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Author Lacovich, V.; Espindola, S.L.; Alloatti, M.; Pozo Devoto, V.; Cromberg, L.E.; Carna, M.E.; Forte, G.; Gallo, J.-M.; Bruno, L.; Stokin, G.B.; Avale, M.E.; Falzone, T.L. url  doi
openurl 
  Title Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons Type Journal Article
  Year 2017 Publication The Journal of Neuroscience : the Official Journal of the Society for Neuroscience Abbreviated Journal J Neurosci  
  Volume (down) 37 Issue 1 Pages 58-69  
  Keywords App; Alzheimer's; axonal transport; splicing; tau; tauopathies  
  Abstract Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically in APP dynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes. SIGNIFICANCE STATEMENT: The tau protein has a relevant role in the transport of cargos throughout neurons. Dysfunction in tau metabolism underlies several neurological disorders leading to dementia. In the adult human brain, two tau isoforms are found in equal amounts, whereas changes in such equilibrium have been associated with neurodegenerative diseases. We investigated the role of tau in human neurons in culture and found that perturbations in the endogenous balance of tau isoforms were sufficient to impair the transport of the Alzheimer's disease-related amyloid precursor protein (APP), although neuronal morphology was normal. Our results provide evidence of a direct relationship between tau isoform imbalance and defects in axonal transport, which induce an abnormal APP metabolism with important implications in neurodegeneration.  
  Address Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires C1428ADN, Argentina  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0270-6474 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28053030 Approved no  
  Call Number ref @ user @ Serial 95902  
Permanent link to this record
 

 
Author Jin, W.-L.; Mao, X.-Y.; Qiu, G.-Z. url  doi
openurl 
  Title Targeting Deubiquitinating Enzymes in Glioblastoma Multiforme: Expectations and Challenges Type Journal Article
  Year 2017 Publication Medicinal Research Reviews Abbreviated Journal Med Res Rev  
  Volume (down) 37 Issue 3 Pages 627-661  
  Keywords Animals; Carcinogenesis/pathology; Deubiquitinating Enzymes/antagonists & inhibitors/*metabolism; Enzyme Inhibitors/pharmacology; Glioblastoma/*enzymology/*therapy; Humans; *Molecular Targeted Therapy; Neoplastic Stem Cells/drug effects/pathology; DUB inhibitor; DUBs; glioblastoma; glioma stem cells; proteasome  
  Abstract Glioblastoma (GBM) is regarded as the most common primary intracranial neoplasm. Despite standard treatment with tumor resection and radiochemotherapy, the outcome remains gloomy. It is evident that a combination of oncogenic gain of function and tumor-suppressive loss of function has been attributed to glioma initiation and progression. The ubiquitin-proteasome system is a well-orchestrated system that controls the fate of most proteins by striking a dynamic balance between ubiquitination and deubiquitination of substrates, having a profound influence on the modulation of oncoproteins, tumor suppressors, and cellular signaling pathways. In recent years, deubiquitinating enzymes (DUBs) have emerged as potential anti-cancer targets due to their targeting several key proteins involved in the regulation of tumorigenesis, apoptosis, senescence, and autophagy. This review attempts to summarize recent studies of GBM-associated DUBs, their roles in various cellular processes, and discuss the relation between DUBs deregulation and gliomagenesis, especially how DUBs regulate glioma stem cells pluripotency, microenvironment, and resistance of radiation and chemotherapy through core stem-cell transcriptional factors. We also review recent achievements and progress in the development of potent and selective reversible inhibitors of DUBs, and attempted to find a potential GBM treatment by DUBs intervention.  
