwork for engineering anatomically correct kidney tissues in vitro and developing personalized medicine applications.
       
  • Induction and Amelioration of Methotrexate-Induced Gastrointestinal
           Toxicity are Related to Immune Response and Gut Microbiota

    • Abstract: Publication date: Available online 2 July 2018Source: EBioMedicineAuthor(s): Bailing Zhou, Xuyang Xia, Peiqi Wang, Shuang Chen, Chaoheng Yu, Rong Huang, Rui Zhang, Yantai Wang, Lian Lu, Fengjiao Yuan, Yaomei Tian, Yingzi Fan, Xueyan Zhang, Yang Shu, Shouyue Zhang, Ding Bai, Lei Wu, Heng Xu, Li Yang As a widely used anticancer and immunosuppressive agent, methotrexate (MTX) can induce multiple adverse drug reactions (ADRs), such as gastrointestinal toxicity, the mechanisms are poorly understood. Gut microbiota has been widely reported to be associated with the onset of multiple diseases as well as treatment outcomes of different drugs. In this study, mucosal injury was observed in MTX-treated mice, leading to significant changes in macrophages (i.e., M1/M2 ratio, P 
       
  • Cytokine Networks and Survivin Peptide-Specific Cellular Immune Responses
           Predict Improved Survival in Patients With Glioblastoma Multiforme

    • Abstract: Publication date: Available online 29 June 2018Source: EBioMedicineAuthor(s): Liu Zhenjiang, Martin Rao, Xiaohua Luo, Davide Valentini, Anna von Landenberg, Qingda Meng, Georges Sinclair, Nina Hoffmann, Julia Karbach, Hans-Michael Altmannsberger, Elke Jäger, Inti Harvey Peredo, Ernest Dodoo, Markus Maeurer PurposeWe investigated serum cytokine and T-cell responses directed against tumour-associated antigens (TAAs) in association with survival of patients with glioblastoma multiforme (GBM).Patients and MethodsPeripheral blood from 205 treatment-naïve patients with glioma (GBM = 145; non-GBM = 60) was obtained on the day of surgery to measure (i) circulating T-cells reacting to viral antigens and TAAs, in the presence or absence of cytokine conditioning with IL-2/IL-15/IL-21 or IL-2/IL-7, and (ii) serum cytokine levels (IL-4, IL-5, IL-6, TNF-α, IFN-γ and IL-17A). Patients were followed-up for at least 1000 days post-surgery. Survivin protein and gene expression in resected GBM tumour tissue were confirmed by immunohistochemistry and real-time polymerase chain reaction, respectively. Antigen-specific T-cell responses were gauged by ICS (intracellular cytokine production). Associations between patient survival and immunological reactivity patterns were analysed using univariate and multivariate statistics.ResultsApproximately 2% of patients with GBM and 18% of patients with non-GBM glioma, were alive beyond 1000 days of surgery. Univariate analysis indicated that the combination of three cytokines (IL-4/IL-5/IL-6, p = .0022; IFN-γ/TNF-α/IL-17A, p = .0083) but not a ‘partial’ combination of these cytokines, the IFN-γ immune response to EBV-EBNA-1 (p 
       
  • The injured brain might need more fat!

    • Abstract: Publication date: Available online 29 June 2018Source: EBioMedicineAuthor(s): Hyacinth I. Hyacinth
       
  • Programming and Regulation of Metabolic Homeostasis by HDAC11

    • Abstract: Publication date: Available online 28 June 2018Source: EBioMedicineAuthor(s): Lei Sun, Caralina Marin de Evsikova, Ka Bian, Alexandra Achille, Elphine Telles, Huadong Pei, Edward Seto Histone deacetylases (HDACs) are enzymes that regulate protein functions by catalyzing the removal of acetyl and acyl groups from lysine residues. They play pivotal roles in governing cell behaviors and are indispensable in numerous biological processes. HDAC11, the last identified and sole member of class IV HDACs, was reported over a decade ago. However, its physiological function remains poorly understood. Here, we report that HDAC11 knockout mice are resistant to high-fat diet-induced obesity and metabolic syndrome, suggesting that HDAC11 functions as a crucial metabolic regulator. Depletion of HDAC11 significantly enhanced insulin sensitivity and glucose tolerance, attenuated hypercholesterolemia, and decreased hepatosteatosis and liver damage. Mechanistically, HDAC11 deficiency boosts energy expenditure through promoting thermogenic capacity, which attributes to the elevation of uncoupling protein 1 (UCP1) expression and activity in brown adipose tissue. Moreover, loss of HDAC11 activates the adiponectin-AdipoR-AMPK pathway in the liver, which may contribute to a reversal in hepatosteatosis. Overall, our findings distinguish HDAC11 as a novel regulator of obesity, with potentially important implications for obesity-related disease treatment.
       
  • Conventional Versus Therapeutic Stents for Airway Malignancies: Novel
           Local Therapies Underway

    • Abstract: Publication date: Available online 28 June 2018Source: EBioMedicineAuthor(s): Paul Zarogoulidis, Chrysanthi Sardeli, Fotis Konstantinou, Konstantinos Sapalidis
       
  • On the Protective Effects of Gene SNPs Against Human Cancer

    • Abstract: Publication date: Available online 27 June 2018Source: EBioMedicineAuthor(s): Hua Tan
       
  • Initial Identification of a Blood-Based Chromosome Conformation Signature
           for Aiding in the Diagnosis of Amyotrophic Lateral Sclerosis

    • Abstract: Publication date: Available online 23 June 2018Source: EBioMedicineAuthor(s): Matthew Salter, Emily Corfield, Aroul Ramadass, Francis Grand, Jayne Green, Jurjen Westra, Chun Ren Lim, Lucy Farrimond, Emily Feneberg, Jakub Scaber, Alexander Thompson, Lynn Ossher, Martin Turner, Kevin Talbot, Merit Cudkowicz, James Berry, Ewan Hunter, Alexandre Akoulitchev BackgroundThe identification of blood-based biomarkers specific to the diagnosis of amyotrophic lateral sclerosis (ALS) is an active field of academic and clinical research. While inheritance studies have advanced the field, a majority of patients do not have a known genetic link to the disease, making direct sequence-based genetic testing for ALS difficult. The ability to detect biofluid-based epigenetic changes in ALS would expand the relevance of using genomic information for disease diagnosis.MethodsAssessing differences in chromosomal conformations (i.e. how they are positioned in 3-dimensions) represents one approach for assessing epigenetic changes. In this study, we used an industrial platform, EpiSwitch™, to compare the genomic architecture of healthy and diseased patient samples (blood and tissue) to discover a chromosomal conformation signature (CCS) with diagnostic potential in ALS. A three-step biomarker selection process yielded a distinct CCS for ALS, comprised of conformation changes in eight genomic loci and detectable in blood.FindingsWe applied the ALS CCS to determine a diagnosis for 74 unblinded patient samples and subsequently conducted a blinded diagnostic study of 16 samples. Sensitivity and specificity for ALS detection in the 74 unblinded patient samples were 83∙33% (CI 51∙59 to 97∙91%) and 76∙92% (46∙19 to 94∙96%), respectively. In the blinded cohort, sensitivity reached 87∙50% (CI 47∙35 to 99∙68%) and specificity was 75∙0% (34∙91 to 96∙81%).InterpretationsThe sensitivity and specificity values achieved using the ALS CCS identified and validated in this study provide an indication that the detection of chromosome conformation signatures is a promising approach to disease diagnosis and can potentially augment current strategies for diagnosing ALS.FundThis research was funded by Oxford BioDynamics and Innovate UK. Work in the Oxford MND Care and Research Centre is supported by grants from the Motor Neurone Disease Association and the Medical Research Council. Additional support was provided by the Northeast ALS Consortium (NEALS).
       
