Faculty Profiles - ISHIKAWA, Tetsuya

Deep proteomicsを用いた高脂肪食摂取マウスにおける腸管透過性亢進メカニズムの検討

CiNii Research

Spermidine enhances the efficacy of adjuvant in HBV vaccination in mice Reviewed

Ito D, Ito H, Ando T, Sakai Y, Ideta T, Ishii KJ, Ishikawa T, Shimizu M.

Hepatology Communications Vol. 24 ( 4 ) page： e0104 2023.4

B型慢性肝炎患者における免疫要素を加味した機能的治癒(Functional Cure)予測因子としてのコアI97L変異の可能性

本多隆, 石上雅敏, 石川哲也

肝臓 Vol. 64 ( Suppl.1 ) page： A352 - A352 2023.4

Proteomic analysis reveals changes in tight junctions in the small intestinal eepithelium of mice fed a high-fat diet Reviewed

Muto H, Honda T, Tanaka T, Yokoyama S, Yamamoto K, Ito T, Imai N, Ishizu Y, Maeda K, Ishikawa T, Adachi S, Sato C, Tsuji NM Ishigami M, Fujishiro M, Kawashima H.

Nutrients Vol. 15 ( 6 ) page： 1473 2023.3

武藤久哲, 本多隆, 水野史崇, 松田宣賢, 犬飼庸介, 山本崇文, 水野和幸, 横山晋也, 田中卓, 山本健太, 伊藤隆徳, 今井則博, 石津洋二, 石川哲也, 石上雅敏, 川嶋啓輝

日本消化器病学会雑誌 Vol. 120 ( 臨増総会 ) page： A308 - A308 2023.3

In Vivo Real-Time Quantum Dots Imaging to Track Transplanted Adipose Stem Cells in Different Inflammatory States of Acute Liver Failure Mice. International journal

Shota Yamada, Hiroshi Yukawa, Koudai Kitamura, Toshiki Mizumaki, Yasuma Yoshizumi, Tomomi Oohara, Eri Nanizawa, Fumika Hirano, Kazuhide Sato, Ayae Sugawara-Narutaki, Tetsuya Ishikawa, Yoshinobu Baba

Cell transplantation Vol. 32 page： 9636897231176442 - 9636897231176442 2023.1

Language：English Publishing type：Research paper (scientific journal)

Stem cell therapy plays an important role in regenerative therapy; however, there is little information on the in vivo dynamics of transplanted stem cells and the influence of the inflammation of affected tissues or organs on these dynamics. In this study, we revealed real-time dynamics of transplanted adipose tissue-derived stem cells (ASCs) and the influence of the inflammatory states on these dynamics in acute liver failure mice. Quantum dots (QDs) labeling did not affect the cytokine profile of ASCs, and intravenously transplanted ASCs labeled with QDs could be detected in real time with high efficiency without laparotomy. Until 30 min after ASC transplantation, no marked differences in the behavior or accumulation of transplanted ASCs in the liver were observed among the three groups with different degrees of liver damage (normal, weak, and strong). However, significant differences in the engraftment rate of transplanted ASCs in the liver were observed among the three groups from 4 h after transplantation. The engraftment rate was inversely correlated with the extent of the liver damage. These data suggested that QDs are useful for in vivo real-time imaging of transplanted cells, and the inflammatory state of tissues or organs may affect the engraftment rate of transplanted cells.

DOI： 10.1177/09636897231176442

Treatment with hepatocyte transplantation in a novel mouse model of persistent liver failure. Reviewed International journal

Yuki Tamaki, Yuria Shibata, Misaki Hayakawa, Nodoka Kato, Ami Machii, Yuma Ikeda, Eri Nanizawa, Yumi Hayashi, Hiroshi Suemizu, Hiroyasu Ito, Tetsuya Ishikawa

