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

Cellular and gene therapy (CGT) products have emerged as a popular approach in regenerative medicine, showing promise in treating various pancreatic and liver diseases in numerous clinical trials. Before these therapies can be tested in human clinical trials, it is essential to evaluate their safety and efficacy in relevant animal models. Such preclinical testing is often required to obtain regulatory approval for investigational new drugs. However, there is a lack of detailed guidance on selecting appropriate animal models for CGT therapies targeting specific pancreatic and liver conditions, such as pancreatitis and chronic liver diseases. In this review, the gastrointestinal committee for the International Society for Cell and Gene Therapy provides a summary of current recommendations for animal species and disease model selection, as outlined by the US Food and Drug Administration, with references to EU EMA and Japan PMDA. We discuss a range of small and large animal models, as well as humanized models, that are suitable for preclinical testing of CGT products aimed at treating pancreatic and liver diseases. For each model, we cover the associated pathophysiology, commonly used metrics for assessing disease status, the pros and limitations of the models, and the relevance of these models to human conditions. We also summarize the use and application of humanized mouse and other animal models in evaluating the safety and efficacy of CGT products. This review aims to provide comprehensive guidance for selecting appropriate animal species and models to help bridge the gap between the preclinical research and clinical trials using CGT therapies for specific pancreatic and liver diseases.

DOI： 10.1016/j.jcyt.2024.11.008

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INTRODUCTION: Cirrhosis is a disease with poor prognosis that requires the development of a novel therapeutic approach alternative to liver transplantation. In this study, we focused on the placenta and aimed to clarify the effects of human placental extract (HPE) on cirrhosis. METHODS: A mouse model of carbon tetrachloride-induced cirrhosis was used to evaluate the effect of HPE administration subcutaneously and compared with the control group (n = 8 for each group). In vitro and in vivo, real time-PCR and immunostaining were performed for HPE mechanistic analysis. Spatial transcriptomics was also performed for detailed analysis of the effect of HPE on cirrhosis. RESULTS: HPE administration improved serum ALT levels compared to control mice. Furthermore, there was a decrease in the number of senescent cells in the liver and the mRNA levels of secrete senescence-associated secretory phenotype factors and Cdkn2a (p16). In vitro, HPE induced macrophage polarization to the anti-inflammatory M2 phenotype. Spatial transcriptomics was also performed to analyze the underlying anti-inflammatory mechanism. The results showed that HPE strongly polarized macrophages to the M2 phenotype, especially in macrophage-rich regions in the liver. Gene expression pathway analysis using spatial transcriptomics also revealed the possibility of improving senescent cell-derived inflammation via mitochondrial function. CONCLUSIONS: HPE improves serum ALT levels via anti-inflammatory mechanisms in macrophages and senescent cells. HPE serves as a novel agent for cirrhosis treatment.

DOI： 10.1016/j.reth.2025.01.017

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Objective: Liver cirrhosis (LC) progression induces intestinal microbiota abnormalities, such as small intestinal bacterial overgrowth (SIBO), and these changes lead to the inflow of gut pathogens and their degradation products into the vessels, causing cirrhotic complications such as hepatic encephalopathy (HE). Methods: To clarify the relationship between the development of overt HE and SIBO, we conducted a three-year observation after assessment of SIBO in patients with LC. Results: In the analysis of 107 patients, with a mean follow-up duration of 29.4 months, 31 were diagnosed with SIBO and 30 with covert HE. In the Cox multivariate regression analysis for prognosis, the Child-Pugh score, blood urea nitrogen level, and the Union for International Cancer Control (UICC) stage of hepatocellular carcinoma were derived using the following five factors: white blood cell count, blood urea nitrogen level, Child-Pugh score, UICC stage, and serum aspartate aminotransferase and alkaline phosphatase levels (p = 0.002, hazard ratio [HR] 3.733, 95% confidence interval [CI] 1.592-8.754, p = 0.001, HR 1.076, 95% CI 1.030-1.123, and p < 0.001, HR 2.767, 95% CI 1.780-4.302, respectively). Furthermore, in the Cox multivariate regression analysis for overt HE development, covert HE and methane-producing SIBO were derived using the following four factors: methane-producing SIBO, UICC stage, covert HE, and serum ammonia levels (p = 0.038, HR 5.008, 95% CI 1.096-22.892 and p = 0.006, HR 8.597, 95% CI 1.881-39.291, respectively). Conclusions: M-SIBO positivity was a significant predictor of overt HE.

DOI： 10.3390/jcm14051491

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Patients with chronic cholestatic liver diseases often experience itch and struggle with this symptom. We discuss the mechanism of itch in patients with chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and others, and their therapies, including ileal bile acid transporter (IBAT) inhibitors. In patients with PBC, there are high serum/plasma concentrations of multiple factors, including bile salts, bilirubin, endogenous opioids, lysophosphatidic acid (LPA), autotaxin, and histamine. Bile salts, bilirubin, LPA, and autotaxin affect itch mediators in the skin and sensory nerves, while the endogenous opioid balance affects mediators in the spinal cord. Itch is sensitized by both the peripheral and central nervous systems. Both mechanisms are involved in itch in patients with chronic cholestatic liver disease. Although IBAT inhibitors have been approved for use in pediatric cholestatic conditions, such as progressive familial intrahepatic cholestasis and Alagille syndrome, IBAT inhibition seems to be a promising treatment for chronic refractory itch in patients with PBC. A traditional non-systematic review results in this narrative review. Multidisciplinary cooperation, involving hepatologists, dermatologists, and pharmacists, could provide better treatment for PBC patients suffering from refractory itch. In conclusion, we summarized the existing knowledge on itch caused by chronic cholestatic liver diseases, especially in PBC with a focus on the mechanisms and therapies. This narrative review provides the mechanisms and therapeutic options for itch in patients with chronic cholestatic liver diseases.

DOI： 10.3390/ijms26051883

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Background/Objectives: Rifaximin is a therapeutic agent for patients with hepatic encephalopathy (HE); however, there is little data on the effects of its long-term (>1 year) administration in Japanese patients with cirrhosis. The effects and safety of 3-year rifaximin treatment on HE was investigated in Japan. Methods: A total of 190 Japanese patients with cirrhosis who were continuously administered rifaximin for more than 1 year suffered overt or covert HE, which was diagnosed by a physician. Laboratory data were collected at baseline, 3, 6, 12, 18, 24, 30, and 36 months following rifaximin administration. We examined the cumulative overt HE incidences, overall survival rates, and hepatic functional reserves following rifaximin treatment. The occurrence of adverse events was also assessed. Results: The levels of ammonia improved significantly after 3 months of rifaximin administration, which continued for 3 years. Serum albumin and prothrombin activity also significantly improved 3 years after initiation of rifaximin treatment. Cumulative overt HE incidences were 12.1%, 19.7%, and 24.9% at 1, 2, and 3 years, respectively. The survival rates following rifaximin treatment were 100%, 88.9%, and 77.8% at 1, 2, and 3 years, respectively. In contrast, renal function and electrolytes did not change following rifaximin administration. Only three (1.6%) patients discontinued rifaximin therapy because of severe diarrhea after 1 year of rifaximin administration. No other serious adverse events were observed. Conclusions: Three years of continuous rifaximin (RFX) treatment was both effective and safe for patients with hepatic encephalopathy. Liver function improved and did not worsen during treatment.

DOI： 10.3390/jcm14041358

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DOI： 10.1007/s12072-025-10784-9

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DOI： 10.3390/livers5010010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Baishideng Publishing Group Inc.  

Hepatitis B virus (HBV) infection causes acute and chronic hepatitis, compensated and decompensated cirrhosis, and hepatocellular carcinoma worldwide. The actual status of HBV infection and its treatment in certain regions of Asian and African countries, including Ethiopia, has not been well-documented thus far. Antiviral therapy for HBV infection can prevent the progression of HBV-related liver diseases and decrease the HBV-related symptoms, such as abdominal symptoms, fatigue, systemic symptoms and others. In Eastern Ethiopia, HBV-infected patients with cirrhosis were found to be positive for the HBV e antigen and to have a higher viral load than those without cirrhosis. Notably, 54.4% of patients practiced khat chewing and 18.1% consumed excessive amounts of alcohol. Tenofovir disoproxil fumarate effectively suppressed HBV DNA in those infected with HBV. It is important to elucidate the actual status of HBV infection in Eastern Ethiopia to eliminate HBV infection worldwide by 2030. HBV vaccination and the educational programs for Health Science students that provide practical strategies could help to reduce HBV infection in Eastern Ethiopia.

DOI： 10.4254/wjh.v17.i1.99209

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Tertiary lymphoid tissues (TLTs) are ectopic lymphoid structures induced by multiple stimuli, including infection and tissue injuries; however, their clinical relevance in disease progression has remained unclear. We demonstrated previously that TLTs develop in mouse and human kidneys with aging and can be a potential marker of kidney injury and prognosis, and therapeutic targets. In addition, we found that two types of unique lymphocytes that emerge with aging, senescence-associated T cells and age-associated B cells, are essential for TLT formation in the kidney. Although TLTs develop with aging in other organs as well, their cellular and molecular components, and clinical significance remain unclear. In the present study, we found that TLTs developed in the liver with aging, and that their cellular and molecular components were similar to those in the kidneys. Notably, senescence-associated T cells and age-associated B cells were also present in hepatic TLTs. Furthermore, analysis of publicly available data on human liver biopsy transcriptomes revealed that the expression of TLT-related genes was elevated in the liver biopsy samples from hepatitis C virus (HCV)-infected patients compared with those without HCV infection and was associated with liver injury and fibrosis. Therefore, we analyzed liver biopsy samples from 47 HCV patients and found that TLTs were present in 87.2% of cases and that the numbers and stages of TLTs were higher in aged patients and cellular and molecular components of TLTs in humans were similar to those in mice. Our findings suggesting that age-dependent TLT formation is a systemic phenomenon across the tissues and aging is also a predisposing factor for TLT formation across organs.

DOI： 10.1371/journal.pone.0311193

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OBJECTIVES: The oral-gut axis is believed to play a role in the pathogenesis of colorectal cancer (CRC). Previous studies have demonstrated the transmission of oral microbiota to the gut, disrupting gut microbial balance and creating a protumorigenic microenvironment conducive to CRC progression. Fusobacterium nucleatum is a putative periodontal pathogen recognized as a specific bacterium that promotes CRC development. However, the possible involvement of other periodontal pathogens in CRC is poorly understood. This study aimed to explore the effects of ingested periodontal pathogens on experimental CRC in mice and elucidate the underlying mechanisms. METHODS: In this study, experimental colitis-induced CRC mouse models were used. The mice were orally administered periodontal pathogens (Porphyromonas gingivalis and Prevotella intermedia) three times a week during the experimental period. The CRC severity between the P. gingivalis-treated and P. intermedia-treated groups was compared. Lumen-associated microbiota (LAM) and mucosa-associated microbiota (MAM) were analyzed in both mouse and human samples. In vitro studies were conducted using intestinal epithelial cells to explore the possible mechanisms by which the periodontal pathogens affect the CRC development. RESULTS: The P. gingivalis-treated group exhibited significantly increased CRC severity compared to the other groups among azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse models. The LAM and MAM exhibited distinct bacterial compositions, and P. gingivalis was enriched more in MAM than in LAM. In vitro adhesion assays revealed that P. gingivalis had higher adhesive capacity to intestinal epithelial cells than P. intermedia and indicated the possible involvement of gingipains in such a capacity. CONCLUSION: P. gingivalis is enriched in MAM, and its subsequent adhesion to intestinal epithelial cells is potentially involved in the progression of CRC.

DOI： 10.1371/journal.pone.0320383

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BACKGROUND: The distribution of body weight in patients with achalasia and after peroral endoscopic myotomy (POEM) has not been investigated. The role of body weight assessment after treatment remains unclear. METHODS: Using the multicenter achalasia cohort, the frequency of underweight (body mass index [BMI] < 18.5 kg/m2) and overweight (BMI ≥ 25.0 kg/m2) and their associated clinical characteristics were analyzed. After POEM, risk factors for insufficient- (underweight persistently) and excessive- (responded to overweight) weight gainers were investigated. The correlation between BMI-increase rate and severity of esophageal symptoms post-POEM was evaluated. RESULTS: Among 3,410 patients, 23.0% and 15.7% were underweight and overweight, respectively. Factors associated with underweight were higher age, female sex, severe symptoms, high lower esophageal sphincter (LES) pressure, and non-dilated esophagus (all p < 0.01). Longitudinal analyses revealed that weight gain post-POEM was achieved after a long duration (≥ 12 months; p < 0.01). In 528 patients post-POEM, the frequency of underweight reduced to 8.3% (p < 0.01). Risk factors for insufficient-weight gain (36.1% of underweight patients) included low BMI (p < 0.01) and high LES pressure (p = 0.03) and conversely for excessive-weight gain. Machine learning models based on patient characteristics successfully predicted insufficient- and excessive-weight gainers with an area under the curve value of 0.74 and 0.75, respectively. Esophageal symptoms post-POEM did not correlate with BMI increase. CONCLUSION: Underweight is not solely a condition of advanced achalasia. After POEM, insufficient- or excessive-weight gainers are not rare and can be predicted preoperatively. Body weight change is an independent nutrition parameter rather than a part of the assessment of residual esophageal symptoms.

DOI： 10.1007/s00535-024-02205-9

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Metabolic dysfunction-associated steatotic liver disease (MASLD) causes cellular senescence due to oxidative stress, endoplasmic reticulum stress, and ectopic fat deposition in the liver. Recently, dasatinib, an antitumor agent, and quercetin, a dietary supplement, were combined as a senolytic drug to eliminate senescent cells. Thus, this study aimed to examine the effects of dasatinib and quercetin administration on removing senescent cells and their therapeutic effects on MASLD in a medaka MASLD model. Dasatinib and quercetin were administered to a medaka MASLD model, which was fed a high-fat diet by dissolving them in aquarium water. The results revealed that senescent cells in the liver were increased in the HFD group but improved in the treatment group. Hematoxylin and eosin staining also showed that treatment improved fat deposition in hepatocytes. In addition, TGFβ1, a driver factor of fibrosis, was reduced in the treatment group. Dasatinib and quercetin eliminated senescent cells in MASLD, attenuated fat deposition, and suppressed fibrosis gene expression. The results indicate that dasatinib and quercetin as senolytic drugs are novel therapeutic agents that reduce MASLD.

DOI： 10.3390/diseases12120317

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Language：English   Publishing type：Research paper (international conference proceedings)  

DOI： 10.1109/GCCE62371.2024.10760734

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AIM: The incidence of and factors involved in gastroesophageal varix-related events in hepatitis C virus-related cirrhosis patients, including decompensated cirrhosis, after direct-acting antiviral therapy are unclear. METHODS: We conducted a multicenter study using prospective data from 478 hepatitis C virus-related cirrhosis patients treated with direct-acting antiviral therapy from February 2019 to December 2021 at 33 Japanese hospitals. Gastroesophageal varices were classified as F1 (small-caliber), F2 (moderately enlarged), or F3 (markedly enlarged) according to the Japanese criteria. Patients without varix or with F1 without red color signs were defined as low-risk varix, and patients with ≥F2 or red color signs or a history of rupture were defined as high-risk varix. Varix-related events were defined as prophylactic treatment or rupture of gastroesophageal varix. RESULTS: The median age was 70 years, 43% of patients had decompensated cirrhosis, and 16% had high-risk varices (13% in compensated and 33% in decompensated, p < 0.001). Sustained virologic response rates were 94.9% for compensated cirrhosis and 91.3% for decompensated cirrhosis (p = 0.120). Across 35.7 months, 25 patients received prophylactic treatment, and four experienced varix rupture. The 3-year incidence rate of varix-related events was 6.2% (3.5% in compensated and 9.9% in decompensated, p = 0.001). In the multivariate analysis, high-risk varix (p < 0.001), high baseline gamma-glutamyl transpeptidase levels (p < 0.001), and virologic failure (p = 0.004) were significantly involved in varix-related events. CONCLUSIONS: The cumulative incidence rate of varix-related events was significantly higher in decompensated cirrhosis than in compensated cirrhosis. Baseline varix status, baseline gamma-glutamyl transpeptidase levels, and virologic response were related to varix-related events after direct-acting antiviral therapy.

DOI： 10.1111/hepr.14131

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Objective Crohn's disease (CD) is a chronic inflammatory bowel disease that is associated with malnutrition. Sarcopenia is a malnutrition condition characterized by skeletal muscle loss that impairs the physical function. We investigated the clinical characteristics of patients with CD with sarcopenia and sarcopenic obesity (sarcopenic-o). Methods The body composition of patients with CD was evaluated using a bioelectrical impedance analysis. The clinical characteristics of patients with sarcopenia and sarcopenic-o were analyzed, and a predictive model for sarcopenia was developed. Patients: Patients with CD recruited from 2019 to 2021 were included. Results Among the 104 patients, 35 (33.7%) and 10 (9.6%) had sarcopenia and sarcopenic-o, respectively. In the sarcopenia group, the skeletal muscle index (SMI) and body mass index (BMI) were lower than those in the control group (SMI, 6.3 kg/m2 vs. 7.7 kg/m2, p<0.01; BMI, 18.8 kg/m2 vs. 22.6 kg/m2, p<0.01), whereas the Crohn's disease activity index (CDAI) was higher than in the control group (114.2 vs. 42.0, p<0.01). The predictive models of sarcopenia using the BMI and CDAI revealed high performance with areas under the receiver operating characteristic curve (AUC) of 0.87 and 0.72, respectively, and high specificity (0.94) and sensitivity (0.71), respectively. Sarcopenic-o patients could not be screened using the BMI (25 kg/m2), and the SMI and body fat percentage were negatively correlated in patients with sarcopenia (p<0.01). Conclusion Sarcopenia and sarcopenic-o are relatively common conditions among patients with CD. Sarcopenia can be predicted using the clinical parameters of BMI and CDAI. Sarcopenic-o can be a severe form of sarcopenia.

DOI： 10.2169/internalmedicine.4420-24

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Among causes of liver failure, liver failure due to lymphocytic infiltration is rare. Unlike typical liver failure, some cases present with severe lactic acidosis and a poor prognosis. We herein report a case of diffuse large B-cell lymphoma with severe lactic acidosis and liver failure. We further discuss the characteristics of similar cases in the literature, suggesting that intrahepatic infiltration by hematological malignant cells should be considered as a differential diagnosis in the presence of severe lactic acidosis and liver failure. This study underscores the importance of early recognition and serves as a reference for future cases.

DOI： 10.2169/internalmedicine.4450-24

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Language：Japanese   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Language：Japanese   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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The onset and progression mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are being studied. We developed and analyzed a new mouse model of obesity by combining maternal Id-like molecule (Maid) and melanocortin-4 receptor (Mc4r) gene deletions. Four mice, each at 12 and 28 weeks of age, were analyzed for each genotype: Maid gene knockout, Mc4r gene knockout, combined Mc4r and Maid gene knockout, and Mc4r gene knockout with a high-fat diet. Mice with a combined deficiency of Mc4r and Maid gene showed significantly more severe obesity compared to all other genotypes, but no liver fibrosis or a decline in metabolic status were observed. In visceral white adipose tissue, Maid and Mc4r gene knockout mice had fewer CD11c-positive cells and lower mRNA expression of both inflammatory and anti-inflammatory cytokines. Furthermore, Maid and Mc4r gene knockout mice showed lower expression of adipocytokines in visceral white adipose tissue and uncoupling protein-1 in scapular brown adipose tissue. The expression of adipocytokines and uncoupling protein-1 is regulated by sympathetic nerve signaling that contribute severe obesity in Maid and Mc4r gene knockout mice. These mechanisms contribute hyperobesity in Maid and Mc4r gene knockout mice.

DOI： 10.1038/s41598-024-72217-1

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Language：Japanese   Publisher：(一財)日本消化器病学会  

肝嚢胞は,増大して圧迫症状や閉塞性黄疸などをきたし,症候性となることがある.内科的治療として嚢胞穿刺排液,硬化療法があるが,再発率が高い.今回われわれは,15年以上の経過で徐々に増大して圧迫症状と閉塞性黄疸をきたした症候性巨大肝嚢胞に対して,嚢胞穿刺排液と嚢胞内洗浄を併用する塩酸ミノサイクリンによる経皮的硬化療法を施行し,著明な嚢胞縮小効果と症状改善を認めた症例を経験したので報告する.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J01118&link_issn=&doc_id=20240919370009&doc_link_id=%2Fck8syokb%2F2024%2F012109%2F009%2F0769-0776%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fck8syokb%2F2024%2F012109%2F009%2F0769-0776%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Metabolic dysfunction-associated steatohepatitis (MASH, previously termed non-alcoholic steatohepatitis (NASH)), is a major complication of obesity that promotes fatty liver disease. MASH is characterized by progressive tissue fibrosis and sterile liver inflammation that can lead to liver cirrhosis, cancer, and death. The molecular mechanisms of fibrosis in MASH and its systemic control remain poorly understood. Here, we identified the secreted-type pro-fibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), as a brown adipose tissue (BAT)-derived adipokine that promotes liver fibrosis in a murine obesity-induced MASH model. BAT-specific or systemic PCPE-1 depletion in mice ameliorated liver fibrosis, whereas, PCPE-1 gain of function in BAT enhanced hepatic fibrosis. High-calorie diet-induced ER stress increased PCPE-1 production in BAT through the activation of IRE-1/JNK/c-Fos/c-Jun signaling. Circulating PCPE-1 levels are increased in the plasma of MASH patients, suggesting a therapeutic possibility. In sum, our results uncover PCPE-1 as a novel systemic control factor of liver fibrosis.

