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ABSTRACT: 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 G(1) 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.
Neoplasia (New York, N.Y.) 08/2011; 13(8):735-47. · 5.48 Impact Factor
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ABSTRACT: 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.
Molecular Cancer 02/2011; 10:16. · 3.99 Impact Factor
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ABSTRACT: 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.
Interfaces 01/2011; 41(3):289-300. · 0.84 Impact Factor
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Albert Y Lin,
Mei-Sze Chua,
Yoon-La Choi,
William Yeh,
Young H Kim,
Raymond Azzi,
Gregg A Adams,
Kristin Sainani,
Matt van de Rijn, Samuel K So,
Jonathan R Pollack
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ABSTRACT: 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).
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.
PLoS ONE 01/2011; 6(2):e16636. · 4.09 Impact Factor
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ABSTRACT: 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 to 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, 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 to 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. CONCLUSION: 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.
Hepatology 09/2009; 51(2):405-14. · 11.66 Impact Factor
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ABSTRACT: 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.
Molecular Cancer 01/2008; 7:19. · 3.99 Impact Factor
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ABSTRACT: Chronic hepatitis B virus (HBV) infection is a serious liver disease that, if left undiagnosed or without appropriate medical management, is associated with a 25% chance of death from cirrhosis or liver cancer. To study the demographics and prevalence of chronic HBV infection and HBV vaccination in the Asian American population, we provided free HBV serological screening and administered a survey to 3163 Asian American adult volunteers in the San Francisco Bay Area between 2001 and 2006. Of those screened, 8.9% were chronically infected with HBV. Notably, one-half to two-thirds (65.4%) of the chronically infected adults were unaware that they were infected. Of those who were not chronically infected, 44.8% lacked protective antibodies against HBV and were likely susceptible to future infection. Men were twice as likely as women to be chronically infected (12.1% versus 6.4%). Asian Americans born in East Asia, Southeast Asia, or the Pacific Islands were 19.4 times more likely to be chronically infected than those born in the United States. Self-reporting of prior vaccination was unreliable to assess protection against HBV. Among the 12% who reported having been vaccinated, 5.2% were chronically infected, and 20.3% lacked protective antibodies. CONCLUSION: Given the high prevalence of unrecognized chronic HBV infection in the Asian American population, we call for healthcare providers to routinely screen Asian adults for HBV, regardless of their vaccination status. Those who test positive should be provided with culturally appropriate information to prevent disease transmission and proper medical management to reduce their risk of liver disease.
Hepatology 11/2007; 46(4):1034-40. · 11.66 Impact Factor
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ABSTRACT: As many as 10% of Asian and Pacific Islander adults in the United States are chronically infected with hepatitis B virus (HBV), and up to two thirds are unaware that they are infected. Without proper medical management and antiviral therapy, up to 25% of Asian and Pacific Islander persons with chronic HBV infection will die of liver disease.
To assess the cost-effectiveness of 4 HBV screening and vaccination programs for Asian and Pacific Islander adults in the United States.
Markov model with costs and benefits discounted at 3%.
Published literature and expert opinion.
Asian and Pacific Islander adults (base-case age, 40 years; sensitivity analysis conducted on ages 20 to 60 years).
Lifetime.
U.S. societal.
A universal vaccination strategy in which all individuals are given a 3-dose vaccination series; a screen-and-treat strategy, in which individuals are given blood tests to determine whether they are chronically infected, and infected persons are monitored and treated; a screen, treat, and ring vaccinate strategy, in which all individuals are tested for chronic HBV infection and close contacts of infected persons are screened and vaccinated if needed; and a screen, treat, and vaccinate strategy, in which all individuals are tested and then vaccinated with a 3-dose series if needed. In all cases, persons found to be chronically infected are monitored and treated if indicated.
Costs (2006 U.S. dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness.
Compared with the status quo, the screen-and-treat strategy has an incremental cost-effectiveness ratio of $36,088 per QALY gained. The screen, treat, and ring vaccinate strategy gains more QALYs than the screen and treat strategy and incurs modest incremental costs, leading to incremental cost-effectiveness of $39,903 per QALY gained compared with the screen and treat strategy. The universal vaccination and screen, treat, and vaccinate strategies were weakly dominated by the other 2 strategies.
Over a wide range of variables, the incremental cost-effectiveness ratios of the screen and treat and screen, treat, and ring vaccinate strategies were less than $50,000 per QALY gained.
