To clarify whether preoperative transcatheter arterial chemoembolization (TAE) improves the prognosis of patients with hepatocellular carcinoma (HCC) after surgery, 120 patients who had undergone hepatectomy for HCC from 1988 to 1994 and satisfied the criteria of stages II and III were enrolled in this study. Forty-four patients underwent preoperative TAE (group A) and 76 patients did not (group B). No significant differences in the outcomes were observed between these two groups. To rectify the comparison, patients with tumors 2 to 8 cm were assigned to groups A1 (n = 24) and B1 (n = 57), and those with tumors > 8 cm were assigned to groups A2 (n = 20) and B2 (n = 19), respectively. Although no significant differences in survival between groups A1 and B1 were found, group A2 presented superior 1-, 2-, and 3-year tumor-free survival rates of 80%, 55%, and 32% and 1-, 3-, and 5-year cumulative survival rates of 90%, 53%, and 42%. These figures are in comparison with the tumor-free survival rates of 50%, 22%, and 11% (p = 0.06), and the cumulative survival rates of 72%, 33%, and 11% (p = 0.01) during the same periods for group B2, respectively. The Cox regression model revealed that for patients with tumors > 8 cm, the relative risk of preoperative TAE for overall survival was 0.38 (p = 0.017), indicating that preoperative TAE might benefit patients with tumors > 8 cm but not those with tumors 2 to 8 cm.

No abstract

Stress-induced premature senescence (SIPS), a state of cell growth arrest due to various stimuli, is implicated in the pathogeneses of hepatic fibrogenesis. Progerin, a permanently farnesylated mutant lamin A protein, likely leads to premature senescence to influent liver diseases. The previous reports showed that activation of insulin-like growth factor-1 (IGF-1) signaling could enhance cell longevity and attenuate liver fibrosis. However, the underlying mechanisms about hepatocyte premature senility in liver fibrosis, and how IGF-1 regulates cell premature aging and fibrogenesis, remain poorly understood. In the present study, we found the augment of hepatocyte oxidation and premature aging, along with the decrease of plasm IGF-1 level in patients with liver fibrosis and CCl 4 -induced liver injury rat models. Nevertheless, IGF-1 gene transfer to CCl 4 rats to overexpress intrahepatic IGF-1 relieved hepatocyte oxidative stress and premature senescence, which was likely mediated by the p53/progerin pathway, to improve hepatic steatosis and fibrogenesis. In vitro, H 2 O 2 caused abnormal accumulation of progerin in nuclear and activation of nuclear p53–progerin interaction to trigger primary rat hepatocyte premature senescence through the p21-independent pathway; while these effects were rescued by prolonged exogenous IGF-1 or the IGF-1 adenovirus vector. Furthermore, the IGF-1 adenovirus vector, transfected to H 2 O 2 -treated hepatocytes, reversed oxidative stress-induced premature senescence via enhancing cytoplasmic AKT1–p53 interaction and subsequently inhibiting nuclear p53–progerin interaction. Consequently, our data illuminate a novel role of IGF-1 in regulating stress-induced hepatocyte premature senescence in liver fibrosis: prolonged IGF-1 relieves oxidative stress-initiated hepatocyte premature senescence via inhibition of nuclear p53–progerin interaction to ameliorate hepatic steatosis and fibrogenesis.

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Widespread contamination of N,N-dimethylformamide (DMF) has been identified in the environment of leather industries and their surrounding residential areas. Few studies have assessed the dose-response relationships between internal exposure biomarkers and liver injury in DMF exposed populations. We assessed urinary N-methylformamide (NMF) and N-acetyl-S-(N-methylcarbamoyl) cysteine (AMCC) and blood N-methylcarbmoylated hemoglobin (NMHb) levels in 698 Chinese DMF-exposed workers and 188 nonDMF- exposed workers using ultraperformance liquid-chromatography tandem mass-spectrometry. Liver injury was defined as having abnormal serum activities of any of the 3 liver enzymes, including alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase. Higher liver injury rates were identified in DMF-exposed workers versus nonDMF-exposed workers (9.17% vs 4.26%, P = .029) and in male versus female workers (11.4% vs 3.2%, P < .001). Positive correlations between environmental exposure categories and internal biomarker levels were identified with all 3 biomarkers undetectable in nonDMF-exposed workers. Lower confidence limit of benchmark dose (BMDL) was estimated using the benchmark dose (BMD) method. Within all study subjects, BMDLs of 14.0 mg/l for NMF, 155 mg/l for AMCC, and 93.3 nmol/g for NMHb were estimated based on dose-response relationships between internal levels and liver injury rates. Among male workers, BMDLs of 10.9 mg/l for NMF, 119 mg/l for AMCC, and 97.0 nmol/g for NMHb were estimated. In conclusion, NMF, AMCC, and NMHb are specific and reliable biomarkers and correlate well with DMF-induced hepatotoxicity. NMF correlates the best with liver injury, while NMHb may be the most stable indicator. Males have a greater risk of liver injury than females upon DMF exposure.

