Hemochromatosis and Wilson disease (WD), characterized by the excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the frequency of p53 mutated alleles in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, we have determined the frequency of p53 mutated alleles in nontumorous liver tissue from WD and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249 (P < 0.001) and C:G to A:T transversions and C:G to T:A transitions at codon 250 (P < 0.001 and P < 0.005) were found in liver tissue from WD cases, and a higher frequency of G:C to T:A transversions at codon 249 (P < 0.05) also was found in liver tissue from hemochromatosis cases. Sixty percent of the WD and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggests nitric oxide as a source of increased oxidative stress. A high level of etheno-DNA adducts, formed from oxyradical-induced lipid peroxidation, in liver from WD and hemochromatosis patients has been reported previously. Therefore, we exposed a wild-type p53 TK-6 lymphoblastoid cell line to 4-hydroxynonenal, an unsaturated aldehyde involved in lipid peroxidation, and observed an increase in G to T transversions at p53 codon 249 (AGG to AGT). These results are consistent with the hypothesis that the generation of oxygen͞ nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WD causes mutations in the p53 tumor suppressor gene.Wilson disease ͉ hemochromatois ͉ p53 ͉ iron ͉ copper ͉ liver carcinogenesis

The specific functions of plasminogen, stromal plasminogen activator, stromal plasminogen activator receptor, and stromal plasminogen activator inhibitor in the progression of the murine soft tissue sarcoma, T241 were investigated. Negation of plasminogen to the tumor blunted the orthotopic growth of the sarcoma in syngeneic mice. The reduced tumor growth was associated with a dramatic increase in tumor-infiltrating F4/80-positive macrophages and a diminution of vessel density, but not with obvious differences in fibrin and collagen deposition, or invasiveness of the tumor. Ablation of plasminogen activation by the tumor stroma only modestly impaired the prolonged growth of the sarcoma, suggesting that tumor cell-produced plasminogen activator is sufficient to mediate productive plasminogen activation. Plasminogen facilitated sarcoma progression, angiogenesis, and suppression of macrophage infiltration in the absence of either stromal urokinase plasminogen activator receptor or stromal plasminogen activator inhibitor. These data demonstrate that tumor cell-produced plasminogen activator and host plasminogen cooperate to facilitate soft tissue sarcoma growth and suppress the accumulation of tumor-infiltrating macrophages.

Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) which detect pathogen-associated molecular patterns (PAMPs) and initiate the innate as well as adaptive immune response. In the present study TLR5 gene from Aseel and White Leghorn was amplified and sequenced by primer walking method. The sequence analysis revealed that Aseel TLR5 shared 97-98% and 98-99% homology with other chicken breeds at nucleotide and amino acid levels, respectively. Further, the TLR5 mRNA expression levels were quantified in different tissues of day-old Aseel and WL chicks by real time PCR assay. TLR5 mRNA expressions were significantly higher in liver, spleen and intestine of Aseel than White Leghorn chicken (P less than 0.01). However, in bone marrow significantly higher expression was observed in WL than Aseel chicken (P less than 0.01) and no significant difference in transcript expression was found in muscle, bursa and heart tissue. In vitro stimulation of PBMCs of Aseel and WL with recombinant flagellin resulted in significantly higher levels of proinflammatory cytokine IL-1â gene expression in Aseel birds than WL. Polymorphisms in ligand binding region, higher transcript expression in tissues at the site of microbial entry and higher pro-inflammatory response to flagellin stimulation in Aseel chicken better immune competence in this native chicken breed.