Publications by authors named "Tatsuya Kanto"

167 Publications

Cluster of Differentiation 44 Promotes Liver Fibrosis and Serves as a Biomarker in Congestive Hepatopathy.

Hepatol Commun 2021 Aug 8;5(8):1437-1447. Epub 2021 Apr 8.

Research Center for Hepatitis and Immunology National Center for Global Health and Medicine Ichikawa Japan.

Congestive hepatopathy (CH) with chronic passive congestion is characterized by the progression of liver fibrosis without prominent inflammation and hepatocellular damage. Currently, the lack of reliable biomarkers for liver fibrosis in CH often precludes the clinical management of patients with CH. To explore fibrosis biomarkers, we performed proteome analysis on serum exosomes isolated from patients with CH after the Fontan procedure. Exosomal cluster of differentiation (CD)44 levels were increased in patients with CH compared to healthy volunteers and was accompanied by increases in serum levels of soluble CD44 and CD44 expression in the liver. To address the roles of CD44 in CH, we established a mouse model of chronic liver congestion by partial inferior vena cava ligation (pIVCL) that mimics CH by fibrosis progression with less inflammation and cellular damage. In the pIVCL mice, enhanced CD44 expression in hepatic stellate cells (HSCs) and deposition of its ligand hyaluronan were observed in the liver. Blood levels of soluble CD44 were correlated with liver fibrosis. The blockade of CD44 with specific antibody inhibited liver fibrosis in pIVCL mice and was accompanied by a reduction in S100 calcium-binding protein A4 expression following activation of HSCs. Chronic liver congestion promotes fibrosis through CD44. This identifies CD44 as a novel biomarker and therapeutic target of liver fibrosis in patients with CH.
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http://dx.doi.org/10.1002/hep4.1721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369942PMC
August 2021

Factors influencing the durability of hepatitis B vaccine responses.

Vaccine 2021 08 31;39(36):5224-5230. Epub 2021 Jul 31.

The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Konodai, Ichikawa, Chiba 272-8516, Japan. Electronic address:

The World Health Organization recommends the implementation of universal hepatitis B (HB) vaccination, and global coverage for this vaccine reached 84% in 2015. In Japan, the policy aimed at preventing mother-to-child transmission of HB virus (HBV) initially commenced as a specific vaccination program for infants born to mothers who were positive for HB surface antigen. In 2016, universal HB vaccination was implemented in this country to cover unvaccinated individuals at risk of horizontal HBV transmission. Although HB vaccination has been shown to be highly efficacious and safe, the issues of vaccine non-responders and of the loss of antibodies directed against HB surface antigen (anti-HBs) in HB vaccine recipients remain. To gain better insight into these problems, we previously performed an immunological analysis on adult vaccine recipients after they received an initial HB vaccination. We found that the course of successful HB vaccination is composed of the following distinct phases: 1) acquisition of anti-HBs antibody, 2) attainment of high anti-HBs antibody titers, and 3) maintenance of acquired anti-HBs antibody levels. In this review, we describe the significance of HB vaccination and suggest a potential means of improving the impact of HB vaccination based on our immunological analysis.
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http://dx.doi.org/10.1016/j.vaccine.2021.07.017DOI Listing
August 2021

Phenotypic Characterization by Single-Cell Mass Cytometry of Human Intrahepatic and Peripheral NK Cells in Patients with Hepatocellular Carcinoma.

Cells 2021 Jun 14;10(6). Epub 2021 Jun 14.

Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba 272-8516, Japan.

Overall response rates of systemic therapies against advanced hepatocellular carcinoma (HCC) remain unsatisfactory. Thus, searching for new immunotherapy targets is indispensable. NK cells are crucial effectors and regulators in the tumor microenvironment and a determinant of responsiveness to checkpoint inhibitors. We revealed the landscape of NK cell phenotypes in HCC patients to find potential immunotherapy targets. Using single cell mass cytometry, we analyzed 32 surface markers on CD56 and CD56 NK cells, which included Sialic acid-binding immunoglobulin-type lectins (Siglecs). We compared peripheral NK cells between HCC patients and healthy volunteers. We also compared NK cells, in terms of their localizations, on an individual patient bases between peripheral and intrahepatic NK cells from cancerous and noncancerous liver tissues. In the HCC patient periphery, CD160CD56 NK cells that expressed Siglec-7, NKp46, and NKp30 were reduced, while CD49aCD56 NK cells that expressed Siglec-10 were increased. CD160 and CD49a on CD56 NK cells were significantly correlated to other NK-related markers in HCC patients, which suggested that CD160 and CD49a were signature molecules. CD49a CX3CR1 Siglec-10 NK cells had accumulated in HCC tissues. Considering further functional analyses, CD160, CD49a, CX3CR1, and Siglec-10 on CD56 NK cells may be targets for immunotherapies of HCC patients.
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http://dx.doi.org/10.3390/cells10061495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231799PMC
June 2021

Hepatitis C virus modulates signal peptide peptidase to alter host protein processing.

Proc Natl Acad Sci U S A 2021 Jun;118(22)

Institute for Advanced Co-Creation Studies, Osaka University, Osaka, 565-0871, Japan;

Immunoevasins are viral proteins that prevent antigen presentation on major histocompatibility complex (MHC) class I, thus evading host immune recognition. Hepatitis C virus (HCV) evades immune surveillance to induce chronic infection; however, how HCV-infected hepatocytes affect immune cells and evade immune recognition remains unclear. Herein, we demonstrate that HCV core protein functions as an immunoevasin. Its expression interfered with the maturation of MHC class I molecules catalyzed by the signal peptide peptidase (SPP) and induced their degradation via HMG-CoA reductase degradation 1 homolog, thereby impairing antigen presentation to CD8 T cells. The expression of MHC class I in the livers of HCV core transgenic mice and chronic hepatitis C patients was impaired but was restored in patients achieving sustained virological response. Finally, we show that the human cytomegalovirus US2 protein, possessing a transmembrane region structurally similar to the HCV core protein, targets SPP to impair MHC class I molecule expression. Thus, SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses.
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http://dx.doi.org/10.1073/pnas.2026184118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179148PMC
June 2021

Effects of a low-intensity resistance exercise program on serum miR-630, miR-5703, and Fractalkine/CX3CL1 expressions in subjects with No exercise habits: A preliminary study.

Hepatol Res 2021 Jul 2;51(7):823-833. Epub 2021 Jun 2.

