Glioblastoma Subclasses Can Be Defined by Activity among Signal Transduction Pathways and Associated Genomic Alterations

Glioblastoma multiforme (GBM) is an umbrella designation that includes a heterogeneous group of primary brain tumors. Several classification strategies of GBM have been reported, some by clinical course and others by resemblance to cell types either in the adult or during development. From a practical and therapeutic standpoint, classifying GBMs by signal transduction pathway activation and by mutation in pathway member genes may be particularly valuable for the development of targeted therapies.We performed targeted proteomic analysis of 27 surgical glioma samples to identify patterns of coordinate activation among glioma-relevant signal transduction pathways, then compared these results with integrated analysis of genomic and expression data of 243 GBM samples from The Cancer Genome Atlas (TCGA). In the pattern of signaling, three subclasses of GBM emerge which appear to be associated with predominance of EGFR activation, PDGFR activation, or loss of the RAS regulator NF1. The EGFR signaling class has prominent Notch pathway activation measured by elevated expression of Notch ligands, cleaved Notch receptor, and downstream target Hes1. The PDGF class showed high levels of PDGFB ligand and phosphorylation of PDGFRbeta and NFKB. NF1-loss was associated with lower overall MAPK and PI3K activation and relative overexpression of the mesenchymal marker YKL40. These three signaling classes appear to correspond with distinct transcriptomal subclasses of primary GBM samples from TCGA for which copy number aberration and mutation of EGFR, PDGFRA, and NF1 are signature events.Proteomic analysis of GBM samples revealed three patterns of expression and activation of proteins in glioma-relevant signaling pathways. These three classes are comprised of roughly equal numbers showing either EGFR activation associated with amplification and mutation of the receptor, PDGF-pathway activation that is primarily ligand-driven, or loss of NF1 expression. The associated signaling activities correlating with these sentinel alterations provide insight into glioma biology and therapeutic strategies

Dibucaine Mitigates Spreading Depolarization in Human Neocortical Slices and Prevents Acute Dendritic Injury in the Ischemic Rodent Neocortex

Spreading depolarizations that occur in patients with malignant stroke, subarachnoid/intracranial hemorrhage, and traumatic brain injury are known to facilitate neuronal damage in metabolically compromised brain tissue. The dramatic failure of brain ion homeostasis caused by propagating spreading depolarizations results in neuronal and astroglial swelling. In essence, swelling is the initial response and a sign of the acute neuronal injury that follows if energy deprivation is maintained. Choosing spreading depolarizations as a target for therapeutic intervention, we have used human brain slices and in vivo real-time two-photon laser scanning microscopy in the mouse neocortex to study potentially useful therapeutics against spreading depolarization-induced injury.We have shown that anoxic or terminal depolarization, a spreading depolarization wave ignited in the ischemic core where neurons cannot repolarize, can be evoked in human slices from pediatric brains during simulated ischemia induced by oxygen/glucose deprivation or by exposure to ouabain. Changes in light transmittance (LT) tracked terminal depolarization in time and space. Though spreading depolarizations are notoriously difficult to block, terminal depolarization onset was delayed by dibucaine, a local amide anesthetic and sodium channel blocker. Remarkably, the occurrence of ouabain-induced terminal depolarization was delayed at a concentration of 1 µM that preserves synaptic function. Moreover, in vivo two-photon imaging in the penumbra revealed that, though spreading depolarizations did still occur, spreading depolarization-induced dendritic injury was inhibited by dibucaine administered intravenously at 2.5 mg/kg in a mouse stroke model.Dibucaine mitigated the effects of spreading depolarization at a concentration that could be well-tolerated therapeutically. Hence, dibucaine is a promising candidate to protect the brain from ischemic injury with an approach that does not rely on the complete abolishment of spreading depolarizations

Basement Membrane Zone Collagens XV and XVIII/Proteoglycans Mediate Leukocyte Influx in Renal Ischemia/Reperfusion

Collagen type XV and XVIII are proteoglycans found in the basement membrane zones of endothelial and epithelial cells, and known for their cryptic anti-angiogenic domains named restin and endostatin, respectively. Mutations or deletions of these collagens are associated with eye, muscle and microvessel phenotypes. We now describe a novel role for these collagens, namely a supportive role in leukocyte recruitment. We subjected mice deficient in collagen XV or collagen XVIII, and their compound mutant, as well as the wild-type control mice to bilateral renal ischemia/reperfusion, and evaluated renal function, tubular injury, and neutrophil and macrophage influx at different time points after ischemia/reperfusion. Five days after ischemia/reperfusion, the collagen XV, collagen XVIII and the compound mutant mice showed diminished serum urea levels compared to wild-type mice (all

QM-cluster model study of CO2 hydration mechanisms in metal-substituted human carbonic anhydrase II

Electrical energy storage need has evolved to lightweight and portable devices such as electric vehicle, drones, robotics, wearables, etc. Current technology of batteries such as Li-Ion or Li-Poly are not able to meet the requirement for future. We have been developing a new type of supercapacitor for this technological barrier. Our supercapacitors are fabricated with inkjet-printing (IJP) technique that uses very precise MEMS based cartridge to print thin-films on planar substrates. We have previously demonstrated metal-insulator-metal (MIM) capacitor fabrication and simulation, as well as stacked MIM supercapacitor fabrication. In this paper, we present electrical characterization (such as charging-discharging cycles) and scanning electron microscopy image for IJP stacked MIM supercapacitor. The electrical characterization validates the charge storage capability of the supercapacitor. We have tested the samples for up to 20 V charging voltage. The corresponding stored charge can be as high as 40 nC, and the charge density is 17.4 C/m3. These solid-state IJP stacked MIM supercapacitors are flexible with high energy-density and safe for prolonged use which can be applicable in electric vehicles, wearables, implantable, drones, and other energy storage applications

Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors

Electrification of vehicles and energy-storage needs of renewables and robotic devices including wearables, implantables, drones, and wireless sensors demands energy storage solution that is not achievable with current battery technology. In this paper, we present the proof-of-concept results of inkjet-printed (IJP) flexible supercapacitors to store energy and power devices for wearables and implantable, as well as other energy storage needs. We have developed a patent-pending technique of stacked Metal-Insulator-Metal (MIM) parallel plate capacitors to form supercapacitor with high energy density. The flexible supercapacitor was fabricated on a thin 25 μm flexible polyimide (PI) film. We have used silver (Ag) nanoparticle (NP) ink for printing the conductive layer and a polymer Poly(4-vinylphenol) ink for printing dielectric layer to fabricate insulation between metal plates. The area of the supercapacitors was 100 mm2. Six coatings of PVP dielectric were printed for proper insulation between two successive metal layers. The measured capacitance of a single MIM capacitor was 996 pF. The measured capacitance of two-stacked MIM capacitors on the same footprint was 1.98 nF. The thickness of two stacked MIM capacitor was 22.3 μm. By stacking more MIM capacitors on the same footprint, supercapacitors can be fabricated that can achieve high energy storage capability within a small footprint, weight, and volume. This IJP supercapacitor, which is flexible yet solid-state with high-performance and safe for long-term use, can play a significant role in wearables, implantable, drones, renewable energy storage, and electric vehicles