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Liver transplantation (LT) is the treatment of choice for patients with hepatocellular carcinoma (HCC). Recurrence of HCC after LT occurs in 10% to 20% of cases. Preclinical studies to evaluate immune checkpoint inhibitors in conjunction with immunosuppressant treatment in transplant recipients have been lacking. Here, we evaluated the efficacy, safety, and mechanism of programmed cell death-1 (PD1) blockade under tacrolimus treatment in transplant recipients.We used a murine allogeneic skin transplantation model and murine syngeneic subcutaneous and orthotopic HCC models and measured the tumor volume and the change in tumor-infiltrating lymphocytes under PD1 blockade and tacrolimus treatment.Tacrolimus treatment prolonged allograft survival in the allogeneic transplantation model and enhanced tumor growth in both subcutaneous and orthotopic HCC models. PD1 blockade suppressed tumor growth and lung metastasis in correlation with the number of infiltrating CD8+ T cells. Under tacrolimus treatment, PD1 blockade still resulted in an antitumor effect accompanied by a significant increase in tumor-infiltrating CD8+ T cells, natural killer cells, dendritic cells, and natural killer T cells. Tacrolimus treatment rescued the acceleration of transplant rejection induced by PD1 blockade in the allogeneic transplantation model.Our data suggest that treatment with high-dose tacrolimus in conjunction with PD1 blockade has an antitumor effect and reduces transplant rejection in mouse models of allograft skin transplantation and HCC. Thus, these results suggest that a clinical trial of PD1 inhibitors for HCC in LT merits consideration.

Background Hepatocyte transplantation has been extensively investigated as an alternative to orthotopic liver transplantation. However, its application in routine clinical practice has been restricted because of low initial engraftment and subsequent repopulation. Methods Using mice as a model, we have developed a minimally invasive and nontoxic preconditioning strategy based on preadministration of antibodies against hepsin to increase donor hepatocyte retention and engraftment rate. Results Liver sinusoid diameters decreased significantly with antihepsin pretreatment, and graft cell numbers increased nearly 2-fold in the recipients' liver parenchyma for 20 days after hepatocyte transplantation. Postoperative complications such as hepatic ischemia injury or apparent immune cell accumulation were not observed in recipients. In a hemophilia B mouse model, antihepsin preconditioning enhanced the expression and clotting activity of coagulation factor IX (FIX) to nearly 2-fold that of immunoglobulin G-treated controls and maintained higher plasma FIX clotting activity relative to the prophylactic range for 50 days after hepatocyte transplantation. Antihepsin pretreatment combined with adeno-associated virus-transduced donor hepatocytes expressing human FIX-Triple, a hyperfunctional FIX variant, resulted in plasma FIX levels similar to those associated with mild hemophilia, which protected hemophilia B mice from major bleeding episodes for 50 days after transplantation. Furthermore, antihepsin pretreatment and repeated transplantation resulted in extending the therapeutic period by 30 days relative to the immunoglobulin G control. Conclusions Thus, this antihepsin strategy improved the therapeutic effect of hepatocyte transplantation in mice with tremendous safety and minimal invasion. Taken together, we suggest that preconditioning with antihepsin may have clinical applications for liver cell therapy.

The efficacy of treatment for advanced hepatocellular carcinoma (HCC) has remained limited. Polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) is a synthetic double-stranded RNA that serves as a viral mimic and induces an immune response. Intratumoral (IT) poly-ICLC injections can induce an autovaccination effect and prime the immune system, whereas intramuscular (IM) injection of poly-ICLC can attract and maintain antigen-specific cytotoxic T lymphocytes in tumors. We found that IT injection of poly-ICLC upregulated the expression of CD83 and CD86 on conventional type 1 dendritic cells in tumors. Combination therapy with IT followed by IM injections of poly-ICLC significantly inhibited tumor growth and increased the tumor-infiltrating CD8

