Unit on Perinatal and Developmental Neurobiology, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Down syndrome (DS) is the leading genetic cause of intellectual disability, affecting ~1/800 newborns. Previously we have shown alterations in N-methyl-D-aspartic acid (NMDA) receptors and neuropeptides (activity-dependant neuroprotective protein, glia fibrillary acidic protein) in a murine model of DS. Cytokines and chemokines have neuromodulatory and neurotransmitter roles and interact with the NMDA receptors. The objective of this study was to evaluate if cytokines and chemokines in the hippocampus and cerebellum are altered in this model. Study DesignWe used 8- to 10-month-old animals from the well-characterized mouse model of DS (Ts65Dn). Learning and memory were assessed in the Morris water maze with the Ts65Dn animals demonstrating a learning deficit. After completion of the behavioral testing, the brains were removed and the hippocampus and cerebellum were separated by microdissection. A panel of cytokines, chemokines, and fractalkine were measured in the protein lysates using a microsphere-based multiplex immunoassay (Luminex xMAP, Millipore) and normalized to total protein concentration. Statistical analysis included the nonparametric Mann-Whitney U for the cytokine, chemokine, and fractalkine levels; p<0.05 was considered significant. ResultsLevels (median [range]) of interleukin (IL)-1β (6.95 [0.11 to 43.5] versus 14.2 [0.2 to 36.8] pg/mL); granulocyte-macrophage colony-stimulating factor (GM-CSF; 3.97 [0.19 to 19.6] versus 19.2 [0.2 to 31.1] pg/mL), and macrophage inflammatory protein (MIP)-1α (20.3 [0.11 to 73.3] versus 37.0 [0.22 to 102.7] pg/mL) in the hippocampus from Ts65Dn were significantly lower compared with the euploid (control) animals. Many cytokines and chemokines were not detected in the hippocampus or cerebellum, and others were detectable but not different between the groups. Conclusion
We found a decreased in GM-CSF, IL-1β, and MIP-1α in the hippocampus of DS pups. All three have known interactions with NMDA receptors and their decline may explain, in part, the learning deficits associated with DS.
[Show abstract][Hide abstract] ABSTRACT: This study tests the hypothesis that pre-diagnostic serum levels of twenty cancer-associated inflammatory biomarkers correlate directly with future development of head & neck, esophageal, and lung cancers in a high-risk prospective cohort.This is a nested case-control pilot study of subjects enrolled in the Golestan Cohort Study, an ongoing epidemiologic project assessing cancer trends in Golestan, Iran. We measured a panel of 20 cytokines, chemokines, and inflammatory molecules using Luminex® technology in serum samples collected two or more years before cancer diagnosis in 78 aerodigestive cancer cases and 81 controls. Data was analyzed using Wilcoxon rank-sum test, odds ratios (OR), ROC areas of discrimination, and multivariate analysis.Biomarkers were profoundly and globally elevated in future esophageal and lung cancer patients compared to controls. Odds ratios were significant for association between several biomarkers and future development of esophageal cancer, including IL-1Rα (35.88), IFNα2 (34), FGF-2 (17.43), GM-CSF (17.43), et al. The same trend was observed among future lung cancer cases for G-CSF (27.68), GM-CSF (13.33), TNF-α (8.55), et al. By contrast, the majority of biomarkers studied showed no significant correlation with future head and neck cancer development.This study provides the first direct evidence that multiple inflammatory biomarkers are coordinately elevated in future lung and esophageal cancer patients two or more years before cancer diagnosis.This article is protected by copyright. All rights reserved.
Cancer Science 07/2014; 105(9). DOI:10.1111/cas.12485 · 3.52 Impact Factor
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