Results depend on the accuracy of the underlying data and assumptions. The long-term effectiveness of new and future HBV treatments is uncertain.
Screening programs for HBV among Asian and Pacific Islander adults are likely to be cost effective. Clinically significant benefits accrue from identifying chronically infected persons for medical management and vaccinating their close contacts. Such efforts can greatly reduce the burden of HBV-associated liver cancer and chronic liver disease in the Asian and Pacific Islander population.
Annals of internal medicine 11/2007; 147(7):460-9. · 16.73 Impact Factor
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ABSTRACT: To determine whether tissue visible light spectroscopy (VLS) used during radiofrequency (RF) ablation of liver tumors could aid in detecting when tissue becomes adequately ablated, locate grossly ablated regions long after temperature and hydration measures would no longer be reliable, and differentiate tumor from normal hepatic tissue based on VLS spectral characteristics.
Studies were performed on human liver in vivo and animal liver ex vivo. In three ex vivo cow livers, RF-induced lesions were created at 80 degrees C. A 28-gauge needle embedded with VLS optical fibers was inserted alongside an RF ablation array, and tissue spectral characteristics were recorded throughout ablation. In one anesthetized sheep in vivo, a VLS needle probe was passed through freshly ablated liver lesions, and ablated region spectral characteristics were recorded during probe transit. In two human subjects, a VLS needle probe was passed through liver tumors in patients undergoing hepatic tumor resection without ablation, and tumor spectral characteristics were recorded during probe transit.
In bovine studies, there was significant change in baseline absorbance (P < .0001) as a result of increased light scattering as liver was ablated. Liver exhibited native differential absorbance peaks at 550 nm that disappeared during ablation, suggesting that optical spectroscopy detects markers of tissue altered during ablation. In sheep, liver gross ablation margins were clearly defined with millimeter resolution during needle transit through the region, suggesting that VLS is sensitive to gross margins of ablation, even after the temperature has normalized. In humans, absorbance decreased as the needle passed from normal tissue into tumor and normalized after emerging from the tumor, suggesting that absence of native liver pigment may serve as a marker for the gross margins and presence of tumors of extrahepatic origin.
In human subjects, VLS during RF liver tumor ablation depicted gross hepatic tumor margins in real time; in animal subjects, VLS achieved monitoring of when and where RF ablation endpoints were achieved, even long after the tissue cooled. Real-time in vivo monitoring and treatment feedback may be possible with the use of real-time VLS sensors placed along side of, or embedded into, the RF probe, which can then be used as an adjunct to standard imaging during tumor localization and RF ablation treatment.
Journal of Vascular and Interventional Radiology 12/2005; 16(11):1473-8. · 2.08 Impact Factor
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ABSTRACT: Transarterial therapy for primary liver cancer is gaining more acceptance. The technique of transarterial treatment of such cancers is, however, quite varied. To determine the value of our approach, we analyzed our experience with transarterial oily chemoinfusion (TOCI) of primary liver cancer over a 4.9-year period. Since 1997, over 300 such procedures have been performed at our institution. We report the results of the first 253 procedures, which were performed using a subsegmental technique with a mixture of doxorubicin, cisplatin, ethiodol, with selective Gelfoam embolization. Actuarial survival rates at 1, 2, and 3 years were calculated with Kaplan-Meier and multivariate analysis was performed by Cox regression. The median overall survival was 28.6 +/- 4.5 months following diagnosis. By univariate analysis, TNM clinical stage I or II, Karnofsky score above 80%, absence of extrahepatic disease, absence of vascular invasion, unifocal disease, pretreatment alpha-fetoprotein levels less than 500 ng/ml, hypervascularity of lesions, and lesion size less than 5 cm were all strong predictors of favorable patient survival at 1, 2, and 3 years (75%, 60%, and 50% respectively). Based on our experience, TOCI with selective embolization has similar survival benefit as the traditional chemoembolization but is associated with fewer complications.
Techniques in Vascular and Interventional Radiology 10/2002; 5(3):127-31.