Biochemistry and biophysics reports Vol. 32 page： 101382 - 101382 2022.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIM: Cell-based transplantation therapy using hepatocytes, hepatic stem cells, hepatocyte-like cells induced from stem cells, etc. is thought to be an attractive alternative to liver transplantation, and have been studied to date. For its clinical application, however, it is extremely important to develop a model that reproduces the pathological conditions with indication for treatment and enables the study for the ideal treatment strategy. METHODS: The transgenic mice which express the thymidine kinase (TK) gene of human herpes simplex virus (HSV) in their hepatocytes with normal immunity has been developed (designated as HSVtk). After ganciclovir (GCV) administration which injure TK-expressing hepatocytes, the primary hepatocytes (PHs) isolated from green fluorescent protein (GFP) transgenic mouse (GFP-tg) were transplanted to HSVtk intrasplenically, and replacement index (RI) with transplanted PHs in the liver, liver histology, and mRNA expressions in the liver were analyzed up to 8 weeks after transplantation. RESULTS: HSVtk without PH transplantation after GCV administration developed persistent liver failure with degenerated hepatocytes, persistent elevation of ALT and hepatic p16 mRNA levels, suggesting the existence of cellular senescence in the base of the disease. When autologous GFP-PHs were transplanted to HSVtk, the transplanted cells were successfully engrafted in the liver. Eight weeks after transplantation, serum ALT levels and liver histology were almost normalized, while RIs varied from 19.8 to 73.8%. Since the hepatic p16 mRNA levels were decreased significantly in these mice, the senescence of hepatocytes associated with liver injury was thought to be resolved. On the other hand, allogenic GFP-PHs transplanted to HSVtk were eliminated as early as 1 week after transplantation. In these mice, hepatic p16 mRNA levels were significantly increased at 8 weeks after transplantation, suggesting the aggravation of hepatocyte senescence. FK506 administration to HSVtk protected the transplanted hepatocytes with allogenic background from rejection at 2 weeks after transplantation, but the condition of mice and the senescent status in the liver seemed worsened. CONCLUSIONS: The mouse model with HSVtk/GCV system was useful for studying the mechanism of liver regeneration and the immune rejection responses in the hepatocyte transplantation treatment. It may also be utilized to develop the effective remedies to avoid immune rejection.

DOI： 10.1016/j.bbrep.2022.101382

Factors associated with the progression of myosteatosis in patients with cirrhosis. Reviewed

Ishizu Y, Ishigami M, Honda T, Imai N, Ito T, Yamamoto K, Yokoyama S, Ishikawa T, Fujishiro M

Nutrition (Burbank, Los Angeles County, Calif.) Vol. 103-104 page： 111777 2022.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Nutrition

Objectives: The presence of myosteatosis is one factor associated with poor prognosis for patients with cirrhosis; however, the factors contributing to worsening myosteatosis are, to our knowledge, unknown. The aim of this study was to clarify the changes in myosteatosis, and the factors involved in these changes. Methods: The present study enrolled 178 patients with cirrhosis who underwent computed tomography twice to measure changes in skeletal muscle attenuation (SMA) at the L3 level. Factors associated with SMA and those associated with changes in SMA were examined. Results: Using linear multiple regression analysis, age (β = –0.22), skeletal muscle index (SMI; skeletal muscle area divided by height squared; β = 0.25), and visceral and subcutaneous fat indices (VFI and SFI; the visceral and subcutaneous fat areas at the umbilical level divided by height squared; β = –0.08, β = –0.06, respectively) were identified as associated with SMA. The 100-d change in SMA was –0.21 ± 1.29 Hounsfield units (HU). Changes in SMI and SMA were positively associated (R = 0.183, P = 0.014), whereas those in VFI and SMA were negatively associated (R = –0.172, P = 0.022). No association was noted between the 100-d changes in SFI and SMA. In patients whose SMI increased and VFI decreased, the 100-d change in SMA was 0.24 ± 1.82 HU, which was marginally different from that in patients whose SMI decreased and VFI increased (–0.44 ± 1.32 HU, P = 0.077). Conclusions: In patients with cirrhosis, myosteatosis progressed, and decreases in SMI and increases in VFI were correlated with its progression.