Benzo [a]pyrene (BaP) is a model compound for the study of polycyclic aromatic hydrocarbon (PAH) carcinogenesis. Upon metabolism, BaP is metabolized to the ultimate metabolite, BaP trans -7,8-diol- anti -9,10-epoxide (BPDE), that reacts with cellular DNA to form BPDE-dG adducts responsible for BaP-induced mutagenicity, carcinogenicity, and teratogenicity. In this study, we employed our developed LC-MS/MS method to detect and quantity BPDE-dG adducts present in 42 normal human umbilical cord blood samples and 42 birth defect cases. We determined that there is no significant difference in the level of BPDE-dG formation between the normal and birth defect groups. This represents the first time to use an LC-MS/MS method to quantify BPDE-dG in human umbilical blood samples. The results indicated that under experimental conditions, BPDE-dG adducts were detected in all the human umbilical cord blood samples from the normal and birth defect groups.

Etheno-DNA adducts are generated by interaction of cellular DNA with exogenous environmental carcinogens and end products of lipid peroxidation. It has been determined that 1,N(6)-etheno-2'-deoxyadenosine (εdA) and 3,N(4)-etheno-2'-deoxycytidine (εdC) adducts formed in human white blood cells can be used to serve as biomarkers of genetic damage mediated by oxidative stress. In this study, we developed an ultrasensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method used to detect and quantify εdA and dC adducts in human white blood cells. The percent recoveries of εdA and dC adducts were found to be 88.9% ± 2.8 and 95.7% ± 3.7, respectively. The detection limits were ∼ 1.45 fmol for εdA and ∼ 1.27 fmol for εdC in 20 μg of human white blood cell DNA samples, both εdA and εdC adducts could be detected using only ∼ 5 μg of DNA per sample. For validation of the method, 34 human blood cell DNA samples were assayed and the results revealed a significant difference (P < 0.01) between levels (fmol/μg DNA) of 0.82 ± 0.83 (standard deviation [SD]) (range: 0.15-3.11) for εdA, 3.28 ± 3.15 (SD) (range: 0.05-9.6) for εdC in benzene-exposed workers; and 0.04 ± 0.08 (SD) (range: 0.0-0.27) for εdA and 0.77 ± 1.02 (SD) (range: 0.10-4.11) for εdC in non-benzene-exposed workers. Our method shows a high sensitivity and specificity when applied to small amounts of human white blood cell DNA samples; background levels of εdA and εdC could be reproducibly detected. The ultrasensitive and simple detection method is thus suitable for applications in human biomonitoring and molecular epidemiology studies.

Etheno-DNA adducts are generated from the metabolism of exogenous carcinogens and endogenous lipid peroxidation. We and others have previously reported that 1,N6-ethenodeoxyadenosine (εdA) and 3,N4-ethenodeoxycytidine (εdC) are present in human urine and can be utilized as biomarkers of oxidative stress. In this study, we report a new ultrasensitive UPLC-ESI-MS/MS method for the analysis of εdA and εdC in human urine, capable of detecting 0.5 fmol εdA and 0.3 fmol εdC in 1.0 mL of human urine, respectively. For validation of the method, 20 human urine samples were analyzed, and the results revealed that the mean levels of εdA and εdC (SD) fmol/µmol creatinine are 5.82 ± 2.11 (range 3.0–9.5) for εdA and 791.4 ± 328.8 (range 116.7–1264.9) for εdC in occupational benzene-exposed workers and 2.10 ± 1.32 (range 0.6–4.7) for εdA and 161.8 ± 200.9 (range 1.8–557.5) for εdC in non-benzene-exposed workers, respectively. The ultrasensitive detection method is thus suitable for applications in human biomonitoring and molecular epidemiology studies.