  • Fatty Acid Metabolism is Associated With Disease Severity After H7N9
           Infection

    • Abstract: Publication date: Available online 23 June 2018Source: EBioMedicineAuthor(s): Xin Sun, Lijia Song, Shuang Feng, Li Li, Hongzhi Yu, Qiaoxing Wang, Xing Wang, Zhili Hou, Xue Li, Yu Li, Qiuyang Zhang, Kuan Li, Chao Cui, Junping Wu, Zhonghua Qin, Qi Wu, Huaiyong Chen BackgroundHuman infections with the H7N9 virus could lead to lung damage and even multiple organ failure, which is closely associated with a high mortality rate. However, the metabolic basis of such systemic alterations remains unknown.MethodsThis study included hospitalized patients (n = 4) with laboratory-confirmed H7N9 infection, healthy controls (n = 9), and two disease control groups comprising patients with pneumonia (n = 9) and patients with pneumonia who received steroid treatment (n = 10). One H7N9-infected patient underwent lung biopsy for histopathological analysis and expression analysis of genes associated with lung homeostasis. H7N9-induced systemic alterations were investigated using metabolomic analysis of sera collected from the four patients by using ultra-performance liquid chromatography-mass spectrometry. Chest digital radiography and laboratory tests were also conducted.FindingsTwo of the four patients did not survive the clinical treatments with antiviral medication, steroids, and oxygen therapy. Biopsy revealed disrupted expression of genes associated with lung epithelial integrity. Histopathological analysis demonstrated severe lung inflammation after H7N9 infection. Metabolomic analysis indicated that fatty acid metabolism may be inhibited during H7N9 infection. Serum levels of palmitic acid, erucic acid, and phytal may negatively correlate with the extent of lung inflammation after H7N9 infection. The changes in fatty acid levels may not be due to steroid treatment or pneumonia.InterpretationAltered structural and secretory properties of the lung epithelium may be associated with the severity of H7N9-infection-induced lung disease. Moreover, fatty acid metabolism level may predict a fatal outcome after H7N9 virus infection.
       
  • Gefitinib and Methotrexate to Treat Ectopic Pregnancies with a
           Pre-Treatment Serum hCG 1000–10,000 IU/L: Phase II Open Label, Single
           Arm Multi-Centre Trial

    • Abstract: Publication date: Available online 22 June 2018Source: EBioMedicineAuthor(s): Monika M. Skubisz, Stephen Tong, Ann Doust, Jill Mollison, Terrance G. Johns, Peter Neil, Miranda Robinson, Siladitya Bhattacharya, Euan Wallace, Nicole Krzys, W. Colin Duncan, Andrew W. Horne BackgroundEctopic pregnancies are a leading cause of maternal mortality. Most are treated surgically. We evaluated the efficacy and safety of combining oral gefitinib (epidermal growth factor receptor inhibitor) with methotrexate to treat larger ectopic pregnancies.MethodsWe performed a phase II, single arm, open label study across four hospitals in Edinburgh and Melbourne. We recruited women with a stable tubal ectopic pregnancy and a pre-treatment serum hCG between 1000 and 10,000 IU/L. We administered intramuscular methotrexate (50 mg/m2) once, and oral gefitinib (250 mg) for seven days. The primary outcome was the percentage successfully treated without needing surgery. To show the treatment is at least 70% effective, 28 participants were required, and 24 or more successfully treated without surgery. Secondary outcomes were safety, tolerability, and time to resolution. This study is registered (ACTRN12611001056987).Findings30 participants with stable tubal ectopic pregnancies were recruited but two withdrew, leaving 28 participants. The median (± range) pre-treatment serum hCG was 2039 (1031–8575) IU/L and nine had pre-treatment hCGs levels>3000 IU/L. The treatment successfully resolved 86% (24/28) cases with a median (±range) time to resolution of 32 (18–67) days. The treatment caused transient rash and diarrhoea, but no serious adverse events.InterpretationCombination gefitinib and methotrexate is at least 70% effective in resolving ectopic pregnancies with a pre-treatment serum hCG 1000–10,000 IU/L. This may be a new way to treat most stable ectopic pregnancies, but needs to be validated via a randomised clinical trial.
       
  • Long-Term Culture of Distal Airway Epithelial Cells Allows Differentiation
           Towards Alveolar Epithelial Cells Suited for Influenza Virus Studies

    • Abstract: Publication date: Available online 22 June 2018Source: EBioMedicineAuthor(s): Aki Imai-Matsushima, Laura Martin-Sancho, Alexander Karlas, Seiichiro Imai, Tamara Zoranovic, Andreas C. Hocke, Hans-Joachim Mollenkopf, Hilmar Berger, Thomas F. Meyer As the target organ for numerous pathogens, the lung epithelium exerts critical functions in health and disease. However, research in this area has been hampered by the quiescence of the alveolar epithelium under standard culture conditions. Here, we used human distal airway epithelial cells (DAECs) to generate alveolar epithelial cells. Long-term, robust growth of human DAECs was achieved using co-culture with feeder cells and supplementation with epidermal growth factor (EGF), Rho-associated protein kinase inhibitor Y27632, and the Notch pathway inhibitor dibenzazepine (DBZ). Removal of feeders and priming with DBZ and a cocktail of lung maturation factors prevented the spontaneous differentiation into airway club cells and instead induced differentiation to alveolar epithelial cells. We successfully transferred this approach to chicken distal airway cells, thus generating a zoonotic infection model that enables studies on influenza A virus replication. These cells are also amenable for gene knockdown using RNAi technology, indicating the suitability of the model for mechanistic studies into lung function and disease.
       
  • Somatic FGFR3 Mutations Distinguish a Subgroup of Muscle-Invasive Bladder
           Cancers with Response to Neoadjuvant Chemotherapy

    • Abstract: Publication date: Available online 22 June 2018Source: EBioMedicineAuthor(s): Zhao Yang, Ruiyun Zhang, Yunxia Ge, Xuying Qin, Xing Kang, Yue Wang, Xu Zhang, Chengli Song, Xiaofang Quan, Haifeng Wang, Haige Chen, Chong Li The administration of neoadjuvant chemotherapy (NAC) preceding radical cystectomy benefits overall survival for patients with muscle-invasive bladder cancer (MIBC). However, the relationship between the genetic profiling of MIBC and NAC response remains unclear. Here, a mutation panel of six cancer-associated genes (TSC1, FGFR3, TERT, TP53, PIK3CA and ERBB2) and an immunohistochemistry (IHC) panel containing eight bladder cancer (BC) biomarkers (EGFR, RRM1, PD-L1, BRCA1, TUBB3, ERCC, ERCC1, aberrantly glycosylated integrin α3β1 (AG) and CK5/6) were developed. BC samples from patients who showed a pathologic response (n = 39) and non-response (n = 13) were applied to the panel analysis. ERBB2, FGFR3 and PIK3CA exclusively altered in the responders group (19/39, 48.7%), in which FGFR3 mutations were significantly enriched in patients with a response in the cohort (14/39, 35.9%; P = 0.01). Additionally, strong expression of ERCC1 was associated with a pathologic response (P = 0.01). However, positive lymph node metastasis (P 
       