Department of Orthopedics, School of Medicine, Kurume University, Kurume, Japan.

Aims: Exercise is effective for the prevention of liver cancer. Exercise exerts biological effects through the regulation of microRNAs (miRNAs) and cytokines/myokines. We aimed to investigate the effects of low-intensity resistance exercise on serum miRNA and cytokine/myokine expressions in subjects with no exercise habits.

Methods: We enrolled seven male subjects with no exercise habits in this prospective before-after study. All subjects performed a low-intensity resistance exercise program (three metabolic equivalents, approximately 20 min/session). Serum miRNA expressions were evaluated using microarrays. We performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of differentially expressed miRNAs before and after exercise. Serum cytokine/myokine expressions were evaluated using a multiplex panel.

Results: All subjects completed the exercise program with no adverse events. In the microarray analysis, seven miRNAs showed a significant change between before and after exercise. Of these, microRNA (miR)-630 and miR-5703 showed a >1.5-fold increase (miR-630: 40.7 vs. 69.3 signal intensity, p = 0.0133; miR-5703: 30.7 vs. 55.9 signal intensity, p = 0.0051). KEGG pathway enrichment analysis showed that miR-630- and miR-5703-related genes were enriched in 37 and 5 pathways, including transforming growth factor-beta and Wnt signaling pathways, respectively. In the multiplex analysis, 12 cytokines/myokines showed significant alteration after exercise compared to before exercise. Of these, fractalkine/CX3CL1 showed the most significant up-regulation by exercise (94.5 vs. 109.1 pg/ml, p = 0.0017).

Conclusions: A low-intensity resistance exercise program was associated with upregulation of serum miR-630, miR-5703, and fractalkine/CX3CL1 expressions in subjects with no exercise habits. Thus, even low-intensity exercise may alter miRNA and cytokine/myokine expressions in humans.
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http://dx.doi.org/10.1111/hepr.13670DOI Listing
July 2021

Myostatin as a fibroblast-activating factor impacts on postoperative outcome in patients with hepatocellular carcinoma.

Hepatol Res 2021 Jul 25;51(7):803-812. Epub 2021 May 25.

Department of Liver Disease, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.

Aim: In patients with liver cirrhosis, high levels of serum myostatin are associated with poor prognosis. We aimed to clarify the influence of myostatin on the prognosis of patients with non-alcoholic fatty liver disease-hepatocellular carcinoma (NAFLD-HCC) without cirrhosis and on the progression of liver fibrosis.

Methods: Serum myostatin levels were evaluated in 234 patients who underwent primary surgical resection for single HCC. To clarify the impact of myostatin on liver fibrosis, we established human primary liver fibroblasts from resected livers, and cultured them in the presence of myostatin.

Results: The median age was 67.4 years, the median L3 skeletal muscle mass index was 44.4 cm /m , and the median body mass index was 23.4 kg/m . Eighty-two (35.0%) patients had sarcopenia (L3 skeletal muscle mass index: men <42, women <38 cm /m ). The etiologies of liver disease were hepatitis B virus (n = 61), hepatitis C virus (n = 86), and non-B non-C hepatitis (n = 87) including NAFLD (n = 74). High preoperative serum myostatin and vascular invasion were independent predictors of poor overall survival (OS). High serum myostatin was associated with poor OS in patients with no sarcopenia (n = 152). In patients without advanced liver fibrosis (Fibrosis stage, 0-2; n = 58), high levels of serum myostatin were also associated with poor OS, regardless of sarcopenia. Serum myostatin levels were increased with the progression of liver fibrosis. Liver fibroblasts were activated and produced collagen following stimulation with myostatin.

Conclusions: In patients with NAFLD-HCC without advanced liver fibrosis, high levels of serum myostatin were associated with poor OS. Myostatin activated primary fibroblasts and stimulated collagen production.
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http://dx.doi.org/10.1111/hepr.13667DOI Listing
July 2021

Applicability of APRI and FIB-4 as a transition indicator of liver fibrosis in patients with chronic viral hepatitis.

J Gastroenterol 2021 05 31;56(5):470-478. Epub 2021 Mar 31.

Department of Liver Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, Tokyo, 272-8516, Japan.

Background And Aims: The usefulness of APRI or FIB-4 is well established as a non-invasive liver fibrosis marker at a point of diagnosis in patients with chronic liver disease. However, their applicability for the monitoring of progression of liver fibrosis over time is yet to be determined. We aimed to clarify the feasibility of APRI and FIB-4 for the longitudinal evaluation of liver fibrosis in patients with chronic hepatitis B and C.

Methods: This is a multi-center retrospective and prospective cohort study, enrolling 1029 patients with HCV and 384 patients with HBV who were histologically diagnosed by liver biopsy. The observation period of retrospective and prospective study was 14 and 12 years, respectively. The APRI and FIB-4 were traced back in cases of histologically diagnosed cirrhosis, and those were prospectively analyzed after biopsy in cases diagnosed as F3 of METAVIR score, respectively.

Results: The averaged APRI and FIB-4 exhibited time-dependent increase in the retrospective study of hepatitis C patients (increase by 0.09/year in APRI and 0.29/year in FIB-4). In the prospective study of untreated hepatitis C patients, such increases were 0.14/year in APRI and 0.40/year in FIB-4, respectively. Neither the average of APRI nor FIB-4 showed a specific tendency with hepatitis B patients and treatment-experienced hepatitis C patients.

Conclusion: The APRI and FIB-4 may serve as a transition indicator of liver fibrosis in anti-viral treatment-naïve patients with chronic hepatitis C.
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http://dx.doi.org/10.1007/s00535-021-01782-3DOI Listing
May 2021

Increased Frequency of Dysfunctional Siglec-7CD57PD-1 Natural Killer Cells in Patients With Non-alcoholic Fatty Liver Disease.

Front Immunol 2021 22;12:603133. Epub 2021 Feb 22.

Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Tokyo, Japan.

