Modelling the potential impact of global hepatitis B vaccination on the burden of chronic hepatitis B in the United States.

About 80% of persons with chronic hepatitis B virus (HBV) infection in the United States are non-US-born. Despite improvements in infant hepatitis B vaccination globally since 2000, work remains to attain the World Health Organization's (WHO) global 2030 goal of 90% vaccination. We explore the impacts on the United States of global progress in hepatitis B vaccination since 2000 and of achieving WHO hepatitis B vaccination goals. We simulated immigrants with HBV infection arriving to the United States from 2000 to 2070 using models of the 10 countries from which the largest numbers of individuals with HBV infection were born. We estimated costs in the United States among these cohorts using a disease simulation model. We simulated three scenarios: a scenario with no progress in infant vaccination for hepatitis B since 2000 (baseline), current (2020) progress and achieving WHO 2030 goals for hepatitis B vaccination. We estimate current hepatitis B vaccination progress since the 2000 baseline in these 10 countries will lead to 468,686 fewer HBV infections, avoid 35,582 hepatitis B-related deaths and save $4.2 billion in the United States through 2070. Achieving the WHO 2030 90% hepatitis B infant vaccination targets could lead to an additional 16,762 fewer HBV infections, 989 fewer hepatitis B-related deaths and save $143 million through 2070. Global hepatitis B vaccination since 2000 reduced prevalence of HBV infection in the United States. Achieving the WHO 2030 infant vaccination goals globally could lead to over one hundred million dollars in additional savings.

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

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.

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

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.

The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors.

CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.

Suppressing N-Myc downstream regulated gene 1 reactivates senescence signaling and inhibits tumor growth in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most lethal malignancy worldwide with no curative therapies. To discover potentially novel therapeutic targets for HCC, we previously studied the gene expression profiles of HCC patients and identified that significant upregulation of N-Myc downstream regulated gene 1 (NDRG1) is associated with more aggressive phenotypes and poorer overall survival of HCC patients. In this study, we further used a loss-of-function approach (RNA interference) to understand the role of NDRG1 in hepatocarcinogenesis. We found that suppression of NDRG1 significantly impaired HCC cell growth through inducing extensive cellular senescence of HCC cells both in vitro and in vivo, accompanied by cell cycle arrest at the G1 phase. The observed antitumor effects of NDRG1 suppression were correlated with activation of major senescence-associated signaling pathways, such as upregulation of tumor suppressors p53, p21 and p16, and decreased phosphorylated Rb. To obtain further insights into the clinical significance of NDRG1-modulated senescence in HCC patients, immunohistochemistry staining of 92 cases of HCC patients was done. We found that high NDRG1 expression (n = 66) is associated with low p21 (n = 82; P < 0.001) and low p16 (n = 86; P < 0.001) levels. In conclusion, this study demonstrated that NDRG1 is a potential therapeutic target for HCC because its suppression triggers senescence of HCC cells through activating glycogen synthase kinase-3ß-p53 pathway, thereby inhibiting tumor progression.

Rational design, synthesis and structural characterization of peptides and peptidomimetics to target Hsp90/Cdc37 interaction for treating hepatocellular carcinoma.

Heat shock protein 90 (Hsp90) and cell division cycle 37 (Cdc37) work together as a molecular chaperone complex to regulate the activity of a multitude of client protein kinases. These kinases belong to a wide array of intracellular signaling networks that mediate multiple cellular processes including proliferation. As a result, Hsp90 and Cdc37 represent innovative therapeutic targets in various cancers (such as leukemia, multiple myeloma, and hepatocellular carcinoma (HCC)) in which their expression levels are elevated. Conventional small molecule Hsp90 inhibitors act by blocking the conserved adenosine triphosphate (ATP) binding site. However, by targeting less conserved sites in a more specific manner, peptides and peptidomimetics (modified peptides) hold potential as more efficacious and less toxic alternatives to the conventional small molecule inhibitors. Using a rational approach, we herein developed bioactive peptides targeting Hsp90/Cdc37 interaction. A six amino acid linear peptide derived from Cdc37, KTGDEK, was designed to target Hsp90. We used in silico computational docking to first define its mode of interaction, and binding orientation, and then conjugated the peptide with a cell penetrating peptide, TAT, and a fluorescent dye to confirm its ability to colocalize with Hsp90 in HCC cells. Based on the parent linear sequence, we developed a peptidomimetics library of pre-cyclic and cyclic derivatives. These peptidomimetics were evaluated for their binding affinity to Hsp90, and bioactivity in HCC cell lines. Among them, a pre-cyclic peptidomimetic demonstrates high binding affinity and bioactivity in HCC cells, causing reduced cell proliferation that is associated with induction of cell apoptosis, and down-regulation of phosphorylated MEK1/2. Overall, this generalized approach of rational design, structural optimization, and cellular validation of 'drug-like' peptidomimetics against Hsp90/Cdc37 offers a feasible and promising way to design novel therapeutic agents for malignancies and other diseases that are dependent on this molecular chaperone complex.

