Publications by authors named "Samuel So"

101 Publications

Prevalence of Hepatitis B Vaccination Coverage and Serologic Evidence of Immunity Among US-Born Children and Adolescents From 1999 to 2016.

JAMA Netw Open 2020 11 2;3(11):e2022388. Epub 2020 Nov 2.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California.

Importance: The World Health Assembly has called for the elimination of hepatitis B and C by 2030. As hepatitis B has no cure, the US strategy to eliminate hepatitis B has focused on prevention through vaccination. However, there are limited data on the trend in vaccine-associated immunity since the US implementation of universal infant hepatitis B vaccination.

Objective: To compare self-reported hepatitis B vaccination coverage among children and adolescents with serologic evidence of immunity and infection in the US from 1999 to 2016.

Design, Setting, And Participants: This population-based cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2016. US-born persons aged 2 to 18 years without missing hepatitis B serologic test results and with reported vaccination history were included. Data were analyzed from September 2017 to June 2018.

Main Outcomes And Measures: The proportion of participants who reported complete vaccination for hepatitis B and who had positive serologic test results indicating immunity.

Results: Of 21 873 children and adolescents, 51.2%% were male, and the mean (SD) age was 10.6 (4.6) years. The survey reported that hepatitis B vaccination coverage increased significantly from 1999 to 2016 (from 62.6% [95% CI, 58.6%-66.4%] to 86.3% [95% CI, 82.9%-89.2%]; P < .001). Vaccine-associated immunity also increased from 1999 to 2016 among children aged 2 to 5 years (from 60.7% [95% CI, 48.8%-71.4%] to 65.2% [95% CI, 57.4%-72.3%]; P = .001) but decreased among children aged 6 to 10 years (from 64.6% [95% CI, 57.7%-70.9%] to 46.5% [95% CI, 39.1%-54.0%]; P < .001), adolescents aged 11 to 13 years (from 68.8% [95% CI, 58.1%-77.8%] to 26.2% [95% CI, 18.6%-35.5%]; P < .001), and adolescents aged 14 to 18 years (from 68.5% [95% CI, 62.9%-73.6%] to 15.6% [95% CI, 12.2%-19.8%]; P < .001). By birth year, serologic evidence of vaccine-associated immunity significantly decreased in the 1994-2003 NHANES birth cohort but not among those born between 1988 and 1993. Non-US-born children and adolescents did not show the same decreasing trend in immunity.

Conclusions And Relevance: In this cross-sectional study, decreasing hepatitis B immunity was observed among US-born children and adolescents in the 1994-2003 NHANES birth cohort despite increasing rates of hepatitis B vaccination coverage. These findings suggest a possible need for surveillance and a booster vaccine dose for hepatitis B as those without serologic evidence of immunity become young adults and may engage in behaviors associated with an increased risk for infection.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.22388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658733PMC
November 2020

Causes and trends in liver disease and hepatocellular carcinoma among men and women who received liver transplants in the U.S., 2010-2019.

PLoS One 2020 18;15(9):e0239393. Epub 2020 Sep 18.

Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Stanford, California, United States of America.

Background And Aims: The national Organ Procurement and Transplant Network (OPTN) reported the major indication for liver transplants in 2018 was for other/unknown causes. This study was undertaken to examine all causes and trends in liver disease and hepatocellular carcinoma (HCC) among adults who received liver transplants in the past 10 years.

Methods: A national cohort study of all adults who received liver transplants from Jan 1, 2010 to Dec 31, 2019 recorded in the OPTN STAR database analyzed by etiology of liver disease and HCC, and gender.

Results: Adult liver transplants increased from 5,731 in 2010 to 8,345 in 2019 (45.6% increase). Between 2010 and 2014, liver disease and HCC associated with hepatitis C (HCV) was the major cause for liver transplantation. Proportion of liver transplants for HCV associated liver disease and HCC has since decreased to 18.7% in 2019 compared with 44.5% in 2010 [25.8%, (95% CI 24.3% to 27.3%), p<0.001], while liver transplants for liver disease and HCC associated with alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) increased from 12.7% to 28.8% [16.1%, (95% CI 14.8% to 17.4%), p<0.001], and from 9.1% to 21.5% [12.4%, (95% CI 11.2% to 13.5%), p<0.001], respectively. When all causes of liver disease were examined, only 1.7% of liver transplants had unspecified causes. The five major causes of liver disease and HCC among men receiving liver transplants in 2019 were ALD (33.1%), HCV (21.9%), NAFLD (18.5%), cholestatic liver disease (5.7%) and hepatitis B (4.9%), while the major causes among women were NAFLD (26.8%), ALD (21.1%), HCV (13.1%), cholestatic liver disease (11.1%), and autoimmune liver disease (5.6%).

Conclusions: Our study found NAFLD in 2017 in women and ALD in 2019 in men have surpassed HCV as the leading causes of liver disease and HCC among adults receiving liver transplants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239393PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500679PMC
November 2020

An NIR-II/MR dual modal nanoprobe for liver cancer imaging.

Nanoscale 2020 Jun;12(21):11510-11517

Molecular Imaging Program at Stanford (MIPS), Bio-X Program, and Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, California 94305-5344, USA.

Hepatocellular carcinoma (HCC) is a malignancy of the liver worldwide and surgical resection remains the most effective treatment. However, it is still a great challenge to locate small lesions and define the border of diffused HCC even with the help of preoperative imaging examination. Here, we reported a rare-earth-doped nanoparticle NaGdF4:Nd 5%@NaGdF4@Lips (named Gd-REs@Lips), which simultaneously performed powerful functions in both magnetic resonance imaging (MRI) and second near-infrared fluorescence window imaging (NIR-II, 1000-1700 nm). Imaging studies on orthotopic models with xenografts established from HCC patients indicated that Gd-REs@Lips efficiently worked as a T2-weighted imaging contrast agent to increase the signal intensity difference between liver cancer tissues and surrounding normal liver tissues on MRI, and it can also serve as a negative NIR-II imaging contrast enabling the precise detection of liver cancer. More importantly, benefiting from the high sensitivity of NIR-II imaging, Gd-REs@Lips allowed the visualization of tiny metastasis lesions (2 mm) on the liver surface. It is expected that the dual NIR-II/MRI modal nanoprobe developed holds high potential to fill the gap between the preoperative imaging detection of cancer lesions and intra-operative guidance, and it further brings new opportunities to address HCC-related medical challenges.
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http://dx.doi.org/10.1039/d0nr00075bDOI Listing
June 2020

Hepatitis B cure: modeling the economics of a potential cost of a cure.

Curr Opin HIV AIDS 2020 05;15(3):208-212

Department of Health Management and Policy, University of Michigan, Ann Arbor, Michigan, USA.

Purpose Of Review: The cure for hepatitis C virus infection has raised hope for a potential hepatitis B virus (HBV) cure, but the high price tag has led to serious questions about the affordability, and thus to access for all. This review discusses cost-effectiveness models, affordability, and access to a potential new cure for chronic HBV infection.

