Papers - NAKASE Hiroshi

胃蜂窩織炎を併発したNASH肝硬変の1剖検例

岩田 徳和, 田中 克典, 矢花 剛, 小関 至, 菊地 剛史, 見田 裕章, 安達 靖代, 吉田 幸成, 足立 靖, 加藤 康夫, 遠藤 高夫, 阿久津 典之, 佐々木 茂, 仲瀬 裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 )  117 ( 臨増総会 ) A385 - A385  2020.07

当科における切除不能・再発胆道癌に対するGemcitabine/cisplatin/S-1(GCS)併用療法の経験

本谷 雅代, 柾木 喜晴, 川上 裕次郎, 石上 敬介, 伊東 文子, 阿久津 典之, 佐々木 茂, 仲瀬 裕志

日本消化器病学会雑誌 ( (一財)日本消化器病学会 )  117 ( 臨増総会 ) A392 - A392  2020.07

対照的な経過を辿った膵動静脈奇形の2例

高田 夢実, 石上 敬介, 平野 雄大, 川上 裕次郎, 柾木 喜晴, 室田 文子, 本谷 雅代, 山口 洋志, 今村 将史, 木村 康利, 岡 俊州, 金戸 宏行, 竹政 伊知朗, 仲瀬 裕志

膵臓 ( (一社)日本膵臓学会 )  35 ( 3 ) A461 - A461  2020.07

IPMNの術前診断におけるSpyGlass DSの有用性

川上 裕次郎, 本谷 雅代, 平野 雄大, 我妻 康平, 石上 敬介, 柾木 喜晴, 室田 文子, 佐々木 茂, 山口 洋志, 今村 将史, 木村 康利, 竹政 伊知朗, 仲瀬 裕志

膵臓 ( (一社)日本膵臓学会 )  35 ( 3 ) A355 - A355  2020.07

穿刺針の太さによるEUS-FNBの診断率の差異

柾木 喜晴, 平野 雄大, 川上 裕次郎, 石上 敬介, 室田 文子, 本谷 雅代, 佐々木 茂, 仲瀬 裕志

膵臓 ( (一社)日本膵臓学会 )  35 ( 3 ) A380 - A380  2020.07

CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients.

Yuki Yamamoto, Hiroshi Nakase, Minoru Matsuura, Shihoko Maruyama, Satohiro Masuda

International journal of molecular sciences   21 ( 12 )  2020.06  [Refereed]  [International journal]

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Tacrolimus has been used to induce remission in patients with steroid-refractory ulcerative colitis. It poses a problem of large individual differences in dosage necessary to attain target blood concentration and, often, this leads to drug inefficacy. We examined the difference in mRNA expression levels of ATP binding cassette transporter B1 (ABCB1) between inflamed and non-inflamed tissues, and the influence of CYP3A5 genotype on tacrolimus therapy. The mRNA expression of CYP3A4 in colonic mucosa and that of cytochrome p450 3A5 (CYP3A5) and ABCB1 in inflamed and non-inflamed areas were examined in 14 subjects. The mRNA expression levels of CYP3A5 were higher than that of CYP3A4. The mRNA expression of ABCB1 was lower in the inflamed than in the non-inflamed mucosa, despite that of CYP3A5 mRNA level being not significantly changed. Hence, the deterioration of the disease is related to the reduction of the barrier in the inflamed mucosa. The relationship between CYP3A5 genotype and blood concentration, dose, and concentration/dose (C/D) ratio of tacrolimus in 15 subjects was studied. The tacrolimus dose to maintain equivalent blood concentrations was lower in CYP3A5*3/*3 than in CYP3A5*1 carriers, and the C/D ratio was significantly higher in the latter. Thus, CYP3A5 polymorphism information played a role in determining the initial dose of tacrolimus. Furthermore, since the effect of tacrolimus appears earlier in CYP3A5*3/*3 than in CYP3A5*1/*1 and *1/*3, it seems necessary to change the evaluation time of therapeutic effect by CYP3A5 genotype. Additionally, the relationship between CYP3A5 genotype and C/D ratio of tacrolimus in colonic mucosa was investigated in 10 subjects. Tacrolimus concentration in the mucosa was two-fold higher in CYP3A5*3/*3 than in CYP3A5*1 carriers, although no significant difference in tacrolimus-blood levels was observed. Therefore, the local concentration of tacrolimus affected by CYP3A5 polymorphism might be related to its therapeutic effect.