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Chronic liver inflammation due to hepatitis virus infection and other major effectors is a major risk factor of HCC. Indoleamine 2,3-dioxygenase 1 (IDO1), a heme enzyme highly expressed upon stimulation with proinflammatory cytokines such as interferon-γ (IFN-γ), is activated to modulate the tumor microenvironment and potentially crucial in the development of certain cancer types. Earlier studies have majorly reported an immunomodulatory function of IDO1. However, the specific role of IDO1 in cancer cells, particularly HCC, remains to be clarified. Analysis of The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) dataset in the current study revealed a significant correlation between IDO1 expression and HCC. We further established inducible IDO1-expressing cell models by coupling lentivirus-mediated knockdown and IFN-γ induction of IDO1 in normal and HCC cells. In functional assays, proliferation and motility-related functions of HCC cells were compromised upon suppression of IDO1, which may partially be rescued by its enzymatic product, kynurenine (KYN), while normal hepatocytes were not affected. Aryl hydrocarbon receptor (AhR), a reported endogenous KYN receptor, is suggested to participate in tumorigenesis. In mechanistic studies, IDO1 activation promoted both AhR and β-catenin activity and nuclear translocation. Immunofluorescence staining and co-immunoprecipitation assays further disclosed interactions between AhR and β-catenin. In addition, we identified a Src-PTEN-PI3K/Akt-GSK-3β axis involved in β-catenin stabilization and activation following IDO1-mediated AhR activation. IDO1-induced AhR and β-catenin modulated the expression of proliferation- and EMT-related genes to facilitate growth and metastasis of HCC cells. Our collective findings provide a mechanistic basis for the design of more efficacious IDO1-targeted therapy for HCC.

The extent of cellular heterogeneity involved in neuronal regeneration after spinal cord injury (SCI) remains unclear. Therefore, we established stress-responsive transgenic zebrafish embryos with SCI. As a result, we found an SCI-induced cell population, termed SCI stress-responsive regenerating cells (SrRCs), essential for neuronal regeneration post-SCI. SrRCs were mostly composed of subtypes of radial glia (RGs-SrRCs) and neuron stem/progenitor cells (NSPCs-SrRCs) that are able to differentiate into neurons, and they formed a bridge across the lesion and connected with neighbouring undamaged motor neurons post-SCI. Compared to SrRCs at the caudal side of the SCI site (caudal-SrRCs), rostral-SrRCs participated more actively in neuronal regeneration. After RNA-seq analysis, we discovered that caveolin 1 ( cav1 ) was significantly upregulated in rostral-SrRCs and that cav1 was responsible for the axonal regrowth and regenerative capability of rostral-SrRCs. Collectively, we define a specific SCI-induced cell population, SrRCs, involved in neuronal regeneration, demonstrate that rostral-SrRCs exhibit higher neuronal differentiation capability and prove that cav1 is predominantly expressed in rostral-SrRCs, playing a major role in neuronal regeneration after SCI.

The extent of cellular heterogeneity involved in neuronal regeneration after spinal cord injury (SCI) remains unclear. Therefore, we established stress-responsive transgenic zebrafish embryos with SCI. As a result, we found an SCI-induced cell population, termed SCI stress-responsive regenerating cells (SrRCs), essential for neuronal regeneration post-SCI. SrRCs were mostly composed of subtypes of radial glia (RGs-SrRCs) and neuron stem/progenitor cells (NSPCs-SrRCs) able to differentiate into neurons, formed a bridge across the lesion and connected with neighbouring undamaged motor neurons post-SCI. Compared to SrRCs at the caudal side of the SCI site (caudal-SrRCs), rostral-SrRCs participated more actively in neuronal regeneration. After RNA-seq analysis, we discovered that caveolin 1 (cav1) was significantly upregulated in rostral-SrRCs and that cav1 was responsible for the axonal regrowth and regenerative capability of rostral-SrRCs. Collectively, we define a specific SCI-induced cell population, SrRCs, involved in neuronal regeneration, demonstrate that rostral-SrRCs exhibit higher neuronal differentiation capability and prove that cav1 is predominately expressed in rostral-SrRCs, playing a major role in neuronal regeneration after SCI.

Upstream open reading frames (uORFs) are known to negatively affect translation of the downstream ORF. The regulatory proteins involved in relieving this inhibition are however poorly characterized. In response to cellular stress, eIF2α phosphorylation leads to an inhibition of global protein synthesis, while translation of specific factors such as CHOP is induced. We analyzed a 105‐nt inhibitory uORF in the transcript of human CHOP (huORFchop) and found that overexpression of the zebrafish or human ENDOU poly(U)‐endoribonuclease (Endouc or ENDOU‐1, respectively) increases CHOP mRNA translation also in the absence of stress. We also found that Endouc/ENDOU‐1 binds and cleaves the huORFchop transcript at position 80G‐81U, which induces CHOP translation independently of phosphorylated eIF2α. However, both ENDOU and phospho‐eIF2α are nonetheless required for maximal translation of CHOP mRNA. Increased levels of ENDOU shift a huORFchop reporter as well as endogenous CHOP transcripts from the monosome to polysome fraction, indicating an increase in translation. Furthermore, we found that the uncapped truncated huORFchop‐69‐105‐nt transcript contains an internal ribosome entry site (IRES), facilitating translation of the cleaved transcript. Therefore, we propose a model where ENDOU‐mediated transcript cleavage positively regulates CHOP translation resulting in increased CHOP protein levels upon stress. Specifically, CHOP transcript cleavage changes the configuration of huORFchop thereby releasing its inhibition and allowing the stalled ribosomes to resume translation of the downstream ORF., Cleavage of CHOP transcripts by zebrafish Endouc and its human orthologue ENDOU positively regulates translation by inducing a conformational change in the inhibitory structure that allows stalled ribosomes to progress.

