PubMed · 8713867
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J C Harwood, A J Harwood. 1996. Screening lambda libraries.. https://doi.org/10.1385/0-89603-402-x%3A211
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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.
OBJECTIVE: To investigate the association between early childhood infections and subsequent development of asthma. DESIGN: Longitudinal birth cohort study. SETTING: Five children's hospitals in five German cities. PARTICIPANTS: 1314 children born in 1990 followed from birth to the age of 7 years. MAIN OUTCOME MEASURES: Asthma and asthmatic symptoms assessed longitudinally by parental questionnaires; atopic sensitisation assessed longitudinally by determination of IgE concentrations to various allergens; bronchial hyperreactivity assessed by bronchial histamine challenge at age 7 years. RESULTS: Compared with children with </=1 episode of runny nose before the age of 1 year, those with >/=2 episodes were less likely to have a doctor's diagnosis of asthma at 7 years old (odds ratio 0.52 (95% confidence interval 0.29 to 0.92)) or to have wheeze at 7 years old (0.60 (0.38 to 0.94)), and were less likely to be atopic before the age of 5 years. Similarly, having >/=1 viral infection of the herpes type in the first 3 years of life was inversely associated with asthma at age 7 (odds ratio 0.48 (0.26 to 0.89)). Repeated lower respiratory tract infections in the first 3 years of life showed a positive association with wheeze up to the age of 7 years (odds ratio 3.37 (1.92 to 5.92) for >/=4 infections v </=3 infections). CONCLUSION: Repeated viral infections other than lower respiratory tract infections early in life may reduce the risk of developing asthma up to school age.
Tissue inhibitors of metalloproteinases (TIMPs) may regulate extracellular matrix turnover and cellular functions by modulating matrix metalloproteinase (MMP) activity and cell proliferation and apoptosis. To investigate the locations and functions of TIMP-4 in human breast cancer, a highly specific polyclonal anti-TIMP-4 peptide antibody (pAb-T4-S61) was developed. The potency and specificity of the purified IgG were characterized by an enzyme-linked immunosorbent assay, immunoblot, and immunohistochemistry. The optimal IgG concentration range was 0.1-10 microg/ml. pAb-T4-S61 did not cross-react with TIMP-1 and TIMP-2 and should not react with TIMP-3 according to the sequence analysis. Parental MDA-MB-435 breast cancer cells were TIMP-4 negative and a TIMP-4 transfected clone, TIMP-4-435-12, produced TIMP-4. Membrane type-1 MMP was detected although TIMP-2 was not found in these cells. Interestingly, the TIMP-4 protein was detected by immunohistochemical staining in infiltrating breast carcinoma cells in tumor tissues. Thus, pAb-T4-S61 is a useful tool to investigate expression patterns and functions of TIMP-4 in cancers.