DOI： 10.1038/s44318-024-00196-0

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BACKGROUND AND AIM: Neutrophil gelatinase-associated lipocalin (NGAL) is characterized by increased expression before the rise in serum creatinine and has been used as a biomarker for the early prediction of acute kidney injury (AKI). However, there have been no comprehensive analyses of its significance in gastrointestinal diseases. This study aimed to analyze the usefulness of measuring urinary NGAL levels in patients with gastrointestinal diseases. METHODS: This study included 171 patients with a wide range of gastrointestinal diseases. Urinary NGAL levels were measured in all patients within 24 h of admission and 72 h later. RESULTS: Urinary NGAL levels were higher in patients with acute pancreatitis and acute cholangitis/cholecystitis than in those with other diseases. Although lower than in these diseases, urinary NGAL tends to be higher in inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, as well as in acute and chronic liver diseases, and is higher in liver cirrhosis as the Child-Pugh grade increases. Furthermore, we found that the group with higher urinary NGAL levels, which continued to increase over time, had worse hospital stays and prognosis. CONCLUSION: Urinary NGAL could be used as an indicator of infectious diseases rather than an indicator of AKI in inflammatory bowel diseases and cirrhosis, and could predict the prognosis of patients with gastrointestinal diseases.

DOI： 10.1002/jgh3.70009

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Herein, we describe a case of olmesartan-associated sprue-like enteropathy, in which improvement in villous atrophy was confirmed using small bowel capsule endoscopy. The patient was a 69-year-old woman who had persistent watery diarrhea (20 bowel movements/day) for 1 year and experienced a weight loss of 10 kg in the same period. Abdominal computed tomography revealed no abnormalities, and blood test results revealed no inflammatory reactions. Upper endoscopy and colonoscopy revealed villous atrophy in the duodenum and terminal ileum. As the patient was administered olmesartan for a long time and capsule endoscopy showed villous atrophy throughout the small bowel, she was diagnosed with olmesartan-associated sprue-like disease. Following the discontinuation of the medication, symptoms of diarrhea soon improved, and repeat capsule endoscopy indicated improvement in small intestinal villous atrophy. Olmesartan-associated sprue-like enteropathy should be considered a differential diagnosis in patients with severe chronic watery diarrhea. Our report is the first in which capsule endoscopy was performed multiple times over a long period for follow-up observation of improvements in the small intestine. In addition, our literature review regarding capsule endoscopy for olmesartan-associated enteritis might aid clinicians in the early diagnosis of the condition and the assessment of treatment efficacy.

DOI： 10.1007/s12328-024-02023-9

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DOI： 10.1002/tee.24070

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12072-024-10707-0

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Other Link： https://link.springer.com/article/10.1007/s12072-024-10707-0/fulltext.html

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Chronic liver injury leads to decreased liver function and increased fibrosis. Fibrosis is not only associated with the development of portal hypertension and carcinogenesis, but with the occurrence of events and a poor prognosis, highlighting the importance of non-invasive fibrosis assessment in patients. In the present study, we searched for markers related to liver fibrosis via proteomic analysis of small extracellular vesicles (sEVs). In the discovery cohort, proteomic analysis was carried out in the sEVs extracted from the sera of 5 patients with decompensated cirrhosis, 5 patients with compensated cirrhosis, and 5 controls without liver disease. Interestingly, in this cohort, fibulin-4 was significantly associated with cirrhosis while in the validation cohort [formed by 191 patients: 7 patients without disease, 16 patients without liver disease (other diseases), 38 patients with chronic liver disease (CLD), 75 patients with cirrhosis of Child-Pugh class A (36 without hepatocellular carcinoma [HCC], 29 with HCC), and 65 patients with cirrhosis of Child-Pugh class B-C (39 without HCC, 26 with HCC)], fibulin-4/CD9 levels increased with cirrhosis progression. Furthermore, the fibulin-4/CD9 ratio was significantly higher in patients with varices. Immunostaining also revealed strong fibulin-4 expression in cholangiocytes within the fibrous areas and mesothelial cells in liver tissue blood vessels. Taken together, our results suggest that fibulin-4, essential for lysyl oxidase activation, might be a new liver fibrosis marker found in the sEVs of patients with cirrhosis.

DOI： 10.1002/2211-5463.13842

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Language：Japanese   Publisher：(株)癌と化学療法社  

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INTRODUCTION: Cirrhosis remains a significant clinical challenge due to its poor prognosis and limited treatment options, creating a high unmet medical need for the development of novel therapies. In this study, we analyzed the effects of a novel approach to treat cirrhosis using platelet-rich plasma-derived extracellular vesicles (PRPEV) in mice. METHODS: PRPEV were collected from platelet-rich plasma using ultrafiltration, and their proteomes were analyzed. The carbon tetrachloride (CCl4)-induced cirrhosis model of mice was used to evaluate the effect of PRPEV administration and compared with the control group (n = 8). In vitro and in vivo mechanistic analyses of PRPEV administration were confirmed using real time-PCR and immunostaining. RESULTS: Gene ontology analysis based on the proteome revealed that PRPEV contain many factors associated with EV and immune responses. In vitro, PRPEV polarize macrophages into an anti-inflammatory phenotype. Following PRPEV administration, there was a decrease in serum alanine aminotransferase levels and reduction in liver fibrosis, while mRNA levels of regenerative factors were upregulated and transforming growth factor β-1 was downregulated. Furthermore, the number of anti-inflammatory macrophages in the liver increased. CONCLUSIONS: PRPEV may contribute to hepatocyte proliferation, anti-inflammation, and anti-fibrogenesis in the liver. This novel concept paves the way for cirrhosis treatment.

DOI： 10.1016/j.reth.2024.10.010

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Language：Japanese   Publisher：(株)癌と化学療法社  

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BACKGROUND: Symptom scales for achalasia after per-oral endoscopic myotomy (POEM) are lacking. This study aimed to propose a new scale based on the conventional Eckardt score (c-ES) and evaluate persistent symptoms that impair patients' quality of life (QOL) post-POEM. METHODS: Dysphagia, regurgitation, and chest pain frequencies were assessed using a 6-point scale modified-ES (m-ES) after POEM, with "occasional" symptoms on the c-ES further subdivided into three-period categories on m-ES. Symptom severity was further evaluated using a 5-point scale ranging from 1 to 5 points, with a score ≥ 3 points defined as persistent symptoms impairing QOL. We analyzed the correlation between the m-ES and severity score, diagnostic performance of the m-ES for persistent symptoms, and overlaps between each residual symptom. RESULTS: Overall, 536 patients (median follow-up period, 2.9 years) post-POEM were included in this multicenter study. Significant correlations were observed between the m-ES and severity scores for dysphagia (r = 0.67, p < 0.01), regurgitation (r = 0.73, p < 0.01), and chest pain (r = 0.85, p < 0.01). Twenty-six patients (4.9%) had persistent symptoms post-POEM, and 23 of them had m-ES-specific symptom frequency ≥ once a month, which was determined as the optimal frequency threshold for screening persistent symptoms. The total m-ES predicted persistent symptoms more accurately than the total c-ES (area under the curve: 0.95 vs. 0.79, p < 0.01). Furthermore, dysphagia and chest pain were the major residual symptoms post-POEM covering 91.4% of regurgitation. CONCLUSIONS: The new post-POEM scale successfully evaluated the QOL-based patient symptom severities. Our study implied the possibility of a simpler scale using residual dysphagia and chest pain.

DOI： 10.1007/s00535-024-02119-6

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

DOI： 10.3390/ijms25105454

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：日本消化器病学会-甲信越支部  

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Several cases of esophageal stenosis caused by cervical vertebral osteophytes have been reported; however, few reports of esophageal stenosis caused by thoracic osteophytes are available. We describe the case of an 86-year-old man with esophageal stenosis caused by a thoracic osteophyte near the tracheal bifurcation. An endoscopic ultrasonography examination was scheduled to determine the cause of acute pancreatitis; however, lacerations observed at the bifurcation following endoscope removal during prior esophagogastroduodenoscopy led us to cancel the ultrasonography to avoid potential esophageal perforation. A review of the present case and six similar previous cases of thoracic osteophyte-associated esophageal stenosis (identified via a systematic search of the PubMed database) demonstrated the clinical importance of a thoracic osteophyte near physiological esophageal stenosis. Esophagogastroduodenoscopy and computed tomography should be performed to screen for vertebral osteophytes before endoscopic ultrasonography, endoscopic retrograde cholangiopancreatography, and transesophageal echocardiography to avoid iatrogenic accidents.

DOI： 10.1002/deo2.260

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：医学図書出版(株)  

われわれは,これまで臓器選択的なハイドロダイナミック遺伝子導入法(hydrodynamic gene delivery:HGD)の研究を行ってきた。本稿では,この方法論を用いた膵臓選択的なヒト膵発癌関連遺伝子導入による,野生型ラット由来の膵癌モデル動物の作製について総説する。変異型KRASG12D遺伝子を導入した個体は,HGD後4週間で主膵管内に膵管内上皮腫瘍性病変(pancreatic intra-epithelial neoplasia:PanIN)が発生し,また腺房-導管異形成(acinar-to-ductal metaplasia:ADM)を認めた。発癌性を高めた条件下では,5週時点でADMの範囲拡大とそれに連続する腺癌および著明な間質増生を認め,浸潤性膵癌へと発展し肝臓,リンパ節,皮下への転移をも認めた。野生型ラットを対象とする臓器選択的な遺伝子導入によりラット膵癌モデルが確立できた。その簡便性と再現性から,本モデルを活用する分子生物学的解析の進歩が早期診断法,新規治療法の開発に寄与すると考える。(著者抄録)

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Language：Japanese   Publisher：(一社)日本内科学会  

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Diversion colitis (DC) is characterized by mucosal inflammation in the defunctioned segment of the colon following a colostomy or ileostomy. The major causes of DC are an increase in the number of aerobic bacteria, a lack of short-chain fatty acids (SCFAs), and immune disorders in the diverted colon. However, its exact pathogenesis remains unknown. Various treatment strategies for DC have been explored, although none have been definitively established. Treatment approaches such as SCFAs, 5-aminosalicylic acid enemas, steroid enemas, and irrigation with fibers have been attempted, yielding various degrees of efficacies in mitigating mucosal inflammation. However, only individual case reports demonstrating the limited effect of the following therapies have been published: leukocytapheresis, dextrose (hypertonic glucose) spray, infliximab, an elemental diet, and coconut oil. The usefulness of probiotics for treating DC has recently been reported. Furthermore, fecal microbiota transplantation (FMT) has emerged as a promising treatment for DC. This review provides an update on the treatment strategies of DC, with a particular focus on FMT and its relationship with the intestinal microbiota. FMT may become the first choice of treatment for some patients in the future because of its low medical costs, ease of use, and minimal side effects. Furthermore, FMT can also be used for postoperative DC prophylaxis.

DOI： 10.12938/bmfh.2024-014

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

Herein, we report a case of a man with a large symptomatic hepatic cyst that gradually enlarged over a follow-up period of 15 years, which eventually caused epigastric fullness and obstructive jaundice. The patient underwent percutaneous cystic drainage followed by sclerotherapy using minocycline hydrochloride combined with intracystic lavage. The treatment resulted in a significant reduction in the hepatic cyst size, symptom improvement, and absence of recurrence for 670 days.

DOI： 10.11405/nisshoshi.121.769

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DOI： 10.1242/dmm.050622

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Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor that typically affects young women in the body and tail of the pancreas. SPN is often asymptomatic in the early stages, so it is initially discovered as a large tumor. In this report, we experienced a case of a relatively small SPN discovered in the setting of acute pancreatitis. Because there have been few reports of SPN being discovered in the situation like our case, we report this case based on a review of the literature.

DOI： 10.1007/s12328-023-01850-6

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Language：Japanese   Publisher：(一財)日本消化器病学会  

肝硬変は多くの場合は,肝障害とそれに引き続く線維化にともなって形成される.そして線維化にともなう門脈圧亢進と肝機能低下からさまざまな症状を引きおこす.本邦では患者数が40万人いる疾患であるが,線維化改善薬が承認されていない現状がある.われわれは,内在の線維化改善・肝再生誘導システムを導き出すことに主眼を置き,線維化改善・再生促進療法の開発に間葉系幹細胞やその細胞外小胞,そしてペプチド製剤を用いて挑んでいる.本稿ではわれわれが進めてきた肝硬変への線維化改善・再生促進療法を目指した,基礎研究から治験までの流れを概説していきたい.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01118&link_issn=&doc_id=20231218410003&doc_link_id=%2Fck8syokb%2F2023%2F012012%2F003%2F0973-0979%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fck8syokb%2F2023%2F012012%2F003%2F0973-0979%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：梵天書房  

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Language：Japanese   Publisher：梵天書房  

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Language：Japanese   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：日本小腸学会  

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Language：Japanese   Publisher：日本小腸学会  

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

OBJECTIVES: High-resolution manometry (HRM) and esophagography are used for achalasia diagnosis; however, achalasia phenotypes combining esophageal motility and morphology are unknown. Moreover, predicting treatment outcomes of per-oral endoscopic myotomy (POEM) in treatment-naïve patients remains an unmet need. METHODS: In this multicenter cohort study, we included 1,824 treatment-naïve patients diagnosed with achalasia. In total, 1,778 patients underwent POEM. Clustering by machine learning (ML) was conducted to identify achalasia phenotypes using patients' demographic data, including age, sex, disease duration, body mass index, and HRM/esophagography findings. ML models were developed to predict persistent symptoms (Eckardt score ≥3) and reflux esophagitis (RE) (Los Angeles grades A to D) after POEM. RESULTS: ML identified three achalasia phenotypes: phenotype 1, type I achalasia with a dilated esophagus (n=676; 37.0%); phenotype 2, type II achalasia with a dilated esophagus (n=203; 11.1%); phenotype 3, late-onset type I-III achalasia with a non-dilated esophagus (n=619, 33.9%). Types I and II achalasia in phenotypes 1 and 2 exhibited different clinical characteristics from those in phenotype 3, implying different pathophysiologies within the same HRM diagnosis. A predictive model for persistent symptoms exhibited an area under the curve (AUC) of 0.70. Pre-POEM Eckardt score ≥6 was the greatest contributing factor for persistent symptoms. The AUC for post-POEM RE was 0.61. CONCLUSION: Achalasia phenotypes combining esophageal motility and morphology indicated multiple disease pathophysiologies. ML helped develop an optimal risk stratification model for persistent symptoms with novel insights into treatment resistance factors.

DOI： 10.1111/den.14714

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INTRODUCTION: Rapid antigen testing (RAT) results are visually read as whether colored line is present or absent. The subjective interpretation potentially misses detecting weak lines due to lower analyte concentration in samples tested, requiring training. Although routine test experience has improved the result readout skills, it consumes time and resources. Therefore, we created a computer-based feedback training method using open-source experimental psychology software, wherein participants accumulate RAT result readout experience by repeatedly responding positive/negative to randomly presented pictures showing RAT results; then, they receive feedback on their answers as correct or incorrect and are asked to stare at the pictures again with the knowledge of correct answer. This study aimed to examine the training effects in improving the skills, using coronavirus disease 2019 (COVID-19) RAT. METHODS: Twenty-two medical technologists were randomly divided into two groups: the feedback-training and test-experience groups. Using several pictures showing positive and negative results of COVID-19 RAT, after examination of their initial result readout skills, feedback-training group received the feedback training, whereas test-experience group performed an equal number of tests without feedback to accumulate test experience, and their skills were examined again. The ratio of "positive" answers to the pictures showing positive results (i.e., hit rate) was statistically analyzed. RESULTS: The feedback-training group showed a significantly higher hit rate after their training, whereas the test-experience group did not. The feedback training effects were manifested in weak line detection. CONCLUSIONS: This computer-based feedback training method can be an effective tool for improving RAT result readout skills.

DOI： 10.1016/j.jiac.2023.10.019

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BACKGROUND: Insulin-like growth factor-1 (IGF-1) is involved in the pathology of non-alcoholic fatty liver disease (NAFLD) and ameliorates fatty infiltration in the liver. It is activated by growth hormone (GH); however, the role of GH-IGF-1 axis in NAFLD developmental phase has not been well identified. Therefore, in this study, we focused on the effect of IGF-1 in NAFLD pathology and GH excretion activation from the pituitary gland by peripheral autonomic neural pathways relaying liver-brain-gut pathway and by central neuropeptides. METHODS: GH and IGF-1 levels were assessed in wild-type and melanocortin-4 receptor knockout mice upon the development of diet-induced NAFLD. The contribution of the peripheral autonomic nervous system connecting the liver-brain-gut axis was assessed by its blockade using capsaicin and that of the central nervous system was assessed by the expression of hypothalamic brain-derived neurotrophic factor (BDNF) and corticotropin-releasing factor (CRH), which activates GH release from the pituitary gland. RESULTS: In the NAFLD mouse models, the levels of GH and IGF-1 increased (p < .05). Further, hepatic fatty infiltration was suppressed even under peripheral autonomic nervous system blockade (p < .001), which inhibited gastric ghrelin expression. In mice with peripheral autonomic nervous blockade, hypothalamic BDNF and CRH were inhibited (p < .05), resulting in GH and IGF-1 excretion, whereas other neuropeptides of somatostatin and cortistatin showed no changes. These complementary effects were canceled in melanocortin-4 receptor knockout mice, which diminished BDNF and CRH release control. CONCLUSIONS: Our study demonstrates that the release of IGF-1 by the nervous system is a key factor in maintaining the pathological homeostasis of NAFLD, suggesting its therapeutic potential.

DOI： 10.1007/s12072-023-10601-1

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BACKGROUND: The progression of liver fibrosis leads to portal hypertension and liver dysfunction. However, no antifibrotic agents have been approved for cirrhosis to date, making them an unmet medical need. Small extracellular vesicles (sEVs) of mesenchymal stem cells (MSCs) are among these candidate agents. In this study, we investigated the effects of sEVs of MSCs, analyzed their distribution in the liver post-administration, whether their effect was dose-dependent, and whether it was possible to collect a large number of sEVs. METHODS: sEVs expressing tdTomato were generated, and their uptake into constituent liver cells was observed in vitro, as well as their sites of uptake and cells in the liver using a mouse model of liver cirrhosis. The efficiency of sEV collection using tangential flow filtration (TFF) and changes in the therapeutic effects of sEVs in a volume-dependent manner were examined. RESULTS: The sEVs of MSCs accumulated mostly in macrophages in damaged areas of the liver. In addition, the therapeutic effect of sEVs was not necessarily dose-dependent, and it reached a plateau when the dosage exceeded a certain level. Furthermore, although ultracentrifugation was commonly used to collect sEVs for research purposes, we verified that TFF could be used for efficient sEV collection and that their effectiveness is not reduced. CONCLUSION: In this study, we identified some unknown aspects regarding the dynamics, collection, and capacity dependence of sEVs. Our results provide important fundamentals for the development of therapies using sEVs and hold potential implications for the therapeutic applications of sEV-based therapies for liver cirrhosis.

DOI： 10.1186/s41232-023-00299-x

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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

BACKGROUND: The development of effective therapies and biomarkers for pancreatic cancer is an unmet clinical need. To address this, we have developed an easy-to-use pancreatic cancer rat animal model via pancreas-targeted hydrodynamic gene delivery of human pancreatic cancer-related genes. Our study aimed to determine the molecular similarity between the pancreatic tumor in the rat model and human pancreatic cancer. METHODS: KRASG12D gene-expressing plasmid was delivered to the pancreas of wild type rats via pancreas-targeted hydrodynamic gene delivery as previously reported. Tissue samples were collected at 5 weeks after the first gene delivery. The tumors developed in the rats were assessed for the expression of oncogenic proteins that are involved in human pancreatic cancer development. RESULTS: The development of a tumor mimicking pancreatic ductal adenocarcinoma was confirmed. The expression levels of Cyclin D1, c-Jun, IL-33, and Zip4 proteins in the tumor were immunohistochemically assessed and the correlation of the proteins was confirmed. The expression pattern showed similarity to that of surgically resected human pancreatic cancer tissues. CONCLUSIONS: Our study findings showing a similar pattern of oncogenic protein expression in novel KRASG12D gene-induced rat pancreatic cancer model and human pancreatic cancer will be useful for establishing novel tumor markers and therapeutic options for pancreatic cancer.