Non-alcoholic fatty liver disease (NAFLD) is a progressive disorder that can develop into liver fibrosis and hepatocellular carcinoma. Natural killer (NK) cells have been shown to protect against liver fibrosis and tumorigenesis, suggesting that they may also play a role in the pathogenesis of NAFLD. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of inhibitory and activating receptors expressed by many cell types, including NK cells. Here, we investigated the phenotypic profiles of peripheral blood and intrahepatic NK cells, including expression of Siglecs and immune checkpoint molecules, and their association with NK cell function in patients with NAFLD. Immune cells in the peripheral blood of 42 patients with biopsy-proven NAFLD and 13 healthy volunteers (HVs) were identified by mass cytometry. The function of various NK cell subpopulations was assessed by flow cytometric detection of intracellular IFN-γ and CD107a/LAMP-1, a degranulation marker, after stimulation. We found that peripheral blood from NAFLD patients, regardless of fibrosis stage, contained significantly fewer total CD56 NK cell and CD56 NK cell populations compared with HVs, and the CD56 cells from NAFLD patients were functionally impaired. Among the Siglecs examined, NK cells predominantly expressed Siglec-7 and Siglec-9, and both the expression levels of Siglec-7 and Siglec-9 on NK cells and the frequencies of Siglec-7CD56 NK cells were reduced in NAFLD patients. Notably, Siglec-7 levels on CD56 NK cells were inversely correlated with PD-1, CD57, and ILT2 levels and positively correlated with NKp30 and NKp46 levels. Further subtyping of NK cells identified a highly dysfunctional Siglec-7CD57PD-1CD56 NK cell subset that was increased in patients with NAFLD, even those with mild liver fibrosis. Intrahepatic NK cells from NAFLD patients expressed elevated levels of NKG2D and CD69, suggesting a more activated phenotype than normal liver NK cells. These data identify a close association between NK cell function and expression of Siglec-7, CD57, and PD-1 that could potentially be therapeutically targeted in NAFLD.
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http://dx.doi.org/10.3389/fimmu.2021.603133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938755PMC
June 2021

Blood angiopoietin-2 predicts liver angiogenesis and fibrosis in hepatitis C patients.

BMC Gastroenterol 2021 Feb 8;21(1):55. Epub 2021 Feb 8.

The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.

Background: Pathological angiogenesis is involved in the development of hepatocellular carcinoma. In patients with chronic hepatitis C (CHC), the level of angiogenic factor angiopoietin (ANGP)-2 is reported to be increased in the blood, correlating with fibrosis. In this study, we aimed to clarify whether blood ANGP-2 is useful as a biomarker for liver angiogenesis and fibrosis in CHC patients and to further reveal the relationship between such pathology in a carbon tetrachloride (CCl)-treated liver fibrosis mouse model.

Methods: Plasma levels of ANGP-2, expression of a liver sinusoidal endothelial cell (LSEC) marker (CD31), collagen deposition (Sirius Red staining) in the liver, clinical fibrosis markers (Mac-2 binding protein glycosylation isomer, virtual touch quantification, and liver stiffness measurement), and liver function (albumin bilirubin score) were examined in CHC patients. To determine the effects of an anti-angiogenic agent on liver fibrosis in vivo, sorafenib was administered to the CCl-treated mice (BALB/c male).

Results: The plasma levels of ANGP-2 were increased in CHC patients compared to healthy volunteers and decreased by the eradication of hepatitis C with direct-acting antivirals. In addition, plasma ANGP-2 levels were correlated with CD31 expression, collagen deposition, clinical fibrosis markers, and liver function. Sorafenib inhibited liver angiogenesis and fibrosis in the CCl-treated mice and was accompanied by decreased ANGP-2 expression in LSECs.

Conclusions: ANGP-2 may serve as a useful biomarker for liver angiogenesis and fibrosis in CHC patients. In addition, angiogenesis and fibrosis may be closely related.
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http://dx.doi.org/10.1186/s12876-021-01633-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871374PMC
February 2021

Macrophages as a source of fibrosis biomarkers for non-alcoholic fatty liver disease.

Immunol Med 2021 Jan 14:1-26. Epub 2021 Jan 14.

The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.

Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) are becoming major liver diseases worldwide. Liver fibrosis and cirrhosis are among the most significant risk factors of hepatocellular carcinoma (HCC) and associated with the long-term prognosis of NAFLD patients. To stratify the risk of HCC in NAFLD patients clinically, the discovery of non-invasive fibrosis markers is needed urgently. Liver macrophages play critical roles in the regulation of inflammation and fibrosis by interacting with hepatic stellate cells (HSCs) and other immune cells. Thus, it is rational to explore feasible biomarkers for liver fibrosis by focusing on macrophage-related factors. We examined serum factors comprehensively in multiple cohorts of NAFLD/NASH patients to determine whether they were correlated with the biopsy-proven fibrosis stage. We found that the serum levels of interleukin (IL)-34, YKL-40 and soluble Siglec-7 (sSiglec7) were closely associated with liver fibrosis and served as diagnostic biomarkers in patients with NAFLD/NASH. In the NAFLD liver, IL-34 was produced by activated fibroblasts, and YKL-40 and sSiglec-7 were secreted from macrophages. The sensitivity and specificity of these markers to detect advanced liver fibrosis varied, supporting the notion that the combination of these markers with other modalities is an option for clinical application.
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http://dx.doi.org/10.1080/25785826.2020.1868664DOI Listing
January 2021

Hepatocyte ploidy and pathological mutations in hepatocellular carcinoma: impact on oncogenesis and therapeutics.

Glob Health Med 2020 Oct;2(5):273-281

Department of Liver Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan.

Hepatocellular carcinoma (HCC) occurs in the chronic liver inflammation such as viral hepatitis, alcoholic and non-alcoholic steatohepatitis. While anti-viral treatment has been significantly improved, the prevalence of HCC remains high and treatment is still challenging. The continuation of hepatocyte death, inflammation, and fibrosis leads to the accumulation of gene alterations, which may trigger carcinogenesis. Hepatocytes are a unique cell type having more than one complete set of 23 chromosomes, termed polyploidy. Due to gene redundancy, hepatocytes may tolerate lethal mutations. Next generation sequencing technology has revealed gene alterations in HCC related to telomere maintenance, Wnt/β-catenin pathway, p53 cell-cycle pathway, epigenetic modifiers, oxidative stress pathway, PI3K/AKT/mTOR, and RAS/RAF/MAPK pathway with or without a chromosomal instability. Some type of driver gene mutations accumulates in hepatocytes and breaks the orchestration of excessive copies of chromosomes, which may lead to unfavorable gene expressions and fuel tumorigenesis. Recently, molecular targeted drugs, developed with the aim of interfering with these signaling pathways, are being used for HCC patients in the clinics. Therefore, a deeper understanding of hepatocyte ploidy and genetic or epigenetic alterations is indispensable for the establishment of novel therapeutic strategies against HCC.
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http://dx.doi.org/10.35772/ghm.2020.01089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731061PMC
October 2020

The transition in the etiologies of hepatocellular carcinoma-complicated liver cirrhosis in a nationwide survey of Japan.