DOI： 10.1016/j.nut.2022.111777

Effect of illness uncertainty on alanine transaminase levels and aspartate aminotransferase levels in patients with nonalcoholic fatty liver disease Reviewed

Naoki Ozawa, Kazuki Sato, Ayumi Sugimura, Shigeyoshi Maki, Taku Tanaka, Kenta Yamamoto, Takanori Ito, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Masatoshi Ishigami, Mitsuhiro Fujishiro, Tetsuya Ishikawa, Shoko Ando

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 84 ( 4 ) page： 857 - 864 2022.11

Language：English Publishing type：Research paper (scientific journal) Publisher：NAGOYA UNIV, SCH MED

Patients with nonalcoholic fatty liver disease (NAFLD) have illness uncertainty. The purpose of this longitudinal study was to investigate the effect of the degree of illness uncertainty in patients with NAFLD on liver function values. We conducted a questionnaire survey and collected blood samples from outpatients with NAFLD. The items in the questionnaire were measured for illness uncertainty using the Japanese version of the Mishel Uncertainty in Illness Scale-Community (MUIS-C). Blood samples were collected at baseline and after 1 year. We divided the patients into two groups: one with high illness uncertainty and the other with low illness uncertainty. We then compared changes in alanine transaminase (ALT) and aspartate aminotransferase (AST) levels over time from baseline using multiple regression analysis. This study analyzed 148 patients with NAFLD; 75 were male and 73 were female, with a mean age of 58.4 +/- 12.3 years. The group with higher illness uncertainty had significantly higher ALT and AST levels at 1 year (b = .185 and .183, respectively) than the group with lower illness uncertainty. High illness uncertainty in patients with NAFLD can lead to higher ALT and AST levels. Healthcare providers must focus on reducing illness uncertainty in patients with NAFLD.

DOI： 10.18999/nagjms.84.4.857

Decreased appetite is associated with the presence of sarcopenia in patients with cirrhosis. Reviewed

Ishizu Y, Ishigami M, Honda T, Imai N, Ito T, Yamamoto K, Yokoyama S, Ishikawa T, Kawashima H

Nutrition (Burbank, Los Angeles County, Calif.) Vol. 103-104 page： 111807 2022.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Nutrition

Objectives: To our knowledge, the relationship between appetite and sarcopenia in patients with cirrhosis is unknown. The aims of this study were to examine the factors associated with decreased appetite and to clarify the relationship between appetite and sarcopenia. Methods: This study included 61 patients with cirrhosis. The patients were asked to describe their appetite using a numerical rating scale (NRS) from 0 (none at all) to 10 (most), with ≤5 defined as decreased appetite. The clinical characteristics, gastrointestinal symptoms as assessed using the Gastrointestinal Symptom Rating Scale, handgrip strength, and skeletal muscle area at the third vertebra were collected retrospectively. Sarcopenia was diagnosed according to the criteria of the Japan Society of Hepatology. The differences in these factors between patients with and without decreased appetite, and the factors associated with the presence of sarcopenia were examined. Results: Alcoholic liver disease was the most common etiology. The median Model for End-Stage Liver Disease score was 8 (interquartile range = 7 - 10) and hepatocellular carcinoma was present in 35 patients. Overall, 36% of the patients with cirrhosis had decreased appetite. Patients with decreased appetite had a higher frequency of abdominal pain and acid reflux–related symptoms and significantly lower handgrip strength than patients without, among both men (P = 0.034) and women (P = 0.017). The multivariate analysis identified a decrease in appetite as a significant factor associated with the presence of sarcopenia (NRS one increase, odds ratio, 0.701; 95% confidence interval, 0.502–0.977; P = 0.036). Conclusion: Decreased appetite was associated with the presence of sarcopenia.

