研究者詳細 - 寺井　崇二

論文 - 寺井　崇二

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【消化器領域における再生医療の現状と展望】間葉系幹細胞,細胞外小胞,ペプチドを用いた肝線維化改善・再生療法を目指して

土屋淳紀, 寺井崇二

日本消化器病学会雑誌 120 ( 12 ) 973 - 979 2023年12月

記述言語：日本語出版者・発行元：(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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その他リンク： 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

MC4R、Maid両遺伝子欠損マウスを用いた慢性アルコール性肝障害モデルマウスの開発

坂牧僚, 酒井規裕, 小川和也, 木村成宏, 荒生祥尚, 阿部寛幸, 上村顕也, 寺井崇二

アルコールと医学生物学 42 44 - 46 2023年12月

MC4R、Maid両遺伝子欠損マウスを用いた慢性アルコール性肝障害モデルマウスの開発

坂牧僚, 酒井規裕, 小川和也, 木村成宏, 荒生祥尚, 阿部寛幸, 上村顕也, 寺井崇二

アルコールと医学生物学 42 44 - 46 2023年12月

EUS-FNAが診断に有用であった原発性舌下腺癌に合併した多発膵腫瘍の1例

渡邊誠, 五十嵐聡, 渡邊浩太朗, 山崎駿, 酒井規裕, 渡邉雄介, 冨永顕太郎, 高橋一也, 上村博輝, 寺井崇二

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 73回・95回 68 - 68 2023年11月

炎症性腸疾患に対する新規治療とバイオ治療再考多剤使用歴のある潰瘍性大腸炎難治例の臨床的特徴

小島雄一, 川田雄三, 冨永顕太郎, 寺井崇二

日本消化器病学会甲信越支部例会・日本消化器内視鏡学会甲信越支部例会抄録集 73回・95回 41 - 41 2023年11月

小腸内細菌異常増殖症(SIBO)の病態と臨床顕性肝性脳症の発症予測における、呼気中水素・メタン分析によるSIBO診断の有用性の検討

坂巻僚, 横山邦彦, 若林拓哉, 小島雄一, 川田雄三, 冨永顕太郎, 水野研一, 上村顕也, 寺井崇二

日本小腸学会学術集会プログラム・抄録集 61回 26 - 26 2023年11月

小腸内細菌異常増殖症(SIBO)の病態と臨床顕性肝性脳症の発症予測における、呼気中水素・メタン分析によるSIBO診断の有用性の検討

坂巻僚, 横山邦彦, 若林拓哉, 小島雄一, 川田雄三, 冨永顕太郎, 水野研一, 上村顕也, 寺井崇二

日本小腸学会学術集会プログラム・抄録集 61回 26 - 26 2023年11月

Achalasia phenotypes and prediction of per-oral endoscopic myotomy outcomes using machine learning. 国際誌

Kazuya Takahashi, Hiroki Sato, Yuto Shimamura, Hirofumi Abe, Hironari Shiwaku, Junya Shiota, Chiaki Sato, Kenta Hamada, Masaki Ominami, Yoshitaka Hata, Hisashi Fukuda, Ryo Ogawa, Jun Nakamura, Tetsuya Tatsuta, Yuichiro Ikebuchi, Hiroshi Yokomichi, Shuji Terai, Haruhiro Inoue

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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Improving diagnostic performance of coronavirus disease 2019 rapid antigen testing through computer-based feedback training using open-source experimental psychology software. 国際誌

Masato Matsuda, Kosuke Itoh, Takahiro Sugai, Yoshiki Hoshiyama, Toshiaki Kikuchi, Shuji Terai

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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Complementary role of peripheral and central autonomic nervous system on insulin-like growth factor-1 activation to prevent fatty liver disease. 国際誌

Itsuo Nagayama, Kenya Kamimura, Takashi Owaki, Masayoshi Ko, Takuro Nagoya, Yuto Tanaka, Marina Ohkoshi, Toru Setsu, Akira Sakamaki, Takeshi Yokoo, Hiroteru Kamimura, Shuji Terai