DOI PubMed

Double small bowel cancers leading to the diagnosis of Lynch syndrome with germline MSH6 mutation in an elderly patient.

Sae Ohwada, Kentaro Yamashita, Tomoe Kazama, Kei Mitsuhashi, Akiko Ichiyanagi, Kohei Nakachi, Hiro-O Yamano, Takayuki Nobuoka, Tatsuya Ito, Wataru Sasao, Hiroshi Nakase

Clinical journal of gastroenterology    2020.06  [Refereed]  [Domestic journal]

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A female patient in her 80s was referred to our hospital because of an ileal tumor identified by capsule endoscopy. FDG-PET suggested double intestinal tumors not only in the ileum but also in the jejunum. The patient has cancer past history including sigmoid colon, rectum, and endometrium, and also had cancer family history fulfilling the revised Amsterdam criteria. Double balloon enteroscopy disclosed two ulcerated tumors in the jejunum and the ileum. Biopsy was diagnosed as adenocarcinoma pathologically, and microsatellite instability-high (MSI-H) genetically. Surgical resection was performed, and the jejunal and the ileal tumors were tubular (T2N0M0) and mucinous adenocarcinoma (T4N0M0), respectively. Germline mutation analysis revealed a pathogenic splice-site mutation in MSH6.

DOI PubMed

Sigmoid colon tumor with G-nas mutation presenting unique morphology.

Gota Sudo, Hironori Aoki, Yuko Omori, Hiromu Suzuki, Hiroshi Nakase

Gastrointestinal endoscopy   92 ( 5 ) 1133 - 1135  2020.06  [Refereed]  [International journal]

DOI PubMed

【無痛大腸内視鏡挿入法-technique & device】総論 軸保持短縮法の基本

山野 泰穂, 吉井 新二, 仲瀬 裕志

Intestine ( (株)日本メディカルセンター )  24 ( 2 ) 99 - 104  2020.06

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＜文献概要＞大腸は柔軟性・伸縮性に富み,かつ複雑であるばかりではなく個人差もあり,多彩な形状を示す管腔臓器である.この大腸にスコープを挿入する方法として軸保持短縮法がある.その内容はストラテジー(戦略)とタクティクス(戦術)に分けて考えると理解しやすい.ストラテジーとは結腸,直腸に5ヶ所の固定点を想定し,これらを直線で結ぶ経路を軸と称し,これになぞらえるように腸管およびスコープを修正し挿入していくことで腸管が過伸展することなく安全,無痛性に挿入できるとした全体構想である.タクティクスとは実際の局面でどのように操作するべきなのかの実践であるが,スコープ軸を保持するように操作することがスコープ動作を掌握するうえで重要である.また腸管はさまざまな形状を示すため,スコープ軸は時に一つとは限らず,これらの軸を最終的には固定点を結んだ軸に一致させることを,机上および実際のUPD画像を通じて解説した.

Intestinal epithelial cell-derived IL-15 determines local maintenance and maturation of intra-epithelial lymphocytes in the intestine.

Yuanbo Zhu, Guangwei Cui, Eiji Miyauchi, Yuki Nakanishi, Hisa Mukohira, Akihiro Shimba, Shinya Abe, Shizue Tani-Ichi, Takahiro Hara, Hiroshi Nakase, Tsutomu Chiba, Atsuko Sehara-Fujisawa, Hiroshi Seno, Hiroshi Ohno, Koichi Ikuta

International immunology   32 ( 5 ) 307 - 319  2020.05  [Refereed]  [International journal]

