研究者詳細 - 寺井　崇二

論文 - 寺井　崇二

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Involvement of DNA Damage Response via the Ccndbp1-Atm-Chk2 Pathway in Mice with Dextran-Sodium-Sulfate-Induced Colitis. 国際誌

Ryoko Horigome, Kenya Kamimura, Yusuke Niwa, Kohei Ogawa, Ken-Ichi Mizuno, Koichi Fujisawa, Naoki Yamamoto, Taro Takami, Tomoyuki Sugano, Akira Sakamaki, Hiroteru Kamimura, Masaaki Takamura, Shuji Terai

Journal of clinical medicine 11 ( 13 ) 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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Daisaikoto improves fatty liver and obesity in melanocortin-4 receptor gene-deficient mice via the activation of brown adipose tissue. 国際誌

Shinichi Morita, Akira Sakamaki, Kyutaro Koyama, Osamu Shibata, Takashi Owaki, Chiyumi Oda, Atsushi Kimura, Taiki Nakaya, Katsuya Ohbuchi, Miwa Nahata, Naoki Fujitsuka, Norihiro Sakai, Hiroyuki Abe, Kenya Kamimura, Shuji Terai

Scientific reports 12 ( 1 ) 10105 - 10105 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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Establishment of a pancreatic cancer animal model using the pancreas-targeted hydrodynamic gene delivery method. 国際誌

Osamu Shibata, Kenya Kamimura, Yuto Tanaka, Kohei Ogawa, Takashi Owaki, Chiyumi Oda, Shinichi Morita, Atsushi Kimura, Hiroyuki Abe, Satoshi Ikarashi, Kazunao Hayashi, Takeshi Yokoo, Shuji Terai

Molecular therapy. Nucleic acids 28 342 - 352 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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多発性出血性膵炎を伴う重度の急性肝不全の一例(A case of severe acute liver failure with multiple hemorrhagic pancreatitis)

神保遼, 荒生祥尚, 山崎華子, 水戸將貴, 小島雄一, 木村成宏, 小林雄司, 林和直, 土屋淳紀, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 70回 np41 - np41 2022年6月

【肝臓と他臓器相関】脂肪性肝疾患における自律神経系を介した消化管ホルモンの関与

大脇崇史, 上村顕也, 永山逸夫, 高昌良, 名古屋拓郎, 井上良介, 薛徹, 寺井崇二

消化器・肝臓内科 11 ( 6 ) 709 - 713 2022年6月

多発性出血性膵炎を伴う重度の急性肝不全の一例(A case of severe acute liver failure with multiple hemorrhagic pancreatitis)

神保遼, 荒生祥尚, 山崎華子, 水戸將貴, 小島雄一, 木村成宏, 小林雄司, 林和直, 土屋淳紀, 寺井崇二

日本消化器病学会甲信越支部例会抄録集 70回 np41 - np41 2022年6月

悪性胆道狭窄に対する治療戦略術後再建腸管例の悪性胆道狭窄に対するバルーン内視鏡下胆道ドレナージの有用性

名古屋拓郎, 寺井崇二, 林和直, 五十嵐聡, 小川光平

日本消化器病学会甲信越支部例会抄録集 70回 np46 - np46 2022年6月

NAFLDにおける肝-脳-腸関連と自律神経の関係

永山逸夫, 上村顕也, 高昌良, 大脇崇史, 名古屋拓郎, 寺井崇二

自律神経 59 ( 2 ) 208 - 211 2022年6月

記述言語：日本語出版者・発行元：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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その他リンク： 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

Diagnostic criteria for acute-on-chronic liver failure and related disease conditions in Japan. 国際誌

Satoshi Mochida, Nobuaki Nakayama, Shuji Terai, Hitoshi Yoshiji, Masahito Shimizu, Akio Ido, Kazuaki Inoue, Takuya Genda, Yasuhiro Takikawa, Taro Takami, Naoya Kato, Masanori Abe, Ryuzo Abe, Ayano Inui, Hiromasa Ohira, Mureo Kasahara, Kazuaki Chayama, Kiyoshi Hasegawa, Atsushi Tanaka

Hepatology research : the official journal of the Japan Society of Hepatology 52 ( 5 ) 417 - 421 2022年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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Development of Dilated Esophagus, Sigmoid Esophagus, and Esophageal Diverticulum in Patients With Achalasia: Japan Achalasia Multicenter Study. 国際誌

Hiroki Sato, Yusuke Fujiyoshi, Hirofumi Abe, Hironari Shiwaku, Junya Shiota, Chiaki Sato, Hiroyuki Sakae, Masaki Ominami, Yoshitaka Hata, Hisashi Fukuda, Ryo Ogawa, Jun Nakamura, Tetsuya Tatsuta, Yuichiro Ikebuchi, Hiroshi Yokomichi, Shuji Terai, Haruhiro Inoue

Journal of neurogastroenterology and motility 28 ( 2 ) 222 - 230 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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Effects of Atezolizumab and Bevacizumab on Adrenal Gland Metastasis of Hepatocellular Carcinoma: A Case Report and Review of Literature.

