PubMed · 256755
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A Hedlin. The immune system.. https://pubmed.ncbi.nlm.nih.gov/256755/
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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.
A microfluidic device coupling immunological and enzymatic assays within a single microchannel has been developed for simultaneous measurements of insulin and glucose. Such a dual-mode (enzyme/immuno) protocol involves precolumn reactions of insulin and glucose with the enzyme-labeled anti-human insulin and glucose-dehydrogenase/NAD+, respectively, followed by the electrophoretic separation of the free antibody, antibody-antigen complex, and the NADH product of the enzymatic reaction. The separation is followed by a postcolumn reaction of the alkaline-phosphatase tracer with the p-NPP substrate and a downstream amperometric detection of the p-nitrophenol and NADH products. Despite the huge concentration difference [millimolar (glucose) and nanomolar (insulin)] and the use of different assay principles, the new biochip responds independently to the corresponding target analytes, with linear dynamic ranges over their clinically relevant ranges. Complete assays, carried out within less than 4 min, lead to good precision (RSD 0.36%) for the insulin/glucose ratio. The resulting biochip allows simultaneous testing for insulin and glucose to be performed more rapidly, easily, and economically, and hence it holds great promise for improved management of diabetes.
Rho1p, an essential Rho-type GTPase in Saccharomyces cerevisiae, activates its effectors in the GTP-bound form. Here, we show that Rho1p in secretory vesicles cannot activate 1,3-beta-glucan synthase, a cell wall synthesizing enzyme, during vesicular transport to the plasma membrane. Analyses with an antibody preferentially reacting with the GTP-bound form of Rho1p revealed that Rho1p remains in the inactive form in secretory vesicles. Rom2p, the GDP/GTP exchange factor of Rho1p, is preferentially localized on the plasma membrane even when vesicular transport is blocked. Overexpression of Rom2p results in delocalization of Rom2p and accumulation of 1,3-beta-glucan in secretory vesicles. Based on these results, we propose that Rho1p is kept inactive in intracellular secretory organelles, resulting in repression of the activity of the cell wall-synthesizing enzyme within cells.