Ciona molecule against microbes-A24 (CiMAM) isolated from the marine chordate Ciona intestinalis is an antimicrobial peptide. To generate CiMAM-expressing transgenic Bacillus subtilis, we constructed a plasmid expressing recombinant CiMAM (rCiMAM) and introduced it into B. subtilis. Transgenic strains C117 and C166 were selected since they were able to highly and stably express rCiMAM. We studied the bactericidal activity of pepsin-digested extracts from rCiMAM-expressing strains against freshwater and euryhaline pathogens that commonly occur in aquaculture ponds and found no difference from that of lactoferricin-expressing strains. The bactericidal activity of 1-mL aliquot from a total 5.5 mL extracted from 5 mL of cultured C117 (1.45 × 108 CFU·mL−1) and C166 (2.17 × 108 CFU·mL−1) against halophilic bacteria was equivalent to the efficacy of 57.06 and 32.35 ng of Tetracycline against Vibrio natriegens, 47.07 and 25.2 ng against V. parahaemolyticus, and 58.17 and 36.55 ng against V. alginolyticus, respectively, indicating higher bactericidal activity of pepsin-extracts from rCiMAM-containing strains against halophilic bacteria compared to that from lactoferricin-containing strains. Since the antibacterial activity of rCiMAM-expressing B. subtilis strains shows higher competence against halophilic pathogens compared to that against freshwater and euryhaline pathogens, these strains are promising candidates to protect marine fish and shellfish from halophilic bacterial infection.

In this study, we reported a novel member of Forkhead box (Fox) proteins found in model zebrafish (Danio rerio). This new gene we cloned was primarily assigned as zgc:162612, which locates on Chromosome 3 at 26,108,033–26,109,322 in the zebrafish genome, but encodes an uncharacterized protein, LOC100037333. After we determined the nucleotide and deduced amino acid sequences of zgc:162612, we found that zgc:162612 is an intronless gene and contains 1290 base pairs encoding 308 amino acid residues. Zgc:162612 protein is composed of a highly conserved DNA-binding domain similar to that of the Fox protein family, but with variable terminal domains. Based on phylogenetic analysis of all known members within the zebrafish Fox protein family, zgc:162612 was clustered into the zebrafish FoxD isoform subfamily. Thus, we confirmed zgc:162612 as the zebrafish FoxD7 gene. The deduced amino acid sequence of zebrafish FoxD7 shared 49, 49, 74, 63 and 74% identities with that of zebrafish FoxD1, FoxD2, FoxD3, FoxD4 and FoxD6, respectively. Compared with all known FoxD proteins in invertebrate and vertebrate species, the zebrafish FoxD7 is categorized in the same monophyletic group along with FoxD of cephalochordate and sea urchin. Whole-mount in situ hybridization demonstrated that zebrafish FoxD7 transcripts represented maternal inheritance and were ubiquitously expressed throughout the whole embryo at 12hpf. Moreover, while FoxD7 transcripts were expressed in the brain, spinal cord, fins and eyes at early developmental stages, they were mainly presented in the telencephalon ventricular zone at late developmental stages, suggesting that FoxD7 may play roles in neurogenesis and organogenesis during development of zebrafish. Taken together, we have defined a previously uncharacterized gene in the zebrafish genome, zgc:162612, and revealed that Zgc:162612 encodes a novel putative transcription factor, thus becoming a new member of the zebrafish FoxD isoform subfamily.

Background Studies showed that the endotoxemia-related biomarker, lipopolysaccharide-binding protein (LBP), is associated with obesity and fatty liver. The level of LBP is reduced after surgical weight loss. This study aimed to verify the change of serum LBP levels after one-year medical weight management in subjects with obesity. Methods and findings A total of 62 subjects with obesity, 39 subjects with overweight, and 21 subjects with normal body mass index were enrolled for a one-year weight management program. Basic information, body composition analysis, clinical data, serum LBP level, and abdominal ultrasonography findings were collected. At baseline, the serum LBP levels of the obese and overweight subjects were significantly higher than that of the normal group (30.9±7.4 and 29.6±6.3 versus 23.1±5.6 μg/mL, respectively, p