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Interleukin-15 (IL-15) is a cytokine critical for maintenance of intestinal intra-epithelial lymphocytes (IELs), especially CD8αα + IELs (CD8αα IELs). In the intestine, IL-15 is produced by intestinal epithelial cells (IECs), blood vascular endothelial cells (BECs) and hematopoietic cells. However, the precise role of intestinal IL-15 on IELs is still unknown. To address the question, we generated two kinds of IL-15 conditional knockout (IL-15cKO) mice: villin-Cre (Vil-Cre) and Tie2-Cre IL-15cKO mice. IEC-derived IL-15 was specifically deleted in Vil-Cre IL-15cKO mice, whereas IL-15 produced by BECs and hematopoietic cells was deleted in Tie2-Cre IL-15cKO mice. The cell number and frequency of CD8αα IELs and NK IELs were significantly reduced in Vil-Cre IL-15cKO mice. By contrast, CD8αα IELs were unchanged in Tie2-Cre IL-15cKO mice, indicating that IL-15 produced by BECs and hematopoietic cells is dispensable for CD8αα IELs. Expression of an anti-apoptotic factor, Bcl-2, was decreased, whereas Fas expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. Forced expression of Bcl-2 by a Bcl-2 transgene partially restored CD8αα IELs in Vil-Cre IL-15cKO mice, suggesting that some IL-15 signal other than Bcl-2 is required for maintenance of CD8αα IELs. Furthermore, granzyme B production was reduced, whereas PD-1 expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. These results collectively suggested that IEC-derived IL-15 is essential for homeostasis of IELs by promoting their survival and functional maturation.

DOI PubMed

Immunological Mechanisms in Inflammation-Associated Colon Carcinogenesis.

Takehiro Hirano, Daisuke Hirayama, Kohei Wagatsuma, Tsukasa Yamakawa, Yoshihiro Yokoyama, Hiroshi Nakase

International journal of molecular sciences   21 ( 9 )  2020.04  [Refereed]  [International journal]

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Patients with chronic inflammatory bowel diseases are at an increased risk of developing colitis-associated cancer (CAC). Chronic inflammation positively correlates with tumorigenesis. Similarly, the cumulative rate of incidence of developing CAC increases with prolonged colon inflammation. Immune signaling pathways, such as nuclear factor (NF)-κB, prostaglandin E2 (PGE2)/cyclooxygenase-2 (COX-2), interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3), and IL-23/T helper 17 cell (Th17), have been shown to promote CAC tumorigenesis. In addition, gut microbiota contributes to the development and progression of CAC. This review summarizes the signaling pathways involved in the pathogenesis following colon inflammation to understand the underlying molecular mechanisms in CAC tumorigenesis.

DOI PubMed

Treatment of inflammatory bowel disease from the immunological perspective.

Hiroshi Nakase

Immunological medicine     1 - 8  2020.04  [Refereed]  [International journal]

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Since 1950, the number of patients with inflammatory bowel disease (IBD) in Japan has been increasing. Recent research data indicate that the pathophysiology of IBD involves abnormalities in disease susceptibility genes, environmental factors and intestinal bacteria. The elucidation of the mechanism of IBD has facilitated therapeutic development based on basic research data. In particular, the emergence of biologics has brought about a paradigm shift in the treatment of IBD. However, there are still IBD patients who are refractory to these biologics. IBD pathophysiology is extremely complex. Therefore, to address these clinical issues, further clinical and basic data are required. The bottom line of IBD drug therapy is still to use the most of recent treatments. Therefore, the physicians should be familiar with the modes of action (MOA) of the available drugs.

DOI PubMed

A Rare Cause of Ileus in a Middle-Aged Japanese Woman.

Tomoya Iida, Yoshiaki Arimura, Hiroshi Nakase

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association   18 ( 4 ) e43  2020.04  [Refereed]  [International journal]

DOI PubMed

大腸がんにおけるAEBP1の発現上昇は腫瘍血管新生を促進する

鈴木 拓, 萬 顕, 山本 英一郎, 新沼 猛, 北嶋 洋志, 甲斐 正広, 仲瀬 裕志

日本臨床分子医学会学術総会プログラム・抄録集 ( 日本臨床分子医学会 )  57回   63 - 63  2020.04

Current Diagnostic and Therapeutic Approaches to Cytomegalovirus Infections in Ulcerative Colitis Patients Based on Clinical and Basic Research Data.