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ABSTRACT: Chronic hepatitis B virus (HBV) infection causes liver cancer and disproportionately affects the Asian community in the U.S. In order to advance HBV and liver cancer awareness and prevention, it is important to identify existing gaps in knowledge and preventive practices among Asian Americans. Therefore, the authors administered a written questionnaire to 199 adults in the Asian-American community of the San Francisco Bay Area, California. Although the majority of adults had at least a college education, knowledge regarding HBV transmission, prevention, symptoms, risks, and occurrence was low. Fewer than 60% reported having been tested for HBV, only 31% reported having been vaccinated against HBV, and only 44% reported having had their children vaccinated. Asians, especially those born in China or Southeast Asia, had significantly poorer knowledge regarding HBV and liver cancer than non-Asians. Those with higher knowledge levels were significantly more likely to have been tested for HBV and to have had their children vaccinated. Younger adults, women, Caucasians, more highly educated individuals, those not born in China or Hong Kong, and those with a personal or family history of liver disease were more likely to have taken preventive action against HBV. Our results suggest that HBV and liver cancer knowledge among Asian Americans, especially Chinese Americans, is poor, and that better knowledge is associated with increased preventive practices. Thus, there is a need for increased HBV education and improved community-based interventions to prevent HBV-related liver disease in the high-risk Asian-American community.
Asian Pacific journal of cancer prevention: APJCP 8(1):127-34. · 0.66 Impact Factor
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ABSTRACT: To assess and alleviate the burden of chronic hepatitis B virus (HBV) infection among low-income, uninsured Asian and Pacific Islanders (APIs) in San Jose, California.
From 2007 to 2008, we provided free HBV testing and follow-up to 510 patients, 74% of whom were foreign-born Vietnamese. Patients were tested for hepatitis B surface antigen and surface antibody. Chronically infected patients who elected to undergo follow-up monitoring were evaluated for liver damage (ALT), liver cancer (AFP), and HBV replication (HBV DNA).
Overall, 17% were chronically infected; 33% of these were unaware that they were infected. Of those who underwent follow-up monitoring, 100% had elevated ALT, 9% had elevated AFP, and 24% had HBV DNA levels that exceeded the threshold for treatment. Patients who were candidates for antiviral therapy were enrolled in drug assistance programs, and those with elevated AFP levels were referred for CT scans. Uninfected patients lacking protective antibodies were provided free HBV vaccinations.
More liver cancer prevention in the medically underserved API community is needed, including universal screening for HBV and follow-up for those chronically infected.
Asian Pacific journal of cancer prevention: APJCP 10(3):383-6. · 0.66 Impact Factor
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ABSTRACT: Chronic hepatitis B in the Asian and Pacific Islander (API) population is among our nation's greatest ethnic and racial health disparities. Despite comprising 4.3% of the population, API make up a disproportionate half of the 1.2-2 million Americans living with chronic hepatitis B. As many as two-thirds of API are not aware of their infection because they have not been tested. This lack of knowledge prevents them from undergoing life-saving liver cancer screening and potential treatment. Likewise, those not protected are unaware that they should be vaccinated. Instead, there is a pervasive lack of awareness among API and healthcare providers. New concerted public health actions are needed to eliminate this major health disparity.
Asian Pacific journal of cancer prevention: APJCP 10(3):507-12. · 0.66 Impact Factor
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ABSTRACT: 3 For Life aims to increase hepatitis B virus (HBV) awareness and reduce the high prevalence of undiagnosed chronic HBV infection and susceptibility among Asian/Pacific Islander (API) adults.
This pilot program offered low-cost HBV vaccination with free HBV testing targeted primarily at foreign-born Chinese adults.
Semimonthly screening and vaccination clinics were held in San Francisco, California, for 1 year.
A total of 1206 adults accessed the program.
Participants paid a discounted fee for a full vaccine series against HBV, hepatitis A virus (HAV), or both. Participants also provided blood samples for HBV serologic testing. Test results, recommendations, and appointment reminders were provided by mail.
We compared the probability of completing a recommended vaccine series by HBV serologic status and sociodemographic characteristics.
Proportions were compared using multivariate logistic regression models.
Nine percent of adults were chronically infected with HBV, and 53% were unprotected. In the latter group, 85% completed the HBV vaccine series. The probability of completing a recommended hepatitis vaccine series was similar across most sociodemographic groups, with slightly higher completion rates among middle-aged and Chinese participants.
Lessons learned from this pilot program have been used toward successful replication in other cities, demonstrating that 3 For Life is an accessible, affordable, reproducible, and sustainable model to increase HBV awareness, testing, and prevention among API adults.
American journal of health promotion: AJHP 23(3):176-81. · 2.37 Impact Factor