Background: Hepatotoxicity is the most severe adverse effect of anti-tuberculosis therapy. Isoniazid&rsquo, s metabolite hydrazine is a mitochondrial complex II inhibitor. We hypothesized that mitochondrial DNA variants are risk factors for drug-induced liver injury (DILI) due to isoniazid, rifampicin or pyrazinamide. Methods: We obtained peripheral blood from tuberculosis (TB) patients before anti-TB therapy. A total of 38 patients developed DILI due to anti-TB drugs. We selected 38 patients with TB but without DILI as controls. Next-generation sequencing detected point mutations in the mitochondrial DNA genome. DILI was defined as ALT &ge, 5 times the upper limit of normal (ULN), or ALT &ge, 3 times the ULN with total bilirubin &ge, 2 times the ULN. Results: In 38 patients with DILI, the causative drug was isoniazid in eight, rifampicin in 14 and pyrazinamide in 16. Patients with isoniazid-induced liver injury had more variants in complex I&rsquo, s NADH subunit 5 and 1 genes, more nonsynonymous mutations in NADH subunit 5, and a higher ratio of nonsynonymous to total substitutions. Patients with rifampicin- or pyrazinamide-induced liver injury had no association with mitochondrial DNA variants. Conclusions: Variants in complex I&rsquo, s subunit 1 and 5 genes might affect respiratory chain function and predispose isoniazid-induced liver injury when exposed to hydrazine, a metabolite of isoniazid and a complex II inhibitor.

Hepatocellular carcinoma (HCC) is associated with a poor prognosis and remains one of the leading causes of cancer death worldwide. Tumor-associated antigens (TAAs) and autoantibodies have been reported as potential markers in different cancers. Here, we employed an immunoproteomic approach to identify TAAs in the sera of patients with hepatitis B virus-related HCC (HBV-HCC). Immunoreactive spots were excised from 2-DE and analyzed by nano-LC–MS/MS. This analysis identified 16 HCC-associated antigens, including hnRNP L. The antigenicity of hnRNP L was further validated by immunoblotting using recombinant proteins. Autoantibodies against hnRNP L were found in 60% patients with HBV-HCC. Using sera from hnRNP L-positive patients, we found that most of these antibodies recognized glycine-rich region in the N-terminus of hnRNP L. In addition, high titers of autoantibodies against hnRNP L were found in HBV-HCC patients' sera and were associated with increased tumor size and reduced survival rate. hnRNP L protein was also found highly expressed in HCC tissue. Knockdown of hnRNP L significantly suppressed cell growth, migration, and invasion in vitro. Our results indicate that an N-terminal epitope of hnRNP L is a potential biomarker for the diagnosis of HBV-HCC and show that hnRNP L contributes to HCC progression. Biological significance In this paper, we employed an immunoproteomic approach to identify TAAs in the sera of patients with hepatitis B virus-related HCC (HBV-HCC). We identified hnRNP L as a tumor-associated antigen in HBV-relative HCC patients. Glycine-rich region located at the N-terminus of hnRNP L constitutes the major epitope. We also demonstrated that hnRNP L is involved in cell proliferation and metastasis.

Objective: This study aimed to investigate the association between serum adiponectin and chronic hepatitis B virus (HBV) infection. Design and Methods: We conducted a campus-based cross-sectional study in Northern Taiwan, an HBV-endemic country. A total of 506 participants, including 147 chronic HBV-infected individuals and 359 healthy controls, were assessed for anthropometric indices, serum adiponectin levels, serum HBV viral load and markers, serum alanine aminotransferase levels and metabolic factors. Results: Older age, male gender, higher alanine aminotransferase, higher body mass index, greater waist circumference, lower fasting glucose, higher triglycerides, and higher adiponectin were associated with chronic HBV infection in univariate analyses. In multivariate analysis, the presence of chronic HBV infection was positively associated with serum adiponectin levels (P < 0.0001) and high adiponectin levels over the 75th percentile (odds ratio, 4.25; 95% confidence interval, 2.36-7.66; P < 0.0001) after adjusting for age, gender, body mass index, and insulin resistance index. Furthermore, serum adiponectin levels were positively associated with HBV viral load in overweight to obese HBV-infected subjects (P = 0.018). Conclusion: Although chronic HBV-infected individuals were heavier than healthy controls, they had significantly higher serum adiponectin levels than healthy counterparts. Additionally, adiponectin levels were positively associated with HBV viral load in overweight to obese HBV-infected subjects. Future research should focus on elucidating adiponectin pathways, which may contribute to the development of adjuvant treatments for chronic HBV infection.

