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Biomedical subjects

James Downing

Publications and source records attributed to James Downing.

5 recordsLinked to original sources

Influence of ethanol on aspirin release from hypromellose matrices.

Release profiles of aspirin from hypromellose matrices in hydro-ethanolic media were studied. Percent aspirin released increased with increasing levels of ethanol in the dissolution media, correlating with the drug's solubility, however, dose dumping of aspirin did not occur. An initial rapid release was observed in media comprising 40% ethanol. Release in these conditions was considered to be both erosion and diffusion-mediated, in contrast to the release in 0, 10, 20 and 30% ethanol media, where erosion-controlled release dominated. Image analysis of matrix swelling indicated a slower initial interaction between ethanol and hypromellose accounting for the initial rapid release. Cloud point studies suggested that ethanol retarded hydration of the polymer.

Anti-Inflammatory Agents, Non-Steroidal↗

Evaluation of seasonal scale first flush pollutant loading and implications for urban runoff management.

This study investigated how the occurrence and magnitude of first flush events in stormwater may influence the effective management of urban runoff pollution. To facilitate the understanding of the first flush phenomenon on a seasonal scale, the City of San Jose, CA carried out an investigation between May 1997 and April 2000 to characterize concentrations of pollutants in local waterbodies during eight storm events. The purpose of the investigation was twofold: (1) To determine if concentrations of specific constituents in stormwater runoff are elevated during the first substantial storm of the wet season, and (2) To identify the physical and environmental conditions surrounding such events. Concentration data for total and dissolved metals, pesticides, polyaromatic hydrocarbons, anions, total suspended solids, total organic carbon, conductivity, gasoline and diesel, and volatile and semi-volatile organics were collected at over 25 sites. Monitoring data analysis focused on identifying physical and environmental conditions yielding increased levels of pollutants during the first substantial storms of the rainy season compared to other storm events. Quantitative analysis focused on metals and anions because most observations for other constituents were below detectable levels. The results suggest that first flush phenomena did not occur consistently throughout most of the stations investigated. The results further suggest that there are specific combinations of site and storm conditions that result in a first flush effect with respect to dissolved metals. Based on the results of this and related investigations, implications for urban runoff management are discussed. For example, if dissolved metals are of principal concern, it may be worthwhile to optimize existing control strategies to minimize pollutant loading from storms that are preceded by an extended dry period.

California↗

FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression.

FMS-like tyrosine kinase 3 (FLT3) is almost universally expressed in B-precursor childhood acute lymphoblastic leukemia (ALL). Cases of ALL with MLL gene rearrangements and those with high hyperdiploidy (> 50 chromosomes) express the highest levels of FLT3, and activating mutations of FLT3 occur in 18% of MLL-rearranged and 28% of hyperdiploid ALL cases. We determined the antileukemic activity of CEP-701, a potent and selective FLT3 inhibitor, in 8 ALL cell lines and 39 bone marrow samples obtained at diagnosis from infants and children with various subtypes of ALL. CEP-701 induced pronounced apoptotic responses in a higher percentage of samples that expressed high levels of FLT3 (74%, n = 23) compared with samples with low levels of expression (8%, n = 13; P = .0003). Sensitivity to FLT3 inhibition was particularly high in samples with MLL gene rearrangements (82%, n = 11; P = .0005), high hyperdiploidy (100%, n = 5; P = .0007), and/or FLT3 mutations (100%, n = 4; P = .0021). Seven of 7 sensitive samples examined by immunoblotting demonstrated constitutively phosphorylated FLT3 that was potently inhibited by CEP-701, whereas 0 of 6 resistant samples expressed constitutively phosphorylated FLT3. We conclude that the FLT3 inhibitor CEP-701 effectively suppresses FLT3-driven leukemic cell survival. Clinical testing of CEP-701 as a novel molecularly targeted agent for the treatment of childhood ALL is warranted.

Age Factors↗

Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis.

Because de novo purine synthesis (DNPS) is a target of widely used antileukemic agents (eg, methotrexate, mercaptopurine), we determined the rate of DNPS and the expression of genes involved in purine metabolism in different subtypes of acute lymphoblastic leukemia (ALL). Among 113 children with newly diagnosed ALL, lymphoblasts with the TEL-AML1 translocation had significantly lower DNPS than all other genetic subtypes of B-lineage ALL or T-lineage ALL (352 +/- 57 versus 1001 +/- 31 or versus 1315 +/- 76 fmol/nmol/h, P <.0001). By assessing the expression of 82 genes involved in purine metabolism (KEGG pathway database) in ALL blasts from 38 patients with B-lineage ALL (14 with TEL-AML1, 24 without), we identified 16 genes that were differentially expressed in TEL-AML1-positive and TEL-AML1-negative ALL (P <.001, false discovery rate [FDR] = 5%). The pattern of expression of these 16 genes discriminated TEL-AML1-positive ALL with a true accuracy of 84% in an independent test set (n = 17, confidence interval 70% to 94%, P <.001). Western blots of selected genes documented corresponding levels of the proteins encoded. Differentially expressed genes included HPRT, IMPDH, PAICS, and GART, all of which were expressed at a significantly lower level in TEL-AML1 ALL. These findings have established that TEL-AML1 ALL has significantly lower de novo purine synthesis and differential expression of genes involved in purine metabolism.

Adolescent↗