PubMed · 4257775
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R A Kantorovich. [The Australian antigen problem].. https://pubmed.ncbi.nlm.nih.gov/4257775/
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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.
Neutrophils isolated from a child with severe leukocyte adhesion deficiency 1 (LAD1) had a complete absence of expression of the CD11/CD18 beta2 integrin family of adhesion molecules, and were shown to be deficient in the in vitro adhesion and migration properties. However, we found that interleukin-8 (IL8), a potent chemoattractant for neutrophils, and sputum sol phase induced these LAD1 neutrophils to migrate through an endothelial cell layer in vitro, and confirmed that this migration was CD18-independent. These findings add to evidence of CD18-independent mechanisms of neutrophil recruitment, in particular neutrophil infiltration into the lungs, where IL8 may be an important recruitment factor.
BACKGROUND: Flow cytometry is potentially suited to the chemosensitivity analysis of peripheral blood or bone marrow subpopulations in patients with leukaemia and myelodysplastic syndromes. METHODS: The use of the fluorescent dye 7-amino-actinomycin (7AAD) on unfixed cells to measure loss of viability at a range of cytosine arabinoside (ara-C) doses was evaluated. A six-tube flow cytometric assay for measuring the sensitivity to ara-C of CD45/side-scatter-gated or of CD34-positive leukemic blasts with 7AAD was established, using fixed stained normal mononuclear cells as an internal standard for quantitation of viable cells following culture. RESULTS: 7AAD dose response curves for 10 patients with acute myeloblastic leukemia (AML) showed a wide range of sensitivities at 2.5-5 microM araC (3.7-97%, mean 54% of control cell viability at 2.5 microM and 4.1-94.6 %, mean 27% at 5 microM). Parallel assays for ATP bioluminescence agreed reasonably well with the 7AAD method, r(s) = 0.78. The chemosensitivity of CD45/SSC-gated blast cells at 2.5 microM araC showed no consistent relationship with the ungated cell populations, such that CD45/SSC-gated blast sensitivity of seven samples ranged from 86% more to 38% less than that of the total population. Similarly, the chemosensitivities of the CD34-gated subpopulations ranged from 51% more to 78% less than those of the total populations. CONCLUSIONS: These results emphasize the necessity of measuring the chemosensitivity of the population of interest rather than of the sample as a whole in heterogeneous clinical material.