J Gastroenterol 2021 02 20;56(2):158-167. Epub 2020 Nov 20.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.

Background: We recently reported the real-world changes in the etiologies of liver cirrhosis (LC) based on nationwide survey data and assessed the etiologies of LC with hepatocellular carcinoma (HCC).

Methods: Fifty-five participants from 68 institutions provided data on 23,637 patients with HCC-complicated LC. The changing trends in etiologies were assessed. We further analyzed the data from 29 hospitals that provided the annual number of newly identified HCC-complicated LC patients from 2008 to 2016 (N = 9362) without any missing years and assessed the transition in the real number of newly identified HCC-complicated LC cases.

Results: In the overall cohort, hepatitis C virus (HCV) infection (60.3%) and hepatitis B virus (HBV) infection (12.9%) were the leading and third-most common causes of HCC-complicated LC in Japan, respectively. HCV infection was found to be the leading cause throughout Japan. The rate of viral hepatitis-related HCC decreased from 85.3 to 64.4%. Among non-viral etiologies, notable increases were observed in nonalcoholic steatohepatitis (NASH)-related HCC (from 1.5 to 7.2%) and alcoholic liver disease (ALD)-related HCC (from 8.5 to 18.6%). Regarding the real number of newly diagnosed patients, the number of patients with viral hepatitis-related HCC decreased, while the number of patients with non-viral HCC, particularly NASH-related HCC, increased.

Conclusions: Viral hepatitis has remained the main cause of HCC in Japan. However, the decrease in viral hepatitis-related HCC, particularly HCV-related HCC highly contributed to the etiological changes. In addition, the increased incidence of non-viral HCC, particularly NASH-related HCC, was involved in the changing etiologies of HCC-complicated LC in Japan.
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http://dx.doi.org/10.1007/s00535-020-01748-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862502PMC
February 2021

Impact of Immune Reconstitution-Induced Hepatic Flare on Hepatitis B Surface Antigen Loss in Hepatitis B Virus/Human Immunodeficiency Virus-1 Coinfected Patients.

J Infect Dis 2021 Jun;223(12):2080-2089

AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.

Background: Hepatitis B surface antigen (HBsAg) loss is an ideal goal for chronic hepatitis B patients. Antiretroviral therapy (ART) in hepatitis B virus/human immunodeficiency virus-1 (HBV/HIV-1)-coinfected patients can lead to hepatic flare (HF) caused by immune reconstitution-induced inflammatory syndrome (IRIS). Here, we investigated the impact of IRIS-HF on HBsAg loss.

Methods: This was a retrospective study of 58 HBV/HIV-1-coinfected subjects HBsAg-positive for ≥6 months before ART initiation and followed for ≥1 year (median 9.9 years) after ART initiation. We examined humoral factors in sera from healthy volunteers, HIV-monoinfected patients, and HBV/HIV-1-coinfected patients with IRIS-HF or acute hepatitis B infection.

Results: During ART, HBsAg loss was observed in 20 of 58 HBV/HIV-1-coinfected patients (34.5%). Of the 58 patients, 15 (25.9%) developed IRIS-HF within 12 months of ART initiation. HBsAg loss was more frequent among patients who developed IRIS-HF (11/15, 73.3%) than those who did not (9/43, 20.9%). Multivariate analysis showed IRIS-HF was an independent predictor of subsequent HBsAg loss. Younger age and higher baseline HBV DNA titer were associated with IRIS-HF. Elevation of sCD163, not CXCL9, CXC10, CXCXL11, or CXCL13, was observed at IRIS-HF.

Conclusions: IRIS-HF was associated with HBsAg loss in HBV/HIV-1-coinfected patients.
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http://dx.doi.org/10.1093/infdis/jiaa662DOI Listing
June 2021

Sofosbuvir plus velpatasvir treatment for hepatitis C virus in patients with decompensated cirrhosis: a Japanese real-world multicenter study.

J Gastroenterol 2021 Jan 1;56(1):67-77. Epub 2020 Oct 1.

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: Real-world data on the efficacy and safety of sofosbuvir plus velpatasvir (SOF/VEL) treatment for patients with hepatitis C virus (HCV)-related decompensated cirrhosis are limited in Japan.

Methods: A total of 190 patients with compensated (108) or decompensated (82) cirrhosis who initiated direct-acting antiviral (DAA) treatment between February 2019 and August 2019 were enrolled. Sustained virologic response (SVR) was defined as undetectable serum HCV-RNA at 12 weeks after the end of treatment (EOT).

Results: The SVR12 rates were 92.6% in patients with compensated cirrhosis and 90.2% in patients with decompensated cirrhosis (p = 0.564), and the treatment completion rates were 98.1% and 96.3%, respectively (p = 0.372). In patients with decompensated cirrhosis, 3 patients discontinued treatment and 2 patients died because of liver-related events. In patients with decompensated cirrhosis with SVR12, 50% of patients with Child-Pugh class B at baseline showed improvement to class A at SVR12, and 27% and 9% of patients with Child-Pugh class C at baseline showed improvement to class B and class A at SVR12, respectively. Patients who achieved SVR12 showed elevated serum albumin levels at the EOT, which were further elevated at SVR12, but no elevated serum albumin levels after the EOT were observed in patients with baseline serum albumin levels less than 2.8 g/dl.

Conclusions: Real-world efficacy of SOF/VEL treatment for patients with decompensated cirrhosis was similar to Japanese phase 3 study, although treatment discontinuation and death related to liver disease occurred. In patients with poor hepatic reserve, whether it improves continuously after viral clearance requires further evaluation.
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http://dx.doi.org/10.1007/s00535-020-01733-4DOI Listing
January 2021

Serum CCL17 level becomes a predictive marker to distinguish between mild/moderate and severe/critical disease in patients with COVID-19.

Gene 2021 Jan 14;766:145145. Epub 2020 Sep 14.

Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan.