Yoshihiro Yokoyama, Tsukasa Yamakawa, Takehiro Hirano, Tomoe Kazama, Daisuke Hirayama, Kohei Wagatsuma, Hiroshi Nakase

International journal of molecular sciences   21 ( 7 )  2020.03  [Refereed]  [International journal]

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Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus (the human herpesvirus 5) and an opportunistic pathogen that primarily infects HIV-positive and other immuno-compromised patients. Retrospective studies in the field of inflammatory bowel disease (IBD) have suggested a relationship between a concomitant colonic HCMV infection and poor outcomes in patients with an ulcerative colitis (UC) due to the presence of HCMV in surgical specimens of patients with a toxic megacolon or a steroid-resistant UC. Therefore, gastroenterologists have focused on the contribution of HCMV infections in the exacerbation of UC. Numerous studies have addressed the benefits of treating colonic HCMV reactivation in UC using an antiviral treatment. However, its clinical relevance remains uncertain as only a few prospective studies have assessed the direct relationship between clinical outcomes and the viral load of HCMV in colonic tissues. HCMV reactivation can be triggered by inflammation according to fundamental research studies. Thus, optimal control of intestinal inflammation is essential for preventing an HCMV reactivation in the intestinal mucosa. Indeed, several reports have indicated the effectiveness of an anti-tumor necrosis factor-alpha (TNFα) treatment in patients with an active UC and concomitant HCMV infections. In this review, we describe the mechanism of HCMV reactivation in UC cases and discuss the current issues regarding diagnosis and treatment of HCMV infections in UC patients.

DOI PubMed

Recanalization of an obstructive pancreaticojejunal anastomosis with direct visualization by using antegrade peroral pancreatoscopy.

Yujiro Kawakami, Shinsuke Koshita, Yoshihide Kanno, Takahisa Ogawa, Toji Murabayashi, Hiroshi Nakase, Kei Ito

Endoscopy    2020.03  [Refereed]  [International journal]

DOI PubMed

New paradigm of B-cell biology regarding the elucidation of a new mechanism of tissue fibrosis in IgG4-related disease.

Hiroshi Nakase, Keisuke Ishigami

The Journal of allergy and clinical immunology   145 ( 3 ) 785 - 787  2020.03  [Refereed]  [International journal]

DOI PubMed

p53-induced ARVCF modulates the splicing landscape and supports the tumor suppressive function of p53.

Natsumi Suzuki, Masashi Idogawa, Shoichiro Tange, Tomoko Ohashi, Yasushi Sasaki, Hiroshi Nakase, Takashi Tokino

Oncogene   39 ( 10 ) 2202 - 2211  2020.03  [Refereed]  [International journal]

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p53 is one of the most important tumor suppressor genes, and the exploration of p53-target genes is important for elucidation of its functional mechanisms. In this study, we identified Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) as a direct target of p53 through ChIP-sequencing analysis. Activated p53 protein was found to bind to two distinct sites in the ARVCF gene, resulting in induction of ARVCF expression at both the mRNA and protein levels. We revealed that the knockdown of ARVCF inhibited p53-induced apoptosis. Interestingly, ARVCF interacted with hnRNPH2, which is involved in pre-mRNA splicing, and ARVCF knockdown induced dynamic changes in alternative splicing patterns. These results suggest that p53-induced ARVCF indirectly, but not directly, regulates p53 target selectivity through splicing alterations of specific genes. Thus, we demonstrated that the induction of ARVCF expression contributed to the tumor suppressive function of p53. Recently, it has been reported that many tumors have thousands of alternative splicing events that are not detectable in normal samples. ARVCF may play a role in alternative splicing events in cancer and may provide clues to explore novel approaches for cancer diagnosis and therapy.

DOI PubMed

次世代シーケンサーによる遺伝子解析を行い得た、肝内胆管粘液癌の一剖検例

柾木 喜晴, 川上 裕次郎, 石上 敬介, 伊東 文子, 阿久津 典之, 本谷 雅代, 佐々木 茂, 足立 靖, 佐々木 泰史, 仲瀬 裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 )  126回・120回   41 - 41  2020.03

消化器がん内視鏡診断・治療の最前線 大腸腫瘍性病変に対するTranslational researchの確立を目指した内視鏡診療

赤保内 正和, 吉井 新二, 鈴木 拓, 山野 泰穂, 仲瀬 裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 )  126回・120回   34 - 34  2020.03