DOI： 10.1016/j.bbrc.2023.06.057

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AIMS: Ursodeoxycholic acid is the first-line treatment for primary biliary cholangitis, and treatment response is one of the factors predicting the outcome. To prescribe alternative therapies, clinicians might need additional information before deciphering the treatment response to ursodeoxycholic acid, contributing to a better patient prognosis. In this study, we developed and validated machine learning (ML) algorithms to predict treatment responses using pretreatment data. METHODS: This multicenter cohort study included collecting datasets from two data samples. Data 1 included 245 patients from 18 hospitals for ML development, and was divided into (i) training and (ii) development sets. Data 2 (iii: test set) included 51 patients from our hospital for validation. An extreme gradient boosted tree predicted the treatment response in the ML model. The area under the curve was used to evaluate the efficacy of the algorithm. RESULTS: Data 1 showed that patients complying with the Paris II treatment response had significantly lower serum alkaline phosphatase and total bilirubin levels than those who did not respond. Three factors, total bilirubin, total protein, and alanine aminotransferase levels were selected as essential variables for prediction. Data 2 showed that patients complying with the Paris II criteria had significantly high prothrombin time and low total bilirubin levels. The area under the curve of extreme gradient boosted tree was good for (ii) (0.811) and (iii) (0.856). CONCLUSIONS: We demonstrated the efficacy of ML in predicting the treatment response for patients with primary biliary cholangitis. Early identification of cases requiring additional treatment with our novel ML model may improve prognosis.

DOI： 10.1111/hepr.13966

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

骨格筋は運動機能に関わる運動器としてだけでなく,さまざまなホルモン様の生理活性物質を分泌する内分泌臓器としての役割も果たしている.肝における代謝を考える場合に,臓器間ネットワークの視点から肝の代謝をとらえることはきわめて重要で,糖・脂質代謝には,肝,脂肪組織(内臓・皮下),筋肉(骨格筋)のネットワークのなかでとらえていく必要がある.2022年10月より日本肝臓学会の社会保険委員会にて肝臓リハビリテーションワーキンググループが作られ,その指針が2023年4月に公開された.サルコペニアにともなう,肝臓疾患における身体的・精神的影響を軽減させ,症状を調整し,生命予後を改善するため,今後この分野は肝臓分野のなかでも注視される領域である.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01118&link_issn=&doc_id=20230921450001&doc_link_id=%2Fck8syokb%2F2023%2F012009%2F001%2F0701-0708%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fck8syokb%2F2023%2F012009%2F001%2F0701-0708%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)癌と化学療法社  

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Conventional drug discovery involves significant steps, time, and expenses; therefore, novel methods for drug discovery remain unmet, particularly for patients with intractable diseases. For this purpose, the drug repurposing method has been recently used to search for new therapeutic agents. Repurposed drugs are mostly previously approved drugs, which were carefully tested for their efficacy for other diseases and had their safety for the human body confirmed following careful pre-clinical trials, clinical trials, and post-marketing surveillance. Therefore, using these approved drugs for other diseases that cannot be treated using conventional therapeutic methods could save time and economic costs for testing their clinical applicability. In this review, we have summarized the methods for identifying repurposable drugs focusing on immunotherapy.

DOI： 10.3390/pharmaceutics15092190

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Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞肝硬変症に対する,抗線維化・再生誘導薬の治験の開発が進んできた.肝臓は他臓器と違い再生力をもつことが特徴である.一つの大きな治療コンセプトとして,肝硬変になった肝臓に対して線維化を改善し,いかに内在の肝臓再生力を誘導するかが重要である.また肝臓領域においては,臨床現場において各種,肝線維化評価の方法も開発されてきた.今後,開発される各種薬剤のmode of actionを理解しながら,適切な治験の実施が求められる.そのなかで,肝硬変のどの病態に対してどのような治療を開発していくかが重要である.

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Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞肝硬変症に対する,抗線維化・再生誘導薬の治験の開発が進んできた.肝臓は他臓器と違い再生力をもつことが特徴である.一つの大きな治療コンセプトとして,肝硬変になった肝臓に対して線維化を改善し,いかに内在の肝臓再生力を誘導するかが重要である.また肝臓領域においては,臨床現場において各種,肝線維化評価の方法も開発されてきた.今後,開発される各種薬剤のmode of actionを理解しながら,適切な治験の実施が求められる.そのなかで,肝硬変のどの病態に対してどのような治療を開発していくかが重要である.

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DOI： 10.1242/dmm.050367

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Language：Japanese   Publisher：日本DDS学会  

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

INTRODUCTION: B-cell lymphoma/leukemia 11B (BCL11B) is a subunit of SWI/SNF chromatin remodeling complexes and functions in cell cycle regulation and apoptosis upon DNA replication stress and damages via transcription. Many malignancies were reported to exhibit changes in BCL11B gene expression; however, no study has focused on the relationship between BCL11B and hepatocellular carcinoma, which potentially exhibits DNA replication stress and damages upon its oncogenesis. Thus, in this study, we examined the molecular characterization of BCL11B expression in hepatocellular carcinoma. METHODS AND RESULTS: The cumulative progression-free survival and overall survival were significantly longer in the clinical cases of BCL11B-negative hepatocellular carcinoma than BCL11B-positve cases. Microarray and real-time PCR analyses in hepatocellular carcinoma cell lines indicated a correlation between BCL11B and GATA6, a gene reported to be correlated with oncogenic activities and resistance to anthracycline, which is often used for hepatocellular carcinoma chemotherapy. Consequently, BCL11B-overexpressing cell lines exhibited resistance to anthracycline in cell growth assays and the resistance has been evidenced by the increased expression of BCL-xL in cell lines. The results were supported by the analyses of human HCC samples showing the correlation between BCL11B and GATA6 expressions. DISCUSSIONS AND CONCLUSION: Our results indicated that overexpression of BCL11B amplifies GATA6 expression in hepatocellular carcinoma in vitro and in vivo that leads to anti-apoptotic signal activation, and induces resistance to chemotherapy, which influenced the postoperative prognosis.

DOI： 10.1002/cam4.6167

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We found an extremely rare case of PVG after a barium swallow examination. This may be related to vulnerable intestinal mucosa in the patient undergoing prednisolone treatment. Conservative therapy should be considered for patients with PVG without bowel ischemia or perforation. Caution should be exercised during barium examination undergoing prednisolone treatment.

DOI： 10.1002/ccr3.7480

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Language：Japanese   Publisher：日本DDS学会  

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Language：Japanese   Publisher：新潟医学会  

重症胆道感染症から敗血症性ショックに至った症例に対してエンドトキシン吸着療法(polymyxin-direct hemoperfusion:PMX-DHP)を行い,急性期から脱却後に手術を施行し得た2例を経験したので報告する.症例1は79歳の男性で,発熱と呼吸困難を主訴に救急外来を受診した.呼吸数36回/分,経皮的動脈血酸素飽和度81%(room air),心拍数71回/分,血圧85/61mmHgとショック状態であった.腹部造影CT検査で胆嚢結石と総胆管の拡張を認め,総胆管結石による重症急性胆管炎と診断した.気管内挿管と急速輸液,ノルアドレナリンの持続静注を開始し,経皮経肝胆道ドレナージを行なったが,敗血症性ショックが遷延したためPMX-DHPを施行した.PMX-DHP開始後4時間程度で循環動態は安定し,ノルアドレナリンの投与を終了した.急性胆管炎発症から3病日目に人工呼吸器管理を終了し,15病日目に内視鏡下に総胆管結石を採石した.29病日目に自宅へ退院となった.発症から3ヵ月後に腹腔鏡下胆嚢摘出術を施行した.術後2年2ヵ月が経過した現在,胆道感染症の再発なく経過している.症例2は86歳の女性で,大動脈弁置換術後のため入院加療中であった.術後21病日目に発熱し,呼吸数34回/分,経皮的動脈血酸素飽和度96%(酸素8L/分投与下),心拍数125回/分,血圧85/41mmHgとショック状態となった.腹部造影CT検査で腫大した胆嚢と周囲の脂肪織濃度の上昇を認め,重症急性胆嚢炎と診断した.急速輸液,ノルアドレナリンの持続静注を開始し,経皮経肝胆嚢ドレナージを施行した.敗血症性ショックが遷延したためPMX-DHPを施行し,血圧は上昇傾向となった.急性胆嚢炎発症から3病日目にノルアドレナリンの投与を終了できた.46病日目にリハビリ目的に他院へ転院となった.発症から3ヵ月後に開腹下胆嚢摘出術を施行した.術後1年6ヵ月が経過した現在,胆道感染症の再発なく経過している.重症胆道感染症により循環動態が不安定な症例では,PMX-DHPは支持療法として治療選択肢の1つになり得る.(著者抄録)

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Language：Japanese   Publisher：新潟医学会  

重症胆道感染症から敗血症性ショックに至った症例に対してエンドトキシン吸着療法(polymyxin-direct hemoperfusion:PMX-DHP)を行い,急性期から脱却後に手術を施行し得た2例を経験したので報告する.症例1は79歳の男性で,発熱と呼吸困難を主訴に救急外来を受診した.呼吸数36回/分,経皮的動脈血酸素飽和度81%(room air),心拍数71回/分,血圧85/61mmHgとショック状態であった.腹部造影CT検査で胆嚢結石と総胆管の拡張を認め,総胆管結石による重症急性胆管炎と診断した.気管内挿管と急速輸液,ノルアドレナリンの持続静注を開始し,経皮経肝胆道ドレナージを行なったが,敗血症性ショックが遷延したためPMX-DHPを施行した.PMX-DHP開始後4時間程度で循環動態は安定し,ノルアドレナリンの投与を終了した.急性胆管炎発症から3病日目に人工呼吸器管理を終了し,15病日目に内視鏡下に総胆管結石を採石した.29病日目に自宅へ退院となった.発症から3ヵ月後に腹腔鏡下胆嚢摘出術を施行した.術後2年2ヵ月が経過した現在,胆道感染症の再発なく経過している.症例2は86歳の女性で,大動脈弁置換術後のため入院加療中であった.術後21病日目に発熱し,呼吸数34回/分,経皮的動脈血酸素飽和度96%(酸素8L/分投与下),心拍数125回/分,血圧85/41mmHgとショック状態となった.腹部造影CT検査で腫大した胆嚢と周囲の脂肪織濃度の上昇を認め,重症急性胆嚢炎と診断した.急速輸液,ノルアドレナリンの持続静注を開始し,経皮経肝胆嚢ドレナージを施行した.敗血症性ショックが遷延したためPMX-DHPを施行し,血圧は上昇傾向となった.急性胆嚢炎発症から3病日目にノルアドレナリンの投与を終了できた.46病日目にリハビリ目的に他院へ転院となった.発症から3ヵ月後に開腹下胆嚢摘出術を施行した.術後1年6ヵ月が経過した現在,胆道感染症の再発なく経過している.重症胆道感染症により循環動態が不安定な症例では,PMX-DHPは支持療法として治療選択肢の1つになり得る.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00990&link_issn=&doc_id=20240628120003&doc_link_id=%2Fdg3nigta%2F2023%2F013707%2F003%2F0243-0248%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2023%2F013707%2F003%2F0243-0248%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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

BACKGROUND AND AIM: Treatment response to ursodeoxycholic acid may predict the prognosis of patients with primary biliary cholangitis (PBC). Recent studies have suggested the benefits of using machine learning (ML) to forecast complex medical predictions. We aimed to predict treatment response in patients with PBC using ML and pretreatment data. METHODS: We conducted a single-center retrospective study and collected data from 194 patients with PBC who were followed up for at least 12 months after treatment initiation. Patient data were analyzed with five ML models, namely random forest, extreme gradient boosting (XGB), decision tree, naïve Bayes, or logistic regression, to predict treatment response using the Paris II criteria. The established models were assessed using an out-of-sample validation. The area under the curve (AUC) was used to evaluate the efficacy of each algorithm. Overall survival and liver-related deaths were analyzed using Kaplan-Meier analysis. RESULTS: Compared to logistic regression (AUC = 0.595, P = 0.0219, 0.031 models), ML analyses showed significantly high AUC in the random forest (AUC = 0.84) and XGB (AUC = 0.83) models; however, the AUC was not significantly high for decision tree (AUC = 0.633) or naïve Bayes (AUC = 0.584) models. Kaplan-Meier analysis showed significantly improved prognoses in patients predicted to achieve the Paris II criteria by XGB (log-rank = 0.005 and 0.007). CONCLUSION: ML algorithms could improve treatment response prediction using pretreatment data, which could lead to better prognoses. In addition, the ML model using XGB could predict the prognosis of patients before treatment initiation.

DOI： 10.1002/jgh3.12915

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Language：Japanese   Publisher：(一社)日本毒性学会  

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Language：Japanese   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：(一社)日本血栓止血学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：新潟県医師会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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

BACKGROUND & AIMS: Decompensated cirrhosis with fibrosis progression causes portal hypertension followed by an oedematous intestinal tract. These conditions weaken the barrier function against bacteria in the intestinal tract, a condition called leaky gut, resulting in invasion by bacteria and bacterial components. Here, we investigated the role of outer membrane vesicles (OMVs) of Escherichia coli which is the representative pathogenic gut-derived bacteria in patients with cirrhosis in the pathogenesis of cirrhosis. METHODS: We investigated the involvement of OMVs in humans using human serum and ascites samples and also investigated the involvement of OMVs from Escherichia coli in mice using mouse liver-derived cells and a mouse cirrhosis model. RESULTS: In vitro, OMVs induced inflammatory responses to macrophages and neutrophils, including the upregulation of C-type lectin domain family 4 member E (Clec4e), and induced the suppression of albumin production in hepatocytes but had a relatively little direct effect on hepatic stellate cells. In a mouse cirrhosis model, administration of OMVs led to increased liver inflammation, especially affecting the activation of macrophages, worsening fibrosis, and decreasing albumin production. Albumin administration weakened these inflammatory changes. In addition, multiple antibodies against bacterial components were increased with a progressing Child-Pugh grade, and OMVs were detected in ascites of patients with decompensated cirrhosis. CONCLUSIONS: In conclusion, OMVs induce inflammation, fibrosis and suppression of albumin production, affecting the pathogenesis of cirrhosis. We believe that our study paves the way for the future prevention and treatment of cirrhosis.

DOI： 10.1111/liv.15539

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

BACKGROUND: The mixing test is useful to investigate the cause of unexpectedly prolonged activated partial thromboplastin time (APTT). Several indexes are available for distinguishing correction from non-correction (ie, factor deficiency from inhibitors), but their performance characteristics may differ because of their different formulas. Furthermore, it is unclear how each index performs under the coexistence of factor deficiency and inhibitors. OBJECTIVES: The objective of this study was to examine the differences in indexes, depending on factor VIII activity (FVIII:C) levels and lupus anticoagulant (LA) titers in test samples. METHODS: APTT was measured in spiked samples with various FVIII:C levels and LA titers, normal pooled plasma (NPP), and their 4:1, 1:1, and 1:4 mixtures. The following 5 indexes were calculated: index of circulating anticoagulant, mixing test normalized ratio, 4:1 and 1:1 percent corrections, and an APTT difference between the 1:1 mixture and NPP. The samples with LA, showing correction, were measured for FVIII:C in a one-stage assay to check parallelism. RESULTS: All indexes showed correction under FVIII deficiency and non-correction under higher LA titers. However, under lower LA titers, some indexes showed non-correction but others showed correction because of dilution effects and variations in formulas and/or sample mix ratios. The differences among the indexes were more pronounced under coexistent FVIII deficiency and LA, even though LA titers were equal in the tested samples; samples with lower FVIII:C showed correction, whereas those with normal FVIII:C showed non-correction. The samples tested for FVIII:C showed non-parallelism. CONCLUSION: Each index had different performance characteristics to LA samples, which were pronounced under low FVIII:C levels in test samples.

DOI： 10.1016/j.rpth.2023.100065

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(株)日本臨床社  

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

The oral cavity is the second most colonized site of Helicobacter pylori after the stomach. This study aimed to compare the genetic relatedness between gastric and oral H. pylori in Japanese patients with early gastric cancer through multilocus sequence typing (MLST) analysis using eight housekeeping genes. Gastric biopsy specimens and oral samples were collected from 21 patients with a fecal antigen test positive for H. pylori. The number of H. pylori allelic profiles ranged from zero to eight since the yield of DNA was small even when the nested PCR was performed. MLST analysis revealed that only one patient had a matching oral and gastric H. pylori genotype, suggesting that different genotypes of H. pylori inhabit the oral cavity and gastric mucosa. The phylogenetic analysis showed that oral H. pylori in six patients was similar to gastric H. pylori, implying that the two strains are related but not of the same origin, and those strains may be infected on separate occasions. It is necessary to establish a culture method for oral H. pylori to elucidate whether the oral cavity acts as the source of gastric infection, as our analysis was based on a limited number of allele sequences.

DOI： 10.3390/ijms24032211

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

AIM: This study aimed to analyze the current trends of drug-induced liver-related adverse events in the Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases. METHODS: The characteristics of implicated drugs were investigated by analyzing big data on drug-induced liver-related adverse events over the past 20 years in FAERS, comparing drug rankings between the JADER and FAERS databases, and calculating rankings of drugs inducing liver-related adverse events using the Medical Dictionary for Regulatory Activities Terminology. RESULTS: In the 452,272 cases registered in FAERS from 1997 to 2019, warfarin, paracetamol, and adalimumab were the drugs most related to DILI. In the 38,919 cases registered in the JADER from 2004 to 2019, sorafenib, nivolumab, and herbal extracts were the drugs most related to DILI. No associations were found between the top 30 drugs in either of the two databases. Notably, the number of drug-induced liver-related adverse event reports and total adverse events has sharply increased in recent years. CONCLUSIONS: Although liver-related adverse events are largely caused by host immunity and other constitutional factors, differences in primary diseases, countries, and historical backgrounds lead to differences in the number of reports. Securing an appropriate database and a mechanism to collect real-time information on the frequency of adverse drug reactions is warranted. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13883

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

AIM: Acute-on-chronic liver failure (ACLF), a disease with poor prognosis, is reportedly caused by cellular senescence due to mitochondrial dysfunction. In this study, we described and analyzed the underlying mechanism of a novel approach for ACLF using ABT263/navitoclax (Navi) that selectively eliminates senescent cells. METHODS: Irradiation-induced senescent hepatocytes were used for in vitro evaluation of the effects of Navi on ACLF (n = 6 for each group). Lipopolysaccharide- and carbon tetrachloride-induced ACLF mouse model was used for in vivo evaluation of the effects of Navi administration compared with the control using one-way or two-way analysis of variance, followed by Student's t-test or Kruskal-Wallis test. The effects on the senescence-associated secretory phenotype (n = 8 for each group) and mitochondrial functions, including adenosine triphosphate concentration and membrane potential (n = 8 for each group), were investigated using real-time polymerase chain reaction, immunohistochemistry, and enzyme analysis. RESULTS: Navi eliminated irradiation-induced senescent hepatocytes in vitro, leading to non-senescent hepatocyte proliferation. Navi eliminated senescent cells in the liver in vivo, resulting in downregulation of mRNA expression of senescence-associated secretory phenotype factors, a decrease of liver enzymes, and upregulated proliferation of non-senescent cells in the liver. Regarding mitochondrial functional assessment in the liver, adenosine triphosphate concentration and membrane potential were upregulated after Navi administration in vitro and in vivo. CONCLUSIONS: Navi may ameliorate ACLF damage by eliminating senescent cells in the liver, downregulating senescence-associated secretory phenotype factors, and upregulating mitochondrial functions. We believe that this novel approach using Navi will pave the way for ACLF treatment.

