Publications
Department of Medicine faculty members published more than 3,000 peer-reviewed articles in 2022.
2003
2,4-Dichlorophenoxyacetic acid (2,4-D) is a widely used broadleaf herbicide that has been associated with acute liver toxicity in exposed humans or animals. Chemically reactive metabolites of 2,4-D are proposed as mediators of 2,4-D-induced hepatotoxicity. The aim of the present study was to investigate a novel reactive metabolite of 2,4-D, namely 2,4-dichlorophenoxyacetyl-S-acyl-CoA (2,4-D-CoA), and to determine its involvement in 2,4-D covalent adduct formation. Thus, incubations of synthetic 2,4-D-CoA (106 microM) with GSH (1 mM) in phosphate buffer (pH 7.4) showed 2,4-D-CoA to be able to transacylate the cysteine sulfhydryl of GSH, resulting in the formation of 2,4-D-S-acyl-glutathione (2,4-D-SG) thioester and reaching a concentration of 65 microM after 1 h of incubation. Under similar conditions, 2,4-D-CoA was shown to covalently bind to nucleophilic groups on human serum albumin (HSA, 30 mg/ml), resulting in time-dependent 2,4-D-HSA covalent adduct formation that reached a maximum of 440 pmol/mg HSA after 1 h of incubation. In addition to these studies, incubations of [1-(14)C]2,4-D (1 mM) with rat hepatocytes showed a time-dependent covalent binding of 2,4-D to hepatocyte protein. Inhibition of acyl-CoA formation by trimethylacetic acid (2 mM) decreased the amount of covalent binding to protein in rat hepatocytes by 50%. These results indicate that 2,4-D-CoA thioester is a reactive metabolite of 2,4-D that may contribute to 2,4-D-protein adduct formation in vivo and therefore the associated hepatotoxicity.
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BACKGROUND
In addition to lower operative mortality, patients undergoing selected cancer operations at high volume centers have improved longterm survival. We sought to determine the overall effect of hospital volume on life expectancy after cancer surgery.
STUDY DESIGN
We used a Markov decision analysis model to estimate life expectancy for patients undergoing resection for pancreatic, lung, or colon cancer. Model inputs included probabilities of operative mortality and longterm survival. For input data, we examined operative mortality (in-hospital or within 30 days) stratified by volume in over 400,000 patients undergoing resection for these three cancers using the national Medicare database (1994-1999). Risks of late mortality were abstracted from published studies (MEDLINE, 1966 to present) to model the effect of hospital volume on longterm survival. In analysis, we first calculated life expectancy for patients undergoing surgery at very low, low, medium, high, and very high volume hospitals. We then explored the effects of various regionalization strategies.
RESULTS
Life expectancy increased steadily with hospital volume for all three cancers. Life expectancy after pancreatic cancer resection increased linearly with hospital volume: from 1.9 years at very low volume centers to 3.6 years at very high volume centers. For lung cancer, life expectancy ranged from 5.4 to 6.6 years. Increases in life expectancy for colon cancer were not as dramatic: from 6.8 at very low volume hospitals to 7.4 years at very high volume hospitals. Differences in life expectancy across volume strata were largely attributable to differences in longterm survival, not operative mortality. From a policy perspective, regionalizing surgery for colon cancer would produce the greatest overall life-expectancy gains, but it would require moving most patients.
CONCLUSIONS
Patients aged 65 and older with pancreatic, lung, and colon cancer have substantially greater life expectancy after cancer resection at higher volume hospitals. Further work is needed to understand the mechanisms underlying differences in performance across hospitals in cancer care.
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2003
2003
The nonreceptor tyrosine kinase focal adhesion kinase (FAK) is a point of convergence for signals from extracellular matrix, soluble factors, and mechanical stimuli. Targeted disruption of the fak gene in mice leads to death at embryonic day 8.5 (E8.5). FAK-/- embryos have severely impaired blood vessel development. Gene expression and in vitro differentiation studies revealed that endothelial cell differentiation was comparable in FAK-/- and wild-type E8.5 embryos. We examined the role of FAK in blood vessel morphogenesis using an in vitro tubulogenesis assay and three different culture systems: FAK+/+ and FAK-/- embryoid bodies, FAK+/+ and FAK-/- endothelial cells, and human umbilical vein endothelial cells expressing antisense FAK, a dominant-negative fragment of FAK, or wild-type FAK. In all of these systems, endothelial cells deficient in FAK expression or function displayed a severely reduced ability to form tubules in Matrigel. These studies demonstrate clearly that the vascular defects in FAK-/- mice result from the inability of FAK-deficient endothelial cells to organize themselves into vascular networks, rather than from defects in tissue-specific differentiation.
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2003