DOI： 10.1016/j.nut.2022.111807

An improved method to assess skeletal muscle mass in patients with liver cirrhosis based on computed tomography images. Reviewed

Sugiyama Y, Ishizu Y, Ando Y, Yokoyama S, Yamamoto K, Ito T, Imai N, Nakamura M, Honda T, Kawashima H, Ishikawa T, Ishigami M

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 52 ( 11 ) page： 937 - 946 2022.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Hepatology Research

Aim: Conventionally, the skeletal muscle area with computed tomography (CT) attenuation ranging from −29 to +150 Hounsfield unit (HU) divided by height squared (the conventional skeletal muscle index [SMI]) was used as an index of skeletal muscle mass. However, it includes fat-infiltrated skeletal muscle, which is known to have poor function. This study aims to determine whether the low-fat SMI, which uses skeletal muscle mass with CT attenuation ranging from +30 to +150 HU, or conventional SMI appropriately reflects the function of skeletal muscle. Methods: We retrospectively analyzed 120 patients with cirrhosis whose handgrip strength was measured. Among them, 48 patients underwent a physical performance assessment such as liver frailty index (LFI) and short physical performance battery (SPPB), and 80 underwent quality of life (QOL) assessment. The relationships between each SMI and handgrip strength, LFI, SPPB, and QOL were evaluated. Results: Low-fat SMI was significantly correlated with handgrip strength (males, R = 0.393, p = 0.002; females, R = 0.423, p < 0.001) and LFI (males, R = −0.535, p = 0.035; females, R = −0.368, p = 0.039), whereas conventional SMI was not. When using low-fat SMI, patients with low skeletal muscle mass had significantly low handgrip strength, LFI, SPPB, and physical and social-related QOL score than those without. By contrast, no significant differences were found for any items when using conventional SMI. Conclusions: Low-fat SMI is a good index of skeletal muscle mass that appropriately reflects skeletal muscle function.

DOI： 10.1111/hepr.13820

Short-term high-fat and high-carbohydrate diets increase susceptibility to liver injury by inducing hepatic procoagulant and proinflammatory conditions with different balances. Reviewed International journal

Eri Nanizawa, Shun Otsuka, Naoyuki Hatayama, Yuki Tamaki, Yumi Hayashi, Tetsuya Ishikawa, Shuichi Hirai, Munekazu Naito

Nutrition (Burbank, Los Angeles County, Calif.) Vol. 101 page： 111710 - 111710 2022.9

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: High-fat diet (HFD) and high-carbohydrate diet (HCD) are strongly linked to nonalcoholic fatty liver disease, a hepatic manifestation of metabolic syndrome. The mechanism of pathologic progression from nonalcoholic fatty liver disease to nonalcoholic steatohepatitis, which is a more severe form associated with inflammation and fibrosis, remains poorly understood. Thus, the aim of this study was to investigate and compare the inflammatory and coagulative state of the liver in short-term HFD- or HCD-fed mice with acute liver injury induced by concanavalin A (Con A). METHODS: Histopathologic evaluation, real-time polymerase chain reaction, and immunohistochemical evaluation were performed on the liver of mice fed HFDs and HCDs for 4 d before and after Con A administration. RESULTS: The liver of the HFD-fed mice had larger fibrinogen/fibrin depositions than those fed the HCD. HCD induced the expression of the proinflammatory cytokine tumor necrosis factor-α in the liver. Moreover, the expression of proinflammatory cytokines and chemokines was further enhanced after Con A stimulation in HCD (e.g., interleukin-1α, interleukin-6 at 1 h), with a strong tendency for inflammatory cell infiltration also found (24 h). CONCLUSIONS: Short-term HCD and HFD increased susceptibility to liver injury. HCD tended to induce more intense inflammation, whereas HFD tended to induce more intense hypercoagulation, suggesting that HCD and HFD may have different mechanisms of pathologic progression to nonalcoholic steatohepatitis.

