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1.  Molecular Imaging of Hepatocellular Carcinoma Xenografts with Epidermal Growth Factor Receptor Targeted Affibody Probes 
BioMed Research International  2013;2013:759057.
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal cancer. It is typically asymptomatic at the early stage, with only 10%–20% of HCC patients being diagnosed early enough for appropriate surgical treatment. The delayed diagnosis of HCC is associated with limited treatment options and much lower survival rates. Therefore, the early and accurate detection of HCC is crucial to improve its currently dismal prognosis. The epidermal growth factor receptor (EGFR) has been reported to be involved in HCC tumorigenesis and to represent an attractive target for HCC imaging and therapy. In this study, an affibody molecule, Ac-Cys-ZEGFR:1907, targeting the extracellular domain of EGFR, was used for the first time to assess its potential to detect HCC xenografts. By evaluating radio- or fluorescent-labeled Ac-Cys-ZEGFR:1907 as a probe for positron emission tomography (PET) or optical imaging of HCC, subcutaneous EGFR-positive HCC xenografts were found to be successfully imaged by the PET probe. Thus, affibody-based PET imaging of EGFR provides a promising approach for detecting HCC in vivo.
PMCID: PMC3654646  PMID: 23710458
2.  Cost-Effectiveness of Nationwide Hepatitis B Catch-up Vaccination Among Children and Adolescents in China 
Hepatology (Baltimore, Md.)  2010;51(2):405-414.
Liver disease and liver cancer associated with childhood-acquired chronic hepatitis B are leading causes of death among adults in China. Despite expanded newborn hepatitis B vaccination programs, approximately 20% of children under age 5 years and 40% of children aged 5-19 years remain unprotected from hepatitis B. Although immunizing them will be beneficial, no studies have examined the cost-effectiveness of hepatitis B catch-up vaccination in an endemic country like China. We examined the cost-effectiveness of a hypothetical nationwide free hepatitis B catch-up vaccination program in China for unvaccinated children and adolescents aged 1 to 19 years. We used a Markov model for disease progression and infections. Cost variables were based on data published by the Chinese Ministry of Health, peer-reviewed Chinese and English publications, and the GAVI Alliance. We measured costs (2008 U.S. dollars and Chinese renminbi), quality-adjusted life years (QALYs), and incremental cost-effectiveness from a societal perspective. Our results show that hepatitis B catch-up vaccination for children and adolescents in China is cost-saving across a range of parameters, even for adolescents aged 15-19 years old. We estimate that if all 150 million susceptible children under 19 were vaccinated, more than 8 million infections and 65,000 deaths due to hepatitis B would be prevented.
The adoption of a nationwide free catch-up hepatitis B vaccination program for unvaccinated children and adolescents in China, in addition to ongoing efforts to improve birth dose and newborn vaccination coverage, will be cost-saving and can generate significant population-wide health benefits. The success of such a program in China could serve as a model for other endemic countries.
PMCID: PMC3245734  PMID: 19839061
Hepatitis B; Vaccination; Cost-Effectiveness Analysis
3.  Disparities in liver cancer incidence by nativity, acculturation, and socioeconomic status in California Hispanics and Asians 
Asians and Hispanics have the highest incidence rates of liver cancer in the US, but little is known about how incidence patterns in these largely immigrant populations vary by nativity, acculturation, and socioeconomic status (SES). Such variations can identify high-priority subgroups for prevention and monitoring.
Incidence rates and rate ratios (IRRs) by nativity among 5,400 Hispanics and 5,809 Asians diagnosed with liver cancer in 1988–2004 were calculated in the California Cancer Registry. Neighborhood ethnic enclave status and SES were classified using 2000 US Census data for cases diagnosed in 1998–2002.
Foreign-born Hispanic males had significantly lower liver cancer incidence rates than US-born Hispanic males in 1988–2004 (e.g., IRR=0.54, 95% confidence interval [CI]=0.50–0.59), whereas foreign-born Hispanic females had significantly higher rates in 1988–1996 (IRR=1.42, 95% CI=1.18–1.71), but not 1997–2004. Foreign-born Asian males and females had up to 5-fold higher rates than the US-born. Among Hispanic females, incidence rates were elevated by 21% in higher-enclave versus lower-enclave neighborhoods, and by 24% in lower- versus higher-SES neighborhoods. Among Asian males, incidence rates were elevated by 23% in higher-enclave neighborhoods and by 21% in lower-SES neighborhoods. In both racial/ethnic populations, males and females in higher-enclave, lower-SES neighborhoods had higher incidence rates.
Nativity, residential enclave status, and neighborhood SES characterize Hispanics and Asians with significantly unequal incidence rates of liver cancer, implicating behavioral or environmental risk factors and revealing opportunities for prevention.