  Address Department of Neurosurgery, General Hospital of Jinan Military Command, Jinan, 250031, P. R. China  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0198-6325 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27775833 Approved no  
  Call Number ref @ user @ Serial 96629  
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Author Jimenez, M.M.; Arias, J.; Carrasquilla, G. url  openurl
  Title Seroprevalence of dengue infection in the municipalities of Armenia, Calarca, La Tebaida and Montenegro in Quindio, 2014 Type Journal Article
  Year 2017 Publication Biomedica : Revista del Instituto Nacional de Salud Abbreviated Journal Biomedica  
  Volume (down) 37 Issue 1 Pages 34-41  
  Keywords Dengue/epidemiology; immunoglobulin G; immunoglobulin M; prevalence; public health, Colombia  
  Abstract INTRODUCTION: Dengue is a serious public health problem in Colombia; it is prevalent in 90% of the municipalities in Quindio. Studies on its seroprevalence are required to address public health interventions. OBJECTIVE: To establish the seroprevalence of dengue infection in neighborhoods with high incidence in the municipalities of Armenia, Calarca, La Tebaida and Montenegro, Quindio, in 2014. MATERIALS AND METHODS: We conducted a probabilistic, stratified, two-stage prevalence study. We interviewed 658 residents in the urban area of the selected municipalities. After they signed the informed consent, we took a blood sample to determine dengue IgG and IgM antibodies. RESULTS: Seroprevalence of IgG in Quindio was 89,4%; in Armenia it was 88,7%, in Calarca, 81,5%, in Montenegro, 91,8% and in La Tebaida 97,8%. IgM was 14, 2% in Quindio; in Armenia it was 11,5%, in Calarca, 13,0%, in Montenegro, 13,1% and in La Tebaida, 28,9%. CONCLUSIONS: We found a high prevalence of both IgG and IgM in the four municipalities. We had positive results for IgM in all age groups, which suggests recent infection. We also found simultaneous seropositivity for IgG and IgM (12.9%), which may indicate infection by another serotype or presence of infection in the past three months. A multisectoral approach is necessary for dengue control in Quindio.  
  Address Eje de Salud Publica, Fundacion Santa Fe de Bogota, Bogota, D.C., Colombia. monica.jimenez@fsfb.org.co  
  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 0120-4157 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28527246 Approved no  
  Call Number ref @ user @ Serial 97637  
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Author Sareddy, G.R.; Viswanadhapalli, S.; Surapaneni, P.; Suzuki, T.; Brenner, A.; Vadlamudi, R.K. url  doi
openurl 
  Title Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway Type Journal Article
  Year 2017 Publication Oncogene Abbreviated Journal Oncogene  
  Volume (down) 36 Issue 17 Pages 2423-2434  
  Keywords Animals; Apoptosis/*drug effects; Cell Differentiation/*drug effects; Cell Line, Tumor; Cell Survival/drug effects; Cell Transformation, Neoplastic; Disease Progression; Enzyme Inhibitors/*pharmacology; Gene Expression Regulation, Neoplastic/drug effects; Glioma/*pathology; Histone Demethylases/*antagonists & inhibitors; Mice; Neoplastic Stem Cells/*drug effects/metabolism/pathology; Signal Transduction/drug effects; Survival Analysis; Transcription, Genetic/drug effects; Unfolded Protein Response/*drug effects  
  Abstract Glioma stem cells (GSCs) have a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we showed that lysine demethylase KDM1A is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A-specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and patient-derived GBMs using both in vitro assays and in vivo orthotopic preclinical models. Our results suggested that KDM1A is highly expressed in GSCs and knockdown of KDM1A using shRNA-reduced GSCs stemness and induced the differentiation. Pharmacological inhibition of KDM1A using NCL-1 and NCD-38 significantly reduced the cell viability, neurosphere formation and induced apoptosis of GSCs with little effect on differentiated cells. In preclinical studies using orthotopic models, NCL-1 and NCD-38 significantly reduced GSCs-driven tumor progression and improved mice survival. RNA-sequencing analysis showed that KDM1A inhibitors modulate several pathways related to stemness, differentiation and apoptosis. Mechanistic studies showed that KDM1A inhibitors induce activation of the unfolded protein response (UPR) pathway. These results strongly suggest that selective targeting of KDM1A using NCL-1 and NCD-38 is a promising therapeutic strategy for elimination of GSCs.  