Hepatology international 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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Analysis of distribution, collection, and confirmation of capacity dependency of small extracellular vesicles toward a therapy for liver cirrhosis. 国際誌

Nobutaka Takeda, Atsunori Tsuchiya, Masaki Mito, Kazuki Natsui, Yui Natusi, Yohei Koseki, Kei Tomiyoshi, Fusako Yamazaki, Yuki Yoshida, Hiroyuki Abe, Masayuki Sano, Taketomo Kido, Yusuke Yoshioka, Junichi Kikuta, Tohru Itoh, Ken Nishimura, Masaru Ishii, Takahiro Ochiya, Atsushi Miyajima, Shuji Terai

Inflammation and regeneration 43 ( 1 ) 48 - 48 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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機能性消化管疾患の病態解明と臨床応用腸管運動機能に関わる組織常在型マクロファージを有する腸管オルガノイドの開発

冨永顕太郎, Wells James, 寺井崇二

Gastroenterological Endoscopy 65 ( Suppl.2 ) 1809 - 1809 2023年10月

重症急性膵炎後Walled-off necrosisの内視鏡治療における最適なステントの選択

五十嵐聡, 林和直, 寺井崇二

Gastroenterological Endoscopy 65 ( Suppl.2 ) 2046 - 2046 2023年10月

高齢者の術後再建腸管結石例に対するダブルバルーン内視鏡下ERCPの検討

林和直, 五十嵐聡, 寺井崇二

Gastroenterological Endoscopy 65 ( Suppl.2 ) 2022 - 2022 2023年10月

自律神経経路を基軸とする脂肪性肝疾患の脂質代謝制御機構の解明と治療薬探索

上村顕也, 大脇崇史, 寺井崇二

日本消化器病学会雑誌 120 ( 臨増大会 ) A452 - A452 2023年10月

脂肪性肝疾患の個別化医療に向けた提案 NAFLDの病態進展に関わるエフェクターを標的とした治療法の開発

上村顕也, 薛徹, 寺井崇二

肝臓 64 ( Suppl.3 ) A743 - A743 2023年10月

Similarity of oncogenic protein expression in KRASG12D gene delivery-based rat pancreatic cancer model to that of human pancreatic cancer. 国際誌

Yuto Tanaka, Kenya Kamimura, Osamu Shibata, Kohei Ogawa, Chiyumi Oda, Hiroyuki Abe, Satoshi Ikarashi, Kazunao Hayashi, Takeshi Yokoo, Toshifumi Wakai, Shuji Terai

Biochemical and biophysical research communications 673 29 - 35 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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Development and validation of machine learning model for predicting treatment responders in patients with primary biliary cholangitis. 国際誌

Naruhiro Kimura, Kazuya Takahashi, Toru Setsu, Yusuke Horibata, Yusuke Kaneko, Haruka Miyazaki, Kohei Ogawa, Yuzo Kawata, Norihiro Sakai, Yusuke Watanabe, Hiroyuki Abe, Hiroteru Kamimura, Akira Sakamaki, Takeshi Yokoo, Kenya Kamimura, Atsunori Tsuchiya, Shuji Terai

Hepatology research : the official journal of the Japan Society of Hepatology 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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多職種の肝炎医療コーディネーターとの連携による,院内におけるC型肝炎患者の拾い上げと紹介率向上の効果

荒生祥尚, 酒井規裕, 薛徹, 渡邉雄介, 木村成宏, 阿部寛幸, 坂牧僚, 上村博輝, 横尾健, 土屋淳紀, 上村顕也, 寺井崇二

肝臓 64 ( Suppl.2 ) A634 - A634 2023年9月

肝疾患に対する再生医療のNew normal New Normalへの提案肝硬変に対する線維化改善を目指したトランスレーショナルリサーチ

土屋淳紀, 渡邉雄介, 寺井崇二

肝臓 64 ( Suppl.2 ) A570 - A570 2023年9月

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