Liver cancer control efforts should especially target foreign-born Asians, US-born Hispanic men, and residents of lower-SES ethnic enclaves.
PMCID: PMC3005535  PMID: 20940276
4.  Suppression of Glypican 3 Inhibits Growth of Hepatocellular Carcinoma Cells through Up-Regulation of TGF-β212 
Neoplasia (New York, N.Y.)  2011;13(8):735-747.
Glypican 3 (GPC3) is a valuable diagnostic marker and a potential therapeutic target in hepatocellular carcinoma (HCC). To evaluate the efficacy of targeting GPC3 at the translational level, we used RNA interference to examine the biologic and molecular effects of GPC3 suppression in HCC cells in vitro and in vivo. Transfection of Huh7 and HepG2 cells with GPC3-specific small interfering RNA (siRNA) inhibited cell proliferation (P < .001) together with cell cycle arrest at the G1 phase, down-regulation of antiapoptotic protein (Bcl-2, Bcl-xL, and Mcl-1), and replicative senescence. Gene expression analysis revealed that GPC3 suppression significantly correlated with transforming growth factor beta receptor (TGFBR) pathway (P = 4.57e-5) and upregulated TGF-β2 at both RNA and protein levels. The effects of GPC3 suppression by siRNA can be recapitulated by addition of human recombinant TGF-β2 to HCC cells in culture, suggesting the possible involvement of TGF-β2 in growth inhibition of HCC cells. Cotransfection of siRNA-GPC3 with siRNA-TGF-β2 partially attenuated the effects of GPC3 suppression on cell proliferation, cell cycle progression, apoptosis, and replicative senescence, confirming the involvement of TGF-β2 in siRNA-GPC3-mediated growth suppression. In vivo, GPC3 suppression significantly inhibited the growth of orthotopic xenografts of Huh7 and HepG2 cells (P < .05), accompanied by increased TGF-β2 expression, reduced cell proliferation (observed by proliferating cell nuclear antigen staining), and enhanced apoptosis (by TUNEL staining). In conclusion, molecular targeting of GPC3 at the translational level offers an effective option for the clinical management of GPC3-positive HCC patients.
PMCID: PMC3156664  PMID: 21847365
5.  Doing Good with Good OR: Supporting Cost-effective Hepatitis B Interventions 
Interfaces  2011;41(3):289-300.
In an era of limited healthcare budgets, mathematical models can be useful tools to identify cost-effective programs and to support policymakers in informed decision making. This paper reports results of our work carried out over several years with the Asian Liver Center at Stanford University, a nonprofit outreach and advocacy organization that is an international leader in the fight against hepatitis B and liver cancer. Hepatitis B is a vaccine-preventable viral disease that, if untreated, can lead to death from cirrhosis and liver cancer. Infection with hepatitis B is a major public health problem, particularly in Asian populations. We used new combinations of decision analysis and Markov models to analyze the cost-effectiveness of several interventions to combat hepatitis B in the United States and China. The results of our OR-based analyses have helped change United States public health policy on hepatitis B screening for millions of people and have helped encourage policymakers in China to enact legislation to provide free catch-up vaccination for hundreds of millions of children. These policies are an important step in eliminating health disparities, reducing discrimination, and ensuring that millions of people who need it can now receive hepatitis B vaccination or lifesaving treatment.
PMCID: PMC3134280  PMID: 21760650
Health care; Economics; Cost-benefit analysis; Decision analysis; Epidemiology; Government services
6.  Soluble Frizzled-7 receptor inhibits Wnt signaling and sensitizes hepatocellular carcinoma cells towards doxorubicin 
Molecular Cancer  2011;10:16.
There are limited therapeutic options for hepatocellular carcinoma (HCC), the most common liver malignancy worldwide. Recent studies have identified the Frizzled-7 receptor (FZD7), important for activation of Wnt-mediated signaling, as a potential therapeutic target for HCC and other cancers.
We hypothesized that the extracellular domain of FZD7 (sFZD7) would be a clinically more relevant therapeutic modality than previously studied approaches to target FZD7. We expressed and purified sFZD7 from E. coli, and tested its functional activity to interact with Wnt3, its ability to inhibit Wnt3-mediated signaling, and its potential for combinatorial therapy in HCC.
sFZD7 pulled down Wnt3 from Huh7 cells, and decreased β-catenin/Tcf4 transcriptional activity in HCC cells. In vitro, sFZD7 dose-dependently decreased viability of three HCC cell lines (HepG2, Hep40, and Huh7, all with high FZD7 and Wnt3 mRNA), but had little effect on normal hepatocytes from three donors (all with low level FZD7 and Wnt3 mRNA). When combined with doxorubicin, sFZD7 enhanced the growth inhibitory effects of doxorubicin against HCC cells in vitro, and against Huh7 xenografts in vivo. Reduced expressions of c-Myc, cyclin D1, and survivin were observed in vitro and in vivo. Additionally, sFZD7 altered the levels of phosphorylated AKT and ERK1/2 induced by doxorubicin treatment in vitro, suggesting that several critical pathways are involved in the chemosensitizing effect of sFZD7.
