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Many frequently prescribed drugs are non-genotoxic carcinogens (NGC) in rodent liver. Their mode of action and health risks for humans remain to be elucidated. Here, we investigated the impact of two model NGC, the anti-epileptic drug phenobarbital (PB) and the contraceptive cyproterone acetate (CPA), on intrahepatic epithelial-mesenchymal crosstalk and on growth of first stages of hepatocarcinogenesis. Unaltered hepatocytes (HC) and preneoplastic HC (HC PREN ) were isolated from rat liver for primary culture. DNA replication of HC and HC PREN was increased by in vitro treatment with 10 µM CPA, but not 1 mM PB. Next, mesenchymal cells (MC) obtained from liver of rats treated with either PB (50 mg/kg bw/day) or CPA (100 mg/kg bw/day), were cultured. Supernatants from both types of MC raised DNA synthesis of HC and HC PREN . This indicates that PB induces replication of HC and HC PREN only indirectly, via growth factors secreted by MC. CPA, however, acts on HC and HC PREN directly as well as indirectly via mesenchymal factors. Transcriptomics and bio-informatics revealed that PB and CPA induce extensive changes in the expression profile of MC affecting many growth factors and pathways. MC from PB-treated rats produced and secreted enhanced levels of HBEGF and GDF15, factors found to suppress apoptosis and/or induce DNA synthesis in cultured HC and HC PREN . MC from CPA-treated animals showed enhanced expression and secretion of HGF, which strongly raised DNA replication of HC and HC PREN . In conclusion, our findings reveal profound effects of two prototypical NGC on the hepatic mesenchyme. The resulting release of factors, which suppress apoptosis and/or enhance cell replication preferentially in cancer prestages, appears to be crucial for tumor promotion by NGC in the liver.

Designing synthetic vaccines from class I major histocompatibility complex (MHC)-binding antigenic peptides requires not only knowledge of the binding affinity of the designed peptide but also predicting the stability of the formed MHC-peptide complex. In order to better investigate structure-stability relationships, we have determined by circular dichroism spectroscopy the thermal stability of a class I MHC protein, HLA-B*2705, in complex with a set of 39 singly substituted peptide analogues. The influence of two anchoring side chains (P3 and P9) was studied by peptide mutation and appropriate site-directed mutagenesis of the HLA-B*2705 binding groove. The side chain at P9 is clearly the one that contributes the most to the thermal stability of the MHC-peptide complexes, as destabilization up to 25 degrees C are obtained after P9 mutation. Interestingly, structure-stability relationships do not fully mirror structure-binding relationships. As important as the C-terminal side chain are the terminal ammonium and carboxylate groups. Removal of a single H-bond between HLA-B27 and the terminal peptide moieties results in thermal destabilization up to 10 degrees C. Depending on the bound peptide and the location of the deleted H-bond, the decrease in the thermal stability of the corresponding complex is quantitatively different. The present study suggests that any peptidic amino acid at positions 3 and 9 promotes refolding of the B27-peptide complex. Once the complex is formed, the C-terminal side chain seems to play an important role for maintaining a stable complex.

Inherited thrombophilia has been suggested as a cause of Legg-Calvé-Perthes disease in up to 75% of patients. This prevalence seems high compared to the prevalence of inherited thrombophilia in other thrombotic disorders (average, 30%). Therefore, we investigated 44 patients with Legg-Calvé-Perthes disease for antithrombin-III, protein-C, and protein-S deficiency and activated protein C (APC) resistance. Three (6.8%) of our patients were positive for APC resistance, and one patient (2.2%) showed deficiency of protein-C activity. Our results suggest that inherited thrombophilia is not associated with avascular necrosis of the femoral head (Legg-Calvé-Perthes disease).

To document our impact on the community's health, Mercy Health Center of Central Iowa has created a "Community Benefits Report"--a 14-page report listing all charitable projects among eight distinct subsidiaries of Mercy Health Center. The Mercy report lists all the charitable works provided to the community in the past year by Mercy Hospital Medical Center, the Mercy Clinic System, the Clark Street House of Mercy, the Bishop Drumm Care Center, and a few smaller affiliate hospitals in rural Iowa. Mercy's community benefits report serves not only as a summary, but as the blueprint for the work Mercy leaders are planning. This documentation helps in many ways, including identifying the needs of Des Moines and central Iowa and showing Mercy's role in meeting those needs.