  • A Systems-Level Analysis Reveals Circadian Regulation of Splicing in
           Colorectal Cancer

    • Abstract: Publication date: Available online 21 June 2018Source: EBioMedicineAuthor(s): Rukeia El-Athman, Luise Fuhr, Angela Relógio Accumulating evidence points to a significant role of the circadian clock in the regulation of splicing in various organisms, including mammals. Both dysregulated circadian rhythms and aberrant pre-mRNA splicing are frequently implicated in human disease, in particular in cancer. To investigate the role of the circadian clock in the regulation of splicing in a cancer progression context at the systems-level, we conducted a genome-wide analysis and compared the rhythmic transcriptional profiles of colon carcinoma cell lines SW480 and SW620, derived from primary and metastatic sites of the same patient, respectively. We identified spliceosome components and splicing factors with cell-specific circadian expression patterns including SRSF1, HNRNPLL, ESRP1, and RBM 8A, as well as altered alternative splicing events and circadian alternative splicing patterns of output genes (e.g., VEGFA, NCAM1, FGFR2, CD44) in our cellular model. Our data reveals a remarkable interplay between the circadian clock and pre-mRNA splicing with putative consequences in tumor progression and metastasis.Graphical Unlabelled Image
       
  • Base Excision Repair Gene Polymorphisms and Wilms Tumor Susceptibility

    • Abstract: Publication date: Available online 21 June 2018Source: EBioMedicineAuthor(s): Jinhong Zhu, Wei Jia, Caixia Wu, Wen Fu, Huimin Xia, Guochang Liu, Jing He Base excision repair (BER) is the main mechanism to repair endogenous DNA lesions caused by reactive oxygen species. BER deficiency is linked with cancer susceptibility and premature aging. Single nucleotide polymorphisms (SNPs) within BER genes have been implicated in various human malignancies. Nevertheless, a comprehensive investigation of their association with Wilms tumor susceptibility is lacking. In this study, 145 cases and 531 sex and age-matched healthy controls were recruited. We systematically genotyped 18 potentially functional SNPs in six core BER pathway genes, using a candidate SNP approach. Logistic regression was employed to evaluate odds ratio (OR) and 95% confidence interval (CI) adjusted for age and gender. Several SNPs showed protective effects against Wilms tumor. Significant associations with Wilms tumor susceptibility were shown for hOGG1 rs1052133 (dominant: adjusted OR = 0.66, 95% CI = 0.45–0.96, P = .030), FEN1 rs174538 (dominant: adjusted OR = 0.66, 95% CI = 0.45–0.95, P = .027; recessive: adjusted OR = 0.54, 95% CI = 0.32–0.93 P = .027), and FEN1 rs4246215 (dominant: adjusted OR = 0.55, 95% CI = 0.38–0.80, P = .002) polymorphisms. Stratified analysis was performed by age, gender, and clinical stage. Moreover, there was evidence of functional implication of these significant SNPs suggested by online expression quantitative trait locus (eQTL) analysis. Our findings indicate that common SNPs in BER genes modify susceptibility to Wilms tumor.
       
  • Immune Characteristics of Chinese Diffuse Large B-Cell Lymphoma Patients:
           Implications for Cancer Immunotherapies

    • Abstract: Publication date: Available online 20 June 2018Source: EBioMedicineAuthor(s): Peng-peng Xu, Chun Sun, Xu Cao, Xia Zhao, Hang-jun Dai, Shan Lu, Jian-jun Guo, Shi-jing Fu, Yu-xia Liu, Su-chun Li, Meng Chen, Ron McCord, Jeff Venstrom, Edith Szafer-Glusman, Elizabeth Punnoose, Astrid Kiermaier, Gang Cheng, Wei-li Zhao Immunotherapeutic agents have demonstrated encouraging signs of clinical utility in non-Hodgkin lymphoma. The goal of this study is to analyze the immune characteristics of Chinese patients with diffuse large B-cell lymphoma (DLBCL) to inform the development of immunotherapies in this patient population. Tumor samples from 211 DLBCL patients were analyzed for cell of origin (COO) and immune characteristics using the NanoString platform as well as MYC protein expression through immunohistochemistry. Lower incidence of the germinal center B-cell (GCB) subtype (93/211, 44.1%) was observed in this cohort. Compared to the GCB subtype, the activated B-cell (ABC) subtype was associated with significantly increased expression of multiple pro-inflammatory gene signatures and decreased expression of anti-inflammatory gene signatures. Instead of affecting the pro-inflammatory genes, MYC protein overexpression showed a negative correlation with the expression of T-cell receptor (TCR) and T regulatory genes as well as the OX40 gene. Regardless of COO, higher PD-L1 or IDO1 gene expression correlated with increased expression of T effector and Interferon-γ gene signatures while the expression of multiple oncogenes including ACTR3B, ERBB2, AKT2 and SMARCD1 was down-regulated. Our findings may thus be helpful in guiding further development of immunotherapies for the different subsets of Chinese DLBCL patients.
       
  • The Puzzle of Predicting Response to Immune Checkpoint Blockade

    • Abstract: Publication date: Available online 20 June 2018Source: EBioMedicineAuthor(s): Mykola Onyshchenko
       
  • Metabolic Syndrome, Adiponectin, Sleep, and the Circadian System

    • Abstract: Publication date: Available online 20 June 2018Source: EBioMedicineAuthor(s): Germaine Cornelissen
       
  • Elucidation of the Strongest Predictors of Cardiovascular Events in
           Patients with Heart Failure

    • Abstract: Publication date: Available online 20 June 2018Source: EBioMedicineAuthor(s): Hiroki Fukuda, Kazuhiro Shindo, Mari Sakamoto, Tomomi Ide, Shintaro Kinugawa, Arata Fukushima, Hiroyuki Tsutsui, Shin Ito, Akira Ishii, Takashi Washio, Masafumi Kitakaze BackgroundIn previous retrospective studies, we identified the 50 most influential clinical predictors of cardiovascular outcomes in patients with heart failure (HF). The present study aimed to use the novel limitless-arity multiple-testing procedure to filter these 50 clinical factors and thus yield combinations of no more than four factors that could potentially predict the onset of cardiovascular events. A Kaplan–Meier analysis was used to investigate the importance of the combinations.MethodsIn a multi-centre observational trial, we prospectively enrolled 213 patients with HF who were hospitalized because of exacerbation, discharged according to HF treatment guidelines and observed to monitor cardiovascular events. After the observation period, we stratified patients according to whether they experienced cardiovascular events (rehospitalisation or cardiovascular death).FindingsAmong 77,562 combinations of fewer than five clinical parameters, we identified 151 combinations that could potentially explain the occurrence of cardiovascular events. Of these, 145 combinations included the use of inotropic agents, whereas the remaining 6 included the use of diuretics without bradycardia or tachycardia, suggesting that the high probability of cardiovascular events is exclusively determined by these two clinical factors. Importantly, Kaplan–Meier curves demonstrated that the use of inotropes or of diuretics without bradycardia or tachycardia were independent predictors of a markedly worse cardiovascular prognosis.InterpretationPatients treated with either inotropic agents or diuretics without bradycardia or tachycardia were at a higher risk of cardiovascular events. The uses of these drugs, regardless of heart rate, are the strongest clinical predictors of cardiovascular events in patients with HF.
       
