Activation Status of Receptor Tyrosine Kinases as an Early Predictive Marker of Response to Chemotherapy in Osteosarcoma

Receptor tyrosine kinases (RTKs) are membrane receptors that play a vital role in various biological processes, in particular, cell survival, cell proliferation, and cell differentiation. These cellular processes are composed of multitiered signaling cascades of kinases starting from ligand binding to extracellular domains of RTKs that activate the entire pathways through tyrosine phosphorylation of the receptors and downstream effectors. A previous study reported that, based on proteomics data, RTKs were a major candidate target for osteosarcoma. In this study, activation profiles of six candidate RTKs, including c-Met, c-Kit, VEGFR2, HER2, FGFR1, and PDGFRα, were directly examined from chemonaive fresh frozen tissues of 32 osteosarcoma patients using a multiplex immunoassay. That examination revealed distinct patterns of tyrosine phosphorylation of RTKs in osteosarcoma cases. Unsupervised hierarchical clustering was calculated using Pearson uncentered correlation coefficient to classify RTKs into two groups—Group A (c-Met, c-Kit, VEGFR2, and HER2) and Group B (FGFR1 and PDGFRα)—based on tyrosine phosphorylation patterns. Nonactivation of all Group A RTKs was associated with shorter overall survival in stage IIB osteosarcoma patients. Percentages of tumor necrosis in patients with inactive Group A RTKs were significantly lower than those in patients with at least one active Group A RTK. Paired primary osteosarcoma cells with fresh osteosarcoma tissue were extracted and cultured for cytotoxicity testing. Primary cells with active Group A RTKs tended to be sensitive to doxorubicin and cisplatin. We also found that osteosarcoma cells with active Group A RTKs were more proliferative than cells with inactive Group A RTKs. These findings indicate that the activation pattern of Group A RTKs is a potential risk stratification and chemoresponse predictor and might be used to guide the optimum chemotherapy regimen for osteosarcoma patients.     

Oxidative DNA damage and influence of genetic polymorphisms among urban and rural schoolchildren exposed to benzene

Traffic related urban air pollution is a major environmental health problem in many large cities. Children living in urban areas are exposed to benzene and other toxic pollutants simultaneously on a regular basis. Assessment of benzene exposure and oxidative DNA damage in schoolchildren in Bangkok compared with the rural schoolchildren was studied through the use of biomarkers.Benzene levels in ambient air at the roadside adjacent to Bangkok schools was 3.95-fold greater than that of rural school areas. Personal exposure to benzene in Bangkok schoolchildren was 3.04-fold higher than that in the rural schoolchildren. Blood benzene, urinary benzene and urinary muconic acid (MA) levels were significantly higher in the Bangkok schoolchildren. A significantly higher level of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in leukocytes and in urine was found in Bangkok children than in the rural children. There was a significant correlation between individual benzene exposure level and blood benzene (r_s = 0.193, P < 0.05), urinary benzene (r_s = 0.298, P < 0.05), urinary MA (r_s = 0.348, P < 0.01), and 8-OHdG in leukocyte (r_s = 0.130, P < 0.05). In addition, a significant correlation between urinary MA and 8-OHdG in leukocytes (r_s = 0.241, P < 0.05) was also found. Polymorphisms of various xenobiotic metabolizing genes responsible for susceptibility to benzene toxicity have been studied; however only the GSTM1 genotypes had a significant effect on urinary MA excretion.Our data indicates that children living in the areas of high traffic density are exposed to a higher level of benzene than those living in rural areas. Exposure to higher level of benzene in urban children may contribute to oxidative DNA damage, suggesting an increased health risk from traffic benzene emission.     

Potential health effects of exposure to carcinogenic compounds in incense smoke in temple workers

Incense smoke is a potential hazard to human health due to various airborne carcinogens emitted from incense burning. This study aimed to evaluate the potential health effects of exposure to benzene, 1,3-butadiene, and polycyclic aromatic hydrocarbons (PAHs) emitted from incense smoke in temple workers. Exposure and health risks were assessed through the measurement of ambient exposure as well as through the use of biomarkers of exposure and early biological effects. Ambient air measurement showed that incense burning generates significantly higher levels of airborne benzene (P<0.01), 1,3-butadiene (P<0.001) and total PAHs (P<0.01) inside the temples, compared to those of the control workplace. Temple workers were exposed to relatively high levels of benzene (45.90 microg/m(3)) 1,3-butadiene (11.29 microg/m(3)) and PAHs (19.56 ng/m(3)), which were significantly higher than those of control workers (P<0.001). The most abundant PAHs were chrysene, B[ghi]P, B[a]P, B[a]F and fluoranthene. Concentrations of B[a]P and B[a]P equivalents in air samples to which temple workers were exposed were 63- and 16-fold, higher, respectively, than those to which control subjects were exposed (P<0.001). Biomarkers of exposure to benzene (blood benzene and the urinary metabolites trans,trans-muconic acid and S-phenylmercapturic acid), 1,3-butadiene (urinary monohydroxy-butenyl mercapturic acid) and PAHs (1-hydroxypyrene) were all significantly higher in temple workers than those in control workers. DNA damage and DNA repair capacity were measured as biomarkers of early biological effects. Temple workers had a significant increase in DNA damage observed as a 2-fold increase in the levels of leukocyte 8-hydroxy-2'-deoxguanosine (8-OHdG) and DNA strand breaks (P<0.001). A significant reduction of DNA repair capacity in temple workers determined by the radiation challenge assay was also observed. These results indicate that exposure to carcinogens emitted from incense burning may increase health risk for the development of cancer in temple workers.