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We followed 145 men with chronic hepatitis B virus (HBV) hepatitis for 10 years to determine whether exposure to aflatoxin, or concomitant exposure to hepatitis C virus (HCV), or family history of hepatocellular carcinoma (HCC) increased the risk of developing HCC. We collected 8 monthly urine samples before beginning follow-up and pooled them to detect aflatoxin metabolite M1 (AFM1). AFM1 was detected in 78 (54%) of the subjects. The risk of HCC was increased 3.3-fold (with a 95% confidence interval of 1.2-8.7) in those with detectable AFM1 (above 3.6 ng/L). This relative risk was adjusted for age and for HCV status. Hepatocellular carcinoma (HCC) is the second most common cause of death from cancer in China, where the mortality rate was 18 per 100,000 person-years in 1990 through 1992. 1 Infection with hepatitis B virus (HBV) and exposure to aflatoxin are both important risk factors for HCC. Ross et al. 2 studied 18,244 men aged 45 to 64 who lived in Shanghai between 1986 and 1989. In a sample of 140 controls who were age-matched to HCC cases, it was found that 15 (11%) were hepatitis B surface antigen (HBsAg)-positive, and 53 (38%) had detectable urinary aflatoxin metabolites or DNAadducts. A later analysis of 50 HCC cases and 267 agematched controls from this study 3 showed that compared with men without HBsAg or urinary aflatoxin biomarkers, relative risks were 7.3 with 95% a confidence interval (2.2, 24) for those only with HBsAg, 3.4 (1.1, 10) for those only with aflatoxin biomarkers, and 59 (17, 212) for those with both. Based on such data, Ross et al. 2 and Qian et al. 3 suggested that reduction of exposure to aflatoxin might prevent a considerable fraction of the HCC in this population.The previous cohort represented the general male population of Shanghai. We chose instead to follow prospectively a representative group of 145 carriers of HBsAg with a history of chronic hepatitis. These men were being cared for at the Medical Oncology Department of the Qidong Liver Cancer Institute/Hospital, Qidong, Jiangsu Province, China. HCC rates are very high in Qidong. The purpose of the study was to determine whether exposure to aflatoxin increased the risk of HCC or of fatal cirrhosis over a 10-year period in patients with HBV hepatitis. A positive finding would suggest that measures to reduce exposure to aflatoxin might also be beneficial to men with chronic HBV hepatitis and could be evaluated in treatment protocols. Because we collected monthly urine samples for 8 months before beginning follow-up, we were able to pool the samples to obtain estimates of long-term average urinary aflatoxin M1 (AFM1) concentrations, and the assay could detect concentrations of AFM1 as low as 3.6 ng/L. These data also give information on the added risks of HCC in men with chronic HBV hepatitis from exposure to hepatitis C virus (HCV) and from a family history of HCC. PATIENTS AND METHODSPopulation-based sampling was used to obtain a representative study cohort. In an earlier study of the prevalence of HBV infection sponsored by...

We assessed the separate and combined effects of hepatitis B virus (HBV), hepatitis C virus (HCV), and aflatoxin in causing hepatocellular carcinoma (HCC) in Qidong, China. A consecutive series of 181 pathologic-diagnosed HCC cases were studied for hepatitis B surface antigen (HBsAg), anti-HBc, HBV X gene sequence, anti-HCV, the 249ser-p53 mutation, and chronic hepatitis pathology. Each of the 181 incident HCC cases had markers for HBV infection and hepatitis pathology; only 6 of 119 cases were coinfected with HCV. The 249ser-p53 mutation was found in 54% (97/181) of HCC cases and in all 7 cases with tissue for analysis from the hepatitis cohort but in none of 42 matched cases from Beijing. The estimated cumulative dose of aflatoxin B1 in these 7 cases ranged from 0.13 to 0.49 mg/kg. Follow-up data through 13.25 years on a cohort of 145 men with chronic HBV hepatitis showed that the relative risk from aflatoxin exposure was 3.5 (1.5-8.1). A similar relative risk was found using 249ser-p53 mutation as a marker for aflatoxin exposure. In conclusion, HBV hepatitis is ubiquitous in Qidong HCC cases, whereas HCV contributes little to its risk. The 249ser-p53 mutation appears to result from coexposure to aflatoxin and HBV infection. Even modest levels of aflatoxin exposure tripled the risk of HCC in HBV-infected men. H epatocellular carcinoma (HCC) is the second most common cancer and kills 300,000 or more people each year in China. 1,2 The close linkage of hepatitis B virus (HBV) to HCC was largely established in epidemiologic studies based on the detection of HBV surface antigen (HBsAg) in sera. In Qidong, China, about 16% of the adult population are seropositive for HBsAg. This marker is not present in every person infected with HBV, however. Early studies had shown that many HBsAg seronegative HCC patients in Qidong had evidence of HBV infection determined by immunohistochemistry 3 or by molecular hybridization in European cases. 4 Fujimoto et al. 5 reported that 23 of 26 HCC cases from Qidong were HBV positive by Southern blot analysis, including 3 HBsAg seronegatives. Paterlini et al. 6 had shown by reverse transcriptase polymerase chain reaction assays that HBV X gene-related transcripts were often found in the diseased and normal hepatic tissues of HBsAg-negative HCC patients. In Japan, many HCC cases attributed to hepatitis C virus (HCV) were found to have markers of HBV infection. 7-9 Zhang et al. 10 reported that PCR analysis of 21 HBsAg seronegative HCC cases in Qidong revealed HBV X gene sequence in the HCC DNA of every case. A recent cohort study in Qidong also showed that HBV worked synergistically with aflatoxin, HCV, and family history to significantly enhance HCC incidence. 11 Using an extensive set of assays, we sought to determine whether HBV infection is virtually ubiquitous in HCC cases in Qidong. Such a finding would have implications for understanding the carcinogenic process