DOI： 10.1111/hepr.13879

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Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.16066

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

DOI： 10.11405/nisshoshi.120.973

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.reth.2022.05.003

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Language：English   Publisher：日本消化器病学会-甲信越支部  

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

Background: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) accounts for 10%-20% of the total HCC numbers. Its clinical features include the occurrence in the younger generation, large tumors, and poor prognosis. The contribution of hepatitis B virus X (HBx) protein in hepatocytes during activation of various oncogenic pathways has been reported. We aimed to assess the possible association between HBx and Yes-associated protein (YAP) expression in the liver tissue and the clinical features of HBV-related HCC. Methods: The relationship between HBx and YAP expression was examined in vivo using HCC tumor and peritumor tissues (n = 55). The clinical information including tumor size, marker, and the prognosis was assessed with protein expressions. The in vitro gene expression analyses were conducted using HBx- and YAP-overexpressing HCC cell lines. Results: Among 19 cases of HBV-related, 17 cases of hepatitis C virus (HCV)-related, and 19 cases of nonviral-related HCC, the HBV-related tumor showed the largest size. The HBx-stained area in the tumor and peritumor tissue showed a significant correlation with tumor size and serum α-fetoprotein level. YAP expression was higher in HBV-related tumor tissue than in the peritumor tissue and HCV-related tumor. Additionally, HBx and YAP protein expressions are correlated and both expressions in the tumor contributed to the poor prognosis. An in vitro study demonstrated that HBx and YAP overexpression in the hepatocytes activate the various oncogenic signaling pathways. Conclusions: Our study demonstrated that YAP expression in the liver of HBV-infected patients might be the key factor in HBV-related HCC development and control of tumor-related features.

DOI： 10.1016/j.bbrep.2022.101352

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

Ulcerative colitis-associated neoplasia (UCAN) harbors unique genetic alterations and mutational tendencies. The clinical application of gene panel testing enables precision medicine by tailoring treatment to individual gene alterations. We hypothesized that gene panel testing may detect clinically important genetic alterations in UCAN, with potential usefulness for the diagnosis and treatment of UCAN. In the present study, gene panel testing was used to identify genetic alterations in UCAN, and the possibility of clinical utility of gene panel testing in UCAN was investigated. The present study included 15 patients with UCAN, and gene panel testing was performed to identify genetic alterations associated with diagnosis and treatment. Genetic alterations of UCAN were compared with those of 203 patients with sporadic colorectal cancer (CRC). APC and PTEN mutations were less frequent, while RNF43 frameshift or nonsense mutations were more frequent in UCAN compared with sporadic CRC. TP53 mutations were identified in 13/15 patients (87%) with UCAN. Notably, 4/15 patients (27%) with UCAN had no genetic alterations other than TP53 mutation, while this occurred in 1/203 patients (0.5%) with sporadic CRC (P<0.001). Microsatellite instability-high was identified in 2/15 patients (13%) with UCAN. Mutational signature 3, which is associated with homologous recombination deficiency, was detected in 14/15 patients (93%) with UCAN, and enriched in UCAN compared with sporadic CRC (P=0.030). In conclusion, gene panel testing can detect important genetic alterations that can be useful for diagnosis and treatment in UCAN, and may provide clinicians with important information for tailored treatment strategies.

DOI： 10.3892/ol.2022.13562

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：梵天書房  

アルコール性肝硬変症例67例(男性86.6%:年齢中央値65歳)を対象に、糖鎖欠損トランスフェリン(CDT)値とγ-GTP値と予後の関連について後方視的に検討した。経過観察期間は3年とした。Cox回帰分析の結果、%CDT値は単変量で有意な予後不良因子であったが多変量では抽出されず、γ-GTP高値が独立した予後不良因子であることが分かった。対象を%CDT値およびγ-GTP値ともに正常値であった12例(1群)、一方が高値であった34例(2群)、両方とも高値であった21例(3群)に分けて予後比較した。その結果、3年生存率は1群が100.0%で有意に予後良好であった。以上より、%CDTかγ-GTPの一方が高値であると予後不良に関連することが示された。

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

Acute pancreatitis is an uncommon occurrence in acute liver failure. Furthermore, such cases are rarely complicated by parenchymal hemorrhages. Herein, we report the case of a 69-year-old male patient with multiple pancreatic parenchymal hemorrhages concomitant with acute liver failure. The patient underwent conservative treatment for acute liver failure caused by hepatitis B virus infection. Plain computed tomography on the 30th day revealed two high-density mass lesions in the pancreatic body and tail, which were suspected to be multiple pancreatic parenchymal hemorrhages. Despite restarting gabexate mesylate, the patient died of multiple organ failure on the 49th day. The clinical information of the present case and our literature review of 61 similar cases in 43 case reports identified via a systematic keyword search of the PubMed database, which described acute pancreatitis concomitant with acute hepatitis and acute liver failure, will aid physicians in the diagnosis and treatment of this rare condition.

DOI： 10.1007/s12328-022-01738-x

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

AIM: Cell-free and concentrated ascites reinfusion therapy (CART) and large-volume paracentesis (LVP) with albumin infusion are useful for managing refractory ascites (RA). However, it remains unclear which therapy is more effective in patients with cirrhosis with RA. METHODS: From June 2018 to March 2022, 25 patients with RA treated with CART or LVP with albumin infusion were enrolled in this multicenter prospective observational study to investigate the number of abdominal paracenteses, albumin preparations used, and drainage volume during an 8-week observation period. RESULTS: Among all patients at entry (median age, 63 years; 52% men; 60% Child-Pugh B and 40% Child-Pugh C), 92% were treated with furosemide (median, 20 mg/day), 92% with spironolactone (25 mg/day), and all with tolvaptan (7.5 mg/day). Patients with RA had a poor health-related quality of life (HRQOL) and prominent ascites-related symptoms. Four of the 20 eligible patients were treated with CART, 11 with LVP with albumin infusion, and five with their combination. The median number of paracenteses, total drainage volume, and albumin infusions were 1.5, 7.4 L, and 0, respectively, in the CART group; 5.0, 22.0 L, and 5.0, respectively, in the LVP group; and 5.0, 30.0 L, and 5.0, respectively in their combination group. The treatment effects did not differ significantly among the three groups regarding weight loss, liver function, renal function, electrolytes, and HRQOL. However, patients treated with CART had fewer paracenteses and albumin infusions than those treated with LVP. CONCLUSIONS: CART and LVP have comparable therapeutic efficacy for RA in patients with cirrhosis.

DOI： 10.1111/hepr.13860

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Publishing type：Research paper (international conference proceedings)   Publisher：IEEE  

DOI： 10.1109/iciibms55689.2022.9971604

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/hepr.13848

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/hepr.13848

Language：Japanese   Publisher：(株)北隆館  

肝硬変に対しては,本来自らが持つ線維化改善能力を促進させる薬剤の開発が行われている。間葉系幹細胞もその中で注目されているものの一つで生体内で"指揮細胞"として働き,肝内の"実働細胞"であるマクロファージに影響し,マクロファージを抗炎症性に変化させ肝硬変の改善に影響を及ぼすことを明らかにしてきた。更に,間葉系幹細胞のエクソソームは非常に重要で特にIFNγで間葉系幹細胞を刺激後に得られるエクソソームは肝硬変マウスに高い治療効果を発揮した。今後間葉系幹細胞,そしてそのエクソソームを用いた治療は高い治療効果を求めて次のステージへと動き始めている。(著者抄録)

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：(一社)日本肥満学会  

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

BACKGROUND: To establish a treatment option for liver fibrosis, the possibility of the drug repurposing theory was investigated, with a focus on the off-target effects of active pharmaceutical ingredients. METHODS: First, several active pharmaceutical ingredients were screened for their effects on the gene expression in the hepatocytes using chimeric mice with humanized hepatocytes. As per the gene expression-based screening assay for 36 medications, we assessed the mechanism of the antifibrotic effect of letrozole, a third-generation aromatase inhibitor, in mouse models of liver fibrosis induced by carbon tetrachloride (CCl4) and a methionine choline-deficient (MCD) diet. We assessed liver histology, serum biochemical markers, and fibrosis-related gene and protein expressions in the hepatocytes. RESULTS: A gene expression-based screening assay revealed that letrozole had a modifying effect on fibrosis-related gene expression in the hepatocytes, including YAP, CTGF, TGF-β, and CYP26A1. Letrozole was administered to mouse models of CCl4- and MCD-induced liver fibrosis and it ameliorated the liver fibrosis. The mechanisms involved the inhibition of the Yap-Ctgf profibrotic pathway following a decrease in retinoic acid levels in the hepatocytes caused by suppression of the hepatic retinol dehydrogenase, Hsd17b13 and activation of the retinoic acid hydrogenase, Cyp26a1. CONCLUSIONS: Letrozole slowed the progression of liver fibrosis by inhibiting the Yap-Ctgf pathway. The mechanisms involved the modification of the Hsd17b13 and Cyp26a1 expressions led to the suppression of retinoic acid in the hepatocytes, which contributed to the activation of Yap-Ctgf pathway. Because of its off-target effect, letrozole could be repurposed for the treatment of liver fibrosis. The third-generation aromatase inhibitor letrozole ameliorated liver fibrosis by suppressing the Yap-Ctgf pathway by partially modifying the Hsd17b13 and Cyp26a1 expressions, which reduced the retinoic acid level in the hepatocytes. The gene expression analysis using chimeric mice with humanized liver revealed that the mechanisms are letrozole specific and, therefore, may be repurposed for the treatment of liver fibrosis.

DOI： 10.1007/s00535-022-01929-w

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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

AIM: Non-alcoholic steatohepatitis (NASH) with fibrosis eventually leads to cirrhosis and hepatocellular carcinoma. Thus, the development of therapies other than dietary restriction and exercise, particularly those that suppress steatosis and fibrosis of the liver and have a long-term beneficial effect, is necessary. We aimed to evaluate the therapeutic effects of the HMGB1 peptide synthesized from box A using the melanocortin-4 receptor-deficient (Mc4r-KO) NASH model mouse. METHODS: We performed short- and long-term administration of this peptide and evaluated the effects on steatosis, fibrosis, and carcinogenesis using Mc4r-KO mice. We also analyzed the direct effect of this peptide on macrophages and hepatic stellate cells in vitro and performed lipidomics and metabolomics techniques to evaluate the effect. RESULTS: Although this peptide did not show direct effects on macrophages and hepatic stellate cells in vitro, in the short-term administration model, we could confirm the reduction of liver damage, steatosis, and fibrosis progression. The results of lipidomics and metabolomics suggested that the peptide might ameliorate NASH by promoting lipolysis via the activation of fatty acid β-oxidation and improving insulin resistance. In the long-term administration model, this peptide prevented progression to cirrhosis but retained the steatosis state, that is, the peptide prevents the progression to "burnt-out NASH." This peptide inhibited carcinogenesis by about one-third. CONCLUSION: This HMGB1 peptide can reduce liver damage, improve fibrosis and steatosis, and inhibit carcinogenesis, suggesting that the peptide would be a new treatment candidate for NASH and can contribute to the long-term prognosis for patients with NASH.

DOI： 10.1111/hepr.13825

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

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic dysregulation and is linked with various cardiovascular complications, which often lead to poor prognostic outcomes. To develop a standard therapy for NAFLD and to urgently address its complications, the current study aimed to investigate the mechanisms of NAFLD-related heart disease and the therapeutic effects of drugs targeting various metabolic pathways. METHODS: To explore the mechanism of NAFLD-related heart disease, a medaka model of high-fat diet-induced NAFLD was utilized. The gross structural, histological, and inflammatory changes in the myocardium were evaluated in a time-dependent manner. In addition, the therapeutic effects of medicines used for NAFLD treatment including, selective peroxisome proliferator-activated receptor α modulator (SPPARMα, pemafibrate), sodium-glucose cotransporter 2 (SGLT2) inhibitor (tofogliflozin), and statin (pitavastatin), and their combinations on heart pathology were evaluated. To determine the mechanisms underlying the therapeutic effects, the expression of genes related to liver inflammation was assessed via whole transcriptome sequencing analysis. RESULTS: The fish with NAFLD-related heart injury presented with cardiomyocyte hypertrophy, which led to cardiac hypertrophy. This morphological change was caused by the infiltration of inflammatory cells, including macrophages and CD4- and CD8-positive lymphocytes, in the cardiac wall and the expression of transforming growth factor beta 1 in the cardiomyocytes. Further, the livers of the fish had upregulated expressions of senescence-associated secretory phenotype-related genes. Treatment with pemafibrate, tofogliflozin, and pitavastatin reduced these changes and, consequently, cardiomyopathy. CONCLUSION: Our results demonstrated that NAFLD-related heart disease was attributed to the senescence-associated secretory phenotype-induced inflammatory activity in the cardiac wall, which resulted in myocardial hypertrophy. Moreover, the effects of SPPARMα, SGLT2 inhibitor, and statin on NAFLD-related heart disease were evident in the medaka NAFLD model.

DOI： 10.1016/j.bbrc.2022.07.117

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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

Background and Aim: Symptoms of primary biliary cholangitis (PBC) frequently impair one's quality of life (QOL). Nonetheless, with improved treatment, the prognosis of PBC also improves. QOL plays an important role in patients with PBC. In this study, we aimed to reevaluate the transition of new symptom development in PBC and its predictive factors. Methods: This retrospective multicenter study enrolled 382 patients with PBC for symptom analysis. The impact of a newly developed symptom on PBC prognosis was investigated by Kaplan-Meier analysis with propensity score matching and logistic progression analysis. Results: The cumulative risk of developing a new symptom after 10 and 20 years of follow-up was 7.6 and 28.2%, and specifically that of pruritus, which was the most common symptom, was 6.7 and 23.3%, respectively. In Cox hazard risk analysis, serum Alb level (hazard ratio [HR], 1.097; 95% confidence interval [CI], 1.033-1.165; P = 0.002), the serum D-Bil level (HR, 6.262; 95% CI, 2.522-15.553, P < 0.001), and Paris II criteria (HR, 0.435; 95% CI, 0.183-1.036; P = 0.037) were significant independent predictors of a new symptom. Kaplan-Meier analysis showed that the overall survival and liver-related death were not significant between patients with and without a new symptom. Conclusion: The cumulative risk of new symptom development is roughly 30% 20 years after diagnosis and could be predicted by factors including serum albumin levels, serum D-Bil level, and Paris II criteria.

DOI： 10.1002/jgh3.12789

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本アルコール・アディクション医学会  

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

BACKGROUND: Following liver transplantation (LT), allograft liver failure can be developed by various causes and requires re-LT. Hence, this study aimed to clarify the characteristics and prognostic factors of patients with allograft liver failure awaiting deceased donor LT (DDLT) in Japan. METHODS: Of the 2686 DDLT candidates in Japan between 2007 and 2016, 192 adult patients listed for re-LT were retrospectively enrolled in this study. Factors associated with waitlist mortality were assessed using the Cox proportional hazards model. The transplant-free survival probabilities were evaluated using the Kaplan-Meier analysis and log-rank test. RESULTS: The median period from the previous LT to listing for re-LT was 1548 days (range, 4-8449 days). Primary sclerosing cholangitis (PSC), which was a primary indication, showed a higher listing probability for re-LT as compared with other primary etiologies. Recurrent liver disease was a leading cause of allograft failure and was more frequently observed in the primary indication of hepatitis C virus (HCV) infection and PSC in contrast with other etiologies. Multivariate analysis identified the following independent risk factors associated with waitlist mortality: age, Child-Turcotte-Pugh (CTP) score, mode for end-stage liver disease (MELD) score, alanine aminotransferase (ALT), and causes of allograft failure. CONCLUSIONS: Recurrent HCV and PSC were major causes of allograft liver failure in Japan. In addition to CTP and MELD scores, either serum ALT levels or causes of allograft failure should be considered as graft liver allocation measures.

DOI： 10.1007/s00535-022-01880-w

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Language：Japanese   Publisher：(株)総合医学社  

＜最近の動向とガイドライン＞●現在までに、C型肝炎に対する有効な治療薬が開発され、またB型肝炎に対して核酸アナログ製剤を中心にコントロールが良好な症例が増え、なお制圧に向け薬剤開発が進んでいる状況である。●一方、アルコールや生活習慣を背景とした肝硬変は増えてきており、肝移植以外の肝硬変に対する治療法の開発は喫緊の課題である。●本項では肝臓再生医療で2019～2021年に著された臨床論文を解説すると同時にその背景や、現在行われている将来の治療の基盤となる基礎研究についても一部述べる。(著者抄録)

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

大量の肝性腹水が腹腔内圧の上昇をもたらし、腹部コンパートメント症候群を発症している状況を腹水前後の膀胱内圧測定、腎静脈流速測定を中心に検討した。対象症例は穿刺前後の膀胱内圧測定、腎静脈の流速測定等が可能であった腹水合併肝硬変8例。穿刺前後の膀胱内圧、尿潜血反応、腎機能、腎静脈流速等を経時的に観察した。末期肝硬変患者が肝腎症候群へ移行する過程で腹水による腹腔内圧の上昇が腎うっ血を併発させ、レニン-アンギオテンシン-アルドステロン系の亢進に関係する可能性が示唆された。(著者抄録)

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Language：Japanese   Publisher：(NPO)日本高齢消化器病学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：医学図書出版(株)  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

大量の肝性腹水が腹腔内圧の上昇をもたらし、腹部コンパートメント症候群を発症している状況を腹水前後の膀胱内圧測定、腎静脈流速測定を中心に検討した。対象症例は穿刺前後の膀胱内圧測定、腎静脈の流速測定等が可能であった腹水合併肝硬変8例。穿刺前後の膀胱内圧、尿潜血反応、腎機能、腎静脈流速等を経時的に観察した。末期肝硬変患者が肝腎症候群へ移行する過程で腹水による腹腔内圧の上昇が腎うっ血を併発させ、レニン-アンギオテンシン-アルドステロン系の亢進に関係する可能性が示唆された。(著者抄録)

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

Serotonin (5-HT) is one of the key bioamines of nonalcoholic fatty liver disease (NAFLD). Its mechanism via autonomic neural signal pathways remains unexplained; hence, we evaluated the involvement of 5-HT and related-signaling pathways via autonomic nerves in NAFLD. Diet-induced NAFLD animal models were developed using wild-type and melanocortin 4 receptor knockout (MC4RKO) mice, and the effects of autonomic neural axis on NAFLD physiology, 5-HT and its receptors (Htrs), and lipid metabolism-related genes were assessed applying hepatic nerve blockade. Hepatic neural blockade retarded the progression of NAFLD by reducing 5-HT in the small intestine, hepatic Htr2a, and hepatic lipogenic genes expression, and HTR2A antagonist reproduced these effects. The effects were milder in MC4RKO, and brain 5-HT and Htr2c expression did not correlate with peripheral neural blockade. Our study demonstrates that the autonomic liver-gut neural axis is involved in the etiology of diet-induced NAFLD and that 5-HT and HTR2A are key factors, implying that the modulation of the axis and use of HTR2A antagonists are potentially novel therapeutic strategies for NAFLD treatment.

DOI： 10.1242/dmm.049612

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The dextran sodium sulfate (DSS)-induced colitis mouse model has been widely utilized for human colitis research. While its mechanism involves a response to double-strand deoxyribonucleic acid (DNA) damage, ataxia telangiectasia mutated (Atm)-checkpoint kinase 2 (Chk2) pathway activation related to such response remains unreported. Recently, we reported that cyclin D1-binding protein 1 (Ccndbp1) activates the pathway reflecting DNA damage in its knockout mice. Thus, this study aimed to examine the contribution of Ccndbp1 and the Atm-Chk2 pathway in DSS-induced colitis. We assessed the effect of DSS-induced colitis on colon length, disease activity index, and histological score and on the Atm-Chk2 pathway and the subsequent apoptosis in Ccndbp1-knockout mice. DSS-induced colitis showed distal colon-dominant Atm and Chk2 phosphorylation, increase in TdT-mediated dUTP-biotin nick end labeling and cleaved caspase 3-positive cells, and histological score increase, causing disease activity index elevation and colon length shortening. These changes were significantly ameliorated in Ccndbp1-knockout mice. In conclusion, Ccndbp1 contributed to Atm-Chk2 pathway activation in the DSS-induced colitis mouse model, causing inflammation and apoptosis of mucosal cells in the colon.

DOI： 10.3390/jcm11133674

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Melanocortin 4 receptor gene-knockout (MC4R-KO) mice are known to develop obesity with a high-fat diet. Meanwhile, daisaikoto, one of Kampo medicines, is a drug that is expected to have therapeutic effects on obesity. Here, we report the efficacy of daisaikoto in MC4R-KO mice. Eight-week-old MC4R-KO male mice (n = 12) were divided into three groups as follows: the SD group, which is fed with a standard diet; the HFD group, fed a high-fat diet; and the DSK group, fed with a high-fat diet containing 10% of daisaikoto. After the four-week observation period, mice in each group were sacrificed and samples were collected. The body weights at 12 weeks were significantly higher in the HFD group than in the other groups, indicating that daisaikoto significantly reduced body weight gain and fat deposition of the liver. The metabolome analysis indicated that degradation of triglycerides and fatty acid oxidation in the liver were enhanced by daisaikoto administration. In MC4R-KO mice, the cytoplasm and uncoupling protein 1 expression of brown adipose tissue was decreased; however, it was reversed in the DSK group. In conclusion, daisaikoto has potentially improved fatty liver and obesity, making it a useful therapeutic agent for obesity and fatty liver.