  • Liposomal Therapy Attenuates Dermonecrosis Induced by Community-Associated
           Methicillin-Resistant Staphylococcus aureus by Targeting α-Type
           Phenol-Soluble Modulins and α-Hemolysin

    • Abstract: Publication date: Available online 20 June 2018Source: EBioMedicineAuthor(s): Heidi Wolfmeier, Sarah C. Mansour, Leo T. Liu, Daniel Pletzer, Annette Draeger, Eduard B. Babiychuk, Robert E.W. Hancock Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), typified by the pulse-field type USA300, is an emerging endemic pathogen that is spreading rapidly among healthy people. CA-MRSA causes skin and soft tissue infections, life-threatening necrotizing pneumonia and sepsis, and is remarkably resistant to many antibiotics. Here we show that engineered liposomes composed of naturally occurring sphingomyelin were able to sequester cytolytic toxins secreted by USA300 and prevent necrosis of human erythrocytes, peripheral blood mononuclear cells and bronchial epithelial cells. Mass spectrometric analysis revealed the capture by liposomes of phenol-soluble modulins, α-hemolysin and other toxins. Sphingomyelin liposomes prevented hemolysis induced by pure phenol-soluble modulin-α3, one of the main cytolytic components in the USA300 secretome. In contrast, sphingomyelin liposomes harboring a high cholesterol content (66 mol/%) were unable to protect human cells from phenol-soluble modulin-α3-induced lysis, however these liposomes efficiently sequestered the potent staphylococcal toxin α-hemolysin. In a murine cutaneous abscess model, a single dose of either type of liposomes was sufficient to significantly decrease tissue dermonecrosis. Our results provide further insights into the promising potential of tailored liposomal therapy in the battle against infectious diseases.
       
  • IL-33 Initiates Vascular Remodelling in Hypoxic Pulmonary Hypertension by
           up-Regulating HIF-1α and VEGF Expression in Vascular Endothelial Cells

    • Abstract: Publication date: Available online 18 June 2018Source: EBioMedicineAuthor(s): Jie Liu, Wang Wang, Lei Wang, Shihao Chen, Bo Tian, Kewu Huang, Chris J. Corrigan, Sun Ying, Wei Wang, Chen Wang IL-33 may play a role in the vascular remodelling of hypoxic pulmonary hypertension (PH) but the precise mechanisms are still unclear. We hypothesized that hypoxia promotes expression of IL-33 and its receptor ST2 on vascular endothelial cells, which in turn leads to dysfunction of vascular endothelial cells and smooth muscle cells contributing to PH. Immunohistochemistry showed that immunoreactivity for IL-33 and ST2 was significantly increased in lung tissue of murine model of hypoxia-induced PH (HPH) and of subjects with bronchiectasis-PH. trans-Thoracic echocardiography showed that haemodynamic changes and right ventricular hypertrophy associated with HPH were significantly abrogated in St2−/− compared with WT mice. Administration of IL-33 further exacerbated these changes in the hypoxia-exposed WT mice. In vitro, hypoxia significantly increased IL-33/ST2 expression by human pulmonary arterial endothelial cells (HPAECs), while exogenous IL-33 enhanced proliferation, adhesiveness and spontaneous angiogenesis of HPAECs. Knockdown of endogenous Il33 or St2 using siRNA transfection significantly suppressed these effects in both normoxic and hypoxic culture-conditions. Deletion of the St2 gene attenuated hypoxia-induced, elevated lung expression of HIF-1α/VEGFA/VEGFR-2/ICAM-1, while administration of exogenous VEGFA partially reversed the attenuation of the haemodynamic indices of PH. Correspondingly, knockdown of the St2 or Hif1α genes almost completely abrogated IL-33-induced expression of HIF-1α/VEGFA/VEGFR-2 by HPAECs in vitro. Further, IL-33-induced angiogenesis by HPAECs was extensively abrogated by knockdown of the Hif1α/Vegfa or Vegfr2 genes. These data suggest that hypoxia induces elevated expression of IL-33/ST2 by HPAECs which, at least partly by increasing downstream expression of HIF-1α and VEGF initiates vascular remodelling resulting in HPH.
       
  • Targeting mPGES-1 as a New Strategy against Neuroblastoma

    • Abstract: Publication date: Available online 12 June 2018Source: EBioMedicineAuthor(s): Valentina Comunanza
       
  • Proapoptotic Cyclic Peptide BC71 Targets Cell-Surface GRP78 and Functions
           as an Anticancer Therapeutic in Mice

    • Abstract: Publication date: Available online 12 June 2018Source: EBioMedicineAuthor(s): Chieh Kao, Ritu Chandna, Abhijeet Ghode, Charlotte Dsouza, Mo Chen, Andreas Larsson, Siau Hoi Lim, Minjun Wang, Zhonglian Cao, Yizhun Zhu, Ganesh S. Anand, Ruowen Ge Glucose regulated protein 78 kDa (GRP78) is a recently emerged target for cancer therapy and a biomarker for cancer prognosis. Overexpression of GRP78 is observed in many types of cancers, with the cell-surface GRP78 being preferentially present in cancer cells and cancer blood vessel endothelial cells. Isthmin (ISM) is a secreted high-affinity proapoptotic protein ligand of cell-surface GRP78 that suppresses angiogenesis and tumor growth in mice. The C-terminal AMOP (adhesion-associated domain in MUC4 and other proteins) domain of ISM is critical in mediating its interaction with human umbilical vein endothelial cells (HUVECs). In this work, we report novel cyclic peptides harboring the RKD motif in the ISM AMOP domain that function as proapoptotic ligands of cell-surface GRP78. The most potent peptide, BC71, binds to GRP78 and converge to tumor in mice. Intravenous administration of BC71 suppressed xenograft tumor growth in mice as a single agent, with significant reduction in tumor angiogenesis and upsurge in apoptosis. Fluorescent-labeled BC71 accumulates in tumor in mice by targeting cell-surface GRP78. We show that BC71 triggers apoptosis via cell-surface GRP78 and activates caspase-8 and p53 signaling pathways in HUVECs. Using amide hydrogen-deuterium exchange mass spectrometry (HDXMS), we identified that BC71 preferentially binds to ATP-bound GRP78 via amino acid residues 244–257 of GRP78. Hence, BC71 serves as a valuable prototype for further development of peptidomimetic anticancer drugs targeting cell-surface GRP78 as well as PET imaging agents for cancer prognosis.Graphical Unlabelled Image
       
  • Calcium-activated Chloride Channel Regulator 1 (CLCA1) Controls Mucus
           Expansion in Colon by Proteolytic Activity

    • Abstract: Publication date: Available online 7 June 2018Source: EBioMedicineAuthor(s): Elisabeth E.L. Nyström, George M.H. Birchenough, Sjoerd van der Post, Liisa Arike, Achim D. Gruber, Gunnar C. Hansson, Malin E.V. Johansson Many epithelial surfaces of the body are covered with protective mucus, and disrupted mucus homeostasis is coupled to diseases such as ulcerative colitis, helminth infection, cystic fibrosis, and chronic obstructive lung disease. However, little is known how a balanced mucus system is maintained. By investigating the involvement of proteases in colonic mucus dynamics we identified metalloprotease activity to be a key contributor to mucus expansion. The effect was mediated by calcium-activated chloride channel regulator 1 (CLCA1) as application of recombinant CLCA1 on intestinal mucus in freshly dissected tissue resulted in increased mucus thickness independently of ion and mucus secretion, but dependent on its metallohydrolase activity. Further, CLCA1 modulated mucus dynamics in both human and mouse, and knock-out of CLCA1 in mice was compensated for by cysteine proteases. Our results suggest that CLCA1 is involved in intestinal mucus homeostasis by facilitating processing and removal of mucus to prevent stagnation. In light of our findings, we suggest future studies to investigate if upregulation of CLCA1 in diseases associated with mucus accumulation could facilitate removal of mucus in an attempt to maintain homeostasis.Graphical Unlabelled Image
       
  • 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

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Hening Zhai, Zhi Li, Miao Peng, Zhaoqi Huang, Tingfeng Qin, Linxi Chen, Hanbing Li, Heng Zhang, Weizhen Zhang, Geyang Xu BackgroundThe 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.MethodsCirculating 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.ResultsPositive 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.InterpretationDeoxycholic acid-TGR5-mTORC1 signaling contributes to the up-regulation of GLP-1 production after RYGB.
       