Recent Findings: A cure does not yet exist for HBV, but the antiviral treatments that are currently available help slow down the progression of disease. There is limited research in the area of cost-effectiveness and economic analysis comparing a potential cure. Our preliminary findings from modeling and economic threshold analysis show that cure could be potentially cost-effective or cost-saving. Governments can possibly use the results of economic models for price negotiations.

Summary: The highest burden of the HBV infection is in low and middle-income countries. Given that the cost of current treatment has dropped dramatically in recent years as the first line treatments have come off patent, the price for a HBV cure needs to be reasonable and affordable to all people.
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http://dx.doi.org/10.1097/COH.0000000000000617DOI Listing
May 2020

An Automated, Quantitative, and Multiplexed Assay Suitable for Point-of-Care Hepatitis B Virus Diagnostics.

Sci Rep 2019 10 30;9(1):15615. Epub 2019 Oct 30.

Department of Electrical Engineering, Stanford University, Stanford, California, 94305, USA.

Hepatitis B virus (HBV) infection has a global reach with high prevalence in resource-limited areas like China and Africa. HBV patients in these areas have limited access to the currently used, costly HBV assays, which are performed in centralized clinical laboratories using single-plexed assays with bulky and expensive instruments. We aim to overcome these limitations by developing a simple and affordable HBV diagnostic platform to allow for timelier diagnosis and intervention of HBV infection. Using giant magnetoresistive (GMR) biosensor chips, we developed an automated and multiplexed quantitative platform for the measurement of a panel of HBV serology markers, including HBV "e" antigen (HBeAg), HBV surface antigen (HBsAg), and the antibody against HBsAg (anti-HBs). Our assay platform was able to detect each HBV marker with high specificity and sensitivity (with three orders of magnitude in dynamic range for each marker). Blinded analysis of HBV patient sera showed excellent correlation between our multiplexed quantitative HBsAg results and the qualitative results obtained using FDA-approved immunoassays, as well as those obtained using quantitative, single-plexed, enzyme-linked immunosorbent assays (ELISAs). The portable, automated, multiplexed, quantitative HBV serology assay platform we designed shows great promise as a more accessible alternative for HBV screening, diagnosis, and treatment monitoring.
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http://dx.doi.org/10.1038/s41598-019-52147-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821925PMC
October 2019

Knowledge, attitudes and medical practice regarding hepatitis B prevention and management among healthcare workers in Northern Vietnam.

PLoS One 2019 14;14(10):e0223733. Epub 2019 Oct 14.

Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Palo Alto, California, United States of America.

Background And Aim: Vietnam's burden of liver cancer is largely due to its high prevalence of chronic hepatitis B virus (HBV) infection. This study aimed to examine healthcare workers' (HCWs) knowledge, attitude and practices regarding HBV prevention and management.

Methods: A cross-sectional survey among health care workers working at primary and tertiary facilities in two Northern provinces in Vietnam in 2017. A standardized questionnaire was administered to randomly selected HCWs. Multivariate regression was used to identify predictors of the HBV knowledge score.

Results: Among the 314 participants, 75.5% did not know HBV infection at birth carries the highest risk of developing chronic infection. The median knowledge score was 25 out of 42 (59.5%). About one third (30.2%) wrongly believed that HBV can be transmitted through eating or sharing food with chronic hepatitis B patients. About 38.8% did not feel confident that the hepatitis B vaccine is safe. Only 30.1% provided correct answers to all the questions on injection safety. Up to 48.2% reported they consistently recap needles with two hands after injection, a practice that would put them at greater risk of needle stick injury. About 24.2% reported having been pricked by a needle at work within the past 12 months. More than 40% were concerned about having casual contact or sharing food with a person with chronic hepatitis B infection (CHB). In multivariate analysis, physicians scored significantly higher compared to other healthcare professionals. Having received training regarding hepatitis B within the last two years was also significantly associated with a better HBV knowledge score.

Conclusions: Findings from the survey indicated an immediate need to implement an effective hepatitis B education and training program to build capacity among Vietnam's healthcare workers in hepatitis B prevention and control and to dispel hepatitis B stigma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223733PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791544PMC
March 2020

Management of hepatitis B infected pregnant women: a cross-sectional study of obstetricians.

BMC Pregnancy Childbirth 2019 Aug 2;19(1):275. Epub 2019 Aug 2.

Asian Liver Center, Stanford University, 780 Welch Road, CJ 130, Palo Alto, CA, 94304-5787, USA.

Background: Our study aims to describe how obstetricians manage pregnant women infected with chronic hepatitis B in a region with a large high-risk population.

Methods: We performed a cross-sectional study among practicing obstetricians in Santa Clara County, California. All obstetricians practicing in Santa Clara County were invited to participate in the study. Obstetricians were recruited in person or by mail to complete a voluntary, multiple choice survey on hepatitis B (HBV). Survey questions assessed basic HBV knowledge and obstetricians' self-reported clinical practices of the management of HBV-infected pregnant women. Pooled descriptive analyses were calculated for the cohort, as well as, correlation coefficients to evaluate the association between reported clinical practices and hepatitis B knowledge.

Results: Among 138 obstetricians who completed the survey, 94% reported routinely testing pregnant women for hepatitis B surface antigen (HBsAg) with each pregnancy. Only 60.9% routinely advised HBsAg-positive patients to seek specialist evaluation for antiviral treatment and monitoring and fewer than half (48.6%) routinely provided them with HBV information. While most respondents recognized the potential complications of chronic HBV (94.2%), only 21% were aware that chronic HBV carries a 25% risk of liver related death when left unmonitored and untreated, and only 25% were aware of the high prevalence of chronic HBV in the foreign-born Asian, Native Hawaiian and Pacific Islander population. Obstetricians aware of the high risk of perinatal HBV transmission were more likely to test pregnant women for HBV DNA or hepatitis B e-antigen in HBV-infected women (r = 0.18, p = 0.033). Obstetricians who demonstrated knowledge of the long-term consequences of untreated HBV infection were no more likely to refer HBV-infected women to specialists for care (r = 0.02, p = 0.831).

Conclusion: Our study identified clear gaps in the practice patterns of obstetricians that can be readily addressed to enhance the care they provide to HBV-infected pregnant women.
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http://dx.doi.org/10.1186/s12884-019-2421-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679424PMC
August 2019

The Hep B Calculator: an online tool for cost-effectiveness analyses of treatment.

Lancet Gastroenterol Hepatol 2019 09 27;4(9):668. Epub 2019 Jul 27.

Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Palo Alto, CA, USA.

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http://dx.doi.org/10.1016/S2468-1253(19)30223-7DOI Listing
September 2019

Knowledge, attitudes and practices of hepatitis B prevention and immunization of pregnant women and mothers in northern Vietnam.

PLoS One 2019 10;14(4):e0208154. Epub 2019 Apr 10.

Asian Liver Center, Stanford University School of Medicine, Palo Alto, California, United States of America.

Background And Aim: Infection at birth due to mother-to-child (MTC) transmission is the most common cause of chronic hepatitis B virus (HBV) infection in Vietnam. This study was undertaken to examine the knowledge, attitudes, and practices of pregnant women and mothers in Vietnam concerning HBV prevention and immunization.

