研究者詳細 - 赤穂　宗一郎

論文 - 赤穂　宗一郎

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【膵・胆道癌の発生・進展メカニズムを探る】膵癌の薬剤耐性メカニズム

寺澤裕之, 堤康一郎, 原田圭, 服部直, 菊池達也, 小幡泰介, 佐藤亮介, 織田崇志, 松三明宏, 宮本和也, 藤井佑樹, 赤穂宗一郎, 内田大輔, 松本和幸, 堀口繁, 大塚基之

胆と膵 45 ( 8 ) 801 - 806 2024年8月

記述言語：日本語出版者・発行元：医学図書出版(株)

膵癌は予後不良な難治癌であるが,その一因として薬剤耐性があげられる。薬剤耐性のメカニズムとして,標的治療が難しいKRAS変異の存在やエピジェネティック機構などの遺伝子変異や薬物代謝の変化,転移・浸潤を促進するEMT,膵癌に特徴的な間質成分の多い腫瘍微小環境,さらにnon-coding RNAによる遺伝子発現の調整などがあり,それらが複合的に影響していると考えられている。この複雑な薬剤耐性メカニズムのさらなる解明がその克服において重要である。(著者抄録)

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【膵・胆道癌の発生・進展メカニズムを探る】膵癌の薬剤耐性メカニズム

胆と膵 45 ( 8 ) 801 - 806 2024年8月

記述言語：日本語出版者・発行元：医学図書出版(株)

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Methylation analysis of DCC gene in saliva samples is an efficient method for non-invasive detection of superficial hypopharyngeal cancer. 国際誌

Ryosuke Hirai, Hideaki Kinugasa, Shumpei Yamamoto, Soichiro Ako, Koichiro Tsutsumi, Makoto Abe, Koji Miyahara, Masahiro Nakagawa, Motoyuki Otsuka

British journal of cancer 2024年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Advances in upper gastrointestinal endoscopic technology have enabled early detection and treatment of hypopharyngeal cancer. However, in-depth pharyngeal observations require sedation and are invasive. It is important to establish a minimally invasive and simple evaluation method to identify high-risk patients. METHODS: Eighty-seven patients with superficial hypopharyngeal cancer and 51 healthy controls were recruited. We assessed the methylation status of DCC, PTGDR1, EDNRB, and ECAD, in tissue and saliva samples and verified the diagnostic accuracy by methylation analyses of their promoter regions using quantitative methylation-specific PCR. RESULTS: Significant differences between cancer and their surrounding non-cancerous tissues were observed in the methylation values of DCC (p = 0.003), EDNRB (p = 0.001), and ECAD (p = 0.043). Using receiver operating characteristic analyses of the methylation values in saliva samples, DCC showed the highest area under the curve values for the detection of superficial hypopharyngeal cancer (0.917, 95% confidence interval = 0.864-0.970), compared with those for EDNRB (0.680) and ECAD (0.639). When the cutoff for the methylation values of DCC was set at ≥0.163, the sensitivity to detect hypopharyngeal cancer was 82.8% and the specificity was 90.2%. CONCLUSIONS: DCC methylation in saliva samples could be a non-invasive and efficient tool for early detection of hypopharyngeal cancer in high-risk patients.

DOI： 10.1038/s41416-024-02654-2

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MicroRNA-34a-5p: A pivotal therapeutic target in gallbladder cancer. 国際誌

Takashi Oda, Koichiro Tsutsumi, Taisuke Obata, Eijiro Ueta, Tatsuya Kikuchi, Soichiro Ako, Yuki Fujii, Tatsuhiro Yamazaki, Daisuke Uchida, Kazuyuki Matsumoto, Shigeru Horiguchi, Hironari Kato, Hiroyuki Okada, Ryota Chijimatsu, Motoyuki Otsuka

Molecular therapy. Oncology 32 ( 1 ) 200765 - 200765 2024年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Gallbladder cancer incidence has been increasing globally, and it remains challenging to expect long prognosis with the current systemic chemotherapy. We identified a novel nucleic acid-mediated therapeutic target against gallbladder cancer by using innovative organoid-based gallbladder cancer models generated from KrasLSL-G12D/+; Trp53f/f mice. Using comprehensive microRNA expression analyses and a bioinformatics approach, we identified significant microRNA-34a-5p downregulation in both murine gallbladder cancer organoids and resected human gallbladder cancer specimens. In three different human gallbladder cancer cell lines, forced microRNA-34a-5p expression inhibited cell proliferation and induced cell-cycle arrest at the G1 phase by suppressing direct target (CDK6) expression. Furthermore, comprehensive RNA sequencing revealed the significant enrichment of gene sets related to the cell-cycle regulators after microRNA-34a-5p expression in gallbladder cancer cells. In a murine xenograft model, locally injected microRNA-34a-5p mimics significantly inhibited gallbladder cancer progression and downregulated CDK6 expression. These results provide a rationale for promising therapeutics against gallbladder cancer by microRNA-34a-5p injection, as well as a strategy to explore therapeutic targets against cancers using organoid-based models, especially for those lacking useful genetically engineered murine models, such as gallbladder cancer.