DOI： 10.1016/j.nut.2022.111710

Functional cureを目指したインターフェロン治療の効果とコア領域の変異測定の有用性

本多隆, 豊田秀徳, 安田諭, 横山晋也, 山本健太, 伊藤隆徳, 今井則博, 石津洋二, 石川哲也, 石上雅敏

肝臓 Vol. 63 ( Suppl.2 ) page： A607 - A607 2022.9

Safety, tolerability, and anti-fibrotic efficacy of the CBP/β-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis: An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study Reviewed

Kimura K, Kanto T, Shimoda S, Harada K, Kimura M, Nishikawa K, Imamura J, Ogawa E, Saio M, Ikura Y, Okusaka T, Inoue K, Ishikawa T, Ieiri I, Kishimoto J, Todaka K, Kamisawa T

EBioMedicine Vol. 80 page： 104069 2022.7

Changes in the gut microbiota after hepatitis C virus eradication. International journal

Takashi Honda, Masatoshi Ishigami, Kenta Yamamoto, Tomoaki Takeyama, Takanori Ito, Yoji Ishizu, Teiji Kuzuya, Masanao Nakamura, Hiroki Kawashima, Ryoji Miyahara, Tetsuya Ishikawa, Yoshiki Hirooka, Mitsuhiro Fujishiro

Scientific reports Vol. 11 ( 1 ) page： 23568 - 23568 2021.12

Language：English Publishing type：Research paper (scientific journal)

The gut microbiota interacts with infectious diseases and affects host immunity. Liver disease is also reportedly associated with changes in the gut microbiota. To elucidate the changes in the gut microbiota before and after hepatitis C virus (HCV) eradication through direct-acting antiviral (DAA) treatment in patients with chronic hepatitis C (CHC), we investigated 42 samples from 14 patients who received DAA therapy for HCV. Fecal samples were obtained before treatment (Pre), when treatment ended (EOT), and 24 weeks after treatment ended (Post24). The target V3-4 region of the 16S rRNA gene from fecal samples was amplified using the Illumina Miseq sequencing platform. The diversity of the gut microbiota did not significantly differ between Pre, EOT, and Post24. Principal coordinates analysis showed that for each patient, the values at Pre, EOT, and Post24 were concentrated within a small area. The linear discriminant analysis of effect size showed that the relative abundances of Faecalibacterium and Bacillus increased at EOT, further increased at Post24, and were significantly increased at Post24 compared to Pre. These suggest that changes in the gut microbiota should be considered as among the various effects observed on living organisms after HCV eradication.

DOI： 10.1038/s41598-021-03009-0

Obesity and myosteatosis: the two characteristics of dynapenia in patients with cirrhosis.

Sugiyama Y, Ishizu Y, Ando Y, Yokoyama S, Yamamoto K, Ito T, Imai N, Nakamura M, Honda T, Kawashima H, Ishikawa T, Ishigami M

European journal of gastroenterology & hepatology Vol. 33 ( 1S Suppl 1 ) page： e916 - e921 2021.12

Language：English Publishing type：Research paper (scientific journal) Publisher：European journal of gastroenterology & hepatology

OBJECTIVE: In patients with liver cirrhosis, the clinical characteristics of dynapenia, a condition in which skeletal muscle mass is maintained but muscle strength is reduced, are not yet known. This study aimed to clarify the characteristics of dynapenia and its impact on quality of life (QOL) in patients with liver cirrhosis. METHODS: We retrospectively analyzed 116 patients with cirrhosis. Based on grip strength and skeletal muscle mass measured by the bioelectrical impedance analysis method, patients were divided into four groups: normal muscle status, dynapenia, pre-sarcopenia (a condition involving only low muscle mass), and sarcopenia. The characteristics of dynapenia and its influence on QOL were examined. RESULTS: Fourteen patients had dynapenia. Liver function did not differ among the four groups. In patients with dynapenia, BMI was highest and computed tomography attenuation of skeletal muscle at the third lumbar spine vertebra was lowest among the four groups. The percentage of patients with both BMI ≥25 kg/m2 and myosteatosis was significantly higher in patients with dynapenia [9/14 (64.3%)] than in those with sarcopenia [2/23 (8.7%), P = 0.004] and pre-sarcopenia [0/18 (0%), P < 0.001] and tended to be higher than those with normal muscle status [16/61 (26.2%), P = 0.065]. The physical QOL in patients with dynapenia was as low as that in those with sarcopenia and significantly lower than that in those with normal muscle status. CONCLUSION: Cirrhotic patients with dynapenia had high BMI and myosteatosis, and impaired physical QOL.