Methods: A cross-sectional survey was conducted in Quang Ninh and Hoa Binh provinces in 2017. A standardized questionnaire was administered to women when they received care at primary and tertiary maternal health clinics. Multivariate regression was used to identify predictors of HBV knowledge and practices.

Results: Among the 380 women surveyed, 50.3% were pregnant and 49.7% were postpartum. Despite 70.3% of participants reported having received information about HBV during their pregnancy, only 10.8% provided correct answers to all questions regarding HBV transmission routes and preventive measures. Around half of the participants incorrectly believed that HBV is transmitted through sneezing, contaminated water or sharing foods with chronic HBV patients. Although 86.1% of participants believed that HBV vaccination is necessary for infants, only 66.1% responded they were definitely willing to have their own child vaccinated within 24 hours. More than a third of participants expressed concern about having casual contacts or sharing foods with chronic HBV patients. In multivariate analysis, having received information about HBV during their pregnancy was significantly associated with better HBV knowledge score. Delivery at provincial level clinics was a strong predictor for perinatal HBV screening and hepatitis B birth dose administration.

Conclusions: The results highlight the need to prioritize educating pregnant women and mothers in future public health campaigns in order to increase knowledge, reduce misperception, and improve hepatitis B vaccine birth dose coverage in Vietnam.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208154PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457574PMC
January 2020

Changing Landscape of Liver Cancer in California: A Glimpse Into the Future of Liver Cancer in the United States.

J Natl Cancer Inst 2019 Jun;111(6):550-556

Stanford Cancer Institute.

Background: Asians and Hispanics currently have the highest incidence rates of hepatocellular carcinoma (HCC) in the United States. The numbers of these minority populations are rapidly increasing, reshaping the demographic in the United States and particularly California, where approximately one-third of US Asians and Hispanics reside. With the changing demographic and rising incidence of HCC that has tripled during the past three decades, it is important to forecast the future burden of HCC by age, sex, and race/ethnicity to plan prevention and control strategies for HCC.

Methods: We used four Surveillance, Epidemiology, and End Results Program registries to obtain incidence data for California during 2000 to 2013, and 14 registries to represent non-California states. We applied age-period-cohort models to estimate future HCC incidence rates, and estimated HCC burden by multiplying incidence forecasts by corresponding US Census population projections.

Results: Our forecasts for California suggest that in 2030 Hispanics and blacks will have the highest HCC incidence rates and Asians the lowest. While incidence among whites, blacks, and Hispanics in California increased successively for each birth year cohort from 1915 through 1955, incidence among Asians in California decreased for each successive birth year cohort from 1915 through 1975. In contrast, consistent declines were not seen among Asians in the rest of the United States. In California, the estimated burden of HCC is 6482 new cases in 2030, where 80.0% of these patients are older than 65 years (vs 44.5% in 2014). The relative increase of burden in 2030 vs 2014 for this 65 years and older age group is especially high among Hispanics (318.3%), whereas it is the lowest among Asians (53.2%) in California.

Conclusions: Prevention efforts in California should target persons currently ages 50 to 64 years who will make up the older age group (>65 years) in 2030, especially among Hispanics with the most rapid increase of HCC burden through 2030.
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http://dx.doi.org/10.1093/jnci/djy180DOI Listing
June 2019

Barriers to Disease Monitoring and Liver Cancer Surveillance Among Patients with Chronic Hepatitis B in the United States.

J Community Health 2019 06;44(3):610-625

Asian Liver Center, Department of Surgery, Stanford University School of Medicine, 780 Welch Road, CJ 130, Palo Alto, CA, 94304-5787, USA.

Chronic hepatitis B infection (CHB) is a condition that needs ongoing care such as monitoring for liver enzymes (ALT) and HBV DNA tests in treated and untreated patients, and annual imaging evaluation for liver cancer. Although follow-up care and treatment might seem straight forward, an estimated two-thirds of those who are aware of their infection are not seeing a health care provider, and more than half of those who are eligible for treatment do not receive it. This study aimed to compile and examine studies related to the barriers of disease monitoring, treatment, and liver cancer surveillance for CHB patients in the United States (US). A total of 4439 studies on monitoring and surveillance of CHB published between 2007 and 2018 were identified through a search of electronic databases. After critical assessment, the authors included 42 studies, divided into categories: 'patient-related barriers'; 'provider-related barriers'; and 'system-related barriers'. Among the patient-related barriers, one of the most frequent factors invoked in failing to have adequate surveillance was lack of patient's knowledge. In the provider-related barrier category, a lack of disease knowledge and adherence to guidelines was frequently reported. For the system-related barrier category, the only recurrent mention was a lack of clarity in guidelines or lack of guidelines from certain national institutions. This review summarizes and highlights the need for long-term disease management improvement of chronic hepatitis B infection for patients and healthcare providers that care for them.
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http://dx.doi.org/10.1007/s10900-018-00604-7DOI Listing
June 2019

Racial/ethnic- and county-specific prevalence of chronic hepatitis B and its burden in California.

Hepatol Med Policy 2018 5;3. Epub 2018 Jun 5.

2Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, CA USA.

Background: In the United States, the highest burden of chronic hepatitis B (CHB) and CHB-related liver cancer is in the state of California, primarily in the San Francisco (SF) Bay and Los Angeles (LA) areas. The aim of this study was to estimate county-specific hepatitis B surface antigen (HBsAg) prevalence and quantify CHB cases by age, race/ethnicity, nativity, and disease activity status.

Methods: Twelve counties in SF Bay Area and three large counties in LA area were included for this analysis. Race/ethnicity-specific prevalence of HBsAg for each county and the state of California as a whole, was estimated by including prevalence data from the National Health and Nutrition Examination Survey and various studies that estimated HBsAg prevalence in US and foreign-born Asian Pacific Islanders, Hispanic, and Black populations. In addition, clinical data of 2000 consecutive CHB patients (collected between 2009 and 2014) from a large clinical consortium in the SF Bay area were used to calculate the age-specific disease burden.

Results: Of the 15 counties analyzed, SF had the highest HBsAg prevalence (1.78%), followed by Santa Clara (1.63%) and Alameda (1.45%). The majority of CHB cases were estimated to be in LA County (83,770), followed by Santa Clara (31,273), and Alameda (23,764). Among the CHB cases, 12.7% is active HBeAg positive, 24.2% is active HBeAg negative, and 10.6% has cirrhosis.

Conclusion: This study confirms and quantifies the current burden of CHB in high endemic counties in the state of California using population-level estimates combined with clinical data including those from the community.
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http://dx.doi.org/10.1186/s41124-018-0034-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987626PMC
June 2018

Disparities in hepatocellular carcinoma incidence by race/ethnicity and geographic area in California: Implications for prevention.

Cancer 2018 09 16;124(17):3551-3559. Epub 2018 Aug 16.

Stanford Cancer Institute, Stanford University School of Medicine, Palo Alto, California.

Background: The incidence of hepatocellular carcinoma (HCC) has been rising rapidly in the United States. California is an ethnically diverse state with the largest number of incident HCC cases in the country. Characterizing HCC disparities in California may inform priorities for HCC prevention.