  • Patients with Concurrent Tuberculosis and Diabetes Have a Pro-Atherogenic
           Plasma Lipid Profile

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Frank Vrieling, Katharina Ronacher, Léanie Kleynhans, Erik van den Akker, Gerhard Walzl, Tom H.M. Ottenhoff, Simone A. Joosten BackgroundType 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.MethodsA 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).ResultsTB 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.ConclusionsTB-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.
       
  • By Targeting Atg7 MicroRNA-143 Mediates Oxidative Stress-Induced Autophagy
           of c-Kit+ Mouse Cardiac Progenitor Cells

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(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.
       
  • Plasma Circulating Extracellular RNAs in Left Ventricular Remodeling
           Post-Myocardial Infarction

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(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.
       
  • Loss of Cardio-Protective Effects at the CDH13 Locus Due to Gene-Sleep
           Interaction: The BCAMS Study

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Ge Li, Dan Feng, Yonghui Wang, Junling Fu, Lanwen Han, Lujiao Li, Struan F.A. Grant, Mingyao Li, Ming Li, Shan Gao Left ventricular mass index (LVMI) provides a metric for cardiovascular disease risk. We aimed to assess the association of adiponectin-related genetic variants resulting from GWAS in East Asians (loci in/near CDH13, ADIPOQ, WDR11FGF, CMIP and PEPD) with LVMI, and to examine whether sleep duration modified these genetic associations in youth. The 559 subjects aged 15–28 years were recruited from the Beijing Child and Adolescent Metabolic Syndrome study. Among the six loci, CDH13 rs4783244 was significantly correlated with adiponectin levels (p = 8.07 × 10−7). The adiponectin-rising allele in rs4783244 locus was significantly associated with decreased LVMI (p = 6.99 × 10−4) after adjusting for classical cardiovascular risk factors, and further for adiponectin levels, while no significant association was found between the other loci and LVMI. Moreover, we observed a significant interaction effect between rs4783244 and sleep duration (p = .005) for LVMI; the genetic association was more evident in long sleep duration while lost in short sleep duration. Similar interaction was found in the subgroup analysis using longitudinal data (p = .025 for interaction). In this young Chinese population, CDH13 rs4783244 represents a key locus for cardiac structure, and confers stronger cardio-protection in longer sleep duration when contrasted with short sleep duration.
       
  • Comprehending a Killer: The Akt/mTOR Signaling Pathways Are Temporally
           High-Jacked by the Highly Pathogenic 1918 Influenza Virus

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Charlene Ranadheera, Kevin M. Coombs, Darwyn Kobasa Previous transcriptomic analyses suggested that the 1918 influenza A virus (IAV1918), one of the most devastating pandemic viruses of the 20th century, induces a dysfunctional cytokine storm and affects other innate immune response patterns. Because all viruses are obligate parasites that require host cells for replication, we globally assessed how IAV1918 induces host protein dysregulation. We performed quantitative mass spectrometry of IAV1918-infected cells to measure host protein dysregulation. Selected proteins were validated by immunoblotting and phosphorylation levels of members of the PI3K/AKT/mTOR pathway were assessed. Compared to mock-infected controls,>170 proteins in the IAV1918-infected cells were dysregulated. Proteins mapped to amino sugar metabolism, purine metabolism, steroid biosynthesis, transmembrane receptors, phosphatases and transcription regulation. Immunoblotting demonstrated that IAV1918 induced a slight up-regulation of the lamin B receptor whereas all other tested virus strains induced a significant down-regulation. IAV1918 also strongly induced Rab5b expression whereas all other tested viruses induced minor up-regulation or down-regulation. IAV1918 showed early reduced phosphorylation of PI3K/AKT/mTOR pathway members and was especially sensitive to rapamycin. These results suggest the 1918 strain requires mTORC1 activity in early replication events, and may explain the unique pathogenicity of this virus.
       
  • Distinct Activities of Glycolytic Enzymes Identify Chronic Lymphocytic
           Leukemia Patients with a more Aggressive Course and Resistance to
           Chemo-Immunotherapy

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Georg Gdynia, Tadeusz Robak, Jürgen Kopitz, Anette Heller, Svetlana Grekova, Katarina Duglova, Gloria Laukemper, Monika Heinzel-Gutenbrunner, Cornelius Gutenbrunner, Wilfried Roth, Anthony D. Ho, Peter Schirmacher, Michael Schmitt, Peter Dreger, Leopold Sellner A higher capacity to grow under hypoxic conditions can lead to a more aggressive behavior of tumor cells. Determining tumor activity under hypoxia may identify chronic lymphocytic leukemia (CLL) with aggressive clinical course and predict response to chemo-immunotherapy (CIT). A metabolic score was generated by determining pyruvate kinase and lactate dehydrogenase, key enzymes of glycolysis, ex vivo in primary CLL samples under normoxic and hypoxic conditions. This score was further correlated with clinical endpoints and response to CIT in 96 CLL patients. 45 patients were classified as metabolic high risk (HR), 51 as low risk (LR). Treatment-free survival (TFS) was significantly shorter in HR patients (median 394 vs 723 days, p = .021). 15 HR patients and 14 LR patients received CIT after sample acquisition. HR patients had a significantly shorter progression-free survival after treatment compared to LR patients (median 216 days vs not reached, p = .008). Multivariate analysis evaluating age, IGHV, TP53 deletion or mutation and 11q22–23 deletion besides the capacity of tumor cells to grow under severe hypoxic conditions identified the metabolic profile as the strongest independent risk factor for shorter TFS (hazard ratio 2.37, p = .011). The metabolic risk can provide prognostic and predictive information complementary to genetic biomarkers and identify patients who might benefit from alternative treatment approaches.
       
  • TP53 Mutation as Potential Negative Predictor for Response of Anti-CTLA-4
           Therapy in Metastatic Melanoma

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(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 
       
  • Identifying Circulating Tumor DNA Mutation Profiles in Metastatic Breast
           Cancer Patients with Multiline Resistance

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(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 PurposeIn 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.MethodA 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.ResultsThe 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.ConclusionctDNA 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.
       
