PubMed · 61026
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1976. Australia antigen subtypes identification. Protocol.. https://pubmed.ncbi.nlm.nih.gov/61026/
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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.
In this study, we examined the potential role of the human immunodeficiency virus (HIV) tat protein in causing the hematopoietic abnormalities frequently observed in HIV-infected individuals. Recombinant tat (r-tat) protein, at concentrations up to 10 micrograms/mL, did not display any stimulatory or inhibitory effect on the survival/proliferative capacity of CD34+ hematopoietic progenitor cells, purified from normal bone marrow (BM). However, exposure of r-tat protein (at concentrations between 10 ng/mL and 10 micrograms/mL) to enriched normal BM macrophages induced the production of a factor(s) in conditioned media that inhibited the in vitro growth of CD34+ cells in liquid cultures and of immature hematopoietic progenitors (day 14 colony-forming unit-granulocyte-macrophage, burst-forming unit-erythroid, and colony-forming unit-megakaryocyte) in semisolid assays. Pre-exposure of r-tat protein with a monoclonal neutralizing anti-tat antibody completely abrogated the inhibitory activity present in BM macrophage culture supernatants. The main factor responsible for this suppressive activity was transforming growth factor-beta 1 (TGF-beta 1), as shown by the ability of a polyclonal anti-TGF-beta 1 neutralizing antibody to almost completely reverse the suppressive effect of BM macrophage supernatants on CD34+ cells. TGF-beta 1 bioassays showed that exposure of r-tat protein to BM macrophages significantly increased the levels of both active and latent forms of TGF-beta 1. These results indicate that the production of TGF-beta 1, one of the most potent negative regulator of hematopoiesis, is increased by HIV tat protein and that such increase could contribute to the derangement of the hematopoietic system in HIV-infected individuals.
Despite the absence of anti-HLA antibodies (Ab) about 10 to 20 percent of renal transplants are lost during the first months from rejection. The role of humoral rejection seems more likely than cellular rejection since they do not respond to standard anti-rejection therapy. We studied 37 patients who rejected their graft despite negative T and B lymphocytes cross-match during the first eight months (m: 59 days, range: 2-240) following kidney transplantation. These patients were compared with 57 patients who experienced a favorable outcome. The sera were tested for the presence of Ab against epidermis of a panel of 5 normal skins and against an epithelial-endothelial hybrid cell line (EA hy 926, Dr C.J.S. Edgell), expressing both endothelial and epithelial antigens. Among the 37 patients who rejected theirs grafts, 8 had anti-keratinocytes Ab, 11 had Ab against epithelial-endothelial hybrid cell line, 9 were positive for both tests. Among the 8 pts who lost their graft before 25 days, 5 were positive for at least our test. Conversely, 7 among the 57 pts with favorable outcome had Ab: 2 against keratinocytes, 5 against hybrid cell line. These data suggest that non anti-HLA Ab may play a role in graft rejection. Furthermore the detection of such Ab prior to transplantation may predict patients at risk of severe rejection. In such cases, plasma exchanges may be proposed if they develop steroid-resistant rejection.