DOI： 10.1097/MEG.0000000000002303

All-atom molecular dynamics study of hepatitis B virus containing pregenome RNA in solution. Reviewed

Fujimoto K, Yamaguchi Y, Urano R, Shinoda W, Ishikawa T, Omagari K, Tanaka Y, Nakagawa A, Okazaki S

The Journal of chemical physics Vol. 155 ( 14 ) page： 145101 2021.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Chemical Physics

Immature hepatitis B virus (HBV) captures nucleotides in its capsid for reverse transcription. The nucleotides and nucleotide analog drugs, which are triphosphorylated and negatively charged in the cell, approach the capsid via diffusion and are absorbed into it. In this study, we performed a long-time molecular dynamics calculation of the entire HBV capsid containing pregenome RNA to investigate the interactions between the capsid and negatively charged substances. Electric field analysis demonstrated that negatively charged substances can approach the HBV capsid by thermal motion, avoiding spikes. The substances then migrate all over the floor of the HBV capsid. Finally, they find pores through which they can pass through the HBV capsid shell. Free energy profiles were calculated along these pores for small ions to understand their permeability through the pores. Anions (Cl−) showed higher free energy barriers than cations (Na+ and K+) through all pores, and the permeation rate of Cl− was eight times slower than that of K+ or Na+. Furthermore, the ions were more stable in the capsid than in the bulk water. Thus, the HBV capsid exerts ion selectivity for uptake and provides an environment for ions, such as nucleotides and nucleotide analog drugs, to be stabilized within the capsid.

DOI： 10.1063/5.0065765

Conditioned medium from stem cells derived from human exfoliated deciduous teeth ameliorates NASH via the Gut-Liver axis. Reviewed

Muto H, Ito T, Tanaka T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Maeda K, Honda T, Ishikawa T, Kato A, Ohshiro T, Kano F, Yamamoto A, Sakai K, Hibi H, Ishigami M, Fujishiro M

Scientific reports Vol. 11 ( 1 ) page： 18778 2021.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports

Non-alcoholic steatohepatitis (NASH) occurrence has been increasing and is becoming a major cause of liver cirrhosis and liver cancer. However, effective treatments for NASH are still lacking. We examined the benefits of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) on a murine non-alcoholic steatohepatitis (NASH) model induced by a combination of Western diet (WD) and repeated administration of low doses of carbon tetrachloride intraperitoneally, focusing on the gut-liver axis. We showed that repeated intravenous administration of SHED-CM significantly ameliorated histological liver fibrosis and inflammation in a murine NASH model. SHED-CM inhibited parenchymal cell apoptosis and reduced the activation of inflammatory macrophages. Gene expression of pro-inflammatory and pro-fibrotic mediators (such as Tnf-α, Tgf-β, and Ccl-2) in the liver was reduced in mice treated with SHED-CM. Furthermore, SHED-CM protected intestinal tight junctions and maintained intestinal barrier function, while suppressing gene expression of the receptor for endotoxin, Toll-like receptor 4, in the liver. SHED-CM promoted the recovery of Caco-2 monolayer dysfunction induced by IFN-γ and TNF-α in vitro. Our findings suggest that SHED-CM may inhibit NASH fibrosis via the gut-liver axis, in addition to its protective effect on hepatocytes and the induction of macrophages with unique anti-inflammatory phenotypes.

