PubMed · 14388317
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O MAKELA, P MAKELA. 1955. A weak B containing anti-B.. https://pubmed.ncbi.nlm.nih.gov/14388317/
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In glioblastoma (GBM), the most frequent and lethal brain tumor, therapies suppressing recurrently altered signaling pathways failed to extend survival. However, in patient subsets, specific genetic lesions can confer sensitivity to targeted agents. By exploiting an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, here, we identify a human GBM subset (∼9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. ERBB3 overexpression is driven by inheritable promoter methylation or post-transcriptional silencing of the oncosuppressor miR-205 and sustains the malignant phenotype. Overexpressed ERBB3 behaves as a specific signaling platform for fibroblast growth factor receptor (FGFR), driving PI3K/AKT/mTOR pathway hyperactivation, and overall metabolic upregulation. As a result, ERBB3 inhibition by specific antibodies is lethal for GBM stem-like cells and xenotransplants. These findings highlight a subset of patients eligible for ERBB3-targeted therapy.
AAV gene therapy vectors have significant clinical promise, but serum neutralization poses a challenge that must be overcome. We have examined the potential of conjugating the AAV surface with activated polyethylene glycol chains to protect the vector from neutralizing antibodies. Two key parameters were investigated: the polymer chain size and the PEG:lysine conjugation ratio. Transduction data revealed that the vector is fully infectious until a critical PEG conjugation reaction ratio was exceeded, and this critical level was found to vary with polymer chain size. At this key conjugation ratio, however, particles were moderately protected from serum neutralization, 2.3-fold over unmodified vector, demonstrating that there is a small window of PEGylation for which particles are still fully infective and benefit from antibody protection. TEM results and structural analysis indicate that the drop of infectivity as the PEG concentration is increased beyond the critical conjugation ratio may be due to a combination of steric interference with viral regions necessary for infection as well as reaction at important lysine residues. However, this first study analyzing the potential of PEG to protect AAV from serum neutralization shows that the approach has promise, which can be further enhanced if the locations of PEG attachment can be more finely controlled.
Isolation of phenotypically-pure cell subpopulations from heterogeneous cell mixtures such as blood is a difficult yet fundamentally important task. Current techniques such as fluorescent activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) require pre-incubation with antibodies which lead to processing times of at least 15-60 min. In this study, we explored the use of antibody-coated microfluidic chambers to negative deplete undesired cell types, thus obtaining an enriched cell subpopulation at the outlet. We used human lymphocyte cell lines, MOLT-3 and Raji, as a model system to examine the dynamic cell binding behavior on antibody coated surfaces under shear flow. Shear stress ranging between 0.75 and 1.0 dyn/cm2 was found to provide most efficient separation. Cell adhesion was shown to follow pseudo-first order kinetics, and an anti-CD19 coated (Raji-depletion) device with approximately 2.6 min residence time was demonstrated to produce 100% pure MOLT-3 cells from 50-50 MOLT-3/Raji mixture. We have developed a mathematical model of the separation device based on the experimentally determined kinetic parameters that can be extended to design future separation modules for other cell mixtures. We conclude that we can design microfluidic devices that exploits the kinetics of dynamic cell adhesion to antibody coated surfaces to provide enriched cell subpopulations within minutes of total processing time.