A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-like Cells

SummaryGlioblastoma harbors a dynamic subpopulation of glioblastoma stem-like cells (GSCs) that can propagate tumors in vivo and is resistant to standard chemoradiation. Identification of the cell-intrinsic mechanisms governing this clinically important cell state may lead to the discovery of therapeutic strategies for this challenging malignancy. Here, we demonstrate that the mitotic E3 ubiquitin ligase CDC20-anaphase-promoting complex (CDC20-APC) drives invasiveness and self-renewal in patient tumor-derived GSCs. Moreover, CDC20 knockdown inhibited and CDC20 overexpression increased the ability of human GSCs to generate brain tumors in an orthotopic xenograft model in vivo. CDC20-APC control of GSC invasion and self-renewal operates through pluripotency-related transcription factor SOX2. Our results identify a CDC20-APC/SOX2 signaling axis that controls key biological properties of GSCs, with implications for CDC20-APC-targeted strategies in the treatment of glioblastoma

Characterization of Functional and Structural Integrity in Experimental Focal Epilepsy: Reduced Network Efficiency Coincides with White Matter Changes

BACKGROUND: Although focal epilepsies are increasingly recognized to affect multiple and remote neural systems, the underlying spatiotemporal pattern and the relationships between recurrent spontaneous seizures, global functional connectivity, and structural integrity remain largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we utilized serial resting-state functional MRI, graph-theoretical analysis of complex brain networks and diffusion tensor imaging to characterize the evolution of global network topology, functional connectivity and structural changes in the interictal brain in relation to focal epilepsy in a rat model. Epileptic networks exhibited a more regular functional topology than controls, indicated by a significant increase in shortest path length and clustering coefficient. Interhemispheric functional connectivity in epileptic brains decreased, while intrahemispheric functional connectivity increased. Widespread reductions of fractional anisotropy were found in white matter regions not restricted to the vicinity of the epileptic focus, including the corpus callosum. CONCLUSIONS/SIGNIFICANCE: Our longitudinal study on the pathogenesis of network dynamics in epileptic brains reveals that, despite the locality of the epileptogenic area, epileptic brains differ in their global network topology, connectivity and structural integrity from healthy brains

Role of NAMPT in Glooblastoma Stem Cells

Mentor: Albert H. Kim From the Washington University Undergraduate Research Digest: WUURD, Volume 9, Issue 1, Fall 2013. Published by the Office of Undergraduate Research. Joy Zalis Kiefer Director of Undergraduate Research and Assistant Dean in the College of Arts & Sciences

Startlers and their Eating Habits

50 pagesMFA theses in English Language and Literature are not available for direct download. Users wishing to access an MFA thesis in this collection may request access by clicking the link to the restricted file(s) and completing the request form. If we have contact information for the author, we will contact them and request permission to provide access. If we do not have contact information or the author denies or does not respond to our inquiry, we will not be able to provide access.10000-01-0

The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma

Glioblastomas are responsible for nearly 60% of malignant primary brain tumors. Those with a mesenchymal (MES) gene expression signature present with worse survival and increased treatment resistance. Performing an extensive gene network analysis, Bhat et al. now identify the TAZ transcriptional coactivator as a master modulator of this severe MES signature. Validating their bioinformatic analysis in patient-derived glioma stem cells and murine neural stem cells, they further observe that TAZ expression is restrained in lower-grade gliomas due to promoter hypermethylation and that TAZ regulates MES genes by directly binding their promoters in complex with TEAD2. This study reveals a direct role for TAZ in driving MES differentiation in malignant gliomas

Highly efficient maternal-fetal Zika virus transmission in pregnant rhesus macaques

<div><p>Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10–12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated.</p></div

Fetal growth as assessed by predicted gestational ages.

<p>The predicted gestational age (pGA) as described by Tarantal [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006378#ppat.1006378.ref035" target="_blank">35</a>] from each of the pregnancies is plotted against the actual day of gestation estimated from breeding activity and animal menstrual records. The pGA was derived from the average of BPD+FL (dashed lines), or the HC (solid lines). <b>A</b> (animal 827577) and <b>B</b> (animal 660875), first trimester infection. <b>C</b> (animal 357676) and <b>D</b> (animal 598248), late second/early third trimester infection.</p

Study layout and viral RNA burden in pregnant rhesus fluids.

<p>(<b>A</b>) Schematic representation of the timeline of infection, sampling for maternal viral burden, and experimental cesarean section, for all animals in the study. Animals received a ZIKV challenge in the first or late second/early third trimesters of pregnancy, and blood and other fluid samples were collected according to the schedule indicated in detail in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006378#ppat.1006378.s001" target="_blank">S1 Fig</a>. (<b>B</b>) ZIKV viral load in pregnant macaque fluids. Viral RNA loads (vRNA copies/ml) measured in plasma, urine, saliva, and amniotic fluid presented individually for the four pregnant animals. The day post-inoculation is indicated below each graph, and gestational age (days) for each animal is indicated above (term = 165±10 days). Limit of assay quantification is 100 copies/mL. Limit of detection is 33 copies/mL. Colors for individual animals are continued through the rest of the Figures, including the Supplementary Figures.</p

Complete blood counts (CBCs) and serum chemistries for pregnant macaques infected with ZIKV.

<p>Animals were infected with 10⁴ PFU of ZIKV. Animals infected in the first or third trimesters are represented by color coding (<b>A</b>) as presented in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006378#ppat.1006378.g001" target="_blank">Fig 1</a>. All animals had CBC analysis performed on EDTA blood and chemistry analysis performed on serum at -7, -3, 0, 1–10 and additional indicated dpi. <b>B.</b> AST blood chemistries, <b>C.</b> ALT serum chemistries, <b>D.</b> CK serum chemistries, <b>E.</b> WBC counts, <b>F.</b> % lymphocytes, <b>G.</b> red blood cell (RBC) counts.</p