COVID-19, a novel coronavirus-related illness, has spread worldwide. Patients with apparently mild/moderate symptoms can suddenly develop severe pneumonia. Therefore, almost all COVID-19 patients require hospitalization, which can reduce limited medical resources in addition to overwhelming medical facilities. To identify predictive markers for the development of severe pneumonia, a comprehensive analysis of serum chemokines and cytokines was conducted using serial serum samples from COVID-19 patients. The expression profiles were analyzed along the time axis. Serum samples of common diseases were enrolled from a BioBank to confirm the usefulness of predictive markers. Five factors, IFN-λ3, IL-6, IP-10, CXCL9, and CCL17, were identified as predicting the onset of severe/critical symptoms. The factors were classified into two categories. Category A included IFN-λ3, IL-6, IP-10, and CXCL9, and their values surged and decreased rapidly before the onset of severe pneumonia. Category B included CCL17, which provided complete separation between the mild/moderate and the severe/critical groups at an early phase of SARS-CoV-2 infection. The five markers provided a high predictive value (area under the receiver operating characteristic curve (AUROC): 0.9-1.0, p < 0.001). Low expression of CCL17 was specifically observed in pre-severe COVID-19 patients compared with other common diseases, and the predictive ability of CCL17 was confirmed in validation samples of COVID-19. The factors identified could be promising prognostic markers to distinguish between mild/moderate and severe/critical patients, enabling triage at an early phase of infection, thus avoiding overwhelming medical facilities.
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http://dx.doi.org/10.1016/j.gene.2020.145145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489253PMC
January 2021

De novo hepatocellular carcinoma in living donor liver grafts: A Japanese multicenter experience.

Hepatol Res 2020 Dec 27;50(12):1365-1374. Epub 2020 Sep 27.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Aim: Direct-acting antivirals for hepatitis C virus have reduced the decompensation risk. Immunosuppressants for transplantation raise the risk of occurrence of de novo malignancies. We assessed the probabilities of and risk factors for de novo hepatocellular carcinoma (HCC) development post-living donor liver transplantation (LDLT).

Methods: We retrospectively evaluated the data of developed HCC in a graft including metastatic HCC post-LDLT from 2779 adult cases collected from nine major liver transplantation centers in Japan.

Results: Of 2779 LDLT adult recipients, 34 (1.2%) developed HCCs in their grafts. Of 34, five HCCs appeared to be de novo because of a longer period to tumor detection (9.7 [6.4-15.4] years) and no HCC within the native liver of the two recipients. The donor origin of three of five de novo HCCs was confirmed using microsatellite analysis in resected tissue. Primary disease of all five was hepatitis C virus-related cirrhosis, of which two were treated with direct-acting antivirals. Four of five developed HCC de novo in the hepatitis B core antibody-positive grafts. De novo HCCs had favorable prognosis; four of five were cured with complete remission. However, recurrent HCC (n = 29) in the graft had a poorer outcome, especially in patients with neutrophil to lymphocyte ratio scores above 4 (median survival time, 262 [19-463] days).

Conclusion: Analysis of the database from major liver transplantation institutes in Japan revealed that de novo HCCs determined by microsatellite analysis were rarely detected, but the majority were successfully treated. LDLT recipients with higher risks of de novo HCC, including those with hepatitis B core antibody-positive grafts, should be carefully followed by surveillance of the liver graft.
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http://dx.doi.org/10.1111/hepr.13565DOI Listing
December 2020

Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C.

JHEP Rep 2020 Oct 18;2(5):100138. Epub 2020 Jun 18.

Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan.

Background & Aims: We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections.

Methods: A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing.

Results: Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens ( <0.01), which was similar to that seen with L31-RAS and Y93-RAS. The prevalence of patients with RASs in either NS3 or NS5A, or in both, increased significantly with increasing numbers of failed regimens. The P32del, which is unique to patients for whom DAA had failed, was linked to the absence of Y93H, the presence of L31F, and previous exposure to IFN plus protease inhibitor regimens.

Conclusions: Failure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV.

Lay Summary: Resistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.
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http://dx.doi.org/10.1016/j.jhepr.2020.100138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424232PMC
October 2020

Dysregulated Expression of the Nuclear Exosome Targeting Complex Component Rbm7 in Nonhematopoietic Cells Licenses the Development of Fibrosis.

Immunity 2020 03;52(3):542-556.e13

Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka 565-0871, Japan; Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka 565-0871, Japan. Electronic address:

Fibrosis is an incurable disorder of unknown etiology. Segregated-nucleus-containing atypical monocytes (SatMs) are critical for the development of fibrosis. Here we examined the mechanisms that recruit SatMs to pre-fibrotic areas. A screen based on cytokine expression in the fibrotic lung revealed that the chemokine Cxcl12, which is produced by apoptotic nonhematopoietic cells, was essential for SatM recruitment. Analyses of lung tissues at fibrosis onset showed increased expression of Rbm7, a component of the nuclear exosome targeting complex. Rbm7 deletion suppressed bleomycin-induced fibrosis and at a cellular level, suppressed apoptosis of nonhematopoietic cells. Mechanistically, Rbm7 bound to noncoding (nc)RNAs that form subnuclear bodies, including Neat1 speckles. Dysregulated expression of Rbm7 resulted in the nuclear degradation of Neat1 speckles, the dispersion of the DNA repair protein BRCA1, and the triggering of apoptosis. Thus, Rbm7 in epithelial cells plays a critical role in the development of fibrosis by regulating ncRNA decay and thereby the production of chemokines that recruit SatMs.
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http://dx.doi.org/10.1016/j.immuni.2020.02.007DOI Listing
March 2020

A prospective trial of vaccine to prevent hepatitis B virus reactivation after hematopoietic stem cell transplantation.

Bone Marrow Transplant 2020 07 18;55(7):1388-1398. Epub 2020 Feb 18.

Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan.

Hepatitis B virus (HBV) reactivation reportedly occurs frequently after hematopoietic stem cell transplantation (HSCT) in resolved HBV-infected patients. Here, 50 patients with resolved HBV infections and scheduled to undergo HSCT were enrolled; all subjects were vaccinated with three doses of hepatitis B vaccine 12 months after HSCT and the incidence of HBV reactivation was monitored. The patients' characteristics were: median age, 61 (34-72) years; male/female, 27/19; allogeneic/autologous, 40/6; bone marrow/peripheral blood stem cells/cord blood, 26/16/4. Of the 46 patients who underwent HSCT, 19 were excluded and did not make it to vaccination due to relapse of underlying disease, HBV reactivation within 12 months of HSCT, or transfer of patients. The remaining 27 were vaccinated 12 months after HSCT and monitored for 2 years. Six showed HBV reactivation, with a 2-year cumulative reactivation incidence of 22.2%; the same incidence was 27.3% only in allogeneic HSCT patients. Factors associated with HBV reactivation included the discontinuation of immunosuppressants (P = 0.0379) and baseline titers of antibody against hepatitis B surface antigen (P = 0.004). HBV reactivation with vaccination following HSCT could occur despite maintenance of serum anti-HBs at more than protective levels.
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http://dx.doi.org/10.1038/s41409-020-0833-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329632PMC
July 2020

Serum soluble sialic acid-binding immunoglobulin-like lectin-7 concentration as an indicator of liver macrophage activation and advanced fibrosis in patients with non-alcoholic fatty liver disease.