DOI： 10.1016/j.omton.2024.200765

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MicroRNA-451a inhibits gemcitabine-refractory biliary tract cancer progression by suppressing the MIF-mediated PI3K/AKT pathway. 国際誌

Taisuke Obata, Koichiro Tsutsumi, Eijiro Ueta, Takashi Oda, Tatsuya Kikuchi, Soichiro Ako, Yuki Fujii, Tatsuhiro Yamazaki, Daisuke Uchida, Kazuyuki Matsumoto, Shigeru Horiguchi, Hironari Kato, Hiroyuki Okada, Motoyuki Otsuka

Molecular therapy. Nucleic acids 34 102054 - 102054 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Gemcitabine is an effective chemotherapeutic agent for biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CCA). However, few other effective agents are currently available, particularly for GEM-refractory BTCs. We previously identified microRNA-451a (miR-451a) as a potential therapeutic target in GBC. To elucidate the antineoplastic effects of miR-451a and its underlying mechanisms, we transfected miR-451a into GBC, gemcitabine-resistant GBC (GR-GBC), and gemcitabine-resistant CCA (GR-CCA) cell lines. Furthermore, mimicking in vivo conditions, tumorigenic GBC organoids and three-dimensional (3D) cell culture systems were employed to investigate the anti-proliferative effects of miR-451a on BTCs, and its effect on stem cell properties. We found that miR-451a significantly inhibited cell proliferation, induced apoptosis, and reduced chemoresistant phenotypes, such as epithelial-mesenchymal transition, in both GBC and GR-GBC. The principal mechanism is probably the negative regulation of the phosphatidylinositol 3-kinase/AKT pathway, partially accomplished by directly downregulating macrophage migration inhibitory factor. The Gene Expression Omnibus database revealed that miR-451a was the most significantly downregulated microRNA in CCA tissues. The introduction of miR-451a resulted in similar antineoplastic effects in GR-CCA. Furthermore, miR-451a reduced cell viability in 3D spheroid models and tumorigenic GBC organoids. These findings suggest that the supplementation of miR-451a is a potential treatment strategy for GEM-refractory BTCs.

DOI： 10.1016/j.omtn.2023.102054

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医学生は、学内演習でもコミュニケーションにおける成長を自覚するのかコロナ禍での挑戦

三好智子, 川端崇義, 猪田宏美, 小崎吉訓, 越智可奈子, 赤穂宗一郎, 座間味義人, 伊野英男, 成瀬恵治, 松川昭博

医学教育 54 ( Suppl. ) 285 - 285 2023年7月

胆嚢オルガノイドを用いた発癌モデルより同定したmiR-34a-5p補充による胆嚢癌治療の開発

織田崇志, 堤康一郎, 小幡泰介, 菊池達也, 松三明宏, 宮本和也, 森本光作, 寺澤裕之, 藤井佑樹, 山崎辰洋, 赤穂宗一郎, 内田大輔, 松本和幸, 堀口繁, 加藤博也, 大塚基之

日本消化器病学会雑誌 120 ( 臨増総会 ) A328 - A328 2023年3月

ウィズコロナ下の学生ワクチン接種実習における岡山大学の工夫と課題について

小崎吉訓, 越智加奈子, 赤穂宗一郎, 三好智子, 山口貴子, 伊野英男, 松川昭博, 伊達勲

医学教育 53 ( Suppl. ) 141 - 141 2022年7月

医学科1年生における手指衛生指導の実践と課題

越智可奈子, 三好智子, 小崎吉訓, 赤穂宗一郎, 小山敏広, 山下範之, 伊野英男, 松川昭博, 伊達勲

医学教育 53 ( Suppl. ) 185 - 185 2022年7月

情熱にあふれた入学者を求む!夏休み高校生メディカルスクール開講とその成果

三好智子, 小崎吉訓, 越智可奈子, 赤穂宗一郎, 山下範之, 山口貴子, 犬飼恭二, 物部和彦, 伊野英男, 伊達勲

医学教育 53 ( Suppl. ) 144 - 144 2022年7月

Modified line-assisted complete closure of the defect after gastric endoscopic full-thickness resection: a pilot study in porcine models. 国際誌