DOI： 10.1038/s41598-022-14371-y

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

This research developed an easy-to-use, reproducible pancreatic cancer animal model utilizing pancreas-targeted hydrodynamic gene delivery to deliver human pancreatic cancer-related genes to the pancreas of wild-type rats. KRAS G12D -induced pancreatic intraepithelial neoplasia lesions showed malignant transformation in the main pancreatic duct at 4 weeks and developed acinar-to-ductal metaplasia, which led to pancreatic ductal adenocarcinoma within 5 weeks, and the gene combination of KRAS G12D and YAP enhanced these effects. The repeat hydrodynamic gene delivery of KRAS G12D  + YAP combination at 4 weeks showed acinar-to-ductal metaplasia in all rats and pancreatic ductal adenocarcinoma in 80% of rats 1 week later. Metastatic tumors in the liver, lymph nodes, and subcutaneous lesions and nervous invasion were confirmed. KRAS G12D and YAP combined transfer contributes to the E- to N-cadherin switch in pancreatic ductal adenocarcinoma cells and to tumor metastases. This pancreatic cancer model will speed up pancreatic cancer research for novel treatments and biomarkers for early diagnosis.

DOI： 10.1016/j.omtn.2022.03.019

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Language：English   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：日本自律神経学会  

肝臓の様々な病態で,肝臓,脳,消化管が種々の因子を介して密接に連関することが明らかになりつつある.我々は,非アルコール性脂肪性肝疾患(NAFLD)でも肝-脳-腸が自律神経を介して連関することを明らかとしてきた.そこで,本稿では,肝疾患と自律神経の関連,これまでの我々の研究結果を紹介したい.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00586&link_issn=&doc_id=20220725290008&doc_link_id=10.32272%2Fans.59.2_208&url=https%3A%2F%2Fdoi.org%2F10.32272%2Fans.59.2_208&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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

The Intractable Hepato-Biliary Disease Study Group of Japan, sponsored by the Ministry of Health, Labor and Wealth, proposed in 2018 that patients with cirrhosis and a Child-Pugh score of 5-9 should be diagnosed as having acute-on-chronic liver failure (ACLF) when a deterioration of liver function ("serum bilirubin level of 5.0 mg/dl or more" and "prothrombin time value of 40% or less of the standardized values and/or international normalization rates of 1.5 or more") caused by severe liver damage develops within 28 days after an acute insult, including alcohol abuse, bacterial infection, gastrointestinal bleeding, and the exacerbation of underlying liver diseases. Disease severity can be classified into 4 grades depending on the extent of the deterioration in organ functions, including liver, kidney, cerebral, blood coagulation, circulatory and respiratory functions. The Study Group has since performed an annual nationwide survey of patients with ACLF diagnosed according to the proposed diagnostic criteria as well as those with disease conditions related to ACLF. A total of 501 patients, including 183 patients diagnosed as having ACLF, seen between 2017 and 2019 were enrolled, and univariate and multivariate analyses revealed that the proposed diagnostic criteria were useful for identifying cirrhotic patients with an unfavorable outcome following an acute insult. Consequently, the Study Group determined that the proposed diagnostic criteria should be used in both clinical practice and clinical research as formal diagnostic criteria.

DOI： 10.1111/hepr.13763

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Background/Aims: Patients with achalasia-related esophageal motility disorders (AEMDs) frequently present with dilated and sigmoid esophagus, and develop esophageal diverticulum (ED), although the prevalence and patients characteristics require further elucidation. Methods: We conducted a multicenter cohort study of 3707 patients with AEMDs from 14 facilities in Japan. Esophagography on 3682 patients were analyzed. Results: Straight (n = 2798), sigmoid (n = 684), and advanced sigmoid esophagus (n = 200) were diagnosed. Multivariate analysis revealed that long disease duration, advanced age, obesity, and type I achalasia correlate positively, whereas severe symptoms and integrated relaxation pressure correlate negatively with development of sigmoid esophagus. In contrast, Grade II dilation (3.5-6.0 cm) was the most common (52.9%), while grade III dilation (≥ 6 cm) was rare (5.0%). We found early onset, male, obesity, and type I achalasia correlated positively, while advanced age correlated negatively with esophageal dilation. Dilated and sigmoid esophagus were found mostly in types I and II achalasia, but typically not found in spastic disorders. The prevalence of ED was low (n = 63, 1.7%), and non-dilated esophagus and advanced age correlated with ED development. Patients with right-sided ED (n = 35) had a long disease duration (P = 0.005) with low integrated relaxation pressure values (P = 0.008) compared with patients with left-sided ED (n = 22). Patients with multiple EDs (n = 6) had lower symptom severity than patients with a single ED (P = 0.022). Conclusions: The etiologies of dilated esophagus, sigmoid esophagus, and ED are considered multifactorial and different. Early diagnosis and optimal treatment of AEMDs are necessary to prevent these conditions.

DOI： 10.5056/jnm21188

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

Regarding the prognosis of cases with advanced-stage hepatocellular carcinoma (HCC), a recent clinical study showed that the immune checkpoint inhibitors atezolizumab plus bevacizumab have superior efficacy to sorafenib. However, only a few reports have focused on their effects on extrahepatic metastases. We herein report a case of HCC in a 59-year-old man with intrahepatic lesions treated successfully by hepatic arterial chemoembolization, radiotherapy, and sorafenib; the extrahepatic lesion in the adrenal gland was treated by atezolizumab plus bevacizumab. The patient showed a tumor-free condition for one year. We have summarized the clinical course and reviewed the literature to underscore the efficacy of atezolizumab plus bevacizumab for treating extrahepatic lesions of HCC.

DOI： 10.2169/internalmedicine.9341-22

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(有)科学評論社  

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

Objectives: Diversion colitis (DC) is an inflammatory disorder caused by interruption of the fecal stream and subsequent nutrient deficiency from luminal bacteria. The utility of fecal microbiota transplantation (FMT) for DC was recently investigated; however, the precise pathogenesis of this condition remains unclear. This study aimed to evaluate the utility of autologous FMT in DC and to determine the related changes in the intestinal microbiota. Methods: Autologous FMT was performed to reestablish the intestinal microbiota in five patients (average age, 64.6 ± 8.3 years) with DC. They underwent double-ended colostomy. We assessed the diverted colon by endoscopy and evaluated the microbiota before and after FMT using the 16S rRNA gene sequencing method. Results: All five patients had mild inflammation (ulcerative colitis endoscopic index of severity [UCEIS] 2-3) in the diverted colon based on the colonoscopic findings. Three patients presented with symptoms, such as tenesmus, mucoid stool, and bloody stool. With FMT treatment, all patients achieved endoscopic remission (UCEIS score of 0 or 1) and symptomatic improvement. We observed a significantly decreased α-diversity in DC patients compared to healthy controls. The frequency of aerobic bacteria, such as Enterobacteriaceae, in the diverted colon decreased after autologous FMT. Conclusions: This study was the first to show that the microbiota in the diverted colon was significantly affected by autologous FMT. Since interruption of the fecal stream is central to the development of DC, FMT can be considered a promising treatment.

DOI： 10.1002/deo2.63

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Gastrointestinal duplications are congenital malformations that are usually observed in pediatric patients. Diagnosis in adulthood is quite rare, and preoperative diagnosis of gastrointestinal duplication is difficult, particularly in the small intestine. We encountered an extremely rare adult case of duplication of the jejunum, which showed a stomach-like form diagnosed using double-balloon enteroscopy (DBE). The patient was an 18-year-old male who had been experiencing upper abdominal pain and vomiting repeatedly without any triggers for 3 years. Various examinations were performed, but no cause of symptoms was found. DBE revealed a narrow opening of the lumen at the upper jejunum, and the lumen was covered with mucosal folds similar to those of the stomach. Enteroclysis via DBE showed a tubular structure on the mesenteric side of the jejunum. We diagnosed a jejunal tubular duplication with ectopic gastric mucosa and underwent partial small bowel resection. The patient's abdominal symptoms resolved. From this, DBE can be a useful tool for diagnosing intestinal duplication in adults. We believe that this case and literature review will facilitate the accurate and prompt diagnosis of small intestinal duplication.

DOI： 10.1007/s12328-022-01596-7

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A 64-year-old woman was receiving oral methotrexate (MTX) for rheumatoid arthritis (RA) for 15 years. She underwent esophagogastroduodenoscopy because of discomfort in the chest. Endoscopic findings revealed an ulcer in the lower esophagus extending to the gastroesophageal junction (EGJ). The ulcer occupied half of the esophageal lumen and had a sharp and clear margin. Magnifying narrow-band imaging endoscopy revealed the deposition of white plaque, and there were few microvessels in the edge and bottom of the ulcer. Histologic examination of the biopsy specimens from the oral edge of the lesion revealed proliferation of atypical lymphoid cells (immunophenotype results: CD20 [+], CD3 [partially +], CD5 [-], and BCL-2 [-]]. The patient was diagnosed with methotrexate-associated lymphoproliferative disorder (MTX-LPD) and was advised to stop MTX intake. After 2 months of stopping MTX, the ulcer was found to be almost regressed and showed signs of healing. MTX-LPD in the lower esophagus extending to the EGJ is extremely rare. This case can help in expanding the understanding of esophageal MTX-LPD.

DOI： 10.1002/deo2.14

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞肝硬変は慢性肝疾患の終着点であり,「肝細胞がんに進行することはあっても肝硬変が戻ることはない」というのが従来の考え方であるが,原因とそれに伴う慢性炎症をきちんとコントロールできた場合には,肝硬変/肝線維化の少なくとも一部は可逆性であるという視点から,まず原因の治療,抗炎症療法が重要である.ただし,これらの治療が有効な症例においても肝線維化が改善するには年余の期間が必要である(新犬山分類の線維化の程度が1段階下降するには通常4～5年かかる).この期間,肝硬変患者は常に合併症や発がんのリスクにさらされている.したがって,これらの対策も並行して進める必要がある.さらに原因治療や抗炎症療法に不応性の症例では,肝不全対策や発がん対策(発がんスクリーニングを含む)がいっそう重要となる.詳細は文献1)を参照されたい.

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00974&link_issn=&doc_id=20220401100086&doc_link_id=issn%3D0022-1961%26volume%3D129%26issue%3D4%26spage%3D867&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0022-1961%26volume%3D129%26issue%3D4%26spage%3D867&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is a disease entity with an increasing incidence, with involvement of several metabolic pathways. Various organs, including the liver, kidneys, and the vasculature, are damaged in NASH, indicating the urgent need to develop a standard therapy. Therefore, this study was conducted to investigate the effects of drugs targeting various metabolic pathways and their combinations on a high-fat diet (HFD)-induced NASH medaka model. METHODS: To investigate the effects of drugs on vascular structures, the NASH animal model was developed using the fli::GFP transgenic medaka fed with HFD at 20 mg/fish daily. The physiological changes, histological changes in the liver, vascular structures in the fin, and serum biochemical markers were evaluated in a time-dependent manner after treatment with selective peroxisome proliferator-activated receptor α modulator (pemafibrate), statin (pitavastatin), sodium-glucose cotransporter 2 inhibitor (tofogliflozin), and their combinations. Furthermore, to determine the mechanisms underlying the effects, whole transcriptome sequencing was conducted using medaka liver samples. RESULTS: Histological analyses revealed significant suppression of fat accumulation and fibrotic changes in the liver after treatment with drugs and their combinations. The expression levels of steatosis- and fibrosis-related genes were modified by the treatments. Moreover, the HFD-induced vascular damages in the fin exhibited milder changes after treatment with the drugs. CONCLUSION: The effects of treating various metabolic pathways on the medaka body, liver, and vascular structures of the NASH medaka model were evidenced. Moreover, to our knowledge, this study is the first to report whole genome sequence and gene expression evaluation of medaka livers, which could be helpful in clarifying the molecular mechanisms of drugs.

DOI： 10.1016/j.bbrc.2022.01.086

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BACKGROUND: Rifaximin is commonly used for hepatic encephalopathy (HE). However, the effects of long-term treatment for Japanese people are limited. Therefore, this study aimed to investigate the effects and safety of long-term treatment with rifaximin on HE. METHODS: A total of 215 patients with cirrhosis administered with rifaximin developed overt or covert HE, which was diagnosed by an attending physician for &gt;12 months. Laboratory data were extracted at pretreatment and 3, 6, and 12 months after rifaximin administration. The long-term effect of rifaximin was evaluated, and the incidence of overt HE during 12 months and adverse events was extracted. RESULTS: Ammonia levels were significantly improved after 3 months of rifaximin administration and were continued until 12 months. There were no serious adverse events after rifaximin administration. The number of overt HE incidents was 9, 14, and 27 patients within 3, 6, and 12 months, respectively. Liver enzymes, renal function, and electrolytes did not change after rifaximin administration. Prothrombin activity is a significant risk factor for the occurrence of overt HE. The serum albumin, prothrombin activity, and albumin-bilirubin (ALBI) scores were statistically improved after 3 and 6 months of rifaximin administration. Moreover, the same results were obtained in patients with Child-Pugh C. CONCLUSIONS: The long-term rifaximin treatment was effective and safe for patients with HE, including Child-Pugh C.

DOI： 10.3390/jcm11061571

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Cyclin D1 binding protein 1 (CCNDBP1) is considered a tumor suppressor, and when expressed in tumor cells, CCNDBP1 can contribute to the viability of cancer cells by rescuing these cells from chemotherapy-induced DNA damage. Therefore, this study focused on investigating the function of CCNDBP1, which is directly related to the survival of cancer cells by escaping DNA damage and chemoresistance. Hepatocellular carcinoma (HCC) cells and tissues obtained from Ccndbp1 knockout mice were used for the in vitro and in vivo examination of the molecular mechanisms of CCNDBP1 associated with the recovery of cells from DNA damage. Subsequently, gene and protein expression changes associated with the upregulation, downregulation, and irradiation of CCNDBP1 were assessed. The overexpression of CCNDBP1 in HCC cells stimulated cell growth and showed resistance to X-ray-induced DNA damage. Gene expression analysis of CCNDBP1-overexpressed cells and Ccndbp1 knockout mice revealed that Ccndbp1 activated the Atm-Chk2 pathway through the inhibition of Ezh2 expression, accounting for resistance to DNA damage. Our study demonstrated that by inhibiting EZH2, CCNDBP1 contributed to the activation of the ATM-CHK2 pathway to alleviate DNA damage, leading to chemoresistance.

DOI： 10.3390/jcm11030851

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BACKGROUND: ONO-1301 is a novel long-lasting prostaglandin (PG) I2 mimetic with inhibitory activity on thromboxane (TX) A2 synthase. This drug can also induce endogenous prostaglandin (PG)I2 and PGE2 levels. Furthermore, ONO-1301 acts as a cytokine inducer and can initiate tissue repair in a variety of diseases, such as pulmonary hypertension, pulmonary fibrosis, cardiac infarction, and obstructive nephropathy. In this study, our aim was to evaluate the effect of ONO-1301 on liver inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH). METHODS: The therapeutic effects of ONO-1301 against liver damage, fibrosis, and occurrence of liver tumors were evaluated using melanocortin 4 receptor-deficient (Mc4r-KO) NASH model mice. The effects of ONO-1301 against macrophages, hepatic stellate cells, and endothelial cells were also evaluated in vitro. RESULTS: ONO-1301 ameliorated liver damage and fibrosis progression, was effective regardless of NASH status, and suppressed the occurrence of liver tumors in Mc4r-KO NASH model mice. In the in vitro study, ONO-1301 suppressed LPS-induced inflammatory responses in cultured macrophages, suppressed hepatic stellate cell (HSC) activation, upregulated vascular endothelial growth factor (VEGF) expression in HSCs, and upregulated hepatocyte growth factor (HGF) and VEGF expression in endothelial cells. CONCLUSIONS: The results of our study highlight the potential of ONO-1301 to reverse the progression and prevent the occurrence of liver tumors in NASH using in vivo and in vitro models. ONO-1301 is a multidirectional drug that can play a key role in various pathways and can be further analyzed for use as a new drug candidate against NASH.

DOI： 10.1186/s41232-021-00191-6

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INTRODUCTION: Various therapies and drugs have been developed to extend the life expectancy of patients with liver cirrhosis. The prolonged prognosis of cirrhotic patients may change the final cause of death in the future. Deep bleeding into the muscle is an uncommon but potentially life-threatening complication of liver cirrhosis. CASE REPORT: A 53-year-old man had undergone transjugular intrahepatic portosystemic shunt treatment for refractory ascites, which successfully controlled it for three years. However, he had started drinking again and experienced acute-on-chronic liver failure. He also had severe back pain. Abdominal computed tomography showed hyperdensities in the retroperitoneum and right pleural cavity. Despite blood infusion, he died from acute-on-chronic liver failure. A pathological autopsy revealed bleeding from the iliopsoas and right diaphragmatic muscle simultaneously, evident from the presence of red blood cells located between the muscle sheaths. Disruption of the small vessels in the skeletal muscle fibers was inferred. CONCLUSION: This is a critical case that underscores the significance of improving available knowledge based on the cause of final death of the patients with cirrhosis, who now have a good long-term prognosis owing to the latest medical developments.

DOI： 10.1007/s12328-022-01591-y

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Deep learning is a subset of machine learning that can be employed to accurately predict biological transitions. Eliminating hepatitis B surface antigens (HBsAgs) is the final therapeutic endpoint for chronic hepatitis B. Reliable predictors of the disappearance or reduction in HBsAg levels have not been established. Accurate predictions are vital to successful treatment, and corresponding efforts are ongoing worldwide. Therefore, this study aimed to identify an optimal deep learning model to predict the changes in HBsAg levels in daily clinical practice for inactive carrier patients. We identified patients whose HBsAg levels were evaluated over 10 years. The results of routine liver biochemical function tests, including serum HBsAg levels for 1, 2, 5, and 10 years, and biometric information were obtained. Data of 90 patients were included for adaptive training. The predictive models were built based on algorithms set up by SONY Neural Network Console, and their accuracy was compared using statistical analysis. Multiple regression analysis revealed a mean absolute percentage error of 58%, and deep learning revealed a mean absolute percentage error of 15%; thus, deep learning is an accurate predictive discriminant tool. This study demonstrated the potential of deep learning algorithms to predict clinical outcomes.

DOI： 10.3390/jcm11020387

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Language：Japanese   Publisher：(一社)日本再生医療学会  

肝硬変症に対する治療として、2003年実施した臨床研究:自己骨髄細胞投与療法により、肝線維化改善とそれに引き続く肝再生の誘導、それに伴う肝機能の改善効果を確認してきた。その後、2017年より、肝硬変症に対する他家脂肪組織由来間葉系幹細胞投与療法の企業治験、現在軽症の肝硬変に対する他家脂肪組織由来間葉系幹細胞の医師主導治験を2021年より実施している。さらに2020年よりHMGB1ペプチドを用いた医師主導治験を実施しており、より効率のいい再生療法の開発を行っている。さらに次のステップとして間葉系幹細胞由来エクソソームを用いた治療の準備を行っている。本稿では、現時点における我々の肝硬変症に対するアプローチを紹介する。(著者抄録)

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The epithelial basal lamina of the small intestine has numerous fenestrations for intraepithelial migration of leukocytes. We have reported dynamic changes of fenestrations in dietary conditions. To investigate this phenomenon, we performed statistical analyses using scanning electron microscopy images of the epithelial basal lamina of rat intestinal villi after removal of the villous epithelium by osmium maceration. We examined structural changes in the number and size of fenestrations in the rat jejunum and ileum under fasted and fed states for 24 h. Our findings revealed that, in the jejunum, the number of free cells migrating into the epithelium through fenestrations increased from 2 h after feeding, resulting in an increase in the fenestration size of intestinal villi; the number of free cells then tended to decrease at 6 h after feeding, and the fenestration size also gradually decreased. By contrast, the increase in the fenestration size by feeding was not statistically significant in the ileum. These findings indicate that the number of migrating cells increases in the upper part of the small intestine under dietary conditions, which may influence the absorption efficiency of nutrients including lipids, as well as the induction of nutrient-induced inflammation.