Exploring Biomolecular Interaction Between the Molecular Chaperone Hsp90 and Its Client Protein Kinase Cdc37 using Field-Effect Biosensing Technology.

Biomolecular interactions play versatile roles in numerous cellular processes by regulating and coordinating functionally relevant biological events. Biomolecules such as proteins, carbohydrates, vitamins, fatty acids, nucleic acids, and enzymes are fundamental building blocks of living beings; they assemble into complex networks in biosystems to synchronize a myriad of life events. Proteins typically utilize complex interactome networks to carry out their functions; hence it is mandatory to evaluate such interactions to unravel their importance in cells at both cellular and organism levels. Toward this goal, we introduce a rapidly emerging technology, field-effect biosensing (FEB), to determine specific biomolecular interactions. FEB is a benchtop, label-free, and reliable biomolecular detection technique to determine specific interactions and uses high-quality electronic-based biosensors. The FEB technology can monitor interactions in the nanomolar range due to the biocompatible nanomaterials used on its biosensor surface. As a proof of concept, the protein-protein interaction (PPI) between heat shock protein 90 (Hsp90) and cell division cycle 37 (Cdc37) was elucidated. Hsp90 is an ATP-dependent molecular chaperone that plays an essential role in the folding, stability, maturation, and quality control of many proteins, thereby regulating multiple vital cellular functions. Cdc37 is regarded as a protein kinase-specific molecular chaperone, as it specifically recognizes and recruits protein kinases to Hsp90 to regulate their downstream signal transduction pathways. As such, Cdc37 is considered a co-chaperone of Hsp90. The chaperone-kinase pathway (Hsp90/Cdc37 complex) is hyper-activated in multiple malignancies promoting cellular growth; therefore, it is a potential target for cancer therapy. The present study demonstrates the efficiency of FEB technology using the Hsp90/Cdc37 model system. FEB detected a strong PPI between the two proteins (KD values of 0.014 µM, 0.053 µM, and 0.072 µM in three independent experiments). In summary, FEB is a label-free and cost-effective PPI detection platform, which offers fast and accurate measurements.

Soluble Frizzled-7 receptor inhibits Wnt signaling and sensitizes hepatocellular carcinoma cells towards doxorubicin.

BACKGROUND: 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. METHODS: 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. RESULTS: sFZD7 pulled down Wnt3 from Huh7 cells, and decreased ß-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. CONCLUSIONS: 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.

Cost-effectiveness of nationwide hepatitis B catch-up vaccination among children and adolescents in China.

UNLABELLED: 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.

San Francisco hep B free: a grassroots community coalition to prevent hepatitis B and liver cancer.

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.

A Humanized Anti-GPC3 Antibody for Immuno-Positron Emission Tomography Imaging of Orthotopic Mouse Model of Patient-Derived Hepatocellular Carcinoma Xenografts.

Glypican-3 (GPC3) is an attractive diagnostic marker for hepatocellular carcinoma (HCC). We previously reported the potential of an 89Zr-labeled murine anti-GPC3 antibody (clone 1G12) for immunoPET imaging of HCC in orthotopic patient-derived xenograft (PDX) mouse models. We now humanized the murine antibody by complementarity determining region (CDR) grafting, to allow its clinical translation for human use. The engineered humanized anti-GPC3 antibody, clone H3K3, retained comparable binding affinity and specificity to human GPC3. H3K3 was conjugated with desferrioxamine (Df) and radiolabeled with 89Zr to produce the PET/CT tracer 89Zr-Df-H3K3. When injected into GPC3-expressing orthotopic HCC PDX in NOD SCID Gamma (NSG) mice, 89Zr-Df-H3K3 showed specific high uptake into the orthotopic PDX and minimal, non-specific uptake into the non-tumor bearing liver. Specificity was demonstrated by significantly higher uptake of 89Zr-Df-H3K3 into the non-blocked PDX mice, compared with the blocked PDX mice (which received prior injection of 100 mg of unlabeled H3K3). Region of interest (ROI) analysis showed that the PDX/non-tumor liver ratio was highest (mean ± SD: 3.4 ± 0.31) at 168 h post injection; this ratio was consistent with biodistribution studies at the same time point. Thus, our humanized anti-GPC3 antibody, H3K3, shows encouraging potential for use as an immunoPET tracer for diagnostic imaging of HCC patients.