  • A Predictive 7-Gene Assay and Prognostic Protein Biomarkers for Non-small
           Cell Lung Cancer

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Nancy Lan Guo, Afshin Dowlati, Rebecca A. Raese, Chunlin Dong, Guoan Chen, David G. Beer, Justine Shaffer, Salvi Singh, Ujala Bokhary, Lin Liu, John Howington, Thomas Hensing, Yong Qian PurposeThis study aims to develop a multi-gene assay predictive of the clinical benefits of chemotherapy in non-small cell lung cancer (NSCLC) patients, and substantiate their protein expression as potential therapeutic targets.Patients and methodsThe mRNA expression of 160 genes identified from microarray was analyzed in qRT-PCR assays of independent 337 snap-frozen NSCLC tumors to develop a predictive signature. A clinical trial JBR.10 was included in the validation. Hazard ratio was used to select genes, and decision-trees were used to construct the predictive model. Protein expression was quantified with AQUA in 500 FFPE NSCLC samples.ResultsA 7-gene signature was identified from training cohort (n = 83) with accurate patient stratification (P = 0.0043) and was validated in independent patient cohorts (n = 248, P 
       
  • Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated
           with Lung Adenocarcinoma

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(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 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.
       
  • Inhibition of Microsomal Prostaglandin E Synthase-1 in Cancer-Associated
           Fibroblasts Suppresses Neuroblastoma Tumor Growth

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(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 Unlabelled Image
       
  • Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Manao Kinoshita, Yuri Hirayama, Kayoko Fujishita, Keisuke Shibata, Youichi Shinozaki, Eiji Shigetomi, Akiko Takeda, Ha Pham Ngoc Le, Hideaki Hayashi, Miki Hiasa, Yoshinori Moriyama, Kazuhiro Ikenaka, Kenji F. Tanaka, Schuichi Koizumi Although psychotropic drugs act on neurons and glial cells, how glia respond, and whether glial responses are involved in therapeutic effects are poorly understood. Here, we show that fluoxetine (FLX), an anti-depressant, mediates its anti-depressive effect by increasing the gliotransmission of ATP. FLX increased ATP exocytosis via vesicular nucleotide transporter (VNUT). FLX-induced anti-depressive behavior was decreased in astrocyte-selective VNUT-knockout mice or when VNUT was deleted in mice, but it was increased when astrocyte-selective VNUT was overexpressed in mice. This suggests that VNUT-dependent astrocytic ATP exocytosis has a critical role in the therapeutic effect of FLX. Released ATP and its metabolite adenosine act on P2Y11 and adenosine A2b receptors expressed by astrocytes, causing an increase in brain-derived neurotrophic factor in astrocytes. These findings suggest that in addition to neurons, FLX acts on astrocytes and mediates its therapeutic effects by increasing ATP gliotransmission.
       
  • Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce
           Temporal Lobe Epilepsy

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Matt R. Kelley, Ross A. Cardarelli, Joshua L. Smalley, Thomas A. Ollerhead, Peter M. Andrew, Nicholas J. Brandon, Tarek Z. Deeb, Stephen J. Moss Mesial temporal lobe epilepsy (mTLE) is the most common form of epilepsy, believed to arise in part from compromised GABAergic inhibition. The neuronal specific K+/Cl− co-transporter 2 (KCC2) is a critical determinant of the efficacy of GABAergic inhibition and deficits in its activity are observed in mTLE patients and animal models of epilepsy. To test if reductions of KCC2 activity directly contribute to the pathophysiology of mTLE, we locally ablated KCC2 expression in a subset of principal neurons within the adult hippocampus. Deletion of KCC2 resulted in compromised GABAergic inhibition and the development of spontaneous, recurrent generalized seizures. Moreover, local ablation of KCC2 activity resulted in hippocampal sclerosis, a key pathological change seen in mTLE. Collectively, our results demonstrate that local deficits in KCC2 activity within the hippocampus are sufficient to precipitate mTLE.
       
  • Enriched Brain Omega-3 Polyunsaturated Fatty Acids Confer Neuroprotection
           against Microinfarction

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Chuanming Luo, Huixia Ren, Xiaoli Yao, Zhe Shi, Fengyin Liang, Jing X. Kang, Jian-bo Wan, Zhong Pei, Kuan-Pin Su, Huanxing Su Cerebral microinfarcts have significant effects on the development of geriatric neurological disorders, including vascular dementia and Alzheimer's disease. However, little is known about the pathophysiological mechanisms involved in the evolution of microinfarcts and potential treatment and prevention against these microvascular ischemic lesions. In the present study, the “single cortical microinfarct model” generated via occluding a penetrating arteriole by femtosecond laser ablation and the “multiple diffuse microinfarcts model” induced by unilateral injection of cholesterol crystals through the internal carotid artery were established to investigate the pathophysiological mechanisms underlying the evolution of microinfarcts and the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on alleviating microinfarct burdens and functional deficits. The occlusion of a single penetrating arteriole led to a distinct cortical microinfarct, which manifested as neuronal loss and occupation of activated glial cells in the ischemic core. Using Fat-1 transgenic mice and fish oil supplements, we demonstrated that both endogenously-generated and exogenously-delivered ω-3 PUFAs significantly inhibited the activation of receptor-interacting serine/threonine protein kinases 1 (RIPK1) and its downstream apoptosis-associated proteins, mitigated cell apoptosis, and anatomically reduced the microinfarct size. The protective effects of ω-3 PUFAs against microinfarcts were further verified in a multiple diffuse microinfarcts model, where ω-3 PUFAs significantly attenuated cell apoptosis as revealed by TUNEL staining, alleviated the diffuse microinfarct burdens and remarkably improved the functional deficits as evidenced by reduced spontaneous anxiety, increased preference for the novel object, and improved hippocampal-based learning and short-term memory. Together, these findings demonstrate that enriched brain ω-3 PUFAs are effective for reducing microinfarct burdens and improving the function deficits, which support the clinical research and application of ω-3 PUFAs in the treatment or prophylaxis in vascular dementia.
       
  • Leptin/Osteopontin Axis Regulated Type 2T Helper Cell Response in Allergic
           Rhinitis with Obesity

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Qingxiang Zeng, Xi Luo, Miaomiao Han, Wenlong Liu, Huabin Li The prevalence of allergic rhinitis (AR) and obesity in children increased concurrently during recent decades. However, the molecular pathway involved in the interaction between obesity and AR is still unclear. We aimed to investigate the interaction between leptin and osteopontin (OPN) and their effect on T helper (TH) response in the development of AR in children. Thirty AR and 30 healthy children with or without obesity were enrolled. Serum leptin and OPN levels were measured and their relationship with TH1/2 cytokines was analyzed. TH cell differentiation and cytokine production in peripheral blood mononuclear cells (PBMCs) stimulated by leptin and/or OPN were analyzed by enzyme linked immunosorbent assay (ELISA). Obese AR mice models were established to verify the effect of obesity on leptin and OPN as well TH regulation. Immunoprecipitation was performed to confirm the interaction between OPN and leptin in CD4+ T cells. Our results showed elevated serum leptin and OPN in AR children correlated with TH2 cytokines expression. Leptin and OPN enhanced TH2 inflammation in house dust mite stimulated PBMCs from AR children synergistically. Obese AR mice showed as more severe inflammatory reaction, symptoms and expression of nasal leptin and OPN compared with other groups. Immunoprecipitation suggested that OPN and leptin may interact with each other and this process may be mediated by α4 integrin and PI3K/AKT pathway in CD4+ T cells. Our data provide evidence that leptin-mediated OPN upregulation promote TH2 inflammation in AR and this process is achieved through the α4 integrin and PI3K/AKT signaling pathways.
       
