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Author Li, M.; Xiao, A.; Floyd, D.; Olmez, I.; Lee, J.; Godlewski, J.; Bronisz, A.; Bhat, K.P.L.; Sulman, E.P.; Nakano, I.; Purow, B. url  doi
openurl 
  Title CDK4/6 inhibition is more active against the glioblastoma proneural subtype Type Journal Article
  Year 2017 Publication Oncotarget Abbreviated Journal Oncotarget  
  Volume 8 Issue 33 Pages 55319-55331  
  Keywords Cdk4/6; glioblastoma; mesenchymal; palbociclib; proneural  
  Abstract Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17 92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM. Consistently, CDK4/6 inhibition with palbociclib preferentially inhibited cell proliferation in vitro in a majority of proneural GSCs versus those of other subtypes. Palbociclib treatment significantly prolonged survival of mice with established intracranial xenografts of a proneural GSC line. We show that most of these sensitive PN GSCs expressed higher levels of CDK6 and had intact Rb1, while two GSC lines with CDK4 overexpression and null Rb1 were highly resistant to palbociclib. Importantly, palbociclib treatment of proneural GSCs upregulated mesenchymal-associated markers and downregulated proneural-associated markers, suggesting that CDK4/6 inhibition induced proneural-mesenchymal transition and underscoring the enhanced role of the E2F cell cycle pathway in the proneural subtype. Lastly, the combination of palbociclib and N,N-diethylaminobenzaldehyde, an inhibitor of the mesenchymal driver ALDH1A3, showed strong synergistic inhibitory effects against proneural GSC proliferation. Taken together, our results reveal that proneural GBM has increased vulnerability to CDK4/6 inhibition, and the proneural subtype undergoes dynamic reprogramming upon palbociclib treatment-suggesting the need for a combination therapeutic strategy.  
  Address Neuro-Oncology Division, Department of Neurology, University of Virginia, Charlottesville, VA, USA  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language (up) Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1949-2553 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28903422 Approved no  
  Call Number ref @ user @ Serial 96569  
Permanent link to this record
 

 
Author Cole, D.C.; Giordano, C.R.; Vasilopoulos, T.; Fahy, B.G. url  doi
openurl 
  Title Resident Physicians Improve Nontechnical Skills When on Operating Room Management and Leadership Rotation Type Journal Article
  Year 2017 Publication Anesthesia and Analgesia Abbreviated Journal Anesth Analg  
  Volume 124 Issue 1 Pages 300-307  
  Keywords  
  Abstract BACKGROUND: Anesthesiology residency primarily emphasizes the development of medical knowledge and technical skills. Yet, nontechnical skills (NTS) are also vital to successful clinical practice. Elements of NTS are communication, teamwork, situational awareness, and decision making. METHODS: The first 10 consecutive senior residents who chose to participate in this 2-week elective rotation of operating room (OR) management and leadership training were enrolled in this study, which spanned from March 2013 to March 2015. Each resident served as the anesthesiology officer of the day (AOD) and was tasked with coordinating OR assignments, managing care for 2 to 4 ORs, and being on call for the trauma OR; all residents were supervised by an attending AOD. Leadership and NTS techniques were taught via a standardized curriculum consisting of leadership and team training articles, crisis management text, and daily debriefings. Resident self-ratings and attending AOD and charge nurse raters used the Anaesthetists' Non-Technical Skills (ANTS) scoring system, which involved task management, situational awareness, teamwork, and decision making. For each of the 10 residents in their third year of clinical anesthesiology training (CA-3) who participated in this elective rotation, there were 14 items that required feedback from resident self-assessment and OR raters, including the daily attending AOD and charge nurse. Results for each of the items on the questionnaire were compared between the beginning and the end of the rotation with the Wilcoxon signed-rank test for matched samples. Comparisons were run separately for attending AOD and charge nurse assessments and resident self-assessments. Scaled rankings were analyzed for the Kendall coefficient of concordance (omega) for rater agreement with associated chi and P value. RESULTS: Common themes identified by the residents during debriefings were recurrence of challenging situations and the skills residents needed to instruct and manage clinical teams. For attending AOD and charge nurse assessments, resident performance of NTS improved from the beginning to the end of the rotation on 12 of the 14 NTS items (P < .05), whereas resident self-assessment improved on 3 NTS items (P < .05). Interrater reliability (across the charge nurse, resident, and AOD raters) ranged from omega = .36 to .61 at the beginning of the rotation and omega = .27 to .70 at the end of the rotation. CONCLUSIONS: This rotation allowed for teaching and resident assessment to occur in a way that facilitated resident education in several of the skills required to meet specific milestones. Resident physicians are able to foster NTS and build a framework for clinical leadership when completing a 2-week senior elective as an OR manager.  
  Address From the Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, Fla  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language (up) Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0003-2999 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27918336 Approved no  
  Call Number ref @ user @ Serial 95061  
Permanent link to this record
 

 
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 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 (up) 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 Polex-Wolf, J.; Yeo, G.S.H.; O'Rahilly, S. url  doi
openurl 
  Title Impaired prohormone processing: a grand unified theory for features of Prader-Willi syndrome? Type Journal Article
  Year 2017 Publication The Journal of Clinical Investigation Abbreviated Journal J Clin Invest  
  Volume 127 Issue 1 Pages 98-99  
  Keywords  
  Abstract Prader-Willi syndrome (PWS) is a complex disorder that manifests with an array of phenotypes, such as hypotonia and difficulties in feeding during infancy and reduced energy expenditure, hyperphagia, and developmental delays later in life. While the genetic cause has long been known, it is still not clear how mutations at this locus produce this array of phenotypes. In this issue of the JCI, Burnett and colleagues used a comprehensive approach to gain insight into how PWS-associated mutations drive disease. Using neurons derived from PWS patient induced pluripotent stem cells (iPSCs) and mouse models, the authors provide evidence that neuroendocrine PWS-associated phenotypes may be linked to reduced expression of prohormone convertase 1 (PC1). While these compelling results support a critical role for PC1 deficiency in PWS, more work needs to be done to fully understand how and to what extent loss of this prohormone processing enzyme underlies disease manifestations in PWS patients.  
  Address  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language (up) Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0021-9738 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27941250 Approved no  
  Call Number ref @ user @ Serial 95907  
Permanent link to this record
 

 
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 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  
  Publisher Place of Publication Editor  
  Language English Summary Language (up) Original Title  
  Series Editor Series Title Abbreviated Series Title  
  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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