Learning Objectives: After completing this course, the reader will be able to: List the top 10 ranked symptoms after discharge suffered by patients with hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE) treatment.Identify the significant factors in the associations between quality of life (QOL) and demographic factors and clinical factors over a period of 2 months in patients with HCC receiving TACE.Design individualized education programs for newly diagnosed and recurrent HCC patients in order to maintain better QOL after treatment. CME This article is available for continuing medical education credit at CME.TheOncologist.com Objective. To (a) explore changes in physical and psychological distress and quality of life (QOL) and (b) identify the significant pre- and postdischarge factors related to changes in physical and mental domains of QOL over a period of 2 months in patients with hepatocellular carcinoma receiving one course of transarterial chemoembolization (TACE) treatment. Methods. A longitudinal prospective design was used, with participants recruited from a teaching hospital in Northern Taiwan. Data were collected three times: within 3 days prior to discharge (T0) and at the fourth (T1) and eighth (T2) weeks after discharge. A set of structured questionnaires was used to assess participants' QOL, symptom distress, anxiety, and depression. Changes in QOL and associated factors were examined using generalized estimating equations. Results. Eighty-nine patients were included in this study. Fatigue was reported to be the most distressful symptom after treatment. Overall QOL improved monthly after discharge. Change in physical QOL 2 months after TACE treatment was associated with age, diagnosis status, level of symptom distress, and depression after discharge. Change in mental QOL was significantly associated with gender, diagnosis status, and anxiety and depression after discharge. Conclusions. Health care providers should pay special attention to patients of older age, those who are male, and those who have higher levels of depression and anxiety after discharge. Designing personalized education programs before discharge for patients with newly diagnosed cancer versus those who have recurrent disease is suggested to help patients maintain a better QOL after discharge.

Background and Aim: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths in Taiwan. HCC with duodenal involvement are rare and are associated with a poor prognosis. The purpose of this retrospective study was to collect clinical information and data regarding survival following various treatments. Methods: Between 1996 and 2009, 21 cases (17 men) were diagnosed with HCC and duodenal invasion and metastases by diagnostic imaging, endoscopy with biopsy, or surgically collected specimens sent to pathology. The clinical course was analyzed from the patients' medical records. Results: Gastrointestinal bleeding was reported in 18/21 patients. Diagnostic imaging showed that the majority of cases involved direct tumor invasion (predominantly from the right liver lobe) and six cases from metastasis. Tumor mass and ulcerations were the most common features noted on endoscopy. In addition to the component therapy and medication treatment, panendoscopic hemostasis, surgery, transcatheter arterial embolization, and radiotherapy were performed for the management of duodenal involvement and gastrointestinal bleeding. Survival duration after duodenal involvement ranged from 0.2 to 57.8 months (mean 10.5 months). Conclusions: Gastrointestinal bleeding in advanced HCC should raise suspicions of duodenal involvement. HCC can involve the duodenum by direct invasion (from either the left or right liver lobes) or metastasis. The prognosis for HCC patients with duodenal involvement is poor, but is improved by supportive care and application of various treatment modalities.

SummaryAcetylation of histone and nonhistone proteins is an important posttranslational modification affecting many cellular processes. Here, we report that NuA4 acetylation of Sip2, a regulatory β subunit of the Snf1 complex (yeast AMP-activated protein kinase), decreases as cells age. Sip2 acetylation, controlled by antagonizing NuA4 acetyltransferase and Rpd3 deacetylase, enhances interaction with Snf1, the catalytic subunit of Snf1 complex. Sip2-Snf1 interaction inhibits Snf1 activity, thus decreasing phosphorylation of a downstream target, Sch9 (homolog of Akt/S6K), and ultimately leading to slower growth but extended replicative life span. Sip2 acetylation mimetics are more resistant to oxidative stress. We further demonstrate that the anti-aging effect of Sip2 acetylation is independent of extrinsic nutrient availability and TORC1 activity. We propose a protein acetylation-phosphorylation cascade that regulates Sch9 activity, controls intrinsic aging, and extends replicative life span in yeast.