Methods: By using data from the Surveillance, Epidemiology, and End Results 18-Registry Database and the California Cancer Registry, age-adjusted HCC incidence in California from 2009 through 2013 was calculated by race/ethnicity and neighborhood ethnic enclave status. A geographic analysis was conducted using Medical Service Study Areas (MSSAs) as the geographic unit, and race/ethnicity-specific standardized incidence ratios (SIRs) were calculated to identify MSSAs with higher-than-expected HCC incidence compared with the statewide average.

Results: During 2009 through 2013, the age-adjusted incidence of HCC in California was the highest in Asians/Pacific Islanders (APIs) and Hispanics (>100% higher than whites), especially those living in more ethnic neighborhoods (20%-30% higher than less ethnic neighborhoods). Of the 542 MSSAs statewide, 42 had elevated HCC incidence (SIR ≥ 1.5; lower bound of 95% confidence interval > 1) for whites, 14 for blacks, 24 for APIs, and 36 for Hispanics. These MSSAs have 24% to 52% higher proportions of individuals below the 100% federal poverty line than other MSSAs.

Conclusions: APIs and Hispanics residing in more ethnic neighborhoods and individuals residing in lower income neighborhoods require more extensive preventive efforts tailored toward their unique risk factor profiles. The current race/ethnicity-specific geographic analysis can be extended to other states to inform priorities for HCC targeted prevention at the subcounty level, eventually reducing HCC burden in the country.
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http://dx.doi.org/10.1002/cncr.31598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436543PMC
September 2018

Population Health And Economic Impacts Of Reaching Chronic Hepatitis B Diagnosis And Treatment Targets In The US.

Health Aff (Millwood) 2018 07;37(7):1033-1040

Samuel So is a professor of surgery at the Stanford University School of Medicine.

The National Academies of Sciences, Engineering, and Medicine have concluded that eliminating the public health problem of chronic hepatitis B is feasible. We examined the economic and public health impact of reaching the World Health Organization targets of having 90 percent of chronic hepatitis B cases diagnosed and 80 percent being treated by 2030 in the United States with an annual incremental increase in screening and treatment rates. To reach the targets by 2030 would require screening approximately 14.5 million adults in at-risk populations to diagnose an estimated 870,000 undiagnosed cases and would result in substantial health gains: an increase of 16.5 million quality-adjusted life-years (QALYs), and reductions in liver-related deaths of 37 percent and in cases of compensated cirrhosis of 24 percent, decompensated liver cirrhosis of 51 percent, and liver cancer of 35 percent. Achieving the targets by 2030 would be highly cost-effective at $103 per QALY and would be cost-saving if the antiviral drug price were no more than $114 per month. Achieving them by 2025 would be cost-saving and would reduce liver-related deaths by 47 percent.
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http://dx.doi.org/10.1377/hlthaff.2018.0035DOI Listing
July 2018

A transfer-RNA-derived small RNA regulates ribosome biogenesis.

Nature 2017 12 29;552(7683):57-62. Epub 2017 Nov 29.

Department of Pediatrics, Stanford University, Stanford, California 94305, USA.

Transfer-RNA-derived small RNAs (tsRNAs; also called tRNA-derived fragments) are an abundant class of small non-coding RNAs whose biological roles are not well understood. Here we show that inhibition of a specific tsRNA, LeuCAG3'tsRNA, induces apoptosis in rapidly dividing cells in vitro and in a patient-derived orthotopic hepatocellular carcinoma model in mice. This tsRNA binds at least two ribosomal protein mRNAs (RPS28 and RPS15) to enhance their translation. A decrease in translation of RPS28 mRNA blocks pre-18S ribosomal RNA processing, resulting in a reduction in the number of 40S ribosomal subunits. These data establish a post-transcriptional mechanism that can fine-tune gene expression during different physiological states and provide a potential new target for treating cancer.
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http://dx.doi.org/10.1038/nature25005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066594PMC
December 2017

5-Hydroxymethylcytosine signatures in cell-free DNA provide information about tumor types and stages.

Cell Res 2017 Oct 18;27(10):1231-1242. Epub 2017 Aug 18.

Departments of Bioengineering and Applied Physics, Stanford University, Stanford, CA 94305, USA.

5-Hydroxymethylcytosine (5hmC) is an important mammalian DNA epigenetic modification that has been linked to gene regulation and cancer pathogenesis. Here we explored the diagnostic potential of 5hmC in circulating cell-free DNA (cfDNA) using a sensitive chemical labeling-based low-input shotgun sequencing approach. We sequenced cell-free 5hmC from 49 patients of seven different cancer types and found distinct features that could be used to predict cancer types and stages with high accuracy. Specifically, we discovered that lung cancer leads to a progressive global loss of 5hmC in cfDNA, whereas hepatocellular carcinoma and pancreatic cancer lead to disease-specific changes in the cell-free hydroxymethylome. Our proof-of-principle results suggest that cell-free 5hmC signatures may potentially be used not only to identify cancer types but also to track tumor stage in some cancers.
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http://dx.doi.org/10.1038/cr.2017.106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630676PMC
October 2017

Perinatal transmission in infants of mothers with chronic hepatitis B in California.

World J Gastroenterol 2017 Jul;23(27):4942-4949

Jennifer C Burgis, Department of Pediatrics, Stanford University, Palo Alto, CA 94304, United States.

Aim: To evaluate maternal hepatitis B virus (HBV) DNA as risk for perinatal HBV infection among infants of HBV-infected women in California.

Methods: Retrospective analysis among infants born to hepatitis B surface antigen (HBsAg)-positive mothers who received post vaccination serologic testing (PVST) between 2005 and 2011 in California. Demographic information was collected from the California Department of Public Health Perinatal Hepatitis B Program databaseand matched to birth certificate records. HBV DNA level and hepatitis B e antigen (HBeAg) status were obtained from three large commercial laboratories in California and provider records if available and matched to mother infant pairs. Univariate analysis compared infected and uninfected infants. Multivariate analysis was restricted to infected infants and controls with complete maternal HBV DNA results using a predefined high HBV DNA level of > 2 × 10 IU/mL, a 5:1 ratio of cases to controls and a two-sided confidence level of 95%.

Results: A total of 17687 infants were born to HBsAg positive mothers in California between Jan 1 2005 and Dec 31, 2011. Among 11473 infants with PVST, only 125 (1.1%) were found to be HBV infected. Among these infected infants, lapses in Advisory Committee on Immunization Practices recommended post exposure prophylaxis (PEP) occurred in only 9 infants. However, PEP errors were not significantly different between infected and uninfected infants. Among the 347 uninfected and infected infants who had maternal HBeAg and HBV DNA level, case-control analysis found HBeAg positivity (70.4% 28.9%, OR = 46.76, 95%CI: 6.05-361.32, < 0.001) and a maternal HBV DNA level ≥ 2 × 10 IU/mL (92.6% 18.5%, OR = 54.5, 95%CI: 12.22-247.55, < 0.001) were associated with perinatal HBV infection. In multivariate logistic regression, maternal HBV DNA level ≥ 2 × 10 IU/mL was the only significant independent predictor of perinatal HBV infection.