DOI： 10.2220/biomedres.43.11

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Due to the developments in the treatment for hepatitis, it is possible to prevent the progression of liver fibrosis and improve patients' prognosis even if it has already led to liver cirrhosis (LC). Consequently, a two-step study was conducted. To begin with, a retrospective study was conducted to identify the potential predictors of non-malignancy-related mortality from LC. Then, we prospectively analyzed the validity of these parameters as well as their association with patients' quality of life. In the retrospective study, 89 cases were included, and the multivariate Cox regression analysis indicated that age (P = 0.012), model for end-stage liver disease (MELD) score (P = 0.012), and annual rate of change of the albumin-bilirubin (ALBI) score (P < 0.001) were significantly associated with LC prognosis. In the prospective study, 70 patients were included, and the patients were divided into cirrhosis progression and non-progression groups. The univariate logistic regression analysis indicated the serum procollagen type III N-terminal peptide level (P = 0.040) and MELD score (P = 0.010) were significantly associated with the annual rate of change of the ALBI score. Furthermore, the mean Chronic Liver Disease Questionnaire score worsened from 5.3 to 4.9 in the cirrhosis progression group (P = 0.034). In conclusion, a longitudinal increase in the ALBI score is closely associated with non-malignancy-related mortality and quality of life.

DOI： 10.1371/journal.pone.0263464

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Objective Esophageal diverticulum is rare, and the concomitance of esophageal motility disorders (EMDs) and the efficacy of novel endoscopic treatment have not been investigated in Japan. Methods An examination including high-resolution manometry (HRM) was performed for patients with both EMDs and epiphrenic diverticulum. EMD-related epiphrenic diverticulum and Zenker's diverticulum were treated using salvage peroral endoscopic myotomy (s-POEM) and endoscopic diverticulotomy, respectively. Results Six cases of epiphrenic diverticulum were diagnosed in this study. Among 125 patients with achalasia and spastic disorders, concomitant epiphrenic diverticulum was observed in 4 (3.2%). Of these, three showed a normal lower esophageal sphincter pressure on HRM, although gastroscopy and esophagography revealed typical findings of an impaired lower esophageal sphincter relaxation. These four patients were successfully treated with s-POEM, and the Eckardt score improved from 6.3 to 0.25 at 32.5 (range: 13-56) months of follow-up, with equivalent treatment efficacy to that observed for achalasia and spastic disorders without epiphrenic diverticulum. In contrast, the two remaining cases of epiphrenic diverticulum had normal esophageal motility. Six cases of Zenker's diverticulum were diagnosed, and endoscopic diverticulotomy was successfully performed in all. The dysphagia score decreased from 2.8 to 0.17 at 14.8 (range: 2-36) months of follow-up. Overall, 12 endoscopic treatments were performed for esophageal diverticulum; no adverse events were observed. Conclusion In epiphrenic diverticulum patients, concomitant EMDs are not rare and should be carefully diagnosed. A normal lower esophageal sphincter pressure on HRM does not always mean a normal lower esophageal sphincter relaxation. S-POEM and endoscopic diverticulotomy are effective minimally invasive treatment options for EMD-related epiphrenic diverticulum and Zenker's diverticulum.

DOI： 10.2169/internalmedicine.8196-21

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The incidence of gastric tube carcinoma (GTC) after esophagectomy for esophageal carcinoma has increased in recent years. Surgical removal of the reconstructed gastric tube is associated with high mortality, and endoscopic submucosal dissection (ESD) is a promising alternative. There are limited reports of ESD for GTC. This study investigated the efficacy and safety of ESD in GTC. This single-center retrospective study examined patients who underwent ESD for GTC after esophagectomy at our institution between 2003 and 2018. The curability of GTC with ESD was evaluated histologically according to the Japanese Gastric Cancer Treatment Guidelines. Patient characteristics and procedural and long-term outcomes were analyzed. Overall, 31 patients (29 men and 2 women; median age, 73 years) with 45 GTC lesions underwent ESD. The mean period between primary esophagectomy and the diagnosis of GTC was 10.6 years. Bleeding during ESD was noted in two patients (6.5%). No other adverse or fatal events such as perforation were noted. Complete resection and curative resection were documented in 80.6% and 48.4% of cases, respectively. The 3-year and 5-year overall survival rates were 67.6% and 47.7%, respectively. The 3-year and 5-year disease-specific survival rates were 100% and 92.9%, respectively. One patient died of GTC, and fourteen patients died of other diseases, including primary carcinoma in five cases. ESD was safe and provided good long-term outcomes in patients with GTC. Regular long-term gastroscopy is required for the early detection of GTC. Patients with GTC after esophagectomy for esophageal carcinoma have a high risk of other primary carcinomas or comorbidities after ESD.

DOI： 10.1155/2022/1631415

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Overt hepatic encephalopathy (HE) is one of the complications of liver cirrhosis (LC), which negatively affects the prognosis and quality of life of patients. Small intestinal bacterial overgrowth (SIBO) is significantly associated with LC and its complications, including HE. We investigated the relationship between SIBO and LC, and the difference between hydrogen-producing and methane-producing SIBO (H-SIBO and M-SIBO, respectively). This is a prospective cohort study of 107 cases. Breath measurements of hydrogen and methane concentrations were performed for the diagnosis of SIBO. The study cohort included 81 males with a median age of 70 (40-86) years, and SIBO was detected in 31 cases (29.0%). There were no significant differences between the SIBO positive and SIBO negative groups. Reclassification into H-SIBO (16 cases) and others (91 cases) was performed, and the Child-Pugh score was only derived in the multivariate logistic analysis (P = 0.028, odds ratio 1.39, 95% confidence interval 1.04-1.85). Furthermore, H-SIBO was significantly associated with covert HE in chi-square test (50.0% vs. 24.2%, P = 0.034). In addition, we evaluated the therapeutic response on SIBO of rifaximin in eight covert HE patients. 20% patients with M-SIBO and 67% patients with H-SIBO showed an improvement of the breath test. In conclusion, H-SIBO, but not M-SIBO, is significantly associated with liver function, and rifaximin might be more effective for covert HE with H-SIBO. Therefore, the diagnosis of SIBO, including the classification as H-SIBO and M-SIBO, might help to determine the choice of treatment for HE.

DOI： 10.1371/journal.pone.0264459

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DOI： 10.1007/s00535-021-01845-5

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DOI： 10.1007/s12328-022-01684-8

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DOI： 10.4254/wjh.v14.i7.1307

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DOI： 10.1097/MD.0000000000031328

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DOI： 10.1016/j.gie.2021.09.029

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DOI： 10.1007/s12328-022-01671-z

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DOI： 10.1111/den.14346

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DOI： 10.1002/jgh3.12832

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DOI： 10.2169/internalmedicine.9038-21

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DOI： 10.1007/s00535-021-01836-6

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DOI： 10.2169/internalmedicine.8728-21

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DOI： 10.1053/j.gastro.2022.05.017

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DOI： 10.5230/jgc.2022.22.e30

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DOI： 10.3389/fonc.2022.970231

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DOI： 10.1007/s12328-022-01627-3

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DOI： 10.1007/s00535-022-01877-5

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DOI： 10.3389/fimmu.2022.1008047

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DOI： 10.1002/jhbp.1157

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DOI： 10.2169/internalmedicine.8721-21

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DOI： 10.4254/wjh.v14.i4.778

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Background: Liver cirrhosis is an end-stage multiple liver disease. Mesenchymal stem cells (MSCs) are an attractive cell source for reducing liver damage and regressing fibrosis; additional therapies accompanying MSCs can potentially enhance their therapeutic effects. Kampo medicines exhibit anti-inflammatory and anti-oxidative effects. Here, we investigated the therapeutic effect of MSCs combined with the Kampo medicine Juzentaihoto (JTT) as a combination therapy in a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. Methods: C57BL/6 mice were administered JTT (orally) and/or MSCs (one time, intravenously). The levels of liver proteins were measured in the sera. Sirius Red staining and hydroxyproline quantitation of hepatic tissues and immune cells were conducted, and their associated properties were evaluated. Liver metabolomics of liver tissues was performed. Results: JTT monotherapy attenuated liver damage and increased serum albumin level, but it did not effectively induce fibrolysis. JTT rapidly reduced liver damage, in a dose-dependent manner, after a single-dose CCl4 administration. Furthermore, JTT-MSC combination therapy attenuated liver damage, improved liver function, and regressed liver fibrosis. The combination increased the CD4+/CD8+ ratio. JTT had stronger effects on NK and regulatory T cell induction, whereas MSCs more strongly induced anti-inflammatory macrophages. The combination therapy further induced anti-inflammatory macrophages. JTT normalized lipid mediators, and tricarboxylic acid cycle- and urea cycle-related mediators effectively. Conclusions: The addition of JTT enhanced the therapeutic effects of MSCs; this combination could be a potential treatment option for cirrhosis.

DOI： 10.1016/j.reth.2021.07.002

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00535-021-01834-8

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Other Link： https://link.springer.com/article/10.1007/s00535-021-01834-8/fulltext.html

Language：Japanese   Publisher：(株)メディカルレビュー社  

＜文献概要＞本稿では,肝疾患領域の細胞を用いた再生医療の現状について概説する。2000年から基礎研究成果を基盤に,2003年から開始された肝硬変症に対する自己骨髄細胞投与療法,その後,血管内皮細胞投与療法,さらに自己脂肪組織細胞投与療法が実施されてきた。また,英国エジンバラ大学のForbesらは,肝硬変症に対して自己マクロファージ細胞投与療法を実施し,一方でSokalらは,代償性肝硬変症から急激に肝不全状態になるacute on chronic liver failure(ACLF)に対する,肝臓から採取した肝前駆細胞の投与療法を実施している。さらに,自己間葉系幹細胞を用いた治験も実施されてきた。日本では2017年より他家間葉系幹細胞投与療法の肝硬変症に対する治験を進めてきた(PhaseI,II)。また,2019年よりES細胞由来の肝臓様細胞を門脈より投与する先天性の尿素酵素欠損症に対する医師主導治験が進んでいる。本稿では,現在進んでいる細胞を用いた肝臓疾患に対する細胞を用いた再生療法を俯瞰し紹介する(図1)。

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01750&link_issn=&doc_id=20211223100008&doc_link_id=issn%3D0289-5803%26volume%3D39%26issue%3D12%26spage%3D37&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0289-5803%26volume%3D39%26issue%3D12%26spage%3D37&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：梵天書房  

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Chronic intestinal pseudo-obstruction (CIPO) is a severe and refractory intestinal motility disorder whose diagnosis currently relies on subjective imaging assessments. Cine magnetic resonance imaging (MRI) may potentially improve the quantitative analysis of gastrointestinal motility; however, suitable CIPO detection parameters should be determined. Cine MRI was performed in seven patients with CIPO and 11 healthy controls. The logarithm of the Mahalanobis distance (x1) and distance variation per time (x2) were used as the original parameters to determine CIPO diagnostic thresholds. Furthermore, the correlation between cine MRI findings and CIPO severity was investigated. Threshold values of α = 1.10 and β = 0.15 for x1 and x2, respectively, produced a CIPO diagnosis sensitivity of 1.00 (7/7) and specificity of 0.82 (9/11). The resulting error was 0.11 (2/18). The two parameters were correlated (Pearson's correlation coefficient: - 0.52). Any of the intestinal tracts of patients with severe CIPO requiring home parenteral nutrition belonged to the region defined by x1 ≥ 1.10 and x2 ≤ 0.15. Cine MRI is effective for the quantitative evaluation of small intestinal motility and CIPO diagnosis when using the abovementioned parameters and can be useful for treatment decision-making. However, these parameters have a wide distribution in healthy volunteers; this may complicate the detection of other disorders.

DOI： 10.1038/s41598-021-02268-1

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BACKGROUND: Data regarding the influence of patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism for patients with liver cirrhosis (LC) are scarce. OBJECTIVE: This study assesses the role of the PNPLA3 polymorphism for the development of LC and its complications by the findings of genetic examinations. METHODS: Patients with LC caused by virus (n = 157), alcohol (n = 104), nonalcoholic fatty liver disease (NAFLD) (n = 106), or autoimmune disease (n = 33) and without LC (n = 128) were enrolled. LC were composed of the present and absent of complications, such as variceal bleeding, hepatic ascites, and/or hepatic encephalopathy. To assess the role of the PNPLA3 polymorphism, odds ratio (OR) for the rs738409 variant was calculated for the patients between (i) with LC and without LC in the entire cohort, and (ii) the present and absent of complications in the patients with LC. RESULTS: There was a significant difference among the patients without LC and those with alcohol, NAFLD related LC in the frequency of G alleles (p < 0.001, both). According to complications of LC, the OR for NAFLD related cirrhosis significantly increased in the presence of the two mutated alleles (OR = 3.165; p = 0.046) when the wild type was used as the reference. However, there were no significant risks for the complications in the virus and alcohol related cirrhosis unless there was a presence of G alleles. CONCLUSION: The PNPLA3 polymorphism was associated with the risk of NAFLD related LC and its complications.

DOI： 10.1159/000521062

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OBJECTIVES: Indications for peroral endoscopic myotomy (POEM) and endoscopic submucosal dissection (ESD) in patients with achalasia concomitant with esophageal carcinoma (EC) are unclear. This study aimed to clarify the role of POEM in cases of achalasia concomitant with EC and to elucidate the indications for ESD and efficient surveillance for EC. METHODS: We conducted a multicenter cohort study at 14 hospitals in Japan, including 3707 cases of achalasia-related esophageal motility disorders (EMDs). Factors contributing to EC risk, the characteristics of EC, and clinical outcomes of POEM/ESD were analyzed. RESULTS: In patients undergoing POEM, screening and surveillance endoscopy throughout a 1-year period resulted in diagnosis of 72.1% new EC cases. Of 62 patients with 123 ECs, 40.3% had multiple or metachronous lesions within 37.5 months. EC was predominantly observed in the middle thoracic esophagus (58.5%) and posteriorly (73.2%). POEM had comparable safety and efficacy in cases of concomitant EC even after ESD. Endoscopic en bloc resection was performed in 95.8% and 89.3% of ECs diagnosed before and after POEM, respectively (P = 0.351); however, ESD on the POEM-line was impaired by fibrosis. Multivariate analysis revealed risk factors for EC, including regular alcohol consumption, a history of smoking, advanced age, and extended disease duration. Alcohol intake and smoking had a synergistic effect on EC development. CONCLUSIONS: Screening and surveillance of POEM help in detecting EC. ESD is feasible in achalasia, although on the POEM-line is challenging. Surveillance endoscopy for EC is recommended for cases with specific risks and a history of ECs.

DOI： 10.1111/den.14197

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Language：Japanese   Publisher：(一社)日本肝臓学会  

症例は50代の女性.30代でC型肝炎ウイルスへの感染を指摘されていたが治療に至らず,継続的な受診も行っていなかった.腹痛と意識消失を主訴に救急搬送され,脾動脈瘤破裂による出血性ショックと診断された.当院で脾動脈瘤塞栓術を施行し,術後経過は良好であった.外来にて直接作用型抗ウイルス薬を導入し,ウイルス学的著効を達成した.CT検査の普及により,脾動脈瘤の偶然の発見も増加していると報告されていて,今後本例のように肝臓以外の疾患での受診を契機に,ウイルス性肝炎や肝硬変の診断から治療に至る症例もある.C型肝炎の未治療者や未受検者,非認識受検者は国内に未だ数多く存在しており,脾動脈瘤に関する文献的考察と,新潟県で実施している肝炎患者の拾い上げの試みについても併せて記載し報告する.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00263&link_issn=&doc_id=20211111030008&doc_link_id=1390852945233297152&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390852945233297152&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞生体臓器は,外界からのさまざまな刺激や病態に対し,臓器連関により恒常性を維持している.この臓器間を繋ぐ要諦の一つが自律神経経路である.これまで肝障害や肝疾患では,さまざまな細胞や液性因子,腸内細菌に焦点を当てた臓器連関の報告が中心であった.今回,自律神経経路を介した臓器連関が肝障害時の肝再生や,脂肪性肝疾患の病態に関与することが明らかとなった.このメカニズムの解明が,難治性疾患の新規治療法の開発にも結び付くと考える.

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Language：Japanese   Publisher：医歯薬出版(株)  

肝臓は再生する臓器として知られているが、持続的な炎症の結果、肝細胞障害、それに伴う線維化形成で、再生力が低下して肝硬変に至る。黄疸や腹水がみられる程度まで進行した肝硬変は非代償性肝硬変といわれ、この病態に対して肝移植は有効な治療であるが、ドナー不足などの問題がある。また、本来このような非代償性肝硬変に至る前に積極的に治療が行えることが理想であるが、線維化の改善、再生促進に有効な治療法が乏しいのが現状である。本稿では肝硬変に対しての新たな治療の選択肢として細胞治療や細胞を用いない細胞フリー治療を間葉系幹細胞とそのエクソソームに絞って紹介をしたい。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00060&link_issn=&doc_id=20211122010006&doc_link_id=%2Faa7ayuma%2F2021%2F027908%2F007%2F0790b0794%26dl%3D3&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2021%2F027908%2F007%2F0790b0794%26dl%3D3&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_4.gif

Language：Japanese   Publisher：(株)日本メディカルセンター  

＜文献概要＞肝臓は再生する臓器として知られているが,持続的な炎症の結果,肝細胞障害,それに伴う線維化形成で,再生力が低下した肝硬変に至る.進行した肝硬変に対して,肝移植は有効な治療であるが,ドナー不足などの問題もあり,新たな治療の選択肢として細胞治療や細胞を用いないセルフリー治療が期待されている.本稿ではとくに細胞治療として間葉系幹細胞,マクロファージを用いた治療,そしてセルフリー治療としてエクソソーム治療に関して紹介したい.

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Language：English  

BACKGROUND: Colorectal mucinous adenocarcinoma is a rare subtype of colorectal cancer and is characterized by an abundance of mucin in the tumor. In addition, the colorectal mucinous adenocarcinoma often demonstrates poor differentiation in the histology of tumor cells and poor prognosis compared with those with adenocarcinoma. Here, we present the case of a young woman with colonic mucinous adenocarcinoma showing significantly rapid progression within four months of immunosuppressant therapy for Henoch-Schönlein purpura. CASE SUMMARY: Here we report a rare case of ascending colon mucinous adenocarcinoma with lymph node and liver metastases which developed and progressed rapidly within four months during the treatment of Henoch-Schönlein purpura using corticosteroids. The systemic screening examinations showed no tumors before the immunosuppressant therapy. Fortunately, the patient was successfully treated with chemotherapy. CONCLUSION: While no direct evidence that the immunosuppressants accelerated the tumor development, the case presenta tion and review of the literature demonstrated that surveillance for malignancies before and during treatment with immunosuppressive agents is essential.

DOI： 10.12998/wjcc.v9.i30.9182

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Language：English   Publisher：日本消化器病学会-甲信越支部  

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The complication of hepatocellular carcinoma (HCC) in Wilson's disease is rare. Wilson's disease treatment using D-penicillamine (DPA) is useful to prevent HCC occurrence; however, it also causes iron accumulation and synergistic radical formation in the liver, which may enhance carcinogenesis. Reported herein is a case of HCC in Wilson's disease treated with DPA for 36 years. The tumor was surgically resected and histologically diagnosed with moderately differentiated HCC surrounded by cirrhotic tissue with fatty infiltration. Rhodanine staining revealed a slight positively stained area in both tumor and surrounding tissues. Information obtained from this case and literature review highlight the feature of HCC in Wilson's disease.

DOI： 10.1002/jgh3.12648

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Language：Japanese   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：日本自律神経学会  

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Language：English   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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

The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs; however, these abilities are lost when chronic liver damage results in decompensated cirrhosis. Cell therapies, such as mesenchymal stem cell (MSC) and macrophage therapies, have attracted attention as potential strategies for mitigating liver fibrosis. Here, we evaluated the therapeutic effects of HMGB1 peptide synthesized from box A of high mobility group box 1 protein. Liver damage and fibrosis were evaluated using a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. The effects of HMGB1 peptide against immune cells were evaluated by single-cell RNA-seq using liver tissues, and those against monocytes/macrophages were further evaluated by in vitro analyses. Administration of HMGB1 peptide did not elicit a rapid response within 36 h, but attenuated liver damage after 1 week and suppressed fibrosis after 2 weeks. Fibrosis regression developed over time, despite continuous liver damage, suggesting that administration of this peptide could induce fibrolysis. In vitro analyses could not confirm a direct effect of HMGB1 peptide against monocyte/macrophages. However, macrophages were the most affected immune cells in the liver, and the number of scar-associated macrophages (Trem2+Cd9+ cells) with anti-inflammatory markers increased in the liver following HMGB1 treatment, suggesting that indirect effects of monocytes/macrophages were important for therapeutic efficacy. Overall, we established a new concept for cell-free therapy using HMGB1 peptide for cirrhosis through the induction of anti-inflammatory macrophages.