  • Mesenchymal Stromal Cells Directly Promote Inflammation by Canonical NLRP3
           and Non-canonical Caspase-11 Inflammasomes

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(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 Unlabelled Image
       
  • Gefitinib for Epidermal Growth Factor Receptor Activated Osteoarthritis
           Subpopulation Treatment

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Heng Sun, Yan Wu, Zongyou Pan, Dongsheng Yu, Pengfei Chen, Xiaoan Zhang, Haoyu Wu, Xiaolei Zhang, Chengrui An, Yishan Chen, Tian Qin, Xiaoyue Lei, Chunhui Yuan, Shufang Zhang, Weiguo Zou, Hongwei Ouyang Osteoarthritis (OA) is a leading cause of physical disability among aging populations, with no available drugs able to efficiently restore the balance between cartilage matrix synthesis and degradation. Also, OA has not been accurately classified into subpopulations, hindering the development toward personalized precision medicine.In the present study, we identified a subpopulation of OA patients displaying high activation level of epidermal growth factor receptor (EGFR). With Col2a1-creERT2; Egfrf/f mice, it was found that the activation of EGFR, indicated by EGFR phosphorylation (pEGFR), led to the destruction of joints. Excitingly, EGFR inhibition prohibited cartilage matrix degeneration and promoted cartilage regeneration. The Food and Drug Administration (FDA)-approved drug gefitinib could efficiently inhibit EGFR functions in OA joints and restore cartilage structure and function in the mouse model as well as the clinical case report.Overall, our findings suggested the concept of the EGFR activated OA subpopulation and illustrated the mechanism of EGFR signaling in regulating cartilage homeostasis. Gefitinib could be a promising disease-modifying drug for this OA subpopulation treatment.
       
  • Mesenchymal Stem Cells Control Complement C5 Activation by Factor H in
           Lupus Nephritis

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Haijun Ma, Chang Liu, Bingyu Shi, Zhuoya Zhang, Ruihai Feng, Minghao Guo, Liwei Lu, Songtao Shi, Xiang Gao, Wanjun Chen, Lingyun Sun Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus (SLE) caused by uncontrolled activation of the complement system. Mesenchymal stem cells (MSCs) exhibit clinical efficacy for severe LN in our previous studies, but the underlying mechanisms of MSCs regulating complement activation remain largely unknown. Here we show that significantly elevated C5a and C5b-9 were found in patients with LN, which were notably correlated with proteinuria and different renal pathological indexes of LN. MSCs suppressed systemic and intrarenal activation of C5, increased the plasma levels of factor H (FH), and ameliorated renal disease in lupus mice. Importantly, MSCs transplantation up-regulated the decreased FH in patients with LN. Mechanistically, interferon-α enhanced the secretion of FH by MSCs. These data demonstrate that MSCs inhibit the activation of pathogenic C5 via up-regulation of FH, which improves our understanding of the immunomodulatory mechanisms of MSCs in the treatment of lupus nephritis.Graphical Unlabelled Image
       
  • Oxysterol Signatures Distinguish Age-Related Macular Degeneration from
           Physiologic Aging

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Jonathan B. Lin, Abdoulaye Sene, Andrea Santeford, Hideji Fujiwara, Rohini Sidhu, Marianne M. Ligon, Vikram A. Shankar, Norimitsu Ban, Indira U. Mysorekar, Daniel S. Ory, Rajendra S. Apte Macrophage aging is pathogenic in numerous diseases, including age-related macular degeneration (AMD), a leading cause of blindness in older adults. Although prior studies have explored the functional consequences of macrophage aging, less is known about its cellular basis or what defines the transition from physiologic aging to disease. Here, we show that despite their frequent self-renewal, macrophages from old mice exhibited numerous signs of aging, such as impaired oxidative respiration. Transcriptomic profiling of aged murine macrophages revealed dysregulation of diverse cellular pathways, especially in cholesterol homeostasis, that manifested in altered oxysterol signatures. Although the levels of numerous oxysterols in human peripheral blood mononuclear cells and plasma exhibited age-associated changes, plasma 24-hydroxycholesterol levels were specifically associated with AMD. These novel findings demonstrate that oxysterol levels can discriminate disease from physiologic aging. Furthermore, modulation of cholesterol homeostasis may be a novel strategy for treating age-associated diseases in which macrophage aging is pathogenic.
       
  • Model Animal Mimicking Human Virus-induced Diabetes

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Keiichiro Mine, Hirokazu Takahashi, Seiho Nagafuchi
       
  • The Promising Role of New Generation HDACis in Anti-Cancer Therapies

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Eric Hervouet
       
  • Epithelial Signaling through the RUNX1/AKT Pathway: A New Therapeutic
           Target in Kidney Fibrosis

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Pierre Galichon
       
  • Predicting Treatment Outcomes: The Case for Hypoxia Gene Signatures

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Laure Marignol
       
  • Liver Imaging in Precision Medicine

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Jiahong Dong, Xiaolong Qi
       
  • RankProd Combined with Genetic Algorithm Optimized Artificial Neural
           Network Establishes a Diagnostic and Prognostic Prediction Model that
           Revealed C1QTNF3 as a Biomarker for Prostate Cancer

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(s): Qi Hou, Zhi-Tong Bing, Cheng Hu, Mao-Yin Li, Ke-Hu Yang, Zu Mo, Xiang-Wei Xie, Ji-Lin Liao, Yan Lu, Shigeo Horie, Ming-Wu Lou Prostate cancer (PCa) is the most commonly diagnosed cancer in males in the Western world. Although prostate-specific antigen (PSA) has been widely used as a biomarker for PCa diagnosis, its results can be controversial. Therefore, new biomarkers are needed to enhance the clinical management of PCa. From publicly available microarray data, differentially expressed genes (DEGs) were identified by meta-analysis with RankProd. Genetic algorithm optimized artificial neural network (GA-ANN) was introduced to establish a diagnostic prediction model and to filter candidate genes. The diagnostic and prognostic capability of the prediction model and candidate genes were investigated in both GEO and TCGA datasets. Candidate genes were further validated by qPCR, Western Blot and Tissue microarray. By RankProd meta-analyses, 2306 significantly up- and 1311 down-regulated probes were found in 133 cases and 30 controls microarray data. The overall accuracy rate of the PCa diagnostic prediction model, consisting of a 15-gene signature, reached up to 100% in both the training and test dataset. The prediction model also showed good results for the diagnosis (AUC = 0.953) and prognosis (AUC of 5 years overall survival time = 0.808) of PCa in the TCGA database. The expression levels of three genes, FABP5, C1QTNF3 and LPHN3, were validated by qPCR. C1QTNF3 high expression was further validated in PCa tissue by Western Blot and Tissue microarray. In the GEO datasets, C1QTNF3 was a good predictor for the diagnosis of PCa (GSE6956: AUC = 0.791; GSE8218: AUC = 0.868; GSE26910: AUC = 0.972). In the TCGA database, C1QTNF3 was significantly associated with PCa patient recurrence free survival (P 
       
  • Recellularization of Decellularized Venous Grafts Using Peripheral Blood:
           A Critical Evaluation

    • Abstract: Publication date: June 2018Source: EBioMedicine, Volume 32Author(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.
       
  • 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

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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 BackgroundModulation of genetic variants on the effect of omega-3 fatty acid supplements on blood lipids is still unclear.MethodsIn 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.FindingsSignificant 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.InterpretationThis 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.
       