Hepatol Res 2020 Apr 26;50(4):466-477. Epub 2019 Dec 26.

The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.

Aim: Non-alcoholic fatty liver disease (NAFLD) is a leading cause of liver disease worldwide. Because liver fibrosis is associated with the long-term prognosis of patients with NAFLD, there is an urgent need for non-invasive markers of liver fibrosis. Sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7) is an immunomodulatory molecule expressed on various immune cells, including macrophages, which plays a key role in liver inflammation and fibrosis in NAFLD. We aimed to determine whether serum levels of soluble Siglec-7 (sSiglec-7) could have utility at a marker of fibrosis in this patient population.

Methods: We examined serum samples from 93 NAFLD patients and 19 healthy donors for macrophage-associated protein, including sSiglec-7, soluble CD163, and YKL-40, and examined their correlation with liver fibrosis scores, tissue elastography, and histological findings. Independent factors associated with advanced fibrosis were analyzed using a logistic regression model and a decision tree. To clarify the source of sSiglec-7, we examined its expression in liver tissue-derived macrophages and cultured monocyte-derived macrophages.

Results: Serum sSiglec-7 levels were significantly higher in NAFLD patients compared with healthy donors, and correlated positively with sCD163 and YKL-40 levels. Serum sSiglec-7 was an independent diagnostic marker with high specificity (96.3%) for advanced fibrosis (F3 and F4) in NAFLD patients. Siglec-7 was mainly expressed on CCR2 macrophages in the liver, and sSiglec-7 production by monocyte-derived macrophages in vitro was increased after stimulation by pro-inflammatory factors.

Conclusions: Elevated serum sSiglec-7 could serve as an independent marker with high specificity for advanced liver fibrosis in patients with NAFLD.
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http://dx.doi.org/10.1111/hepr.13464DOI Listing
April 2020

Transition in the etiology of liver cirrhosis in Japan: a nationwide survey.

J Gastroenterol 2020 Mar 25;55(3):353-362. Epub 2019 Nov 25.

Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa-cho 1-1, Nishinomiya, Hyogo, 663-8501, Japan.

Background: To assess the recent real-world changes in the etiologies of liver cirrhosis (LC) in Japan, we conducted a nationwide survey in the annual meeting of the Japan Society of Hepatology (JSH).

Methods: We investigated the etiologies of LC patients accumulated from 68 participants in 79 institutions (N = 48,621). We next assessed changing trends in the etiologies of LC by analyzing cases in which the year of diagnosis was available (N = 45,834). We further evaluated the transition in the real number of newly identified LC patients by assessing data from 36 hospitals with complete datasets for 2008-2016 (N = 18,358).

Results: In the overall data, HCV infection (48.2%) was the leading cause of LC in Japan, and HBV infection (11.5%) was the third-most common cause. Regarding the transition in the etiologies of LC, the contribution of viral hepatitis-related LC dropped from 73.4 to 49.7%. Among the non-viral etiologies, alcoholic-related disease (ALD) and nonalcoholic steatohepatitis (NASH)-related LC showed a notable increase (from 13.7 to 24.9% and from 2.0 to 9.1%, respectively). Regarding the real numbers of newly diagnosed patients from 2008 to 2016, the numbers of patients with viral hepatitis-related LC decreased, while the numbers of patients with non-viral LC increased.

Conclusions: HCV has remained the main cause of LC in Japan; however, the contribution of viral hepatitis as an etiology of LC is suggested to have been decreasing. In addition, non-viral LC, such as ALD-related LC and NASH-related LC, is suggested to have increased as etiologies of LC in Japan.
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http://dx.doi.org/10.1007/s00535-019-01645-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026312PMC
March 2020

Nationwide survey on activities of regional core centers for the management of liver disease in Japan: Cumulative analyses by the Hepatitis Information Center 2009-2017.

Hepatol Res 2020 Feb 18;50(2):165-173. Epub 2019 Dec 18.

Hepatitis Information Center, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.

Aim: Regional core centers for the management of liver disease, which are located in every prefecture in Japan, not only take the lead in hepatitis care in their respective regions, but also serve a wide range of other functions, such as education, promotion of hepatitis testing, treatment, and research.

Method: Since fiscal year 2010, the Hepatitis Information Center has conducted surveys of regional core centers throughout Japan regarding information about their facilities, programs for patient support, training, and education of medical personnel.

Results: By compiling and analyzing the results of these surveys, we have elucidated the status of regional core centers and the issues they currently have. We found that regional core centers have come to play widely varied roles in hepatitis treatment and have expanded their programs. These surveys also suggest that uniform accessibility of hepatitis treatment has been implemented throughout Japan.

Conclusion: To continue serving their diverse roles, regional core centers require further development of hepatitis care networks that include specialized institutions, primary care physicians, and local and central governments; as well as collaboration with other professions and groups.
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http://dx.doi.org/10.1111/hepr.13458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027808PMC
February 2020

Serum milk fat globule-EGF factor 8 (MFG-E8) as a diagnostic and prognostic biomarker in patients with hepatocellular carcinoma.

Sci Rep 2019 10 31;9(1):15788. Epub 2019 Oct 31.

Department of Liver Disease, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.

Current serum hepatocellular carcinoma (HCC) biomarkers are insufficient for early diagnosis. We aimed to clarify whether serum MFG-E8 can serve as a diagnostic or prognostic biomarker of HCC. Serum MFG-E8 levels of 282 HCC patients, who underwent primary hepatectomy, were examined by ELISA. We also quantified serum MFG-E8 levels in patients with chronic hepatitis (CH), liver cirrhosis (LC), as well as in healthy volunteers (HVs). Serum MFG-E8 levels were significantly lower in HCC patients than in HVs regardless of the etiology of liver disease (3.6 ± 0.1 vs 5.8 ± 0.2 ng/mL, p < 0.0001), and recovered after treatment of HCC. Serum MFG-E8 levels in CH and LC patients were comparable to those in HVs. Serum MFG-E8 could detect HCCs, even α-fetoprotein (AFP)-negative or des-γ-carboxy prothrombin (DCP)-negative HCCs, in CH and LC patients. Our new HCC prediction model using MFG-E8 and DCP (Logit(p) = 2.619 - 0.809 × serum MFG-E8 + 0.0226 × serum DCP) distinguished HCC patients from CH and LC patients with an area under the curve of 0.923, a sensitivity of 81.1%, and a specificity of 89.8%. Futhermore, low preoperative serum MFG-E8 was an independent predictor of poor overall survival. Thus, serum MFG-E8 could serve as a feasible diagnostic and prognostic biomarker for HCC.
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http://dx.doi.org/10.1038/s41598-019-52356-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823494PMC
October 2019

Hepatocellular carcinoma with non-B and non-C hepatitis origin: epidemiology in Japan and surgical outcome.