p53-upregulated modulator of apoptosis (PUMA) plays an essential role in p53-dependent apoptosis following DNA damage. PUMA also mediates apoptosis independent of p53. In this study, we investigated the role and mechanism of PUMA induction in response to serum starvation in p53-deficient cancer cells. Following serum starvation, the binding of Sp1 to the PUMA promoter significantly increased, whereas inhibition of Sp1 completely abrogated PUMA induction. p73 was found to be upregulated by serum starvation and mediate PUMA induction through the p53-binding sites in the PUMA promoter. Sp1 and p73beta appeared to cooperatively activate PUMA transcription, which is inhibited by the phosphoinsitide 3-kinase (PI3K)-protein kinase B (AKT) pathway. Furthermore, knockdown of PUMA suppressed serum starvation-induced apoptosis in leukemia cells. Our results suggest that transcription factors Sp1 and p73 mediate p53-independent induction of PUMA following serum starvation to trigger apoptosis in human cancer cells.

Tumor cell survival is highly dependent on the expression of certain pro-survival Bcl-2 family proteins. An attractive therapeutic approach is to inhibit these proteins using agents that mimic the Bcl-2 homology 3 (BH3) domains of the proapoptotic Bcl-2 family members, which neutralize these proteins by binding to their surface hydrophobic grooves. A number of BH3 mimetic peptides and small molecules have been described, a few of which have advanced into clinical trials. Recent studies have highlighted ABT-737, a bona fide BH3 mimetic and potent inhibitor of antiapoptotic Bcl-2 family members, as a promising anticancer agent. This review summarizes recent advances in understanding the mechanisms of action of BH3 domains and several classes of BH3 mimetics, as well as the prospects of using these agents to improve cancer therapy.

About 170 million Chinese are infected chronically with HBV and 10% suffer from chronic hepatitis. Around half a million Chinese die from hepatitis B caused hepatocellular carcinoma and endstage cirrhosis each year. From 1983 to the present, a controlled clinical trial involving 80,000 children on a universal hepatitis B vaccination programme to prevent chronic hepatitis, hepatocellular carcinoma, and endstage cirrhosis was implemented in Qidong, China. A pilot study demonstrated that the HBsAg rate reached the adult level before the fifth year of age, and neonatal vaccination with either plasma-derived or recombinant hepatitis B vaccines provided a similar 75% protective efficacy against HBV infection. The high rate of follow-up and blood tests coverage of the cohorts provided data to show 75% protection at the tenth to eleventh years of age against serum HBsAg and also against prolonged hepatic dysfunction. The strategy of controlling hepatitis B nationwide was based on the universal immunisation of newborns, beginning in cities and then the rural areas. The largescale vaccine source was provided by domestic plants through technology transfer, first providing plasma-derived vaccine replaced completely by recombinant DNA vaccine in 1997. An official survey in 1999 using a cluster sampling of 25,878 children from 31 provinces reported an average coverage rate of three dose of hepatitis B vaccination of 70.7%, being higher in urban areas. KEY WORDS: HBV; hepatitis B; vaccination; EPI HEPATITIS B INFECTION: A MAJOR HEALTH ISSUE OF CHINASeveral studies have estimated that 10 to 15% of people in China were chronically infected with HBV depending on the detection method and the way of selection and coverage size of the populations. Taking 13% as the estimated rate [Chen et al., 1990], it was calculated that about 170 million of the 1.3 billion Chinese people are chronically infected with HBV. However, the viral load by nucleic acid-based tests (NAT assays) indicate that HBV infection rates were usually underestimated. About 10% of the HBV carriers were estimated to have chronic hepatitis B, mostly in middle age. HBV was demonstrated to be the main cause of hepatocellular carcinoma (HCC) and end-stage cirrhosis. In association with the high HBV infection rate, liver cancer ranks second among the total cancer mortality in China. The age-adjusted mortality rate of HCC was reported to be 23 Â 10 À5/10 5 /yr [Li and Peto, 1996]. The annual deaths from HCC in China with 1.3-billion population was then estimated to be about 300,000. A recent study reported higher mortality rate of HCC in China, causing 384,000 deaths per year (Liu et al., unpublished data). End-stage cirrhosis, mainly HBV related, caused about 150,000 deaths per year. These data showed that HBV killed about half a million mainland Chinese each year. This virus ranks only second to tobacco as the major killer of Chinese at the present time and in the decades to come. Therefore, universal hepatitis B vaccination of neonates, the most cost-effective approach ...

Overexpression of epidermal growth factor receptor (EGFR) is found in over 80% of head and neck squamous cell carcinomas (HNSCC) and associated with poor clinical outcomes. EFGR selective tyrosine kinase inhibitors (TKIs) or antibodies have recently emerged as promising treatments for solid tumors, including HNSCC, though the response rate to these agents is low. p53 upregulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 family protein, is required for apoptosis induced by p53 and various chemotherapeutic agents. In this study, we show that PUMA induction is correlated with EGFR-TKI sensitivity, and is mediated through the p53 family protein p73b and inhibition of the PI3K/AKT pathway. In some HNSCC cells, the gefitinib-induced degradation of oncogenic DNp63 seems to facilitate p73-mediated PUMA transcription. Inhibiting PUMA expression by small hairpin RNA (shRNA) impairs gefitinib-induced apoptosis. Furthermore, PUMA or BH3 mimetics sensitize HNSCC cells to gefitinib-induced apoptosis. Our results suggest that PUMA induction through p73 represents a new mechanism of EGFR inhibitor-induced apoptosis, and provide potential ways for enhancing and predicting the sensitivity to EGFR-targeted therapies in HNSCC.

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