Conclusion: In California, transmission is low and most infected infants receive appropriate PEP and vaccination. Maternal HBV DNA ≥ 2 × 10 IU/mL is associated with high risk of perinatal infection.
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http://dx.doi.org/10.3748/wjg.v23.i27.4942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526764PMC
July 2017

Reversal of cancer gene expression correlates with drug efficacy and reveals therapeutic targets.

Nat Commun 2017 07 12;8:16022. Epub 2017 Jul 12.

Department of Pediatrics, Institute for Computational Health Sciences, University of California, San Francisco, 550 16th Street, San Francisco, California 94143, USA.

The decreasing cost of genomic technologies has enabled the molecular characterization of large-scale clinical disease samples and of molecular changes upon drug treatment in various disease models. Exploring methods to relate diseases to potentially efficacious drugs through various molecular features is critically important in the discovery of new therapeutics. Here we show that the potency of a drug to reverse cancer-associated gene expression changes positively correlates with that drug's efficacy in preclinical models of breast, liver and colon cancers. Using a systems-based approach, we predict four compounds showing high potency to reverse gene expression in liver cancer and validate that all four compounds are effective in five liver cancer cell lines. The in vivo efficacy of pyrvinium pamoate is further confirmed in a subcutaneous xenograft model. In conclusion, this systems-based approach may be complementary to the traditional target-based approach in connecting diseases to potentially efficacious drugs.
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http://dx.doi.org/10.1038/ncomms16022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510182PMC
July 2017

Computational Discovery of Niclosamide Ethanolamine, a Repurposed Drug Candidate That Reduces Growth of Hepatocellular Carcinoma Cells In Vitro and in Mice by Inhibiting Cell Division Cycle 37 Signaling.

Gastroenterology 2017 06 8;152(8):2022-2036. Epub 2017 Mar 8.

Asian Liver Center and Department of Surgery, Stanford University School of Medicine, Stanford University, Stanford, California.

Background & Aims: Drug repositioning offers a shorter approval process than new drug development. We therefore searched large public datasets of drug-induced gene expression signatures to identify agents that might be effective against hepatocellular carcinoma (HCC).

Methods: We searched public databases of messenger RNA expression patterns reported from HCC specimens from patients, HCC cell lines, and cells exposed to various drugs. We identified drugs that might specifically increase expression of genes that are down-regulated in HCCs and reduce expression of genes up-regulated in HCCs using a nonparametric, rank-based pattern-matching strategy based on the Kolmogorov-Smirnov statistic. We evaluated the anti-tumor activity of niclosamide and its ethanolamine salt (NEN) in HCC cell lines (HepG2, Huh7, Hep3B, Hep40, and PLC/PRF/5), primary human hepatocytes, and 2 mouse models of HCC. In one model of HCC, liver tumor development was induced by hydrodynamic delivery of a sleeping beauty transposon expressing an activated form of Ras (v12) and truncated β-catenin (N90). In another mouse model, patient-derived xenografts were established by implanting HCC cells from patients into livers of immunocompromised mice. Tumor growth was monitored by bioluminescence imaging. Tumor-bearing mice were fed a regular chow diet or a chow diet containing niclosamide or NEN. In a separate experiment using patient-derived xenografts, tumor-bearing mice were given sorafenib (the standard of care for patients with advanced HCC), NEN, or niclosamide alone; a combination of sorafenib and NEN; or a combination sorafenib and niclosamide in their drinking water, or regular water (control), and tumor growth was monitored.

Results: Based on gene expression signatures, we identified 3 anthelmintics that significantly altered the expression of genes that are up- or down-regulated in HCCs. Niclosamide and NEN specifically reduced the viability of HCC cells: the agents were at least 7-fold more cytotoxic to HCCs than primary hepatocytes. Oral administration of NEN to mice significantly slowed growth of genetically induced liver tumors and patient-derived xenografts, whereas niclosamide did not, coinciding with the observed greater bioavailability of NEN compared with niclosamide. The combination of NEN and sorafenib was more effective at slowing growth of patient-derived xenografts than either agent alone. In HepG2 cells and in patient-derived xenografts, administration of niclosamide or NEN increased expression of 20 genes down-regulated in HCC and reduced expression of 29 genes up-regulated in the 274-gene HCC signature. Administration of NEN to mice with patient-derived xenografts reduced expression of proteins in the Wnt-β-catenin, signal transducer and activator of transcription 3, AKT-mechanistic target of rapamycin, epidermal growth factor receptor-Ras-Raf signaling pathways. Using immunoprecipitation assays, we found NEN to bind cell division cycle 37 protein and disrupt its interaction with heat shock protein 90.

Conclusions: In a bioinformatics search for agents that alter the HCC-specific gene expression pattern, we identified the anthelmintic niclosamide as a potential anti-tumor agent. Its ethanolamine salt, with greater bioavailability, was more effective than niclosamide at slowing the growth of genetically induced liver tumors and patient-derived xenografts in mice. Both agents disrupted interaction between cell division cycle 37 and heat shock protein 90 in HCC cells, with concomitant inhibition of their downstream signaling pathways. NEN might be effective for treatment of patients with HCC.
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http://dx.doi.org/10.1053/j.gastro.2017.02.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447464PMC
June 2017

Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study.