Natsuki Ishikawa, Kenya Kamimura, Saori Endo, Soichi Ishii, Kazuya Ogawa, Norihiro Sakai, Hiroyuki Abe, Masayoshi Ko, Osamu Shibata, Youhei Koseki, Junji Yokoyama, Akira Sakamaki, Shuji Terai

Internal medicine (Tokyo, Japan) 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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老化細胞除去治療のAcute on chronic liverfailureに対する効果の検証

渡邉雄介, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.1 ) A371 - A371 2022年4月

肝硬変-合併症の管理(含む門脈圧亢進症) 水素型の小腸内細菌異常増殖は肝疾患の不顕性肝性脳症と筋肉量低下に関連する

坂牧僚, 土屋淳紀, 寺井崇二

肝臓 63 ( Suppl.1 ) A64 - A64 2022年4月

【革新的技術が変える肝疾患診療】間葉系幹細胞・エクソソームを用いた肝硬変治療

土屋淳紀, 寺井崇二

消化器・肝臓内科 11 ( 4 ) 494 - 499 2022年4月

Relative Dose Intensityに基づく高齢者レンバチニブ投与における全生存期間の検討

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

肝臓 63 ( Suppl.1 ) A302 - A302 2022年4月

Utility of autologous fecal microbiota transplantation and elucidation of microbiota in diversion colitis. 国際誌

Kentaro Tominaga, Atsunori Tsuchiya, Takeshi Mizusawa, Asami Matsumoto, Ayaka Minemura, Kentaro Oka, Motomichi Takahashi, Tomoaki Yoshida, Yuichi Kojima, Kohei Ogawa, Yuzo Kawata, Nao Nakajima, Naruhiro Kimura, Hiroyuki Abe, Toru Setsu, Kazuya Takahashi, Hiroki Sato, Satoshi Ikarashi, Kazunao Hayashi, Ken-Ichi Mizuno, Junji Yokoyama, Yosuke Tajima, Masato Nakano, Yoshifumi Shimada, Hitoshi Kameyama, Toshifumi Wakai, Shuji Terai

DEN open 2 ( 1 ) e63 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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Intestinal duplication diagnosed preoperatively with double-balloon enteroscopy: an extremely rare case report and literature review.

Yusuke Niwa, Kentaro Tominaga, Yuzo Kawata, Takamasa Kobayashi, Takeshi Mizuwasa, Kazuya Takahashi, Hiroki Sato, Junji Kohisa, Satoshi Abe, Kenya Kamimura, Junji Yokoyama, Hirokazu Kawai, Hideaki Sugino, Hajime Umezu, Yumiko Hirai, Masato Nakano, Yoshifumi Shimada, Hitoshi Kameyama, Toshifumi Wakai, Shuji Terai

Clinical journal of gastroenterology 15 ( 2 ) 381 - 387 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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Methotrexate-associated proliferative disorder in the lower esophagus extending to the gastroesophageal junction: A case report. 国際誌

Yuki Hojo, Masafumi Takatsuna, Satoshi Ikarashi, Hiroteru Kamimura, Rika Kimura, Masaki Mito, Yusuke Watanabe, Yusuke Tani, Junji Yokoyama, Shuji Terai

DEN open 2 ( 1 ) e14 2022年4月

記述言語：英語

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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肝線維化研究Revisited-肝臓学のBiologyからTranslationalへヒト肝細胞キメラマウスを用いた薬剤のスクリーニングドラッグリポジショニングによる肝線維化治療薬の探索・メカニズムの検証

酒井規裕, 上村顕也, 寺井崇二

肝臓 63 ( Suppl.1 ) A174 - A174 2022年4月

脂肪性肝疾患における自律神経系経路を介した脂質代謝制御の解明と治療薬スクリーニング

上村顕也, 大脇崇史, 寺井崇二

肝臓 63 ( Suppl.1 ) A254 - A254 2022年4月

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