PubMed · 5924963
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S M Beiser, B F Erlanger. 1966. Antibodies which react with nucleic acids.. https://pubmed.ncbi.nlm.nih.gov/5924963/
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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.
Recent data suggest that sepsis stimulates macrophage apoptosis (Ao) with subsequent induction of macrophage dysfunction. Nuclear factor-kappaB (NFkappaB) activation has been linked to Ao in either a pro- or antiapoptotic role. Glucans are biological response modifiers which exert antisepsis activity. This investigation examined the effect of (1-3)-beta-D-glucan receptor binding by a high affinity ligand on Ao and NFkappaB activation in U937 cells in the presence or absence of LPS. A high affinity glucan ligand (IC50 = 23 nM) activated NFkappaB, but did not induce Ao or significantly alter LPS induced U937 Ao. These data indicate that: i) modulation of the macrophage (1-3)-beta-D-glucan receptor stimulates NFkappaB; ii) does not induce Ao or significantly diminish LPS induced Ao and iii) activation of the U937 FAS receptor does not alter the relative Ao responses in glucan and LPS treated cells.
Three-dimensional (3-D) reconstruction of images provided by confocal scanning laser microscopy (CSLM) is a powerful tool in a morpho-functional approach to cutaneous innervation studies. To investigate mechanoreceptors in the hand, a study of Merkel complexes was performed in human finger. A double fluorescent-conjugated immunolabeling with antibodies against neurofilament (NF 200) and cytokeratin (CK 20) on floating, thick cutaneous samples (80 to 100 microm), was used. After acquisition of serial optical planes by CSLM, reconstruction was performed with 3-D reconstruction software tools. Merkel cells were clearly labeled with CK 20, whereas nerve components were only NF 200 reactive. The cells, localized on the basal lamina of the epidermis, were usually arranged in clusters of five to eight cells. Each cell was connected to a nerve process ramification originating from a unique fiber. Quantitative data, compiled from a sample of 25 Merkel complexes, gave a mean cell diameter of 13 +/- 1 microm and a mean nerve fiber size of 3 +/- 1 microm. Surface measurements were done on a single reconstructed cluster with a mean and standard error which only refers to the optical 3-D resolution. It gives a surface of 12 +/- 1 microm2 for the contact zone between cell and nerve fiber and a cluster area of about 500 microm2. The great precision of reconstructed images provides a detailed analysis of spatial relationships between abutting nerve fibers and Merkel cells. Data interpretation is improved with complementary ultrastructural and physiological studies results, and this allows an accurate investigation of cutaneous sensory endings.