  • Activation of AMPK for a Break in Hepatic Lipid Accumulation and
           Circulating Cholesterol

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(s): Marc Foretz, Benoit Viollet
       
  • Vitamin D as a Potential Therapeutic Target and Prognostic Marker for
           Colorectal Cancer

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(s): Vasile V. Bintintan
       
  • The Engagement Between Vitamin D and the Immune System: Is Consolidation
           by a Marriage to Be Expected'

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(s): Jan Damoiseaux, Joost Smolders
       
  • Microbial Effects on Immunity in HIV: Virus, Gender or Sexual Preference
           Induced'

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(s): Nichole R. Klatt, Jennifer A. Manuzak
       
  • Preoperative Prediction of Node Metastases in Bladder Cancer Patients
           Using Genomic and Clinicopathologic Data

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(s): Marco Moschini, Francesco Montorsi
       
  • Tandem Repeats and Repeatomes: Delving Deeper into the ‘Dark
           Matter’ of Genomes

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(s): Anthony J. Hannan
       
  • The Tumor Microenvironment: A Druggable Target for Metastatic Disease'

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(s): EBioMedicine
       
  • Lighting a Fire in the Tumor Microenvironment Using Oncolytic
           Immunotherapy

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Correlates of Protection Against SIVmac251 Infection in Rhesus Macaques
           Immunized With Chimpanzee-Derived Adenovirus Vectors

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • A Validated Clinical Risk Prediction Model for Lung Cancer in Smokers of
           All Ages and Exposure Types: A HUNT Study

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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>20 years in 1995–97. After a median of 15·2 years, 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 11·6 years.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 6 years. Only 22% of ever-smokers would need screening to identify 81·85% of all lung cancers within 6 years.Our model of seven variables is simple, accurate, and useful for screening selection.
       
  • Effect of Trinucleotide Repeats in the Huntington's Gene on Intelligence

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(s): Jessica K. Lee, Amy Conrad, Eric Epping, Kathy Mathews, Vincent Magnotta, Jeffrey D. Dawson, Peg Nopoulos BackgroundHuntington'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.MethodsWe 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.FindingsThe 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.InterpretationHTT 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.
       
  • A Genomic-clinicopathologic Nomogram for the Preoperative Prediction of
           Lymph Node Metastasis in Bladder Cancer

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Genetic restriction of antigen-presentation dictates allergic
           sensitization and disease in humanized mice

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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 BackgroundImmunoglobulin(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.ObjectiveTo determine the key factors for sensitization and allergy towards a given allergen.MethodsWe 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.ResultsAcute 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.ConclusionsWe 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.
       
  • A Systems Approach to Refine Disease Taxonomy by Integrating Phenotypic
           and Molecular Networks

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Salmonella Typhi Colonization Provokes Extensive Transcriptional Changes
           Aimed at Evading Host Mucosal Immune Defense During Early Infection of
           Human Intestinal Tissue

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Integrative (epi) Genomic Analysis to Predict Response to
           Androgen-Deprivation Therapy in Prostate Cancer

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Genomic Response to Vitamin D Supplementation in the Setting of a
           Randomized, Placebo-Controlled Trial

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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 BackgroundVitamin 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.MethodsIn 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.FindingsAllocation 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 
       
  • Reduced Cortical Excitability, Neuroplasticity, and Salivary Cortisol in
           11–13-Year-Old Children Born to Women with Gestational Diabetes Mellitus
           

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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 BackgroundChildren 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.MethodsUsing 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.FindingsGDM-exposed children had reduced cortical excitability (p = .003), LTD-like neuroplasticity (p = .005), and salivary cortisol (p 
       
  • Therapeutic Injury and Tumor Regrowth: Tumor Resection and Radiation
           Establish the Recurrent Glioblastoma Microenvironment

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(s): Daniel J. Silver, Justin D. Lathia
       
  • Mass Spectrometric Identification of Urinary Biomarkers of Pulmonary
           Tuberculosis

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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 BackgroundTuberculosis (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.MethodsWe 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.ResultsWe 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.ConclusionUrinary 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.FundingThis study was funded by Weill Cornell Medicine, the National Institute of Allergy and Infectious Diseases, the Clinical and Translational Science Center at Weill Cornell, the NIH Fogarty International Center grants, and the NIH Tuberculosis Research Unit (Tri-I TBRU).
       
  • Predominant Asymmetrical Stem Cell Fate Outcome Limits the Rate of Niche
           Succession in Human Colonic Crypts

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Prognostic Role of Gene Mutations in Chronic Myelomonocytic Leukemia
           Patients Treated With Hypomethylating Agents

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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 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 TET2mut/ASXL1wt 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, RUNX1mut (Hazard Ratio [HR] = 2.00, p = .011), CBLmut (HR = 1.90, p = 0.03) genotypes and higher WBC (log10(WBC) HR = 2.30, p = .005) independently predicted worse OS while the TET2mut/ASXL1wt 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.
       
  • Development and Validation of a 28-gene Hypoxia-related Prognostic
           Signature for Localized Prostate Cancer

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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 BackgroundHypoxia 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.MethodHypoxia 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).ResultsA 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 
       
  • The Novel Pathogenesis of Retinopathy Mediated by Multiple RTK Signals is
           Uncovered in Newly Developed Mouse Model

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Adipocyte-derived Lysophosphatidylcholine Activates Adipocyte and Adipose
           Tissue Macrophage Nod-Like Receptor Protein 3 Inflammasomes Mediating
           Homocysteine-Induced Insulin Resistance

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • 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

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Interventions Targeting Glucocorticoid-Krüppel-like Factor
           15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in
           Spinal Muscular Atrophy Mice

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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 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 Smn2B/− 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.
       
  • DNA Methylation Patterns in Normal Tissue Correlate more Strongly with
           Breast Cancer Status than Copy-Number Variants

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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 Unlabelled Image
       
  • SOX30 Inhibits Tumor Metastasis through Attenuating Wnt-Signaling via
           Transcriptional and Posttranslational Regulation of β-Catenin in Lung
           Cancer

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Roles of Alternative RNA Splicing of the Bif-1 Gene by SRRM4 During the
           Development of Treatment-induced Neuroendocrine Prostate Cancer

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Inhibition of HDACs-EphA2 Signaling Axis with WW437 Demonstrates Promising
           Preclinical Antitumor Activity in Breast Cancer

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Hydroxylase Activity of ASPH Promotes Hepatocellular Carcinoma Metastasis
           Through Epithelial-to-Mesenchymal Transition Pathway

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Circulating Salivary miRNA hsa-miR-221 as Clinically Validated Diagnostic
           Marker for Hand, Foot, and Mouth Disease in Pediatric Patients

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and
           Immunity in α-Synuclein Aggregation Disorders

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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.
       
  • Corrigendum to “Fecal Clostridium Symbiosum for Noninvasive Detection of
           Early and Advanced Colorectal Cancer: Test and Validation Studies”
           [Ebiomedicine 25 (2017) 32–40]

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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
       
  • Corrigendum to “Heterologous Two-dose Vaccination with Simian Adenovirus
           and Poxvirus Vectors Elicits Long-lasting Cellular Immunity to Influenza
           Virus A in Healthy Adults” [EBioMedicine 29 (2018) 146–154]

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(s): L. Coughlan, S. Sridhar, R. Payne, M. Edmans, A. Milicic, N. Venkatraman, B. Lugonja, L. Clifton, C. Qi, P.M. Folegatti, A.M. Lawrie, R. Roberts, H. de Graaf, P. Sukhtankar, S.N. Faust, D.J.M. Lewis, T. Lambe, A.V.S. Hill, S.C. Gilbert
       
  • Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers
           Cholesterol in Rodent and Primate Preclinical Models

    • Abstract: Publication date: May 2018Source: EBioMedicine, Volume 31Author(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 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.
       
 
 
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