DOI： 10.1186/s41232-021-00177-4

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

The liver is a highly regenerative organ; however, its regeneration potential is reduced by chronic inflammation with fibrosis accumulation, leading to cirrhosis. With an aim to tackle liver cirrhosis, a life-threatening disease, trials of autologous bone marrow cell infusion (ABMi) therapy started in 2003. Clinical studies revealed that ABMi attenuated liver fibrosis and improved liver function in some patients; however, this therapy has some limitations such as the need of general anesthesia. Following ABMi therapy, studies have focused on specific cells such as mesenchymal stromal cells (MSCs) from a variety of tissues such as bone marrow, adipose tissue, and umbilical cord tissues. Particularly, studies have focused on gaining mechanistic insights into MSC distribution and effects on immune cells, especially macrophages. Several basic studies have reported the use of MSCs for liver cirrhosis models, while a number of clinical studies have used autologous and allogeneic MSCs; however, there are only a few reports on the obvious substantial effect of MSCs in clinical studies. Since then, studies have analyzed and identified the important signals or components in MSCs that regulate immune cells, such as macrophages, under cirrhotic conditions and have revealed that MSC-derived exosomes are key regulators. Researchers are still seeking the best approach and filling the gap between basic and clinical studies to treat liver cirrhosis. This paper highlights the timeline of basic and clinical studies analyzing ABMi and MSC therapies for cirrhosis and the scope for future studies and therapy.

DOI： 10.1186/s41232-021-00178-3

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Acute upper gastrointestinal bleeding (UGIB) is a common disorder and a gastroenterological emergency. With the development of new techniques and devices, the survivability after gastrointestinal bleeding is improving. However, at the same time, we are facing the difficulty of severely complicated cases with various diseases. For example, while endoscopic examination with a normal diameter endoscope is essential for the diagnosis and treatment of UGIB, there are several cases in which it cannot be used. In these cases, transnasal endoscopy (TNE) may be a viable treatment option. This report reviews current hemostatic devices for endoscopic treatment and the safety and efficiency of using TNE in complicated cases. The latter will be demonstrated in a case report where TNE was employed in a patient with severe esophageal stenosis. This review summarizes the advances made in the devices used and will provide further ideas for the physician in terms of combining these devices and TNE.

DOI： 10.3390/medicines8090053

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Language：Japanese   Publisher：医歯薬出版(株)  

＜Key Point＞・これまで安静が基本とされていた肝硬変患者の運動については、サルコペニア対策からも最近はレジスタンス運動を含む、積極的な運動介入が推奨される傾向にある。・患者の状態(静脈瘤、腹水、肝肺症候群、サルコペニアなどの合併)に注意しながら、運動介入程度を決定していく。・"FITT"を構築して行うことが基本となるが、個人の状況に応じた継続可能な日常活動を、医師の外来診療、管理栄養士の栄養指導の際に医療機関側からアドバイスして背中を押してあげることも重要になってくる。(著者抄録)

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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ABSTRACT: Gastrointestinal bleeding, hepatic encephalopathy (HE), and hepatocarcinogenesis are associated with the prognosis of patients with liver cirrhosis (LC). Proton pump inhibitors (PPIs) have been used to prevent bleeding, however the effects of PPIs on overall survival have not yet been elucidated. Therefore, this multicenter retrospective study aimed to assess the effect of PPI on the prognosis and HE occurrence of the patients with liver cirrhosis in Japan.A total of 456 patients diagnosed with LC at the 4 institutes during the study period (2010-2014) were assessed. PPI-treated and non-treated patients were compared using propensity score matching analysis. Primary and secondary endpoints of the study were set as the occurrence of HE and overall survival, respectively.A comparison of all cases showed a significantly poorer hepatic reserve function in the PPI-treated patients. The propensity-score matching analysis was performed and 120 PPI-treated patients were 1:1 matched with non-treated patients. The analysis revealed a higher incidence of HE in the PPI-treated than in the non-treated patients (P = .032; hazard ratio [HR], 2.162; 95% confidence interval [CI], 1.066-4.176), but the prognosis of PPI-treated patients was no worse than that of non-treated patients (P = .676; HR, 1.101; 95% CI, 0.702-1.726).This retrospective study showed that PPI administration for the patients with liver cirrhosis may partly be related to the increased incidence of HE but not worsen the patient prognosis.

DOI： 10.1097/MD.0000000000026902

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Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV) colitis are opportunistic infections that occur during immunosuppressive treatments for ulcerative colitis (UC). The prognosis of PJP and CMV colitis is very poor. We herein report a rare case of a 74-year-old UC patient with PJP and CMV colitis that was successfully treated with intensive therapy. PJP progresses rapidly, so the timing and choice of treatment are critical. Furthermore, a literature review of similar cases suggested that prophylactic therapy for opportunistic infections might be important, especially in the elderly. This case will serve as a reference for successful treatment in future cases.

DOI： 10.2169/internalmedicine.7953-21

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Background: Current guidelines recommend the temporary discontinuation of anticoagulants before colonoscopic polypectomy, but the effect of this practice on reducing the risk of delayed bleeding after hot snare polypectomy (HSP) and endoscopic mucosal resection (EMR) remains unclear. Our aim was to assess the impact of anticoagulants on the risk of colorectal delayed bleeding after HSP and EMR, and evaluate the necessity of drug withdrawal. Methods: We reviewed the clinical data of patients with colorectal polyps using antithrombotic drugs who underwent HSP and/or EMR between January 2016 and September 2020 at Nagaoka Red Cross Hospital. After excluding antiplatelet users, patients were classified into those who continued anticoagulants [continuation group: 50 patients (93 lesions)] and those who discontinued anticoagulants [discontinuation group: 87 patients (190 lesions)]. Results: Delayed bleeding occurred in 12 lesions, and there was no significant difference in the incidence rates between the continuation and the discontinuation groups (3.2% vs. 4.7%; P=0.756). Logistic regression analysis showed that continued use of anticoagulants was not a significant risk factor for delayed bleeding compared to anticoagulant discontinuation (odds ratio, 0.670; 95% CI, 0.177-2.537; P=0.556). There was no significant difference in the incidence rate and risk of delayed bleeding, regardless of the length of the anticoagulant withdrawal period. Conclusions: Continued use of anticoagulants, compared to their discontinuation, did not increase the risk of colorectal delayed bleeding after HSP and EMR. Our results suggest that current guideline recommendations for anticoagulant withdrawal before colonoscopic polypectomy may be reconsidered. Trial Registration: UMIN000040449.

DOI： 10.21037/jgo-21-3

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DOI： 10.1111/hepr.13687

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

DOI： 10.1093/gastro/goaa061

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

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

DOI： 10.1002/hep.32077

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BACKGROUND & AIMS: Tolvaptan, vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. In this study, we conducted a genome-wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan's efficacy for patients with hepatic ascites. METHODS: From 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non-responder; increase of body weight [BW]) and 333 controls (responder; >1.5 kg decrease of BW) were included in the GWAS and replication study. RESULTS: Genome-wide association study showed 5 candidate SNPs around the miR818, KIAA1109, and SVEP1 genes. After validation and performing a replication study, an SNP (rs2991364) located in the SVEP1 gene was found to have a significant genome-wide association (OR = 3.55, P = 2.01 × 10-8 ). Multivariate analyses showed that serum sodium (Na), blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR = 0.92, P = .003; OR = 1.02, P = .02 and OR = 3.98, P = .000008, respectively). Based on a prediction model of logistic regression analysis in a population with the rs2991364 risk allele, the failure probability (=exp (score: 22.234 + BUN*0.077 + Na*-0.179) (1 + exp (score)) was determined for the detection of non-responders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, specificity was 70% and AUC was 0.774. CONCLUSION: SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score (>38.6%) can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.

DOI： 10.1111/liv.15022

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The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japan Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

DOI： 10.1007/s00535-021-01788-x

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The first edition of the clinical practice guidelines for liver cirrhosis was published in 2010, and the second edition was published in 2015 by the Japanese Society of Gastroenterology (JSGE). The revised third edition was recently published in 2020. This version has become a joint guideline by the JSGE and the Japanese Society of Hepatology (JSH). In addition to the clinical questions (CQs), background questions (BQs) are new items for basic clinical knowledge, and future research questions (FRQs) are newly added clinically important items. Concerning the clinical treatment of liver cirrhosis, new findings have been reported over the past 5 years since the second edition. In this revision, we decided to match the international standards as much as possible by referring to the latest international guidelines. Newly developed agents for various complications have also made great progress. In comparison with the latest global guidelines, such as the European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases (AASLD), we are introducing data based on the evidence for clinical practice in Japan. The flowchart for nutrition therapy was reviewed to be useful for daily medical care by referring to overseas guidelines. We also explain several clinically important items that have recently received focus and were not mentioned in the last editions. This digest version describes the issues related to the management of liver cirrhosis and several complications in clinical practice. The content begins with a diagnostic algorithm, the revised flowchart for nutritional therapy, and refracted ascites, which are of great importance to patients with cirrhosis. In addition to the updated antiviral therapy for hepatitis B and C liver cirrhosis, the latest treatments for non-viral cirrhosis, such as alcoholic steatohepatitis/non-alcoholic steatohepatitis (ASH/NASH) and autoimmune-related cirrhosis, are also described. It also covers the latest evidence regarding the diagnosis and treatment of liver cirrhosis complications, namely gastrointestinal bleeding, ascites, hepatorenal syndrome and acute kidney injury, hepatic encephalopathy, portal thrombus, sarcopenia, muscle cramp, thrombocytopenia, pruritus, hepatopulmonary syndrome, portopulmonary hypertension, and vitamin D deficiency, including BQ, CQ and FRQ. Finally, this guideline covers prognosis prediction and liver transplantation, especially focusing on several new findings since the last version. Since this revision is a joint guideline by both societies, the same content is published simultaneously in the official English journal of JSGE and JSH.

DOI： 10.1111/hepr.13678

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BACKGROUND: Obstructive sleep apnea (OSA) has been suggested as an independent risk factor for nonalcoholic fatty liver disease (NAFLD), and continuous positive airway pressure (CPAP) is the first-line therapy for OSA. AIM: To clarify the efficacy of effective CPAP therapy on NAFLD of OSA patients by serum markers and transient elastography (TE) using FibroScan® (Echosens, Paris, France). METHODS: We prospectively enrolled 123 consecutive patients with OSA who met the indications for CPAP. Liver fibrosis and steatosis were assessed using TE. Before and after 6 mo of CPAP therapy, serum markers and TE were assessed for all patients. The mean usage rate of CPAP therapy for 6 mo was arbitrarily calculated in each patient and expressed as "mean compliance index" (m-CI). RESULTS: In 50 OSA patients with NAFLD, both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were significantly decreased after 6 mo of CPAP therapy. Univariate analysis showed that decreased body weight (BW), decreased body mass index (BMI), decreased AST level, decreased hemoglobin A1c, and high m-CI were significantly related with improved ALT level. In multivariate regression model adjusted for quantities of BW change during 6 mo of CPAP therapy, high m-CI tended to improve ALT level (P = 0.051). All 17 OSA patients with NAFLD, high m-CI and no BMI changes showed significant improvements in AST and ALT levels. Meanwhile, no significant changes in TE data or serum fibrosis markers were seen. CONCLUSION: Some NAFLD could be associated with chronic intermittent hypoxia due to OSA independent of BW changes. In those cases, adequate reoxygenation from effective CPAP therapy may improve NAFLD.

DOI： 10.12998/wjcc.v9.i19.5112

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DOI： 10.14309/ajg.0000000000001367

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DOI： 10.2169/internalmedicine.5054-20

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Language：Japanese   Publisher：(株)癌と化学療法社  

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BACKGROUND: Involuntary weight loss related to cachexia is common in patients with advanced cancer, but the association between body composition changes and survival is still unclear in pancreatic cancer. METHODS: We retrospectively reviewed the clinical outcomes of 55 patients with advanced pancreatic cancer undergoing palliative therapy or best supportive care (BSC). The skeletal muscle index (SMI), visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI), and visceral to subcutaneous adipose tissue area ratio (VSR) were calculated based on the cross-sectional area on two sets of computed tomography images obtained at cancer diagnosis and 1 month later before treatment. The prognostic value of body composition indexes at diagnosis and the changes in those indexes over 1 month was then evaluated. RESULTS: In total, 45 patients (81.8%) received chemotherapy, chemoradiation, or radiation therapy, whereas the remaining patients underwent BSC. There were 27 patients (49.1%) who had low SMI at cancer diagnosis. Univariate analysis showed no significant associations between the baseline body composition indexes including SMI, VATI, SATI, and VSR and survival. Meanwhile, male sex (HR, 2.79; 95% CI, 1.16-6.71, p = 0.022) and higher decrease in VATI over 1 month (HR, 2.41; 95% CI, 1.13-5.13, p = 0.023) were identified as independent risk factors for mortality in multivariate analysis. CONCLUSION: Rapid decline in VAT over 1 month is closely associated with poorer survival in unresectable advanced pancreatic cancer. A short-term assessment of body composition changes may be a rational approach to predict prognosis in these patients.

DOI： 10.1002/cam4.3964

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Physical inactivity is one of the causes of most metabolic syndromes. The incidence of metabolic syndrome is expected to increase in the near future because of the reduced opportunities for exercise caused by COVID-19. Non-alcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease. Changes in diet and lifestyle have led to a dramatic increase in the prevalence of NAFLD in the world. NAFLD is characterized by excessive triglyceride (TG) accumulation in the hepatocytes due to both increased inflow of free fatty acids and de novo hepatic lipogenesis. Thus far, no study quantitatively assessed the liver fat deposition after a rapid decline in physical activity. Herein, we describe a case of a 17-year-old Japanese boy with severe fat infiltration of the liver, due to a rapid decline in physical activity, treated at our facility. Our rehabilitation and nutritional support teams administered appropriate exercise and nutrition support to reduce weight and improve liver dysfunction. Our findings support dietary changes and exercise therapy to manage such cases.

DOI： 10.7759/cureus.16530

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Language：Japanese   Publisher：(NPO)日本高齢消化器病学会  

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(株)癌と化学療法社  

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DOI： 10.15403/jgld-3437

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The number of patients with non-alcoholic steatohepatitis (NASH) and inflammatory bowel disease (IBD) is increasing. This study elucidates the effect of both NASH and IBD on hepatocellular carcinoma (HCC) using a mouse model combining NASH and IBD. The melanocortin 4 receptor-deficient (Mc4r-KO) mice were divided into four groups with or without a high-fat diet (HFD) and with or without dextran sulfate sodium (DSS) to induce colitis, and the differences in liver damage and occurrence of HCC were analyzed. In the HFD + DSS group, the body weight, liver weight/body weight ratio, and serum levels of albumin and alanine aminotransferase were significantly lower than those in the HFD group. We further found that steatosis was significantly lower and lobular inflammation was significantly higher in the HFD + DSS group than those in the HFD group, and that individual steatosis and lobular inflammation state in the HFD + DSS mice varied. We detected HCC only in the HFD + DSS group, and mice with severe steatosis and mild colitis were found to be at high risk of HCC. Presently, the prediction of HCC is very difficult. In some cases, severe colitis reverses the fat accumulation due to appetite loss. Our findings clearly showed that severe steatohepatitis and mild colitis are simultaneously essential for the occurrence of HCC in patients with NASH and IBD.

DOI： 10.1016/j.bbrc.2021.05.097

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Basic and clinical research have shown that the expression of molecules involved in the hepatocellular carcinoma (HCC) cell signaling pathway is related to the sensitivity to molecular-targeted agents. We herein report a case of HCC that was effectively treated with lenvatinib after a poor response to sorafenib. The tumor showed a high expression of fibroblast growth factor receptor 4, which is reportedly related to the sensitivity to lenvatinib in vitro. The information obtained from this case and from our literature review highlights the importance of assessing the expression of the molecules involved in tumors for effective precision medicine.

DOI： 10.2169/internalmedicine.6580-20

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A 40-year-old man with slightly depressed (0-IIc) type gastric cancer of the pyloric anterior gastric area underwent pre-operative screening for tetralogy of Fallot and endoscopic submucosal dissection (ESD) and was tested for Helicobacter pylori antigens and antibodies. Both tests were negative. He did not have a history of eradication. Pathological diagnosis of ESD showed a well-differentiated adenocarcinoma. The tumor was CD10-positive, MUC5AC-negative, and MUC6-confocal positive; it showed differentiation with gastrointestinal phenotype. Moreover, the tumor cells were lysozyme-positive, resembling Paneth cells. Mucosal glands exhibited intestinal metaplasia on the anal side of the tumor lesion. On the oral side of the tumor, metaplasia was non-existent, with normal pyloric glands present in the mucosal layer. The patient was not infected with H. pylori ; however, intestinal metaplasia existed around the early gastric cancer. This suggested that the intestinal metaplasia occurred due to bile reflux, and the gastric neoplasia arose with the metaplasia without an H. pylori infection. This case may potentially help explain gastric cancer development in the absence of H. pylori infection.

DOI： 10.1055/a-1396-3854

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Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real-world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1-75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2-357). Adverse events occurred in 12.7%. Life-threatening complications occurred in 0.5%, but there were no treatment-related deaths. During a median follow-up period of 46.1 months (range 1-113), the 3-year overall survival rate, relapse-free survival rate, cause-specific survival rate, and larynx-preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment. Clinical trials registry number: UMIN000008276.

DOI： 10.1002/cam4.3927

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Language：Japanese   Publisher：日本消化器病学会-甲信越支部  

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Language：English   Publisher：日本消化器病学会-甲信越支部  

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Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for pancreatic tumors and subepithelial lesions (SEL) of the gastrointestinal tract are effective for histological diagnosis. There are also reports that tissue sampling is possible with a smaller number of punctures by EUS-guided fine-needle biopsy (EUS-FNB). In this study, we retrospectively compared the diagnostic abilities of EUS-FNA and EUS-FNB. We examined 130 patients who underwent EUS-FNA/EUS-FNB for pancreatic tumors and SEL from July 2018 to January 2021. None of the cases underwent rapid on-site evaluation. There were 94 and 36 cases in the EUS-FNA and EUS-FNB groups, respectively. The median tumor size in the EUS-FNB group was 30 mm, which was significantly larger than the EUS-FNA group (p = 0.02). In addition, transgastric puncture was significantly more common in the EUS-FNB group (p = 0.01). The EUS-FNA and EUS-FNB groups had a sensitivity of 82.9% and 91.7% and an accuracy rate of 85.1% and 91.7%, respectively. However, both procedures had a comparable diagnostic ability.

DOI： 10.3390/diagnostics11060965

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We herein report a rare case of HCC metastases to the ovary and peritoneum in a 61-year-old female patient who has achieved 11-year survival with multidisciplinary therapy. The patient was diagnosed with HCC during balloon angioplasty performed for Budd-Chiari syndrome in 1994 and underwent partial hepatectomy twice. Five years after the second hepatectomy, allochronic recurrence of a single nodule detected in S8 was treated by radiofrequency ablation, followed by percutaneous ethanol injection therapy and stereotactic body radiotherapy. However, her α-fetoprotein level rose to 1862 ng/mL within one year and computed tomography revealed a large pelvic tumor suggesting HCC metastasis to the ovary. The subsequent laparotomy revealed one 11-cm left ovarian tumor, one small right ovarian nodule, and numerous peritoneal nodules. Bilateral salpingo-oophorectomy and peritoneal resection of as many nodules as possible were performed. Combination therapy with intravenous 5-fluorouracil plus cisplatin and ramucirumab monotherapy effectively suppressed tumor progression with maintenance of hepatic functional reserve, and she has achieved long-term survival of 11 years, illustrating that multidisciplinary therapy with favorable hepatic functional reserve maintenance can contribute to long-term survival in HCC with extrahepatic spread.

DOI： 10.1007/s12328-021-01434-2

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Video 1Multiple sewing needles are retrieved from the stomach endoscopically using the tip of a magnet tube.

DOI： 10.1016/j.vgie.2021.01.007

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BACKGROUND: Achalasia has been reported to be associated with esophageal cancers (ECs). However, owing to the rarity of achalasia, details of achalasia-related ECs are not well investigated. METHOD: The incidence of ECs in Japanese patients with achalasia and achalasia-related esophageal motility disorders (EMDs) was estimated, and risk factors for achalasia-related ECs were determined. Characteristics of ECs and treatment courses were also analyzed. RESULTS: Between 2010 and 2019, 2714 Japanese patients with achalasia and achalasia-related EMDs were recorded in 7 high-volume centers; 24 patients (21 men, 3 women) developed ECs. The incidence of ECs was estimated at 0.078 and 0.28 per 100 person-years from the onset and the diagnosis of disease, respectively. Kaplan-Meier estimate suggested that, in addition to a long history of achalasia, advanced age, male sex, and regular alcohol consumption were statistically significant risk factors for EC development. A prevalence of 40 ECs (12.5% multiple lesions, and 22.7% metachronal lesions) was also noted, predominantly distributed over the thoracic esophagus. All were histologically diagnosed as squamous cell carcinoma. Superficial ECs were successfully treated with endoscopic treatment in all cases, except one. Achalasia-related Barret esophagus was extremely rare, and Barret adenocarcinoma was not detected in our cohort. CONCLUSION: The high relative risk of ECs was clarified in Japanese achalasia patients, although the absolute risk remained low. Therefore, surveillance endoscopy may be recommended in limited patients with several aforementioned risk factors determined. Superficial cancer can be treated with endoscopic treatment. Multiple and metachronal ECs should be screened.