Authors:
Christina Fitzmaurice Christine Allen Ryan M Barber Lars Barregard Zulfiqar A Bhutta Hermann Brenner Daniel J Dicker Odgerel Chimed-Orchir Rakhi Dandona Lalit Dandona Tom Fleming Mohammad H Forouzanfar Jamie Hancock Roderick J Hay Rachel Hunter-Merrill Chantal Huynh H Dean Hosgood Catherine O Johnson Jost B Jonas Jagdish Khubchandani G Anil Kumar Michael Kutz Qing Lan Heidi J Larson Xiaofeng Liang Stephen S Lim Alan D Lopez Michael F MacIntyre Laurie Marczak Neal Marquez Ali H Mokdad Christine Pinho Farshad Pourmalek Joshua A Salomon Juan Ramon Sanabria Logan Sandar Benn Sartorius Stephen M Schwartz Katya A Shackelford Kenji Shibuya Jeff Stanaway Caitlyn Steiner Jiandong Sun Ken Takahashi Stein Emil Vollset Theo Vos Joseph A Wagner Haidong Wang Ronny Westerman Hajo Zeeb Leo Zoeckler Foad Abd-Allah Muktar Beshir Ahmed Samer Alabed Noore K Alam Saleh Fahed Aldhahri Girma Alem Mulubirhan Assefa Alemayohu Raghib Ali Rajaa Al-Raddadi Azmeraw Amare Yaw Amoako Al Artaman Hamid Asayesh Niguse Atnafu Ashish Awasthi Huda Ba Saleem Aleksandra Barac Neeraj Bedi Isabela Bensenor Adugnaw Berhane Eduardo Bernabé Balem Betsu Agnes Binagwaho Dube Boneya Ismael Campos-Nonato Carlos Castañeda-Orjuela Ferrán Catalá-López Peggy Chiang Chioma Chibueze Abdulaal Chitheer Jee-Young Choi Benjamin Cowie Solomon Damtew José das Neves Suhojit Dey Samath Dharmaratne Preet Dhillon Eric Ding Tim Driscoll Donatus Ekwueme Aman Yesuf Endries Maryam Farvid Farshad Farzadfar Joao Fernandes Florian Fischer Tsegaye Tewelde G/Hiwot Alemseged Gebru Sameer Gopalani Alemayehu Hailu Masako Horino Nobuyuki Horita Abdullatif Husseini Inge Huybrechts Manami Inoue Farhad Islami Mihajlo Jakovljevic Spencer James Mehdi Javanbakht Sun Ha Jee Amir Kasaeian Muktar Sano Kedir Yousef S Khader Young-Ho Khang Daniel Kim James Leigh Shai Linn Raimundas Lunevicius Hassan Magdy Abd El Razek Reza Malekzadeh Deborah Carvalho Malta Wagner Marcenes Desalegn Markos Yohannes A Melaku Kidanu G Meles Walter Mendoza Desalegn Tadese Mengiste Tuomo J Meretoja Ted R Miller Karzan Abdulmuhsin Mohammad Alireza Mohammadi Shafiu Mohammed Maziar Moradi-Lakeh Gabriele Nagel Devina Nand Quyen Le Nguyen Sandra Nolte Felix A Ogbo Kelechi E Oladimeji Eyal Oren Mahesh Pa Eun-Kee Park David M Pereira Dietrich Plass Mostafa Qorbani Amir Radfar Anwar Rafay Mahfuzar Rahman Saleem M Rana Kjetil Søreide Maheswar Satpathy Monika Sawhney Sadaf G Sepanlou Masood Ali Shaikh Jun She Ivy Shiue Hirbo Roba Shore Mark G Shrime Samuel So Samir Soneji Vasiliki Stathopoulou Konstantinos Stroumpoulis Muawiyyah Babale Sufiyan Bryan L Sykes Rafael Tabarés-Seisdedos Fentaw Tadese Bemnet Amare Tedla Gizachew Assefa Tessema J S Thakur Bach Xuan Tran Kingsley Nnanna Ukwaja Benjamin S Chudi Uzochukwu Vasiliy Victorovich Vlassov Elisabete Weiderpass Mamo Wubshet Terefe Henock Gebremedhin Yebyo Hassen Hamid Yimam Naohiro Yonemoto Mustafa Z Younis Chuanhua Yu Zoubida Zaidi Maysaa El Sayed Zaki Zerihun Menlkalew Zenebe Christopher J L Murray Mohsen Naghavi

JAMA Oncol 2017 Apr;3(4):524-548

Institute for Health Metrics and Evaluation, University of Washington, Seattle.

Importance: Cancer is the second leading cause of death worldwide. Current estimates on the burden of cancer are needed for cancer control planning.

Objective: To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 32 cancers in 195 countries and territories from 1990 to 2015.

Evidence Review: Cancer mortality was estimated using vital registration system data, cancer registry incidence data (transformed to mortality estimates using separately estimated mortality to incidence [MI] ratios), and verbal autopsy data. Cancer incidence was calculated by dividing mortality estimates through the modeled MI ratios. To calculate cancer prevalence, MI ratios were used to model survival. To calculate YLDs, prevalence estimates were multiplied by disability weights. The YLLs were estimated by multiplying age-specific cancer deaths by the reference life expectancy. DALYs were estimated as the sum of YLDs and YLLs. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. Countries were categorized by SDI quintiles to summarize results.

Findings: In 2015, there were 17.5 million cancer cases worldwide and 8.7 million deaths. Between 2005 and 2015, cancer cases increased by 33%, with population aging contributing 16%, population growth 13%, and changes in age-specific rates contributing 4%. For men, the most common cancer globally was prostate cancer (1.6 million cases). Tracheal, bronchus, and lung cancer was the leading cause of cancer deaths and DALYs in men (1.2 million deaths and 25.9 million DALYs). For women, the most common cancer was breast cancer (2.4 million cases). Breast cancer was also the leading cause of cancer deaths and DALYs for women (523 000 deaths and 15.1 million DALYs). Overall, cancer caused 208.3 million DALYs worldwide in 2015 for both sexes combined. Between 2005 and 2015, age-standardized incidence rates for all cancers combined increased in 174 of 195 countries or territories. Age-standardized death rates (ASDRs) for all cancers combined decreased within that timeframe in 140 of 195 countries or territories. Countries with an increase in the ASDR due to all cancers were largely located on the African continent. Of all cancers, deaths between 2005 and 2015 decreased significantly for Hodgkin lymphoma (-6.1% [95% uncertainty interval (UI), -10.6% to -1.3%]). The number of deaths also decreased for esophageal cancer, stomach cancer, and chronic myeloid leukemia, although these results were not statistically significant.

Conclusion And Relevance: As part of the epidemiological transition, cancer incidence is expected to increase in the future, further straining limited health care resources. Appropriate allocation of resources for cancer prevention, early diagnosis, and curative and palliative care requires detailed knowledge of the local burden of cancer. The GBD 2015 study results demonstrate that progress is possible in the war against cancer. However, the major findings also highlight an unmet need for cancer prevention efforts, including tobacco control, vaccination, and the promotion of physical activity and a healthy diet.
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http://dx.doi.org/10.1001/jamaoncol.2016.5688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103527PMC
April 2017

The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013.

Lancet 2016 Sep 7;388(10049):1081-1088. Epub 2016 Jul 7.

Division of Infectious Diseases, Imperial College, London, UK. Electronic address:

Background: With recent improvements in vaccines and treatments against viral hepatitis, an improved understanding of the burden of viral hepatitis is needed to inform global intervention strategies. We used data from the Global Burden of Disease (GBD) Study to estimate morbidity and mortality for acute viral hepatitis, and for cirrhosis and liver cancer caused by viral hepatitis, by age, sex, and country from 1990 to 2013.

Methods: We estimated mortality using natural history models for acute hepatitis infections and GBD's cause-of-death ensemble model for cirrhosis and liver cancer. We used meta-regression to estimate total cirrhosis and total liver cancer prevalence, as well as the proportion of cirrhosis and liver cancer attributable to each cause. We then estimated cause-specific prevalence as the product of the total prevalence and the proportion attributable to a specific cause. Disability-adjusted life-years (DALYs) were calculated as the sum of years of life lost (YLLs) and years lived with disability (YLDs).

Findings: Between 1990 and 2013, global viral hepatitis deaths increased from 0·89 million (95% uncertainty interval [UI] 0·86-0·94) to 1·45 million (1·38-1·54); YLLs from 31·0 million (29·6-32·6) to 41·6 million (39·1-44·7); YLDs from 0·65 million (0·45-0·89) to 0·87 million (0·61-1·18); and DALYs from 31·7 million (30·2-33·3) to 42·5 million (39·9-45·6). In 2013, viral hepatitis was the seventh (95% UI seventh to eighth) leading cause of death worldwide, compared with tenth (tenth to 12th) in 1990.

Interpretation: Viral hepatitis is a leading cause of death and disability worldwide. Unlike most communicable diseases, the absolute burden and relative rank of viral hepatitis increased between 1990 and 2013. The enormous health loss attributable to viral hepatitis, and the availability of effective vaccines and treatments, suggests an important opportunity to improve public health.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(16)30579-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100695PMC
September 2016

Evaluation of the first open-access hepatitis B and safe injection online training course for health professionals in China.

