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- Bandopadhayay, Pratiti, et al.
(författare)
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BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
- 2014
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 20:4, s. 912-925
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.Experimental Design:We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.Results:Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index.Conclusion:JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.
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| 3. |
- Yu, Zhang, et al.
(författare)
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Distinction between bacterial and viral infections by serum measurement of human neutrophil lipocalin (HNL) and the impact of antibody selection
- 2016
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Ingår i: JIM - Journal of Immunological Methods. - : Elsevier BV. - 0022-1759 .- 1872-7905. ; 432, s. 82-86
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Tidskriftsartikel (refereegranskat)abstract
- The distinction between acute infections of bacterial or viral causes is clinically important, but often very difficult even for experienced doctors. Previous studies indicated that serum measurements of HNL (Human Neutrophil Lipocalin) might be a superior diagnostic means in this regard, but also indicated that the antibody conformation of the HNL assay might have an impact on the diagnostic performance. The aim of the present report was to examine this further. Methods: Several different (n = 24) HNL ELISA assays were developed using different combinations of monoclonal and polyclonal HNL antibodies. Sera were collected from healthy persons (n = 188) and from 155 patients with acute infections.before any antibiotics treatment. The patients were diagnosed as having bacterial (n = 69) or viral causes (n = 86) of their infections. Plasma and serum were also examined by Western blotting using HNL-specific polyclonal antibodies. Results: The optimal assay format for the distinction between bacterial and viral infection resulted in an area under the receiver operating characteristics curve (AuROC) for S-HNL of 0.98. (95% CI 0.94-1.00) as compared to 0.83 (0.76-0.88) for blood neutrophil counts and 0.69 (0.61-0.76) for S-CRP. Results also showed that different assay formats of HNL identified monomeric and dimeric HNL differently, the monomeric HNL being elevated in viral infections and the dimeric HNL being elevated in bacterial infections. Conclusion: We conclude that serum theasurement of HNL is a superior diagnostic means to distinguish between acute infections caused by bacteria or virus. For optimal clinical performance the immunoassay should address conformational epitopes in the dimeric HNL.
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