Yasushi Yamasaki, Masayasu Ohmori, Junki Toyosawa, Soichiro Ako, Hiroyuki Okada

Endoscopy international open 10 ( 5 ) E609-E615 2022年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background and study aims Closure after endoscopic full-thickness resection (EFTR) is challenging. We previously developed a simple endoscopic closure method: line-assisted complete closure (LACC). We performed a pilot study using porcine models to evaluate the feasibility of modified LACC after gastric EFTR. Patients and methods Six live pigs were included. EFTR (greater curvature of the gastric antrum [n = 3] and anterior wall of the gastric body [n = 3]) was performed under general anesthesia and the defect after EFTR was closed by modified LACC. The pigs were observed until postoperative day 4 (Day 4). The closure site was endoscopically evaluated and the presence or absence of peritonitis and fluid leakage was evaluated. The outcomes were the success rate of modified LACC on the day of the procedure, maintenance of defect closure, presence of peritonitis or leakage, and clinical course. Results Once complete closure was successfully achieved in all cases, maintenance of closure on Day 4 was not achieved. However, there was neither peritonitis nor fluid leakage. The defect was completely covered by surrounding tissues on Day 4 and the clinical course was good in all cases. Conclusions The feasibility of modified LACC after gastric EFTR was demonstrated in porcine models. Further improvement is needed to maintain defect closure.

DOI： 10.1055/a-1785-8589

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Fever and electrocoagulation syndrome after colorectal endoscopic submucosal dissection for patients with immunosuppressants and steroids. 国際誌

Shumpei Yamamoto, Hideaki Kinugasa, Yasushi Yamasaki, Mami Hirai, Soichiro Ako, Kensuke Takei, Shoko Igawa, Eriko Yasutomi, Shohei Oka, Masayasu Ohmori, Toshihiro Inokuchi, Keita Harada, Sakiko Hiraoka, Kazuhiro Nouso, Takehiro Tanaka, Hiroyuki Okada

DEN open 2 ( 1 ) e83 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Transient fever and electrocoagulation syndrome after colorectal endoscopic submucosal dissection (ESD) remain a challenge. The aim of this study was to assess the risk factors of post-ESD fever and post-ESD coagulation syndrome (PECS), focusing on the involvement of immunosuppressive drugs and steroids (IM). METHODS: This retrospective analysis included 510 patients who underwent colorectal ESD at Okayama University Hospital from 2015 to 2020. The incidence rate, clinical outcome, and factors associated with post-ESD fever and PECS were investigated. RESULTS: Post-ESD fever and PECS occurred in 63 patients (12.4%) and 43 patients (8.4%), respectively. In multivariate analysis, the American Society of Anesthesiologists Physical Status ≥3, the use of immunosuppressants or prednisolone ≥5mg (IM group), and injury to muscle layer/perforation were significantly associated with post-ESD fever. In PECS, IM group, tumors located on the right side, treatment time ≥60 min, injury to the muscle layer, and multiple lesions were independent risk factors. Both post-ESD fever and PECS improved conservatively in the IM group, and no serious complication was observed. CONCLUSIONS: The use of IM was a risk factor for both post-ESD fever and PECS. However, there were no serious complications in colorectal ESD for patients taking IM.

DOI： 10.1002/deo2.83

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【Liquid biopsyは膵癌の診断・治療をどう変えるか?】膵癌診断・治療においてliquid biopsyは腫瘍マーカーを凌駕するか?

衣笠秀明, 能祖一裕, 加藤博也, 赤穂宗一郎, 岡田裕之

胆と膵 43 ( 1 ) 77 - 81 2022年1月

記述言語：日本語出版者・発行元：医学図書出版(株)

次世代シークエンサーとデジタルPCRの登場はliquid biopsyをめざましく進歩させた。従来法の生検と異なり、非侵襲的にリアルタイムで情報取得が可能であり、近年もっとも注目されている手法である。しかし、本邦の膵癌ガイドラインにおいて、膵癌診断法のひとつとして腫瘍マーカーがあげられているものの、liquid biopsyに関しては明記されていない。診断、フォローアップ、予後予測、治療効果予測などに関して、liquid biopsyの有用性が相次いで報告されており、その活躍の場は今後ますます増えてくると思われる。しかし、liquid biopsyが腫瘍マーカーを凌駕する側面はあるものの、簡便なモニタリングとして腫瘍マーカーが役立つ場面も多い。現状においては、liquid biopsyと腫瘍マーカーを融合し、おのおのの利点を組み合わせながら診断、フォローアップ、予後予測、治療効果予測の精度を高めていくべきと考える。(著者抄録)