BMC Med Educ 2016 Mar 8;16:81. Epub 2016 Mar 8.

Asian Liver Center at Stanford University, 780 Welch Road, CJ130, 94304, Palo Alto, CA, USA.

Background: Despite the high prevalence of chronic hepatitis B virus (HBV) infection in China, HBV infection prevention and long-term care knowledge of health professionals is inadequate. To address this knowledge gap, we developed an open-access evidence-based online training course, "KnowHBV", to train health professionals on prevention of HBV transmission and safe injections. We conducted an evaluation of the course with health professionals in China to examine its effectiveness in improving knowledge and learner's satisfaction of the course.

Methods: Between July and December 2011, 1015 health professionals from selected hospitals and disease control institutions of Shandong province registered for the course and 932 (92 %) completed the three-module course. Participants' demographic information, pre- and post-course knowledge test results and learner's feedback were collected through the course website.

Results: Pre-course knowledge assessment confirmed gaps in HBV transmission routes, prevention and long-term care knowledge. Only 50.4 % of participants correctly identified all of the transmission routes of HBV, and only 40.7 % recognized all of the recommended tests to monitor chronically infected persons. The number of participants that answered all six multi-part multiple-choice knowledge questions correctly increased from 183 (19.7 %) before taking the course to 395 (42.4 %) on their first attempt upon completion of the course. Over 90 % of the 898 participants who completed the learner-feedback questionnaire rated the course as 'good' or 'very good'; over 94 % found the course instructional design helpful; 57.5 %, 65.7 % and 68.5 % reported that half or more than half of the course content in modules 1, 2 and 3 respectively provided new information; and 93.2 % of the participants indicated they preferred the online learning over traditional face-to-face classroom learning.

Conclusions: The "KnowHBV" online training course appears to be an effective online training tool to improve HBV prevention and care knowledge of the health professionals in China.
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http://dx.doi.org/10.1186/s12909-016-0608-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782342PMC
March 2016

Cost-Effectiveness and Cost Thresholds of Generic and Brand Drugs in a National Chronic Hepatitis B Treatment Program in China.

PLoS One 2015 4;10(11):e0139876. Epub 2015 Nov 4.

Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Stanford, CA, 94305, United States of America.

Chronic liver disease and liver cancer associated with chronic hepatitis B (CHB) are leading causes of death among adults in China. Although newborn hepatitis B immunization has successfully reduced the prevalence of CHB in children, about 100 million Chinese adults remain chronically infected. If left unmanaged, 15-25% will die from liver cancer or liver cirrhosis. Antiviral treatment is not necessary for all patients with CHB, but when it is indicated, good response to treatment would prevent disease progression and reduce disease mortality and morbidity, and costly complications. The aim of this study is to analyze the cost-effectiveness of generic and brand antiviral drugs for CHB treatment in China, and assessing various thresholds at which a highly potent, low resistance antiviral drug would be cost-saving and/or cost-effective to introduce in a national treatment program. We developed a Markov simulation model of disease progression using effectiveness and cost data from the medical literature. We measured life-time costs, quality adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs), and clinical outcomes. The no treatment strategy incurred the highest health care costs ($12,932-$25,293) per patient, and the worst health outcomes, compared to the antiviral treatment strategies. Monotherapy with either entecavir or tenofovir yielded the most QALYs (14.10-19.02) for both HBeAg-positive and negative patients, with or without cirrhosis. Threshold analysis showed entercavir or tenofovir treatment would be cost saving if the drug price is $32-75 (195-460 RMB) per month, highly cost-effective at $62-110 (379-670 RMB) per month and cost-effective at $63-120 (384-734 RMB) per month. This study can support policy decisions regarding the implementation of a national health program for chronic hepatitis B treatment in China at the population level.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139876PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633043PMC
June 2016

Suppression of ATAD2 inhibits hepatocellular carcinoma progression through activation of p53- and p38-mediated apoptotic signaling.

Oncotarget 2015 Dec;6(39):41722-35

Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.

The ATPase family, AAA domain containing 2 (ATAD2) is highly expressed in multiple cancers. We aim to understand the clinical and biological significance of ATAD2 over-expression in hepatocellular carcinoma (HCC), as a means to validate it as a therapeutic target in HCC. We demonstrated that ATAD2 was over-expressed in HCC patients, where high ATAD2 levels were significantly correlated with aggressive phenotypes such as high AFP levels, advanced tumor stages, and vascular invasion. Using RNA interference, suppression of ATAD2 in HCC cell lines decreased cell viability, migration, and invasion, and induced apoptosis in vitro. Furthermore, we identified p53 and p38 as key proteins that mediate apoptosis induced by ATAD2 suppression. In HCC cells, we demonstrated that ATAD2 directly interacted with MKK3/6, which prevented p38 activation and therefore inhibited p38-mediated apoptosis. In vivo, suppression of ATAD2 impaired the growth of HepG2 and Hep3B subcutaneous xenografts, accompanied by enhanced apoptosis and p-p53 and p-p38 levels. Our results validate that ATAD2 is an important negative regulator of apoptosis, and that neutralizing its activity has promising anti-tumor effects in HCC cells.
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http://dx.doi.org/10.18632/oncotarget.6152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747184PMC
December 2015

NDRG1 promotes growth of hepatocellular carcinoma cells by directly interacting with GSK-3β and Nur77 to prevent β-catenin degradation.

Oncotarget 2015 Oct;6(30):29847-59

Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.

The N-myc downstream regulated gene 1 (NDRG1) is significantly associated with advanced tumor stages and poor survival of hepatocellular carcinoma (HCC), thereby implicating it as a potential target for HCC treatment. We aim to further understand its biological roles in hepatocarcinogenesis, as a means to exploit it for therapeutic purposes. By screening using the ProtoArray® Human Protein Microarrays, we identified glycogen synthase kinase 3β (GSK-3β) and the orphan nuclear receptor (Nur77) as potential interaction partners of NDRG1. These interactions were confirmed in HCC cell lines in vitro by co-immunoprecipitation; and co-localizations of NDRG1 with GSK-3β and Nur77 were observed by immunofluorescence staining. Additionally, high levels of NDRG1 competitively bind to GSK-3β and Nur77 to allow β-catenin to escape degradation, with consequent elevated levels of downstream oncogenic genes. In vivo, we consistently observed that NDRG1 suppression in HCC xenografts decreased β-catenin levels and its downstream target Cyclin D1, with concomitant tumor growth inhibition. Clinically, the over-expression of NDRG1 in HCC patient samples is positively correlated with GSK-3β-9ser (|”‚ R | = 0.28, p = 0.01), Nur77 (|”‚ R | = 0.42, p < 0.001), and β-catenin (| R |= 0.32, p = 0.003) expressions. In conclusion, we identified GSK-3β and Nur77 as novel interaction partners of NDRG1. These protein-protein interactions regulate the turnover of β-catenin and subsequent downstream signaling mediated by β-catenin in HCC cells, and provides potential targets for future therapeutic interventions.
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http://dx.doi.org/10.18632/oncotarget.4913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745767PMC
October 2015

Tankyrase inhibitors attenuate WNT/β-catenin signaling and inhibit growth of hepatocellular carcinoma cells.

