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Author Vershkov, D.; Benvenisty, N. url  doi
openurl 
  Title Human pluripotent stem cells in modeling human disorders: the case of fragile X syndrome Type Journal Article
  Year 2017 Publication Regenerative Medicine Abbreviated Journal Regen Med  
  Volume 12 Issue (up) 1 Pages 53-68  
  Keywords disease modeling; drug discovery; embryonic stem cells; fragile X syndrome; human pluripotent stem cells; neural differentiation  
  Abstract Human pluripotent stem cells (PSCs) generated from affected blastocysts or from patient-derived somatic cells are an emerging platform for disease modeling and drug discovery. Fragile X syndrome (FXS), the leading cause of inherited intellectual disability, was one of the first disorders modeled in both embryonic stem cells and induced PCSs and can serve as an exemplary case for the utilization of human PSCs in the study of human diseases. Over the past decade, FXS-PSCs have been used to address the fundamental questions regarding the pathophysiology of FXS. In this review we summarize the methodologies for generation of FXS-PSCs, discuss their advantages and disadvantages compared with existing modeling systems and describe their utilization in the study of FXS pathogenesis and in the development of targeted treatment.  
  Address The Azrieli Center for Stem Cells & Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel  
  Corporate Author Thesis  
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  Language English Summary Language Original Title  
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  Series Volume Series Issue Edition  
  ISSN 1746-0751 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27900874 Approved no  
  Call Number ref @ user @ Serial 95909  
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Author Li, M.; Zhao, H.; Ananiev, G.E.; Musser, M.T.; Ness, K.H.; Maglaque, D.L.; Saha, K.; Bhattacharyya, A.; Zhao, X. url  doi
openurl 
  Title Establishment of Reporter Lines for Detecting Fragile X Mental Retardation (FMR1) Gene Reactivation in Human Neural Cells Type Journal Article
  Year 2017 Publication Stem Cells (Dayton, Ohio) Abbreviated Journal Stem Cells  
  Volume 35 Issue (up) 1 Pages 158-169  
  Keywords Drug discovery; Fmr1; Fmrp; Fragile X syndrome; High throughput; Induced pluripotent stem cells; Luciferase  
  Abstract Human patient-derived induced pluripotent stem cells (hiPSCs) provide unique opportunities for disease modeling and drug development. However, adapting hiPSCs or their differentiated progenies to high throughput assays for phenotyping or drug screening has been challenging. Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and a major genetic cause of autism. FXS is caused by mutational trinucleotide expansion in the FMR1 gene leading to hypermethylation and gene silencing. One potential therapeutic strategy is to reactivate the silenced FMR1 gene, which has been attempted using both candidate chemicals and cell-based screening. However, molecules that effectively reactivate the silenced FMR1 gene are yet to be identified; therefore, a high throughput unbiased screen is needed. Here we demonstrate the creation of a robust FMR1-Nluc reporter hiPSC line by knocking in a Nano luciferase (Nluc) gene into the endogenous human FMR1 gene using the CRISPR/Cas9 genome editing method. We confirmed that luciferase activities faithfully report FMR1 gene expression levels and showed that neural progenitor cells derived from this line could be optimized for high throughput screening. The FMR1-Nluc reporter line is a good resource for drug screening as well as for testing potential genetic reactivation strategies. In addition, our data provide valuable information for the generation of knockin human iPSC reporter lines for disease modeling, drug screening, and mechanistic studies. Stem Cells 2017;35:158-169.  
  Address Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin, USA  
  Corporate Author Thesis  
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  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1066-5099 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27422057 Approved no  
  Call Number ref @ user @ Serial 95937  
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Author Tahara, T.; Hirata, I.; Nakano, N.; Nagasaka, M.; Nakagawa, Y.; Shibata, T.; Ohmiya, N. url  doi
openurl 
  Title Comprehensive DNA Methylation Profiling of Inflammatory Mucosa in Ulcerative Colitis Type Journal Article
  Year 2017 Publication Inflammatory Bowel Diseases Abbreviated Journal Inflamm Bowel Dis  
  Volume 23 Issue (up) 1 Pages 165-173  
  Keywords  
  Abstract INTRODUCTION: Aberrant DNA methylation frequently occurs in the inflammatory mucosa in ulcerative colitis (UC) and is involved in UC-related tumorigenesis. We performed comprehensive DNA methylation profiling of the promoter regions of the inflamed rectal mucosae of patients with UC. DESIGN: The methylation status of the promoter CpG islands (CGIs) of 45 cancer/inflammation or age-related candidate genes and the LINE1 repetitive element were examined in the colonic mucosae of 84 cancer-free patients with UC by bisulfite pyrosequencing. Methylation status of selected genes (DPYS, N33, MIR1247, GSTP1, and SOX11) was also determined in 14 neoplastic lesions (5 with high-grade dysplasia and 9 with carcinoma) and 8 adjacent tissues derived from 12 patients. An Infinium HumanMethylation450 BeadChip array was used to characterize the methylation status of >450,000 CpG sites for 10 patients with UC. RESULTS: Clustering analysis based on the methylation status of the candidate genes clearly distinguished the inflammatory samples from the noninflammatory samples. The hypermethylation of the promoter CGIs strongly correlated with increased disease duration, which is a known risk factor for the development of colon cancer. Genome-wide methylation analyses revealed a high rate of hypermethylation in the severe phenotype of UC, particularly at the CGIs. Exclusively hypermethylated promoter CGIs in the severe phenotypes were significantly related to genes involved in biosynthetic processes, the regulation of metabolic processes, and nitrogen compound metabolic processes. CONCLUSION: Our findings suggest the potential utility of DNA methylation as a molecular marker and therapeutic target for UC-related tumorigenesis.  
