Biomedical subjects

Steve Hobbs

Publications and source records attributed to Steve Hobbs.

4 recordsLinked to original sources

PubMed2004

Micro parallel liquid chromatography: enabling technology for discovery analytical chemistry.

Since the introduction of combinatorial chemistry, compound libraries have undergone a significant increase in size and diversity. The ensuing expansion and diversification of compound libraries have resulted in increased demand for analytical throughput. Following the evolution of new technologies for generating lead compounds and targets and the desire to increase research and development productivity, analytical chemistry is now gaining attention as a bottleneck that would benefit from advances in instrumentation for increased analytical throughput. The commercial introduction of the Veloce trade mark micro parallel liquid chromatography system from Nanostream offers discovery analytical chemists the capability to analyze 24 samples in parallel with as little as 0.5 microl of sample. The system offers a scalable analytical approach to address bottlenecks in historically underserved areas, such as compound library purity screening, as well as higher value-added applications, such as log P determination and aqueous solubility assessment. This article describes the Veloce system and presents representative data from several discovery analytical applications.

Chemistry Techniques, Analytical↗

PubMed2003

Viral delivery of P450 reductase recapitulates the ability of constitutive overexpression of reductase enzymes to potentiate the activity of mitomycin C in human breast cancer xenografts.

Indolequinones such as mitomycin C (MMC) require enzymatic bioreduction to yield cytotoxic moieties. An attractive approach to overcome the potential variability in reductive bioactivation between tumors is to exploit specific enzyme-bioreductive drug combinations in an enzyme-directed gene therapy (GDEPT) approach. To this end, human breast cancer cell lines (T47D, MDA468, and MDA231) that overexpress either DT-diaphorase (DTD) or NADPH:cytochrome P450 reductase (P450R) have been developed. Cytotoxicity of MMC was evaluated in the panel of cell lines following aerobic or anoxic exposure in vitro. DTD and/or P450R overexpression sensitized cells to MMC in air with no further increase in the cytotoxicity of MMC under anoxia. The most profound effect was seen in the MDA468 cells, where a 27-fold increase in potency was observed for MMC in the DTD-overexpressing cell line. The MMC sensitization achieved through DTD and P450R overexpression in MDA468 cells was maintained in vivo. Xenografts established from the clonal lines exhibited significant tumor control following MMC treatment (treated/control [T/C] 17% and 51% for DTD and P450R xenografts, respectively) that was not seen in wild-type tumors (T/C 102%). Delivery of a clinically relevant adenoviral vector encoding P450R to MDA468 wild-type tumors yielded comparable P450R activity to that seen in the P450R clonal xenografts and resulted in greater MMC sensitization (T/C 46%). The model systems developed will facilitate the identification of novel indolequinone agents that are targeted toward a specific enzyme for bioactivation and are consequently of potential use in a GDEPT approach.

Adenoviridae↗

PubMed2003

Nursing workforce supply data trends in Hawaii.

Surveys of the nursing workforce in Hawaii over the last six years point to an increasing shortage of nurses. Data trends reveal a nursing workforce that is older than the rest of the U.S. with more ethnic and gender diversity. Strategies are needed to ensure adequate numbers and levels of nurses to meet the health care needs of the people of Hawaii.

Age Distribution↗

PubMed2002

Overexpression of BclXL in a human ovarian carcinoma cell line: paradoxic effects on chemosensitivity in vitro versus in vivo.

The effect of overexpressing the antiapoptotic protein BclXL in a human ovarian carcinoma cell line has been investigated in terms of sensitivity to the 2 major drugs used to treat this disease, paclitaxel and cisplatin. Stable transfection of BclXL into CH1 cells, which are relatively sensitive to cisplatin, resulted in around 2.7-fold higher expression in comparison with empty vector controls. However, this level of overexpression did not result in significant resistance in vitro to paclitaxel or cisplatin at the 50% inhibition level, using either short-term (4-day) growth inhibition or longer term colony-forming assays. By contrast, parallel subcutaneous xenograft models of these isogenic ovarian carcinoma cells in vivo, differing only in BclXL status, showed that this low-level BclXL overexpression conferred significant resistance to both paclitaxel and cisplatin in comparison with parent, nontransfected tumours. Whereas parent non-BclXL transfected tumours were highly responsive, with the disappearance of tumours for at least 50 days post treatment, tumours overexpressing BclXL grew back after 30 and 20 days after treatment with paclitaxel and cisplatin, respectively. These differences in responsiveness to paclitaxel in vivo were not attributable to any significant changes in the delivery of drug to the tumour. These data suggest that the responsiveness of ovarian cancer to paclitaxel and cisplatin in vivo, and therefore perhaps clinically, is influenced by levels of the antiapoptotic protein BclXL. Such effects may be missed in vitro when using short-term growth inhibition or clonogenic assays.

Animals↗