Glob Health Med 2019 Oct;1(1):23-29

Department of Surgery, Division of Hepatobiliary Pancreatic Surgery, The University of Tokyo, Tokyo, Japan.

During the last two decades, there has been a dramatic increase in so-called non-B non-C hepatocellular carcinoma (NBNC HCC) in Japan. Majority of NBNC HCC are considered as so-called metabolic HCC and some could be related to occult HBV infection. Although there have been some reports on histological features predominant in metabolic HCC, very few specific driver genes for NBNC HCC have been reported. Most of the NBNC HCC are found incidentally and are relatively large in size. Since liver function is generally normal or subnormal, such patients have a higher chance for undergoing curative surgery. Although there has been slightly conflicting long-term outcomes reported for NBNC HCC, slightly better outcomes may be expected compared to other etiologies after curative surgery. However, risk of recurrence depends on the background liver. NBNC HCC in cirrhotic patients have a persistently higher risk of tumor recurrence requiring a long-term postoperative surveillance. It would be safe to conclude at this moment that NBNC HCCs should be treated using the same surgical strategy as HCCs with viral origin, same operative indications and same follow-up protocol.
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http://dx.doi.org/10.35772/ghm.2019.01018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731089PMC
October 2019

Efficient and practical dissemination of information on viral hepatitis in Japan: an effort by the Hepatitis Information Center, National Center for Global Health and Medicine.

Glob Health Med 2019 Oct;1(1):20-22

Hepatitis Information Center, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan.

One of the important missions of the Hepatitis Information Center is to disseminate information regarding liver disease. The Hepatitis Information Center, National Center for Global Health and Medicine (NCGM) has been endeavoring to ensure that reliable and up-to-date information on liver disease is accessible to all people, regardless of age, disability, and background. Described here are several initiatives with regard to the dissemination of information about liver disease including: ) Education tool for youth, ) Conversion of materials on liver diseases into audio format for the visually impaired, and ) Hepatic Disease Medical Navigation System (Hepatic Navi). Hepatic Navi is a web-based search tool that informs users of the location and other information concerning medical centers where people can be tested for the hepatitis virus for free or at reduced cost. Hepatic Navi consolidates data from 47 prefectures into one database. The system depicts data an interface that can be accessed anywhere with a PC, tablet, smart phone, or mobile phone. As a result, it has become possible for anyone from anywhere to access information on hepatitis virus testing. By using Hepatic Navi, it is anticipated that general people in need feel free to access to the testing and further treatment for virus hepatitis.
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http://dx.doi.org/10.35772/ghm.2019.01028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731436PMC
October 2019

Immune Determinants in the Acquisition and Maintenance of Antibody to Hepatitis B Surface Antigen in Adults After First-Time Hepatitis B Vaccination.

Hepatol Commun 2019 Jun 22;3(6):812-824. Epub 2019 Apr 22.

National Center for Global Health and Medicine Research Center for Hepatitis and Immunology Ichikawa Japan.

Global implementation of a birth-dose hepatitis B (HB) vaccine has significantly reduced the prevalence of hepatitis B virus (HBV) carriers. Durable and sufficient titers of antibodies to hepatitis B surface antigen (anti-HBs) are desirable for vaccinees to gain resistance to HBV exposure. However, the existence of primary nonresponders and vaccinees who lost anti-HBs over time remains a challenge for the strategy of HBV elimination. We thus aim to clarify the mechanisms of acquisition and maintenance of vaccine-induced anti-HBs in healthy adults. We retrospectively analyzed the vaccination records of 3,755 first-time HB-vaccinated students and also traced the acquired antibody transition of 392 first-time vaccinees for 10 consecutive years. To understand the cellular and humoral immune response, we prospectively examined peripheral blood from 47 healthy first-time HB-vaccinated students, 62 booster-vaccinated health care workers, and 20 individuals who maintained their anti-HBs. In responders, a significant increase of follicular helper T (Tfh) cells, activated plasmablasts, and plasma cells was observed in first-time-vaccinated but not booster-vaccinated persons. We also discovered memory B cells and antibody-secreting cells were more abundant in individuals who maintained anti-HBs. According to vaccination records, higher anti-HBs antibody titer acquisition was related to the longer term maintenance of anti-HBs, the level of which was positively correlated with prevaccination levels of serum interferon-γ and related chemokines. The second series of vaccination as a booster provided significantly higher anti-HBs antibody titers compared to the initial series. : Coordinated activation of Tfh and B-cell lineages after HB vaccination is involved in the acquisition and maintenance of anti-HBs. Our findings support the rationale of preconditioning the immune status of recipients to ensure durable vaccine responses.
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http://dx.doi.org/10.1002/hep4.1357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545872PMC
June 2019

Liver disease secondary to congenital heart disease in children.

Expert Rev Gastroenterol Hepatol 2019 Jul 26;13(7):651-666. Epub 2019 May 26.

b Department of Pediatric Hepatology and Gastroenterology , Eastern Yokohama Hospital , Kanagawa , Japan.