  Address Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, 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 0950-9232 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27893719 Approved no  
  Call Number ref @ user @ Serial 96621  
Permanent link to this record
 

 
Author Clark, P.A.; Gaal, J.T.; Strebe, J.K.; Pasch, C.A.; Deming, D.A.; Kuo, J.S.; Robins, H.I. url  doi
openurl 
  Title The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells Type Journal Article
  Year 2017 Publication Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia Abbreviated Journal J Clin Neurosci  
  Volume (down) 36 Issue Pages 120-124  
  Keywords Antineoplastic Agents, Alkylating/*pharmacology; Cell Line, Tumor; Cell Proliferation/drug effects/radiation effects; Cell Survival/drug effects/radiation effects; Cells, Cultured; DNA Modification Methylases/genetics/*metabolism; DNA Repair Enzymes/genetics/*metabolism; Dacarbazine/*analogs & derivatives/pharmacology; *Electromagnetic Fields; Glioblastoma/genetics/*metabolism; Humans; Neoplastic Stem Cells/drug effects/radiation effects; Neurons/drug effects/radiation effects; Tumor Suppressor Proteins/genetics/*metabolism; Cancer stem cells; Glioblastoma; MGMT methylation; Temozolomide; Tumor treating fields  
  Abstract A recent Phase 3 study of newly diagnosed glioblastoma (GBM) demonstrated the addition of tumor treating fields (TTFields) to temozolomide (TMZ) after combined radiation/TMZ significantly increased survival and progression free survival. Preliminary data suggested benefit with both methylated and unmethylated O-6-methylguanine-DNA methyl-transferase (MGMT) promoter status. To date, however, there have been no studies to address the potential interactions of TTFields and TMZ. Thus, the effects of TTFields and TMZ were studied in vitro using patient-derived GBM stem-like cells (GSCs) including MGMT expressing (TMZ resistant: 12.1 and 22GSC) and non-MGMT expressing (TMZ sensitive: 33 and 114GSC) lines. Dose-response curves were constructed using cell proliferation and sphere-forming assays. Results demonstrated a 10-fold increase in TMZ resistance of MGMT-expressing (12.1GSCs: IC50=160muM; 22GSCs: IC50=44muM) compared to MGMT non-expressing (33GSCs: IC50=1.5muM; 114GSCs: IC50=5.2muM) lines. TTFields inhibited 12.1 GSC proliferation at all tested doses (50-500kHz) with an optimal frequency of 200kHz. At 200kHz, TTFields inhibited proliferation and tumor sphere formation of both MGMT GSC subtypes at comparable levels (12.1GSC: 74+/-2.9% and 38+/-3.2%, respectively; 22GSC: 61+/-11% and 38+/-2.6%, respectively; 33GSC: 56+/-9.5% and 60+/-7.1%, respectively; 114 GSC: 79+/-3.5% and 41+/-4.3%, respectively). In combination, TTFields (200kHz) and TMZ showed an additive anti-neoplastic effect with equal efficacy for TTFields in both cell types (i.e., +/- MGMT expression) with no effect on TMZ resistance. This is the first demonstration of the effects of TTFields on cancer stem cells. The expansion of such studies may have clinical implications.  
  Address University of Wisconsin Carbone Cancer Center, UWSMPH, United States; Division of Hematology and Oncology, Department of Medicine, UWSMPH, United States; William S Middleton Memorial Veterans Hospital, Madison, WI, United States; Department of Neurology, UWSMPH, United States; Department of Human Oncology, UWSMPH, United States. Electronic address: hirobins@wisc.edu  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0967-5868 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27865821 Approved no  
  Call Number ref @ user @ Serial 96622  
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