DOI： 10.1007/s00535-021-01763-6

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Situs inversus abdominus is a congenital abnormality characterized by the mirror image positioning of the abdominal organs, making it difficult to diagnosis and treatment of many diseases. Here, we report a rare case of gastric varices in situs inversus abdominus patient. A 55-year-old man was diagnosed with F2-shaped gastric varices associated with alcoholic cirrhosis. Abdominal dynamic computed tomography showed situs inversus abdominus, and gastric varices with a gastrorenal shunt. Due to the complex anatomy, emergency interventional radiology during bleeding was extremely difficult. Therefore, after thorough consultation, we decided to treat gastric varices prophylactically by balloon-occluded retrograde transvenous obliteration. After treatment, the patient's clinical course was generally good, with no adverse events, and the gastric varices disappeared. It is important to assess anatomical positioning using three-dimensional reconstruction computed tomography images before treatment, to adequately prepare, including selecting appropriate devices (i.e., catheters and sheath). Although preventive treatment of gastric varices is controversial, in cases with anatomical complexity, preventive treatment with sufficient preparation would be recommended. To the best of our knowledge, there are no reports of treatment for gastric varices in situs inversus abdominus patient. This case will serve as a reference for successful treatment in future cases.

DOI： 10.1007/s12328-020-01332-z

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BACKGROUND: Biochemical response to treatment in patients with primary biliary cholangitis (PBC) reflects prognosis. However, the best predictive criteria to detect biochemical response remain undetermined. In addition, because these criteria need > 6 months until definition, parameters that can estimate its results before initiating treatment are needed. METHODS: We conducted a single-center retrospective study on 196 patients with PBC, followed up for at least 12 months after initiating treatment. RESULTS: Kaplan-Meier analysis showed that Paris II (p = 0.002) and Rotterdam criteria (p = 0.001) could estimate the overall survival of PBC patients, whereas Paris II (p = 0.001), Rotterdam (p = 0.001), and Rochester criteria (p= 0.025) could estimate liver-related deaths. Cox hazard analysis revealed Paris II and Rotterdam criteria as significantly independent predictors of overall survival (hazard ratio (HR) 3.948, 95% CI 1.293-12.054, p = 0.016 and HR 6.040, 95% CI 1.969-18.527, p = 0.002, respectively) and liver-related deaths (HR 10.461, 95% CI 1.231-88.936, p = 0.032 and HR 10.824, 95% CI 1.252-93.572, p = 0.032, respectively). The results of Paris II criteria could be estimated by serum prothrombin time (Odds ratio (OR) 1.052, 95% CI 1.008-1.098, p = 0.021) and alanine transaminase level (OR 0.954, 95% CI 0.919-0.991, p = 0.014) whereas, those of Rotterdam criteria could be estimated by serum albumin level (OR 3.649, 95% CI 1.098-12.128, p = 0.035) at the time of diagnosis. CONCLUSIONS: This study highlights the best prediction criteria and pre-treatment parameters that facilitate the prognosis of PBC patients.

DOI： 10.1007/s12072-021-10163-0

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Background and Aim: In Japan, corticosteroids have been commonly used as a part of multidisciplinary therapy for patients with acute liver failure and late-onset hepatic failure. However, there is controversy regarding the development of infections and other complications. In this study, the influence of corticosteroids on patient outcomes after liver transplantation was investigated. Methods: This study included 167 patients with acute liver failure and late-onset hepatic failure who underwent liver transplantation between 2010 and 2015. The effects of pretransplant corticosteroid therapy on patient outcomes were evaluated using a database constructed by the subcommittee for fulminant hepatitis in the Intractable Hepato-Biliary Diseases Study Group of Japan. Results: The subacute type and the median total bilirubin levels were higher in those receiving corticosteroids than in those not receiving corticosteroids. Although infections tended to be higher in patients receiving corticosteroids, pretransplant corticosteroid administration did not affect the survival rates. The duration from corticosteroid initiation to liver transplantation was longer in patients who developed infections. The survival rates, however, did not differ between patients with and without infections. Conclusions: Corticosteroids were administered to patients with poor prognoses. Otherwise, the overall outcome in those administered corticosteroids was not significantly different from that in those administered without corticosteroids. Although infectious complications tended to occur, they were generally controllable and nonfatal. Pretransplant corticosteroid therapy may be permissible, with regarding for infections and performed within the minimum duration.

DOI： 10.1002/jgh3.12508

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Mesenchymal stromal cells (MSCs) are used for ameliorating liver fibrosis and aiding liver regeneration after cirrhosis; Here, we analyzed the therapeutic potential of small extracellular vesicles (sEVs) derived from interferon-γ (IFN-γ) pre-conditioned MSCs (γ-sEVs). γ-sEVs effectively induced anti-inflammatory macrophages with high motility and phagocytic abilities in vitro, while not preventing hepatic stellate cell (HSC; the major source of collagen fiber) activation in vitro. The proteome analysis of MSC-derived sEVs revealed anti-inflammatory macrophage inducible proteins (e.g., annexin-A1, lactotransferrin, and aminopeptidase N) upon IFN-γ stimulation. Furthermore, by enabling CX3CR1+ macrophage accumulation in the damaged area, γ-sEVs ameliorated inflammation and fibrosis in the cirrhosis mouse model more effectively than sEVs. Single cell RNA-Seq analysis revealed diverse effects, such as induction of anti-inflammatory macrophages and regulatory T cells, in the cirrhotic liver after γ-sEV administration. Overall, IFN-γ pre-conditioning altered sEVs resulted in efficient tissue repair indicating a new therapeutic strategy.

DOI： 10.1038/s41536-021-00132-4

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The etiology of non-alcoholic fatty liver disease (NAFLD) consists of various factors, including neural signal pathways. However, the molecular mechanisms of the autonomic neural signals influencing NAFLD progression have not been elucidated. Therefore, we examined the involvement of the gut-liver neural axis in NAFLD development and tested the therapeutic effect of modulation of this axis in this study. To test the contribution of the gut-liver neural axis, we examined NAFLD progression with respect to body weight, hepatic steatosis, fibrosis, intestinal tight junction, microbiota and short-chain fatty acids in NAFLD models of choline-deficient defined L-amino-acid and high-fat diet-fed mice with or without blockades of autonomic nerves from the liver. Blockade of the neural signal from the liver to the gut in these NAFLD mice models ameliorated the progression of liver weight, hepatic steatosis and fibrosis by modulating serotonin expression in the small intestine. It was related to the severity of the liver pathology, the tight junction protein expression, microbiota diversity and short-chain fatty acids. These effects were reproduced by administrating serotonin antagonist, which ameliorated the NAFLD progression in the NAFLD mice models. Our study demonstrated that the gut-liver neural axis is involved in the etiologies of NAFLD progression and that serotonin expression through this signaling network is the key factor of this axis. Therefore, modulation of the gut-liver neural axis and serotonin antagonist ameliorates fatty and fibrotic changes in non-alcoholic fatty liver, and can be a potential therapeutic target of NAFLD.This article has an associated First Person interview with the first author of the paper.

DOI： 10.1242/dmm.048922

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Double filtration plasmapheresis (DFPP) is an apheretic technique that selectively removes high molecular weight substances using a plasma component filter. DFPP has been used to treat positive-sense RNA virus infections, mainly chronic hepatitis C virus (HCV) infection, because of its ability to directly eliminate viral particles from blood plasma from 2008 to about 2015, before direct-acting antiviral agents was marketed. This effect has been termed virus removal and eradication by DFPP. HCV is a positive-sense RNA virus similar to West Nile virus, dengue virus and the SARS and Middle East respiratory syndrome coronaviruses. SARS-CoV-2 is classified same viral species. These viruses are all classified in Family Flaviviridae which are family of single-stranded plus-stranded RNA viruses. Viral particles are 40-60 nm in diameter, enveloped and spherical in shape. We present a rare case of HCV removal where an RNA virus infection that copresented with virus-associated autoimmune hepatitis was eliminated using DFPP. Our results indicate that DFPP may facilitate prompt viraemia reduction and may have novel treatment applications for SARS-CoV-2, that is, use of therapeutic plasma exchange for fulminant COVID-19.

DOI： 10.1136/bcr-2020-236984

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Cisplatin (CDDP) is one of the chemotherapeutic drugs being used to treat various cancers. Although effective in many cases, as high doses of CDDP cause cytotoxic effects that may worsen patients' condition, therefore, a marker of sensitivity to CDDP is necessary to enhance the safety and efficiency of CDDP administration. This study focused on adipose most abundant 2 (APM2) to examine its potential as a marker of CDDP sensitivity. The relationship of APM2 expression with the mechanisms of CDDP resistance was examined in vitro and in vivo using hepatocellular carcinoma (HCC) cells, tissues and serum of HCC patients (n = 71) treated initially with intrahepatic arterial infusion of CDDP followed by surgical resection. The predictability of serum APM2 for CDDP sensitivity was assessed in additional 54 HCC patients and 14 gastric cancer (GC) patients. APM2 expression in CDDP-resistant HCC was significantly higher both in serum and the tissue. Bioinformatic analyses and histological analyses demonstrated upregulation of ERCC6L (DNA excision repair protein ERCC6-like) by APM2, which accounts for the degree of APM2 expression. The serum APM2 level and chemosensitivity for CDDP were assessed and cut-off value of serum APM2 for predicting the sensitivity to CDDP was determined to be 18.7 µg/mL. The value was assessed in HCC (n = 54) and GC (n = 14) patients for its predictability of CDDP sensitivity, resulted in predictive value of 77.3% and 100%, respectively. Our study demonstrated that APM2 expression is related to CDDP sensitivity and serum APM2 can be an effective biomarker of HCC and GC for determining the sensitivity to CDDP.Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000028487).

DOI： 10.1038/s41598-021-85498-7

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BACKGROUND: This study examined demographics, comorbidities and healthcare resource use (HCRU) and costs among Japanese patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). METHODS: We conducted a repeated cross-sectional analysis of the Medical Data Vision (MDV) claims database, from January 2011 to March 2018. Demographics were described at index date and by calendar year; a "NASH" subpopulation included patients with ≥ 1 claim for NASH at any time. Prevalence of pre-specified comorbidities of interest and data-emergent top comorbidities were estimated. All-cause HCRU and costs were quantified by calendar year. Outcomes were compared between 2011 and 2017 using partially overlapping t tests. RESULTS: 58,958 patients (mean age 61.6 years; 55.5% male) were included. 1139 patients (2%) were in the NASH subpopulation. At baseline, comorbid cardiovascular disease (69.4%), diabetes (62.1%) and hyperlipidaemia (54.4%) were most prevalent; comorbidity prevalence increased with age. Mean outpatient visits decreased from 9.36 per patient in 2011 to 7.80 in 2017; mean inpatient admissions increased (both p < 0.001 for 2011 vs 2017). Mean total all-cause healthcare costs ranged from \322,206 to \340,399 per patient per year between 2011 and 2017. Although total all-cause healthcare costs did not change significantly (p = 0.552), cost burden shifted from the outpatient to inpatient setting between 2011 and 2017. All-cause healthcare resource use/costs were generally higher for the NASH subgroup compared with the overall population. CONCLUSIONS: There is a high burden of disease among Japanese NAFLD/NASH patients, including a high prevalence of comorbidities which generally increase with age. Accordingly, substantial all-cause HCRU and costs were incurred.

DOI： 10.1007/s00535-021-01759-2

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INTRODUCTION: Although hepatitis B virus infection is well-described, the additional risk posed by oral bleeding in individuals with chronic hepatitis B virus infection has not been determined. This study aimed to determine the quantity of hepatitis B virus in the saliva of carriers in Japan, as a means of understanding the potential risk for horizontal transmission. METHODS: Saliva samples from 48 confirmed hepatitis B virus carriers were included in the analysis. Hepatitis B virus concentrations and the presence of occult blood as periodontal disease were evaluated in each sample. RESULTS: Hepatitis B surface antigen was identified in 46 of the 48 samples (98%), with hepatitis B virus DNA identified in 19 of the 48 saliva samples (40%). Occult blood was detected in 32 (67%) samples with the prevalence increasing as a function of age (r = 0.413; P = 0.003). There was a significantly positive correlation between hepatitis B virus DNA levels in the serum and saliva specimens (r = 0.895; P < 0.001). CONCLUSIONS: Occult blood in saliva was detected in most participants. The detection of hepatitis B virus DNA correlated positively with hepatitis B virus in the serum and occult blood in the saliva. Therefore, improved care of periodontal disease among older people is important for preventing horizontal transmission of hepatitis B virus.

DOI： 10.1016/j.jiac.2020.10.028

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It is reported that an increase in aerobic bacteria, a lack of short-chain fatty acids (SCFAs), and immune disorders in the diverted colon are major causes of diversion colitis. However, the precise pathogenesis of this condition remains unclear. The aim of the present study was to examine the microbiota, intestinal SCFAs, and immunoglobulin A (IgA) in the diverted colon. Eight patients underwent operative procedures for colostomies. We assessed the diverted colon using endoscopy and obtained intestinal samples from the diverted colon and oral colon in these patients. We analyzed the microbiota and SCFAs of the intestinal samples. The bacterial communities were investigated using a 16S rRNA gene sequencing method. The microbiota demonstrated a change in the proportion of some species, especially Lactobacillus, which significantly decreased in the diverted colon at the genus level. We also showed that intestinal SCFA values were significantly decreased in the diverted colon. Furthermore, intestinal IgA levels were significantly increased in the diverted colon. This study was the first to show that intestinal SCFAs were significantly decreased and intestinal IgA was significantly increased in the diverted colon. Our data suggest that SCFAs affect the microbiota and may play an immunological role in diversion colitis.

DOI： 10.1016/j.bbrep.2020.100892

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Background: Although type 2 diabetes mellitus (T2DM) is a known risk factor for hepatocellular carcinoma (HCC) development, the annual incidence in diabetes patients is far below the threshold of efficient surveillance. This study aimed to elucidate the risk factors for HCC in diabetic patients and to determine the best criteria to identify surveillance candidates. Methods: The study included 239 patients with T2DM who were diagnosed with non-viral HCC between 2010 and 2015, with ≥ 5 years of follow-up at diabetes clinics of 81 teaching hospitals in Japan before HCC diagnosis, and 3277 non-HCC T2DM patients from a prospective cohort study, as controls. Clinical data at the time of and 5 years before HCC diagnosis were collected. Results: The mean patient age at HCC diagnosis was approximately 73 years, and 80% of the patients were male. The proportion of patients with insulin use increased, whereas the body mass index (BMI), proportion of patients with fatty liver, fasting glucose levels, and hemoglobin A1c (HbA1c) levels decreased significantly in 5 years. In the cohort study, 18 patients developed HCC during the mean follow-up period of 4.7 years with an annual incidence of 0.11%. Multivariate logistic regression analyses showed that the FIB-4 index was an outstanding predictor of HCC development along with male sex, presence of hypertension, lower HbA1c and albumin levels, and higher BMI and gamma-glutamyl transpeptidase levels. Receiver-operating characteristic analyses showed that a FIB-4 cut-off value of 3.61 could help identify high-risk patients, with a corresponding annual HCC incidence rate of 1.1%. Conclusion: A simple calculation of the FIB-4 index in diabetes clinics can be the first step toward surveillance of HCC with a non-viral etiology.

DOI： 10.1007/s00535-020-01754-z

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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DOI： 10.2169/internalmedicine.6906-20

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We observed a rare case of two different digestive paraneoplastic syndromes that improved with the treatment of the neoplasms. The first syndrome was chronic intestinal pseudo-obstruction (CIPO), which is a subtype of paraneoplastic syndromes called a paraneoplastic neurological syndrome (PNS). The second was Stauffer's syndrome, which is a unique paraneoplastic syndrome characterised by non-metastatic intrahepatic cholestasis associated with neoplasms. Here, we report the case of a 55-year-old man who presented with two concurrent paraneoplastic syndromes in the digestive system. The intestinal pseudo-obstruction and elevated biliary enzyme levels improved as the lung cancer responded to chemotherapy. In this case, CIPO as a PNS led to the detection of lung cancer. To our knowledge, this is the first report of Stauffer's syndrome caused by lung adenocarcinoma.

DOI： 10.1136/bcr-2020-240161

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Jaundice may be persistent in drug-induced liver injury associated with vanishing bile duct syndrome. However, recurrent jaundice is atypical, following bile flow restoration. Here, we report a 28-year-old man with prolonged, recurrent jaundice (more than 300 days) and combined immunodeficiency (CID) of B-cells, T-cells, and natural killer (NK) cells. Hypogammaglobulinemia was observed throughout his hospitalization, and peripheral blood flow cytometry detected a few B-cells (2% of CD19 + cells and 2% of CD20 + cells). We further detected the dysfunction of T-cells and NK cells. Based on these findings, CID was diagnosed. We presumed that hypogammaglobulinemia was related to the jaundice. After regular injections of intravenous immunoglobulin (IVIG), the stool color gradually turned brown. However, the color returned to white as IgG levels decreased. The brown-to-white stool pattern was repeated with another IVIG administration, suggesting that the patient's serum immunoglobulin levels were related to the jaundice. On follow-up, IVIG was performed every two to three weeks, and his total bilirubin improved gradually. Immunoglobulin replacement therapy could be one of the treatment choices for jaundice with CID.

DOI： 10.1007/s12328-021-01347-0

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DOI： 10.14309/ajg.0000000000000703

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AIM: Disease characteristics of primary biliary cholangitis have changed recently. However, detailed studies on the subject have been limited. Therefore, we aimed to clarify disease characteristics of patients with recent primary biliary cholangitis using the cohort from Niigata University and 21 affiliated hospitals. METHODS: Overall, 508 patients were enrolled in this study from 1982 to 2016, divided into three cohorts according to their year of diagnosis: ≤1999, 2000-2009 and ≥2010. We compared differences in clinical characteristics, response to ursodeoxycholic acid and prognosis. RESULTS: The male-to-female ratio increased incrementally from 1:16.4 (≤1999) to 1:3.8 (≥2010) (P < 0.001). In women, the median age at diagnosis increased incrementally from 54.0 years (≤1999) to 60.5 years (≥2010) (P < 0.001) and serum albumin decreased gradually (P = 0.001), which might have affected the increase in the Fibrosis-4 Index and albumin-bilirubin score. The ursodeoxycholic acid response rate according to the Barcelona criteria increased incrementally from 26.7% (≤1999) to 78.4% (≥2010) (P < 0.010), and those according to other criteria (Paris-I, Rotterdam and Toronto) were approximately ≥80% in all cohorts. Ten-year survival rate in the ≤1999 and 2000-2009 cohorts were 98.6% and 95.6%, respectively. These earlier cohorts were also characterized by a higher rate of asymptomatic state and mild histology (83.5% [≤1999] and 84.7% [2000-2009], and 93.6% [≤1999] and 91.1% [2000-2009]). CONCLUSIONS: Patients with primary biliary cholangitis were characterized by older age at diagnosis and an increase in male to female ratio as well as higher response rates of ursodeoxycholic acid and longer survival, resulting from the early recognition of primary biliary cholangitis.

DOI： 10.1111/hepr.13586

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Language：Japanese   Publisher：(有)科学評論社  

researchmap

Language：Japanese   Publisher：(一社)日本肝臓学会  

researchmap

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

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength that occurs with aging or in association with various diseases. The condition is prevalent worldwide and occurs more frequently in patients with chronic diseases owing to the intrinsic relationship of muscles with glucose, lipid, and protein metabolism. Liver cirrhosis is characterized by the progression of necro-inflammatory liver diseases, which leads to fibrosis, portal hypertension, and a catabolic state, which causes loss of muscle tissue. Sarcopenia is of significant concern in the state of liver cirrhosis because sarcopenia has been associated with higher mortality, increased hospital admissions, worse post-liver transplant outcomes, decreased quality of life, and increased risk for other complications associated with cirrhosis. Therefore, sarcopenia is also an important feature of liver cirrhosis, representing a negative prognostic factor and influencing mortality. An increased understanding of sarcopenia could lead to the development of novel therapeutic approaches that could help improve the cognitive impairment of cirrhotic patients; therefore, we present a review of the mechanisms and diagnosis of sarcopenia in liver disease and existing therapeutic approaches.

DOI： 10.3390/ijms22031425