: Hepatic fibrosis and hepatocellular carcinoma (HCC) can develop in children with congenital heart disease. Although hepatic fibrosis and HCC are prone to develop after the Fontan operation, they can also develop in patients suffering from congenital heart disease who have not undergone Fontan operation. : The history of cardiac hepatopathy including Fontan-associated liver disease is described. Patient characteristics, liver histology, imaging examinations and blood tests are reviewed to elucidate the mechanism of cardiac hepatopathy. In addition, a flowchart for the follow-up management of cardiac hepatopathy in children with congenital heart disease is proposed. : Congestion and low cardiac output are the main causes of cardiac hepatopathy. Advanced hepatic fibrosis is presumed to be associated with HCC. HCC can develop in both adolescents and young adults. Regardless of whether the Fontan operation is performed, children with a functional single ventricle and chronic heart failure should be regularly examined for cardiac hepatopathy. There is no single reliable laboratory parameter to accurately detect cardiac hepatopathy; hepatic fibrosis indices and elastography have shown inconsistent results for detection of this disease. Further studies using liver specimen-confirmed patients and standardization of evaluation protocols are required to clarify the pathogenesis of cardiac hepatopathy.
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http://dx.doi.org/10.1080/17474124.2019.1621746DOI Listing
July 2019

Programmed cell death ligand 1 (PD-L1) blockade attenuates metastatic colon cancer growth in cAMP-response element-binding protein (CREB)-binding protein (CBP)/β-catenin inhibitor-treated livers.

Oncotarget 2019 Apr 30;10(32):3013-3026. Epub 2019 Apr 30.

Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo 113-8677, Japan.

Immune checkpoint blockade with specific antibodies can accelerate anti-tumor immunity, resulting in clinical responses in patients with various types of cancer. However, these antibodies achieve only partial tumor regression. Thus, a wide variety of treatment combinations based on programmed death-ligand 1 (PD-L1) pathway inhibition are under development to enhance such therapeutic effects. In this study, the effects of combination treatment using PRI-724, a selective inhibitor of CBP/β-catenin, and an anti-PD-L1 antibody were examined in a mouse model of colon cancer liver metastasis. Mice were inoculated with SL4 colon cancer cells to produce metastatic liver tumors. The combination treatment resulted in regression of tumor growth, whereas monotherapy with each treatment individually failed to exhibit any anti-tumor activity. In addition, co-administration of the inhibitor and antibody induced CD8CD44CD62L cells and interferon (IFN)-γ production in CD8 T-cells in the liver compared with that in control mice. Administration of an anti-CD8 antibody mitigated the anti-tumor effects of the combined treatment of PRI-724 and anti-PD-L1 antibody. In conclusion, targeting CBP/β-catenin, combined with PD-1/PD-L1 immune checkpoint blockade, shows potential as a new therapeutic strategy for treating liver metastasis during colon cancer.
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http://dx.doi.org/10.18632/oncotarget.26892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508964PMC
April 2019

High serum interleukin-34 level is a predictor of poor prognosis in patients with non-viral hepatocellular carcinoma.

Hepatol Res 2019 Sep 29;49(9):1046-1053. Epub 2019 May 29.

Division of Gastroenterology, Kurume University School of Medicine, Kurume, Japan.

Aims: We aimed to investigate the impact of interleukin (IL)-34 and YKL-40, regulators of hepatic fibrosis and tumor growth, on the prognosis of patients with non-viral hepatocellular carcinoma (HCC).

Methods: We enrolled 159 non-viral HCC patients (age, 70.8 ± 8.5 years; female/male, 43/116). Of these, 86 patients were alive and 73 patients had died at the censor time point. Serum IL-34 and YKL-40 levels were quantified by enzyme-linked immunosorbent assay. Patients were stratified by the median level of serum IL-34 to examine its effect on survival. Multivariate analysis and random forest analysis were used to evaluate the impact of IL-34 and YKL-40 on the prognosis of non-viral HCC patients.

Results: Interleukin-34 (hazard ratio [HR] 1.30; 95% confidence interval [CI], 1.13-1.49; P ≤ 0.01), tumor size (HR 1.63; 95% CI, 1.37-1.94; P ≤ 0.01), and tumor number (HR 1.53; 95% CI, 1.25-1.87; P ≤ 0.01) were independent predictive factors for survival. Furthermore, the survival rates were significantly lower in the high IL-34 group than in the low IL-34 group (5-year survival rates, 34.7% vs. 59.8%, respectively; P < 0.05). In the random forest analysis for survival, IL-34 was the third-highest ranking factor, following tumor size and number. In a stratification analysis, serum α-fetoprotein level and Fibrosis-4 index were independent positive risk factors for high serum IL-34 level. YKL-40 was not associated with prognosis in either the multivariate or random forest analysis.

Conclusion: Interleukin-34 was an independent factor for survival of non-viral HCC patients. Interleukin-34 might be associated with prognosis through tumor and hepatic fibrosis factors.
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http://dx.doi.org/10.1111/hepr.13350DOI Listing
September 2019

Bone morphogenetic protein 4 provides cancer-supportive phenotypes to liver fibroblasts in patients with hepatocellular carcinoma.

J Gastroenterol 2019 Nov 2;54(11):1007-1018. Epub 2019 Apr 2.

The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1, Kohnodai, Ichikawa, Chiba, 272-8516, Japan.

Background: Cancer-associated fibroblasts (CAFs) are essential constituents of cancer-supportive microenvironments. The high incidence of hepatocellular carcinoma (HCC) in advanced fibrosis patients implies that fibroblasts have a promoting effect on HCC development. We aimed to explore the regulators of phenotypes and function of CAFs in the liver.

Methods: We established primary cancer-associated fibroblasts (CAFs) and non-cancerous liver fibroblasts (NFs) from 15 patients who underwent HCC resection. We compared phenotypes, capacity of cytokine/chemokine production and gene expression profiles between pairs of CAFs and NFs from the same donors. We examined resected tissue from additional 50 patients with HCC for immunohistochemical analyses.

Results: The CAFs expressed more ACTA2 and COL1A1 than the NFs, suggesting that CAFs are more activated phenotype. The CAFs produced larger amounts of IL-6, IL-8 and CCL2 than the NFs, which led to invasiveness of HuH7 in vitro. We found that Bone Morphogenetic Protein-4 (BMP4) is up-regulated in CAFs compared to NFs. The CAF phenotype and function were gained by BMP4 over-expression or recombinant BMP4 given to fibroblasts, all of which decreased with BMP4 knockdown. In tissues obtained from the patients, BMP4-positive cells are mainly observed in encapsulated fibrous lesions and HCC. Positive expression of BMP4 in HCC in resected tissues, not in fibroblasts, was associated with poorer postoperative overall survival in patients with HCC.

Conclusion: Endogenous and exogenous BMP4 activate liver fibroblasts to gain capacity of secreting cytokines and enhancing invasiveness of cancer cells in the liver. BMP4 is one of the regulatory factors of CAFs functioning in the microenvironment of HCC.
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http://dx.doi.org/10.1007/s00535-019-01579-5DOI Listing
November 2019
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