DOI： 10.1038/s41598-021-98254-8

Transient deterioration of albumin-bilirubin scores in early post-dose period of molecular targeted therapies in advanced hepatocellular carcinoma with 50% or higher liver occupation: A STROBE-compliant retrospective observational study. International journal

Hisanori Muto, Teiji Kuzuya, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Masatoshi Ishigami, Mitsuhiro Fujishiro

Medicine Vol. 100 ( 31 ) page： e26820 2021.8

Language：English Publishing type：Research paper (scientific journal)

ABSTRACT: Real-world clinical cases of molecularly targeted agent (MTA) administration to patients with advanced hepatocellular carcinoma (HCC) with ≥50% liver occupation have been reported, but treatment outcomes have rarely been described. We have encountered several cases in which albumin-bilirubin (ALBI) scores deteriorated markedly and C-reactive protein (CRP) levels elevated in the early post-dose period. The present study therefore investigated early clinical changes in ALBI score and CRP levels after initiating MTA in advanced HCC patients with ≥50% liver occupation, focusing on antitumor response at 6 weeks.This retrospective study included 46 HCC patients with liver occupation ≥50% and 191 patients with <50%, Child-Pugh score ≤7, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1, who were treated with sorafenib or lenvatinib as first-line systemic therapy at our hospital between June 2011 and January 2020. We analyzed their medical records up to March 2020 and investigated the outcomes and changes in CRP and ALBI scores classified according to antitumor response at 6 weeks.Overall survival was significantly longer in patients with partial response (PR) + stable disease (SD) (13.7 months) than in patients with progressive disease (PD) (1.7 months, P < .001) in the ≥50% group. Patients with antitumor response of PR + SD at 6 weeks in the ≥50% group showed more marked deterioration of ALBI score at 2 weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. Focusing on patients with PD at 6 weeks, ALBI score deteriorated over time in both groups. Regarding CRP, on 6-week PR + SD patients, a significant increase in CRP levels at 1 and 2 weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2 weeks.In MTA treatment for patients with ≥50% liver occupation, to obtain an antitumor response of PR + SD, adequate management might be important considering transient deteriorated ALBI scores and elevated CRP levels.

DOI： 10.1097/MD.0000000000026820

Amino Acid Polymorphism in Hepatitis B Virus Associated With Functional Cure. Invited Reviewed

Honda T, Yamada N, Murayama A, Shiina M, Aly HH, Kato A, Ito T, Ishizu Y, Kuzuya T, Ishigami M, Murakami Y, Tanaka T, Moriishi K, Nishitsuji H, Shimotohno K, Ishikawa T, Fujishiro M, Muramatsu M, Wakita T, Kato T

Cellular and molecular gastroenterology and hepatology Vol. 12 ( 5 ) page： 1583 - 1598 2021.8

Language：English Publishing type：Research paper (scientific journal) Publisher：Cellular and Molecular Gastroenterology and Hepatology

Background & Aims: To provide an adequate treatment strategy for chronic hepatitis B, it is essential to know which patients are expected to have a good prognosis and which patients do not require therapeutic intervention. Previously, we identified the substitution of isoleucine to leucine at amino acid 97 (I97L) in the hepatitis B core region as a key predictor among patients with stable hepatitis. In this study, we attempted to identify the point at which I97L affects the hepatitis B virus (HBV) life cycle and to elucidate the underlying mechanisms governing the stabilization of hepatitis. Methods: To confirm the clinical features of I97L, we used a cohort of hepatitis B e antigen–negative patients with chronic hepatitis B infected with HBV-I97 wild-type (wt) or HBV-I97L. The effects of I97L on viral characteristics were evaluated by in vitro HBV production and infection systems with the HBV reporter virus and cell culture-generated HBV. Results: The ratios of reduction in hepatitis B surface antigen and HBV DNA were higher in patients with HBV-I97L than in those with HBV-I97wt. HBV-I97L exhibited lower infectivity than HBV-I97wt in both infection systems with reporter HBV and cell culture-generated HBV. HBV-I97L virions exhibiting low infectivity primarily contained a single-stranded HBV genome. The lower efficiency of cccDNA synthesis was demonstrated after infection of HBV-I97L or transfection of the molecular clone of HBV-I97L. Conclusions: The I97L substitution reduces the level of cccDNA through the generation of immature virions with single-stranded genomes. This I97L-associated low efficiency of cccDNA synthesis may be involved in the stabilization of hepatitis.

DOI： 10.1016/j.jcmgh.2021.07.013