We propose that sFZD7 is a feasible therapeutic agent with specific activity, which can potentially be combined with other chemotherapeutic agents for the improved management of HCC.
PMCID: PMC3050858  PMID: 21314951
7.  San Francisco Hep B Free: A Grassroots Community Coalition to Prevent Hepatitis B and Liver Cancer 
Journal of Community Health  2010;36(4):538-551.
Chronic hepatitis B is the leading cause of liver cancer and the largest health disparity between Asian/Pacific Islanders (APIs) and the general US population. The Hep B Free model was launched to eliminate hepatitis B infection by increasing hepatitis B awareness, testing, vaccination, and treatment among APIs by building a broad, community-wide coalition. The San Francisco Hep B Free campaign is a diverse public/private collaboration unifying the API community, health care system, policy makers, businesses, and the general public in San Francisco, California. Mass-media and grassroots messaging raised citywide awareness of hepatitis B and promoted use of the existing health care system for hepatitis B screening and follow-up. Coalition partners reported semi-annually on activities, resources utilized, and system changes instituted. From 2007 to 2009, over 150 organizations contributed approximately $1,000,000 in resources to the San Francisco Hep B Free campaign. 40 educational events reached 1,100 healthcare providers, and 50% of primary care physicians pledged to screen APIs routinely for hepatitis B. Community events and fairs reached over 200,000 members of the general public. Of 3,315 API clients tested at stand-alone screening sites created by the campaign, 6.5% were found to be chronically infected and referred to follow-up care. A grassroots coalition that develops strong partnerships with diverse organizations can use existing resources to successfully increase public and healthcare provider awareness about hepatitis B among APIs, promote routine hepatitis B testing and vaccination as part of standard primary care, and ensure access to treatment for chronically infected individuals.
PMCID: PMC3130910  PMID: 21125320
Hepatitis B; Liver cancer; Asian Americans; Pacific Islander Americans; Community networks; Healthcare coalitions
8.  The burden of liver cancer in Asians and Pacific Islanders in the Greater San Francisco Bay Area, 1990 through 2004 
Cancer  2007;109(10):2100-2108.
No previous U.S. study has examined time trends in the incidence rate of liver cancer in the high-risk Asian/Pacific Islander population. We evaluated liver cancer incidence trends in Chinese, Filipino, Japanese, Korean, and Vietnamese males and females in the Greater San Francisco Bay Area of California between 1990 and 2004.
Populations at risk were estimated using the cohort component demographic method. Annual percentage changes (APCs) in age-adjusted incidence rates of primary liver cancer among Asians/Pacific Islanders in the Greater Bay Area Cancer Registry were calculated using joinpoint regression analysis.
The incidence rate of liver cancer between 1990 and 2004 did not change significantly in Asian/Pacific Islander males or females overall. However, the incidence rate declined, albeit statistically non-significantly, in Chinese males (APC =−1.6% [95% confidence interval (CI) =−3.4%, 0.3%], Japanese males (APC = −4.9%, 95% CI =−10.7%, 1.2%), and Japanese females (APC =−3.6%, 95% CI =−8.9%, 2.0%). Incidence rates remained consistently high for Vietnamese, Korean, and Filipino males and females. Trends in the incidence rate of hepatocellular carcinoma were comparable to those for liver cancer. While disparities in liver cancer incidence between Asians/Pacific Islanders and other racial/ethnic groups diminished between 1990–1994 and 2000–2004, those among Asian subgroups increased.
Liver cancer continues to affect Asian/Pacific Islander Americans disproportionately, with consistently high incidence rates in most subgroups. Culturally targeted prevention methods are needed to reduce the high rates of liver cancer in this growing population in the U.S.
PMCID: PMC2777532  PMID: 17385214
Asian Americans; epidemiology; hepatocellular carcinoma; liver cancer; surveillance
9.  Blockade of Wnt-1 signaling leads to anti-tumor effects in hepatocellular carcinoma cells 
Molecular Cancer  2009;8:76.
Hepatocellular carcinoma (HCC) is an aggressive cancer, and is the third leading cause of cancer death worldwide. Standard therapy is ineffective partly because HCC is intrinsically resistant to conventional chemotherapy. Its poor prognosis and limited treatment options make it critical to develop novel and selective chemotherapeutic agents. Since the Wnt/β-catenin pathway is essential in HCC carcinogenesis, we studied the inhibition of Wnt-1-mediated signaling as a potential molecular target in HCC.