Hepatitis B and liver cancer knowledge and practices among healthcare and public health professionals in China: a cross-sectional study.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is the leading cause of liver disease and liver cancer and a major source of health-related discrimination in China. To better target HBV detection and prevention programs, it is necessary to assess existing HBV knowledge, educational resources, reporting, and preventive practices, particularly among those health professionals who would be responsible for implementing such programs. METHODS: At the China National Conference on the Prevention and Control of Viral Hepatitis on April 26-29, 2004, the Asian Liver Center at Stanford University partnered with the China Foundation for Hepatitis Prevention and Control to distribute a voluntary written questionnaire to Chinese healthcare and public health professionals from regional and provincial Chinese Centers for Disease Control and Prevention, health departments, and medical centers. Correct responses to survey questions were summed into a total knowledge score, and multivariate linear regression was used to compare differences in the score by participant characteristics. RESULTS: Although the median score was 81% correct, knowledge about HBV was inadequate, even among such highly trained health professionals. Of the 250 participants who completed the survey, 34% did not know that chronic HBV infection is often asymptomatic and 29% did not know that chronic HBV infection confers a high risk of cirrhosis, liver cancer, and premature death. Furthermore, 34% failed to recognize all the modes of HBV transmission and 30% did not know the importance of the hepatitis B vaccine in preventing liver disease. Respondents who reported poorer preventive practices, such as not having personally been tested for HBV and not routinely disposing of used medical needles, scored significantly lower in HBV knowledge than those who reported sound preventive practices. Of note, 38% of respondents reported positive HBsAg results to patients' employers and 25% reported positive results to patients' schools, thereby subjecting those with positive results to potential discriminatory practices. CONCLUSIONS: These results indicate that there is a need for development of effective educational programs to improve HBV knowledge among health professionals and the general public to avoid missed vaccination opportunities, reduce misconceptions, and eliminate discrimination based on chronic hepatitis B in China.

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

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.

Blockade of Wnt-1 signaling leads to anti-tumor effects in hepatocellular carcinoma cells.

BACKGROUND: 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/beta-catenin pathway is essential in HCC carcinogenesis, we studied the inhibition of Wnt-1-mediated signaling as a potential molecular target in HCC. RESULTS: 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 beta-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 beta-catenin/Tcf4 transcriptional activities, which were associated with down-regulation of the endogenous beta-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. CONCLUSION: 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.

3 For Life: a model pilot program to prevent hepatitis B virus infection and liver cancer in Asian and Pacific Islander Americans.

PURPOSE: 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. DESIGN: This pilot program offered low-cost HBV vaccination with free HBV testing targeted primarily at foreign-born Chinese adults. SETTING: Semimonthly screening and vaccination clinics were held in San Francisco, California, for 1 year. SUBJECTS: A total of 1206 adults accessed the program. INTERVENTION: 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. MEASURES: We compared the probability of completing a recommended vaccine series by HBV serologic status and sociodemographic characteristics. ANALYSIS: Proportions were compared using multivariate logistic regression models. RESULTS: 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. CONCLUSIONS: 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.

Small interfering RNA targeting CDC25B inhibits liver tumor growth in vitro and in vivo.

BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.

Cost-effectiveness of screening and vaccinating Asian and Pacific Islander adults for hepatitis B.

BACKGROUND: 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. OBJECTIVE: To assess the cost-effectiveness of 4 HBV screening and vaccination programs for Asian and Pacific Islander adults in the United States. DESIGN: Markov model with costs and benefits discounted at 3%. DATA SOURCES: Published literature and expert opinion. TARGET POPULATION: Asian and Pacific Islander adults (base-case age, 40 years; sensitivity analysis conducted on ages 20 to 60 years). TIME HORIZON: Lifetime. PERSPECTIVE: U.S. societal. INTERVENTIONS: 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. OUTCOME MEASURES: Costs (2006 U.S. dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness. RESULTS OF BASE-CASE ANALYSIS: 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. RESULTS OF SENSITIVITY ANALYSIS: 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. LIMITATIONS: Results depend on the accuracy of the underlying data and assumptions. The long-term effectiveness of new and future HBV treatments is uncertain. CONCLUSIONS: 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.

Sprouty 2, an inhibitor of mitogen-activated protein kinase signaling, is down-regulated in hepatocellular carcinoma.

The Sprouty proteins are increasingly being recognized to be deregulated in various types of cancers. This deregulation is often associated with aberrant signaling of receptor tyrosine kinases and its downstream effectors, leading to the mitogen-activated protein kinase (MAPK) signaling pathway. In human hepatocellular carcinoma, where the MAPK activity is enhanced via multiple hepatocarcinogenic factors, we observed a consistent reduced expression of the sprouty 2 (Spry2) transcript and protein in malignant hepatocytes compared with normal or cirrhotic hepatocytes. The expression pattern of Spry2 in hepatocellular carcinoma resembles that of several potential tumor markers of hepatocellular carcinoma and also that of several angiogenic factors and growth factor receptors. In contrast to previous studies of Spry2 down-regulation in other cancers, we have ruled out loss of heterozygosity or the methylation of promoter sites, two common mechanisms responsible for the silencing of genes with tumor suppressor properties. Functionally, we show that Spry2 inhibits both extracellular signal-regulated kinase signaling as well as proliferation in hepatocellular carcinoma cell lines, whereas knocking down Spry2 levels in NIH3T3 cells causes mild transformation. Our study clearly indicates a role for Spry2 in hepatocellular carcinoma, and an understanding of the regulatory controls of its expression could provide new means of regulating the angiogenic switch in this hypervascular tumor, thereby potentially controlling tumor growth.

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

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.