37 research outputs found
NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts
Cancer stem cells (CSCs) are thought to be critical for the engraftment and long-term growth of many tumors, including glioblastoma (GBM). The cells are at least partially spared by traditional chemotherapies and radiation therapies, and finding new treatments that can target CSCs may be critical for improving patient survival. It has been shown that the NOTCH signaling pathway regulates normal stem cells in the brain, and that GBMs contain stem-like cells with higher NOTCH activity. We therefore used low-passage and established GBM-derived neurosphere cultures to examine the overall requirement for NOTCH activity, and also examined the effects on tumor cells expressing stem cell markers. NOTCH blockade by gamma-secretase inhibitors (GSIs) reduced neurosphere growth and clonogenicity in vitro, whereas expression of an active form of NOTCH2 increased tumor growth. The putative CSC markers CD133, NESTIN, BMI1, and OLIG2 were reduced following NOTCH blockade. When equal numbers of viable cells pretreated with either vehicle (dimethyl sulfoxide) or GSI were injected subcutaneously into nude mice, the former always formed tumors, whereas the latter did not. In vivo delivery of GSI by implantation of drug-impregnated polymer beads also effectively blocked tumor growth, and significantly prolonged survival, albeit in a relatively small cohort of animals. We found that NOTCH pathway inhibition appears to deplete stem-like cancer cells through reduced proliferation and increased apoptosis associated with decreased AKT and STAT3 phosphorylation. In summary, we demonstrate that NOTCH pathway blockade depletes stem-like cells in GBMs, suggesting that GSIs may be useful as chemotherapeutic reagents to target CSCs in malignant gliomas
ITC Commentary on the Prediction of Digoxin Clinical Drug–Drug Interactions from In Vitro Transporter Assays
Corrigendum to “Prevention and control of postoperative nausea and vomiting in post-craniotomy patients” [Best Practice & Research Clinical Anaesthesiology 2007; 21(4): 575-593]
Recommended from our members
Bond Bundle Analysis of Ketosteroid Isomerase
Bond bundle analysis is used to investigate enzymatic
catalysis
in the ketosteroid isomerase (KSI) active site. We identify the unique
bonding regions in five KSI systems, including those exposed to applied
oriented electric fields and those with amino acid mutations, and
calculate the precise redistribution of electron density and other
regional properties that accompanies either enhancement or inhibition
of KSI catalytic activity. We find that catalytic enhancement results
from promoting both inter- and intra-molecular electron density redistribution,
between bond bundles and bond wedges within the KSI-docked substrate
molecule, in the forward direction of the catalyzed reaction. Though
the redistribution applies to both types of perturbed systems and
is thus suggestive of a general catalytic role, we observe that bond
properties (e.g., volume vs energy vs electron count) can respond independently and disproportionately
depending on the type of perturbation. We conclude that the resulting
catalytic enhancement/inhibition proceeds via different mechanisms,
where some bond properties are utilized more by one type of perturbation
than the other. Additionally, we find that the correlations between
bond wedge properties and catalyzed reaction barrier energies are
additive to predict those of bond bundles and atomic basins, providing
a rigorous grounding for connecting changes in local charge density
to resulting shifts in reaction barrier energy
Structure property relationships in the design of alloy composition: Moving beyond electron to atom ratios
Recommended from our members
Mechanisms for cleavage and intergranular embrittlement in Fe
The mechanism of cleavage in bcc Fe has been investigated with electronic structure calculations and compared to similar calculations modeling cleavage in other bcc materials (Li, Nb, Mo). It has been found in the BCC materials we have studied that those known to undergo (100) cleavage show enhancement of the density of states (DOS) on the virtual surface layer as the material is strained to failure. Using total energy calculations it is shown that there is a point of inflection (corresponding to the point of maximum force versus displacement) in the total energy at nearly the same point as the maximum enhancement in the DOS. We conjecture that this point represents the transition state for the fracture process. Extending these ideas, the electronic structure near a Fe(111) grain boundary has been calculated both with and without segregated P. We find clear evidence for the formation of a P band of states, suggesting the existence of P-P interactions within the segregated layer. A chemical model of strain-induced bond failure is suggested in which bonds parallel to the fracture surface compete with the cohesive Fe-Fe bonds normal to the surface. 7 refs., 5 figs