  Address *Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan; and daggerDepartment of Gastroenterology, Tanimukai Hospital Japan, Nishinomiya, Japan  
  Corporate Author Thesis  
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  Language English Summary Language Original Title  
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  Series Volume Series Issue Edition  
  ISSN 1078-0998 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27930411 Approved no  
  Call Number ref @ user @ Serial 96375  
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Author Miranda, A.; Blanco-Prieto, M.; Sousa, J.; Pais, A.; Vitorino, C. url  doi
openurl 
  Title Breaching barriers in glioblastoma. Part I: Molecular pathways and novel treatment approaches Type Journal Article
  Year 2017 Publication International Journal of Pharmaceutics Abbreviated Journal Int J Pharm  
  Volume 531 Issue (up) 1 Pages 372-388  
  Keywords Glioblastoma; Molecular mechanisms; Temozolomide; Therapeutic advances; Therapeutic resistance  
  Abstract Glioblastoma multiforme (GBM) is the most common primary brain tumour, and the most aggressive in nature. The prognosis for patients with GBM remains poor, with a median survival time of only 1-2 years. The treatment failure relies on the development of resistance by tumour cells and the difficulty of ensuring that drugs effectively cross the dual blood brain barrier/blood brain tumour barrier. The advanced molecular and genetic knowledge has allowed to identify the mechanisms responsible for temozolomide resistance, which represents the standard of care in GBM, along with surgical resection and radiotherapy. Such resistance has motivated the researchers to investigate new avenues for GBM treatment intended to improve patient survival. In this review, we provide an overview of major obstacles to effective treatment of GBM, encompassing biological barriers, cancer stem cells, DNA repair mechanisms, deregulated signalling pathways and autophagy. New insights and potential therapy approaches for GBM are also discussed, emphasizing localized chemotherapy delivered directly to the brain, immunotherapy, gene therapy and nanoparticle-mediated brain drug delivery.  
  Address Faculty of Pharmacy, University of Coimbra, Portugal; Pharmacometrics Group of the Centre for Neurosciences and Cell Biology (CNC), University of Coimbra, Portugal. Electronic address: csvitorino@ff.uc.pt  
  Corporate Author Thesis  
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  Language English Summary Language Original Title  
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  Series Volume Series Issue Edition  
  ISSN 0378-5173 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28755993 Approved no  
  Call Number ref @ user @ Serial 96574  
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Author Voss, D.M.; Spina, R.; Carter, D.L.; Lim, K.S.; Jeffery, C.J.; Bar, E.E. url  doi
openurl 
  Title Disruption of the monocarboxylate transporter-4-basigin interaction inhibits the hypoxic response, proliferation, and tumor progression Type Journal Article
  Year 2017 Publication Scientific Reports Abbreviated Journal Sci Rep  
  Volume 7 Issue (up) 1 Pages 4292  
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  Abstract We have previously shown that glioblastoma stem cells (GSCs) are enriched in the hypoxic tumor microenvironment, and that monocarboxylate transporter-4 (MCT4) is critical for mediating GSC signaling in hypoxia. Basigin is involved in many physiological functions during early stages of development and in cancer and is required for functional plasma membrane expression of MCT4. We sought to determine if disruption of the MCT-Basigin interaction may be achieved with a small molecule. Using a cell-based drug-screening assay, we identified Acriflavine (ACF), a small molecule that inhibits the binding between Basigin and MCT4. Surface plasmon resonance and cellular thermal-shift-assays confirmed ACF binding to basigin in vitro and in live glioblastoma cells, respectively. ACF significantly inhibited growth and self-renewal potential of several glioblastoma neurosphere lines in vitro, and this activity was further augmented by hypoxia. Finally, treatment of mice bearing GSC-derived xenografts resulted in significant inhibition of tumor progression in early and late-stage disease. ACF treatment inhibited intratumoral expression of VEGF and tumor vascularization. Our work serves as a proof-of-concept as it shows, for the first time, that disruption of MCT binding to their chaperon, Basigin, may be an effective approach to target GSC and to inhibit angiogenesis and tumor progression.  
  Address Department of Neurological Surgery, Case Western Reserve University School of Medicine and The Case Comprehensive Cancer Center, Cleveland, OH, USA. eli.bar@case.edu  
  Corporate Author Thesis  
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  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 2045-2322 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28655889 Approved no  
  Call Number ref @ user @ Serial 96580  
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