Oncotarget 2015 Sep;6(28):25390-401

Asian Liver Center and Department of Surgery, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.

Deregulated WNT/β-catenin signaling contributes to the development of a subgroup of hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide. Within this pathway, the tankyrase enzymes (TNKS1 and TNKS2) degrade AXIN and thereby enhance β-catenin activity. We evaluate TNKS enzymes as potential therapeutic targets in HCC, and the anti-tumor efficacy of tankyrase inhibitors (XAV939, and its novel nitro-substituted derivative WXL-8) in HCC cells. Using semi-quantitative RT-PCR, we found significantly elevated levels of TNKS1/2 mRNA in tumor liver tissues compared to adjacent non-tumor livers, at protein levels only TNKS1 is increased. In HepG2, Huh7cells, siRNA-mediated knockdown suppression of endogenous TNKS1 and TNKS2 reduced cell proliferation, together with decreased nuclear β-catenin levels. XAV939 and WXL-8 inhibited cell proliferation and colony formation in HepG2, Huh7, and Hep40 cells (p < 0.05), with stabilization of AXIN1 and AXIN2, and decreased β-catenin protein levels. XAV939 and WXL-8 also attenuated rhWNT3A-induced TOPflash luciferase reporter activity in HCC cells, indicating reduced β-catenin transcriptional activity, consistent with decreased nuclear β-catenin levels. In vivo, intra-tumor injections of XAV939 or WXL-8 significantly inhibited the growth of subcutaneous HepG2 xenografts (P < 0.05). We suggest that tankyrase inhibition is a potential therapeutic approach for treating a subgroup HCC with aberrant WNT/β-catenin signaling pathway.
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http://dx.doi.org/10.18632/oncotarget.4455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694839PMC
September 2015

Medical training fails to prepare providers to care for patients with chronic hepatitis B infection.

World J Gastroenterol 2015 Jun;21(22):6914-23

Stephanie D Chao, Department of Surgery, Stanford University School of Medicine, Asian Liver Center at Stanford University, School of Medicine, Palo Alto, CA 94304, United States.

Aim: To investigate physicians' knowledge including chronic hepatitis B (CHB) diagnosis, screening, and management in various stages of their training.

Methods: A voluntary 20-question survey was administered in Santa Clara County, CA where Asian and Pacific Islanders (API) account for a third of the population. Among the 219 physician participants, there were 63 interns, 60 second-year residents, 26 chief residents and 70 attending physicians. The survey asked questions regarding respondents' demographics, general hepatitis B virus knowledge questions (i.e., transmission, prevalence, diagnostic testing, prevention, and treatment options), as well as, self-reported practice behavior and confidence in knowledge.

Results: Knowledge about screening and managing patients with CHB was poor: only 24% identified the correct tests to screen for CHB, 13% knew the next steps for patients testing positive for CHB, 18% knew the high prevalence rate among API, and 31% knew how to screen for liver cancer. Wald chi-square analysis determined the effect of training level on knowledge; in all cases except for knowledge of liver cancer screening (P = 0.0032), knowledge did not significantly increase with length in residency training or completion of residency.

Conclusion: Even in a high-risk region, both medical school and residency training have not adequately prepared physicians in the screening and management of CHB.
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http://dx.doi.org/10.3748/wjg.v21.i22.6914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462732PMC
June 2015

Copy number gain of granulin-epithelin precursor (GEP) at chromosome 17q21 associates with overexpression in human liver cancer.

BMC Cancer 2015 Apr 11;15:264. Epub 2015 Apr 11.

Department of Surgery, The University of Hong Kong, Hong Kong, China.

Background: Granulin-epithelin precursor (GEP), a secretory growth factor, demonstrated overexpression in various human cancers, however, mechanism remain elusive. Primary liver cancer, hepatocellular carcinoma (HCC), ranks the second in cancer-related death globally. GEP controlled growth, invasion, metastasis and chemo-resistance in liver cancer. Noted that GEP gene locates at 17q21 and the region has been frequently reported to be amplified in subset of HCC. The study aims to investigate if copy number gain would associate with GEP overexpression.

Methods: Quantitative Microsatellite Analysis (QuMA) was used to quantify the GEP DNA copy number, and fluorescent in situ hybridization (FISH) was performed to consolidate the amplification status. GEP gene copy number, mRNA expression level and clinico-pathological features were analyzed.

Results: GEP DNA copy number determined by QuMA corroborated well with the FISH data, and the gene copy number correlated with the expression levels (n = 60, r = 0.331, P = 0.010). Gain of GEP copy number was observed in 20% (12/60) HCC and associated with hepatitis B virus infection status (P = 0.015). In HCC with increased GEP copy number, tight association between GEP DNA and mRNA levels were observed (n = 12, r = 0.664, P = 0.019).

Conclusions: Gain of the GEP gene copy number was observed in 20% HCC and the frequency comparable to literatures reported on the chromosome region 17q. Increased gene copy number contributed to GEP overexpression in subset of HCC.
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http://dx.doi.org/10.1186/s12885-015-1294-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403714PMC
April 2015

Suppressing the CDC37 cochaperone in hepatocellular carcinoma cells inhibits cell cycle progression and cell growth.

Liver Int 2015 Apr 25;35(4):1403-15. Epub 2014 Aug 25.

Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.

Background & Aims: The molecular cochaperone CDC37 regulates the activities of multiple protein kinases, and is an attractive broad-spectrum target in many types of cancers in which it is over-expressed. This study investigates the antitumour effects of inhibiting CDC37 in human hepatocellular carcinoma (HCC).

Methods: A total of 91 patients were enrolled for CDC37 mRNA detection by using quantitative real-time PCR. Cell proliferation, gene expression changes and tumourigenicity were determined by targeting CDC37 using RNA interference in human hepatoma cell lines.

Results: We confirmed the significant over-expression of CDC37 transcript and protein in HBV-associated HCC patients. Using a CDC37-specific small oligo-siRNA, we silenced CDC37 expression in HepG2 and Huh7 hepatoma cell lines, and observed inhibition of in vitro cell proliferation, cell cycle arrest at the G1 phase, and enhanced apoptosis. Specifically, we found concomitant down-regulation of Cyclin D1, CDK4, and pRB (S807/811 and S795) upon CDC37 suppression, which could mediate the arrest of cell cycle progression at the G1 phase. Gene expression profiling further identified several genes involved in cell proliferation, cell cycle progression, and apoptosis that are regulated by CDC37 suppression. Huh7 cells with stable knockdown of CDC37 showed decreased in vitro colony formation ability, and significantly slowed xenograft growth in vivo.

Conclusions: On the basis of the observed antitumour effects of inhibiting CDC37 expression, we propose that CDC37 is a promising therapeutic target in HCC. Its ability to regulate multiple pathways makes it potentially valuable in treating the heterogeneous subtypes of this malignancy.
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http://dx.doi.org/10.1111/liv.12651DOI Listing
April 2015