Background/Purpose: Hepatocellular carcinoma (HCC) has been the leading cause of cancer death in Taiwan since the 1980s. A two-stage screening intervention was introduced in 1996 and has been implemented in a limited number of hospitals. The present study assessed the costs and health outcomes associated with the introduction of screening intervention, from the perspective of the Taiwanese government. The cost-effectiveness analysis aimed to assist informed decision making by the health authority in Taiwan. Methods: A two-phase economic model, 1-year decision analysis and a 60-year Markov simulation, was developed to conceptualize the screening intervention within current practice, and was compared with opportunistic screening alone. Incremental analyses were conducted to compare the incremental costs and outcomes associated with the introduction of the intervention. Sensitivity analyses were performed to investigate the uncertainties that surrounded the model. Results: The Markov model simulation demonstrated an incremental cost-effectiveness ratio (ICER) of NT$498,000 (US$15,600) per life-year saved, with a 5% discount rate. An ICER of NT$402,000 (US$12,600) per quality-adjusted life-year was achieved by applying utility weights. Sensitivity analysis showed that excess mortality reduction of HCC by screening and HCC incidence rates were the most influential factors on the ICERs. Scenario analysis also indicated that expansion of the HCC screening intervention by focusing on regular monitoring of the high-risk individuals could achieve a more favorable result. Conclusion: Screening the population of high-risk individuals for HCC with the two-stage screening intervention in Taiwan is considered potentially cost-effective compared with opportunistic screening in the target population of an HCC endemic area.

The proportion of B-HCC cases in Taiwan has progressively decreased over the last 20 years. It was not really due to an overall decrease in B-HCC but due to an increase in HCV-related HCC. The identification of potential HCV endemic areas in Taiwan has consequently become important.Data were collected retrospectively from eight Taiwan medical centers from 1981 to 2001, the geographical variations of male C-HCC townships in Taiwan were illustrated on maps. Goodness of fit was used to compare the anti-HCV prevalence in townships and cities, with the mean anti-HCV prevalence for Taiwan as a whole. Township-, city-, and county-specific prevalence of anti-HCV was presented as the median, ranges, and SMRs.Geographic variation can be analyzed in only 263 townships and cities. The maps were designed on the basis of different SMRs. The mean anti-HCV prevalence for male HCC patients in Taiwan was 31.9% (95% confidence interval: 30.7-33.0). Twenty-five townships distributed throughout central-western and south-western Taiwan have significantly higher prevalence (P0.05) (12 townships SMR/= 2; 13 townships 1.5/= SMR2). Twenty-two townships have significantly lower prevalence (P0.05) (6 townships 0.5/= SMR1; 16 townships SMR0.5). Four different patterns of geographic variation in different counties were also noted and demonstrated.We successfully highlighted some potential high HCV endemic townships in Taiwan.

Severe intrahepatic cholestasis with low serum gamma-glutamyltranspeptidase (gamma-GT) activity is exceptionally rare in adult patients, and its association with multi-genetic alterations of bile salt transporters has not been reported. We investigated a 25-year-old man presenting with a four-year history of jaundice. Laboratory and radiographic examinations revealed clinical pictures of progressive intrahepatic cholestasis with low gamma-GT. Serial liver histopathology demonstrated cirrhosis resulting from progressive persistent cholestatic injury. Genetic sequencing studies for the entire coding exons of ATP8B1 and ABCB11 uncovered a heterozygous missense mutation 1798 C->T (R600W) in ATP8B1, and a homozygous nucleotide substitution 1331 T->C (V444A) in ABCB11. In conclusion, this is a rare case of adult onset progressive intrahepatic cholestasis with low gamma-GT associated with heterozygous ATP8B1 mutation and homozygous ABCB11 polymorphism. Further studies are necessary to investigate the impact of heterozygous R600W mutation and whether other cholestatic disorders are multi-genetic.

Background and Aim: Peritoneal metastasis is an uncommon manifestation of hepatocellular carcinoma (HCC). The aim of the present paper was to investigate the characteristics and survival of HCC patients with peritoneal metastases. Methods: From January 1985 to December 2004, we retrospectively reviewed the records of 53 Taiwanese HCC patients with peritoneal metastases. Results: Peritoneal metastases were detected at the time of HCC diagnosis (synchronously) in 10 patients and after the initial therapy for the primary tumors (metachronously) in 43 patients. The mean time for development of the metachronous peritoneal metastases was similar whether the primary cancer was treated with surgery (24 months) or transarterial chemoembolization (22.2 months). The single patient whose primary cancer was treated with supportive care alone developed peritoneal metastasis only 7.5 months after detection of the primary cancer. Surgical resection of the peritoneal metastases was possible in two-thirds of the 43 metachronous patients. The median survival for those who received surgery for these metastases was 12.5 months vs. 2.1 months for those without surgery (P = 0.0013). However, there was no difference in survival if patients were stratified to Child-Pugh grade. Conclusions: Peritoneal metastases of HCC are rare and can occur synchronously or metachronously. Though increased long-term survival was found in patients who had surgical removal of peritoneal metastases, the main determinant of better survival is Child-Pugh grade.

