Biomedical subjects

D E Johnson

Publications and source records attributed to D E Johnson.

At least 37 records · Page 2Linked to original sources

PubMed2001

Intratumoral spread and increased efficacy of a p53-VP22 fusion protein expressed by a recombinant adenovirus.

In vitro experiments have demonstrated intercellular trafficking of the VP22 tegument protein of herpes simplex virus type 1 from infected cells to neighboring cells, which internalize VP22 and transport it to the nucleus. VP22 also can mediate intercellular transport of fusion proteins, providing a strategy for increasing the distribution of therapeutic proteins in gene therapy. Intercellular trafficking of the p53 tumor suppressor protein was demonstrated in vitro using a plasmid expressing full-length p53 fused in-frame to full-length VP22. The p53-VP22 chimeric protein induced apoptosis both in transfected tumor cells and in neighboring cells, resulting in a widespread cytotoxic effect. To evaluate the anti-tumor activity of p53-VP22 in vivo, we constructed recombinant adenoviruses expressing either wild-type p53 (FTCB) or a p53-VP22 fusion protein (FVCB) and compared their effects in p53-resistant tumor cells. In vitro, treatment of tumor cells with FVCB resulted in enhanced p53-specific apoptosis compared to treatment with equivalent doses of FTCB. However, in normal cells there was no difference in the dose-related cytotoxicity of FVCB compared to that of FTCB. In vivo, treatment of established tumors with FVCB was more effective than equivalent doses of FTCB. The dose-response curve to FVCB was flatter than that to FTCB; maximal antitumor responses could be achieved using FVCB at doses 1 log lower than those obtained with FTCB. Increased antitumor efficacy was correlated with increased distribution of p53 protein in FVCB-treated tumors. This study is the first demonstration that VP22 can enhance the in vivo distribution of therapeutic proteins and improve efficacy in gene therapy.

Adenoviruses, Human↗

PubMed2001

Assessing the potential toxicity of new pharmaceuticals.

Optimizing chemical structures to create potentially safe drugs during discovery and early development relies on a combination of predictive algorithms, screening, formal toxicology studies, and early clinical trials. Early in the process three critical questions emerge that must be answered by a detailed "profiling" approach. These questions are: 1) is there a correlation between the chemical structure and potential toxicity that can be used to optimize structures of lead compounds, 2) can specific markers of potential toxicity can be identified carly and used as mechanistic decision-making screens, and 3) will exposures (plasma levels) in animal studies correlate with exposures encountered in the clinic thereby providing "coverage" for safety? Depending on the therapeutic class of compounds being considered and the level of knowledge available, feedback loops of information can be established to guide the development process.

Clinical Trials as Topic↗

PubMed2001

The effects of several supplementation frequencies on forage use and the performance of beef cattle consuming dormant tallgrass prairie forage.

Two experiments were conducted to quantify the impact on forage use and performance of varying supplementation frequency of cattle consuming forage diets across a range of frequencies. In both experiments, a common supplement was used that contained a relatively high concentration of CP (43%) and was fed at the following frequencies: 1) 2 d/wk; 2) 3 d/wk; 3) 5 d/wk; and 4) 7 d/wk. In Exp. 1, 120 Hereford x Angus cows (BW = 537 kg) grazing winter tallgrass-prairie range were supplemented at the various frequencies from December 7 until calving (average calving date = 3/7/99). All treatments provided the same quantity of supplement on a weekly basis (12.74 kg, as-fed) but divided the amount delivered on a given day equally among the number of supplementation events for that treatment. Less BW was lost from December 7 through calving (linear effect, P = 0.02) as frequency of supplementation increased, but the magnitude of difference in weight change was relatively small. Body condition responded similarly through early February (linear effect, P = 0.02), although treatment effects were not as distinct at calving (cubic effect, P = 0.11). In Exp. 2, 16 ruminally fistulated Hereford x Angus steers (BW = 257 kg) were blocked by weight and assigned to one of the four frequencies of supplementation. Steers were offered tallgrass prairie hay (73.5% NDF, 4.8% CP) ad libitum and were supplemented at a rate (relative to BW) similar to that of the cows in Exp. 1. Increasing frequency of supplementation increased (linear effect, P < or = 0.02) forage OM intake, OM and NDF digestion, and digestible OM intake. However, the most prominent differences in forage OM intake tended (cubic effect, P = 0.07) to occur with the two extreme frequencies of supplementation. In conclusion, forage use was improved with an increased frequency of supplementation, but the impact on performance is not likely to be large unless extreme differences in frequency occur.

Ammonia↗

PubMed2001