We demonstrated that Wnt-1 is highly expressed in human hepatoma cell lines and a subgroup of human HCC tissues compared to paired adjacent non-tumor tissues. An anti-Wnt-1 antibody dose-dependently decreased viability and proliferation of Huh7 and Hep40 cells over-expressing Wnt-1 and harboring wild type β-catenin, but did not affect normal hepatocytes with undetectable Wnt-1 expression. Apoptosis was also observed in Huh7 and Hep40 cells after treatment with anti-Wnt-1 antibody. In these two cell lines, the anti-Wnt-1 antibody decreased β-catenin/Tcf4 transcriptional activities, which were associated with down-regulation of the endogenous β-catenin/Tcf4 target genes c-Myc, cyclin D1, and survivin. Intratumoral injection of anti-Wnt-1 antibody suppressed in vivo tumor growth in a Huh7 xenograft model, which was also associated with apoptosis and reduced c-Myc, cyclin D1, and survivin expressions.
Our results suggest that Wnt-1 is a survival factor for HCC cells, and that the blockade of Wnt-1-mediated signaling may offer a potential pathway-specific therapeutic strategy for the treatment of a subgroup of HCC that over-expresses Wnt-1.
PMCID: PMC2759906  PMID: 19778454
10.  Small interfering RNA targeting CDC25B inhibits liver tumor growth in vitro and in vivo 
Molecular Cancer  2008;7:19.
Using gene expression profiling, we previously identified CDC25B to be significantly highly expressed in hepatocellular carcinoma (HCC) compared to non-tumor liver. CDC25B is a cell cycle-activating phosphatase that positively regulates the activity of cyclin-dependent kinases, and is over-expressed in a variety of human malignancies. In this study, we validated the over-expression of CDC25B in HCC, and further investigated its potential as a therapeutic target for the management of HCC.
Quantitative real-time polymerase chain reaction and immunohistochemical staining of patient samples confirmed the significant over-expression of CDC25B in HCC compared to non-tumor liver samples (P < 0.001). Thus, intefering with the expression and activity of CDC25B may be a potential way to intervene with HCC progression. We used RNA interference to study the biological effects of silencing CDC25B expression in HCC cell lines (Hep3B and Hep40), in order to validate its potential as a therapeutic target. Using small oligo siRNAs targeting the coding region of CDC25B, we effectively suppressed CDC25B expression by up to 90%. This was associatetd with significant reductions in cell growth rate, cell migration and invasion through the matrigel membrane, and caused significant cell cycle delay at the G2 phase. Finally, suppression of CDC25B significantly slowed the growth of Hep40 xenografts in nude mice.
Our data provide evidence that the inhibition of CDC25B expression and activity lead to suppression of tumor cell growth and motility, and may therefore be a feasible approach in the clinical management of HCC.
PMCID: PMC2276234  PMID: 18269767
11.  Comparative Profiling of Primary Colorectal Carcinomas and Liver Metastases Identifies LEF1 as a Prognostic Biomarker 
PLoS ONE  2011;6(2):e16636.
We sought to identify genes of clinical significance to predict survival and the risk for colorectal liver metastasis (CLM), the most common site of metastasis from colorectal cancer (CRC).
Patients and Methods
We profiled gene expression in 31 specimens from primary CRC and 32 unmatched specimens of CLM, and performed Significance Analysis of Microarrays (SAM) to identify genes differentially expressed between these two groups. To characterize the clinical relevance of two highly-ranked differentially-expressed genes, we analyzed the expression of secreted phosphoprotein 1 (SPP1 or osteopontin) and lymphoid enhancer factor-1 (LEF1) by immunohistochemistry using a tissue microarray (TMA) representing an independent set of 154 patients with primary CRC.
Supervised analysis using SAM identified 963 genes with significantly higher expression in CLM compared to primary CRC, with a false discovery rate of <0.5%. TMA analysis showed SPP1 and LEF1 protein overexpression in 60% and 44% of CRC cases, respectively. Subsequent occurrence of CLM was significantly correlated with the overexpression of LEF1 (chi-square p = 0.042), but not SPP1 (p = 0.14). Kaplan Meier analysis revealed significantly worse survival in patients with overexpression of LEF1 (p<0.01), but not SPP1 (p = 0.11). Both univariate and multivariate analyses identified stage (p<0.0001) and LEF1 overexpression (p<0.05) as important prognostic markers, but not tumor grade or SPP1.
Among genes differentially expressed between CLM and primary CRC, we demonstrate overexpression of LEF1 in primary CRC to be a prognostic factor for poor survival and increased risk for liver metastasis.
PMCID: PMC3044708  PMID: 21383983

Results 1-11 (11)