According to current guidelines of hepatocellular carcinoma (HCC) treatment, multiple HCCs are usually not suitable for surgical resection. However, surgical resection is still possible for patients with multiple HCCs. The role of hepatic resection vs transarterial chemoembolization (TACE) for multiple HCCs should be further clarified. We retrospectively enrolled 1065 patients with multiple HCCs. Among them, 294 received surgical resection, 367 received transarterial chemoembolization (TACE), and 404 received chemotherapy or supportive care. Three staging systems (TNM, CLIP, and BCLC) were used for comparison of stage-specific survival between different treatment modalities. The median survival of multiple HCC patients who received surgical resection was 37.9 months, while it was 17.3 months in TACE group, and 2.8 months in supportive group (P < .001). The 1-year, 3-year, 5-year survival rates for surgical group were 77.4%, 51.9%, and 36.6%, respectively. Kaplan-Meier survival analysis demonstrated that patients who received surgical resections had the best survival, followed by TACE and supportive care. For patients of the same stage, surgical resection yields better results than TACE. Surgery could offer better survival than TACE for patients either within or beyond Milan’s criteria. Our results indicate that if patients have preserved liver functions, hepatic resection is helpful, even for patients with multiple HCCs.

Hepatitis delta virus (HDV) encodes two isoforms of delta antigens (HDAgs). The small form of HDAg (SHDAg) is required for HDV RNA replication, while the large form of HDAg (LHDAg) is required for viral assembly. Using tandem affinity purification method combined with mass spectrometry, we found that linker histone H1e bound to SHDAg. The binding domain of SHDAg to histone H1e was mapped to the N-terminal 67 amino acids. Oligomerization of SHDAg was required for its interaction with histone H1e. LHDAg barely bound to histone H1e and was masked at N-terminus. The binding domain of histone H1e to SHDAg was mapped to its central globular domain. HDV replication was inhibited by N- or C-terminal deletion mutants of histone H1e and was rescued by wild-type histone H1e. We conclude that histone H1e plays a significant role in HDV replication through forming protein complex with SHDAg.

A 47-year-old man with chronic hepatitis B had progressive elevated alpha-fetoprotein of 2 years' duration. A pancreatic tail tumor, instead of liver tumor, was detected. He underwent elective distal pancreatectomy and splenectomy and the pathology turned out to be acinar cell carcinoma of the pancreas. Serum level of alpha-fetoprotein returned to normal soon after surgery. No cancer recurrence was noted after 3 years of follow-up. Alpha-fetoprotein is commonly used as a tumor marker to screen for hepatocellular carcinoma in high-risk patients. However, elevated alpha-fetoprotein could occur in a much rarer disease, acinar cell carcinoma of the pancreas.

To evaluate whether the tumour suppressor gene, PPP2R1B, is involved in pathogenesis of hepatocellular carcinoma (HCC), reverse transcription-polymerase chain reaction (RT-PCR) and cDNA sequencing were performed. Eleven of 38 (29%) tumours and 1 of 34 (3%) corresponding non-tumour tissues showed coexpression of wild-type and aberrant mRNA. Various deletions were found in aberrant transcripts. Southern blot analysis did not show gene deletion in tumours, suggesting abnormal RNA splicing may be involved. These data suggest the possibility that aberrant transcripts of PPP2R1B might be associated with the development of HCC.

Background/purpose Taiwan is a hyperendemic area of liver diseases. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the two major etiologies of liver diseases in Taiwan. This study investigated the seroprevalence of HBV and HCV in Taiwan. Methods Since 1996, a series of outreach community-based screening programs for liver diseases have been available to the general population aged ≥ 18 years. Blood samples were obtained from the subjects and sent for hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) tests. Results The prevalence of HBsAg(+) was 17.3% (27,210/157,720), while the prevalence of anti-HCV(+) was 4.4% (6904/157,720). Geographic variation in HBV and HCV seroprevalence was found, with the highest anti-HCV positive rate in Miaoli County, Chiayi County, Chiayi City, and Yunlin County, and the highest HBsAg positive rate in Keelung City and Yilan City. The HBsAg positive rate progressively decreased after the age of 50 years, while the anti-HCV positive rate progressively increased after the age of 20 years. The estimated total number of HBsAg carriers in the general population > 20 years old is 3,067,307, while the estimated number of anti-HCV positive patients is 423,283. Conclusion This study estimated a 17.3% seroprevalence of HBV and a 4.4% seroprevalence of HCV in Taiwan. Significant geographic variations in the seroprevalence of HBV and HCV were found. These data suggest the importance of modifying programs for the prevention and treatment of chronic viral hepatitis in Taiwan to reflect its varying prevalence and epidemiology. [ J Formos Med Assoc 2007; 106(2):148-155]

Primary effusion lymphoma (PEL) is an unusual form of non-Hodgkin's lymphoma, which is characterized by lymphomatous effusion in body cavities, but no associated mass lesions. It is usually associated with an immunodeficient state most often with the human immunodeficiency virus (HIV). We describe a 54-year-old man with HIV-negative PEL, with a history of hepatitis B virus-related liver cirrhosis. Both abdominal and pleural cavities were involved; no solid tumor masses were found and bone marrow investigations were normal. The ascites and pleural effusion contained numerous pleomorphic lymphoid cells. Immunophenotyping was positive for CD138. Chromosome study showed complex cytogenetics. The genomic human herpesvirus-8 was detected in the lymphoma cells. It is postulated that the immuno-suppressed state in this patient may have been caused by cirrhosis. The patient received four cycles of chemotherapy of CHOP and Picibanil (OK-432) intraperitoneal administration. However, no durable remission was achieved. Adefovir failed to halt the progressive liver failure after the development of YMDD mutant related to lamivudine. He died of sepsis and hepatic failure.

We previously demonstrated that the enhancer of rudimentary homolog (ERH) gene is required for the expression of multiple cell cycle and DNA damage response (DDR) genes. The present study investigated the role of ERH and its target DNA damage repair genes in hepatocellular carcinoma cells. We observed positive correlation between ERH and ataxia telangiectasia and Rad3 related (ATR) expression in liver tissues. Expression of ERH, ATR as well as checkpoint kinase 1 (CHK1) were higher in HCCs than in normal liver tissues. Knocking-down ERH augmented ultraviolet light induced DNA damage in HepG2 cells. ATR protein level is reduced upon ERH depletion as a result of defect in the splicing of ATR mRNA. Consequently, the ATR effector kinase Chk1 failed to be phosphorylated upon ultraviolet light or hydroxyurea treatment in ERH knocked-down HepG2 cells. Finally, we observed Chk1 inhibitor AZD7762 enhanced the effect of doxorubicin on inhibiting growth of HCC cells in vitro and in vivo. This study suggested that ERH regulates the splicing of the DNA damage response proteins ATR in HCC cells and targeting DNA damage response by Chk1 inhibitor augments chemotherapy to treat HCC cells.

Background/Aims: The survival rates of patients with hepatocellular carcinoma (HCC) were investigated over the past 20 years to clarify the long-term survival trend. Methods: A total of 11 312 patients with HCC from seven medical centers from 1986 to 2002 were included. Survival was analyzed by correlating data with the national mortality databank. Results: Multivariate analysis showed that the following factors were associated with shorter survival: male sex, younger age, hepatitis B virus, earlier year of diagnosis, alpha fetoprotein higher than 400 ng/mL, alanine aminotransferase (ALT) higher than two times the upper normal limit, higher aspartate aminotransferase (AST)/ALT ratio, central or southern Taiwan residence, and rural areas residence. Patients diagnosed during 1998–2002 showed the highest survival rate, followed by patients diagnosed during 1994–1997, 1990–1993, and 1986–1989, respectively. Conclusions: There are geographic variations in the survival rates of patients with HCC. Survival has been improving gradually over the past 20 years, probably due to earlier detection of HCC or to improved patient care.

Background/Aims: Hepsin is a type II transmembrane protein predominantly expressed in the liver and has been implicated in participation in blood coagulation pathway and epithelial carcinogenesis. The aim of this current study is to investigate the role of hepsin in hepatocarcinogenesis. Methods: Quantitative real-time RT-PCR was used to investigate the expression levels of hepsin in a total of 50 paired hepatocellular carcinomas (HCCs) and the corresponding non-tumor liver tissues. Hepsin was transfected to the hepsin-non-expressing SK-HEP-1 cells to study the change of cell proliferation. Results: In 62% (31/50) patients, the expression levels of hepsin in non-tumor liver tissues are at least twofold higher than those in the corresponding HCC tissues. Positive hepatitis B surface antigen was more often detected in patients with hepsin underexpressed in the HCC tissues (74.2% vs. 31.6%, P=0.007). Patients with hepsin underexpressed in the HCC tissues survived shorter time than those without hepsin underexpression in the HCC tissues. The cell proliferation and for a colony formation of SK-HEP-1 HCC cells were inhibited by hepsin. Conclusions: Most HCC patients had hepsin underexpressed in the HCC tissues. These patients survived for a shorter time compared with those without hepsin underexpression in the HCC tissues. Hepsin expression could inhibit cell proliferation and colony formation of HCC cells.