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Statins Inhibit Inflammatory Cytokine Production by Macrophages and Acinar-to-Ductal Metaplasia of Pancreatic Cells. 国際誌

Soichiro Ako, Yaroslav Teper, Linda Ye, James Sinnett-Smith, Oscar J Hines, Enrique Rozengurt, Guido Eibl

Gastro hep advances 1 ( 4 ) 640 - 651 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND AIMS: Animal data show that the presence of an oncogenic Kras mutation in pancreatic acinar cells leads to acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN), and pancreatic ductal adenocarcinoma (PDAC). Inflammatory macrophages play an important role in the formation of ADMs and transition to PanINs. Epidemiologically, statins are associated with a reduced risk of PDAC. We investigated whether statins inhibit inflammatory cytokine production in macrophages and whether this leads to reduced ADM formation. METHODS: The efficacy of statins on inflammatory cytokine production in 2 macrophage cell lines was measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of macrophage-conditioned medium on ADM in primary pancreatic acinar cells was investigated. Mouse pancreatic tissue samples were analyzed for macrophage numbers, cytokine levels, and neoplastic/dysplastic area. RESULTS: Lipophilic statins prevented inflammatory cytokine production in Raw264.7 and J774A.1 cells stimulated by lipopolysaccharide. The inhibitory effect of statins was mediated by inhibition of mevalonate and geranylgeranyl pyrophosphate synthesis and disruption of the actin cytoskeleton but not by a reduction in intracellular cholesterol. Treatment of macrophages with lipophilic statins also blocked ADM formation of primary pancreatic acinar cells. Furthermore, oral administration of simvastatin was associated with a reduction in the number of intrapancreatic macrophages, decreased inflammatory cytokine levels in the pancreas, and attenuated ADM/PanIN formation in mice. CONCLUSION: Our data support the hypothesis that statins oppose early PDAC development by their effects on macrophages and ADM formation. The inhibitory actions of statins on macrophages may collaborate with direct inhibitory effects on transformed pancreatic epithelial cells, which cumulatively may reduce early PDAC development and progression.

DOI： 10.1016/j.gastha.2022.04.012

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Plasma KRAS mutations predict the early recurrence after surgical resection of pancreatic cancer. 国際誌

Soichiro Ako, Hironari Kato, Kazuhiro Nouso, Hideaki Kinugasa, Hiroyuki Terasawa, Hiroshi Matushita, Saimon Takada, Yosuke Saragai, Sho Mizukawa, Shinichiro Muro, Daisuke Uchida, Takeshi Tomoda, Kazuyuki Matsumoto, Shigeru Horiguchi, Daisuke Nobuoka, Ryuichi Yoshida, Yuzo Umeda, Takahito Yagi, Hiroyuki Okada

Cancer biology & therapy 22 ( 10-12 ) 1 - 7 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The technique to analyze circulating tumor DNA (ctDNA) in body fluid (so-called "liquid biopsy") is recently developed. AIMS: Our aim was to assess the utility of liquid biopsy for predicting progression of pancreatic ductal adenocarcinoma (PDAC) after surgical resection or chemotherapy. METHODS: A total of 72 patients with PDAC were retrospectively enrolled for this study, 33 treated surgically and 39 given chemotherapy, either FOLFIRINOX (oxaliplatin/irinotecan/fluorouracil/leucovorin) or gemcitabine plus nab-paclitaxel. Prior to treatment, patients were screened for the presence of KRAS mutations (G12D and G12V) in plasma using droplet digital polymerase chain reaction, and outcomes were compared. RESULTS: KRAS mutations were identified in plasma samples of 12 patients (36%) underwent surgical resection. Patients with plasma KRAS mutations had significantly shorter disease-free survival (DFS) and overall survival (p < .01 and p = .01, respectively). Of 10 clinical variables analyzed, plasma KRAS mutation was the factor predictive of DFS in multivariate analysis (RR = 3.58, 95% CI: 1.36-9.60; p = .01). Although 12 patients (31%) given chemotherapy tested positive for plasma KRAS mutations, there was no demonstrable relation between plasma KRAS mutations and progression-free survival (PFS) or overall survival (OS) (p = .35 and p = .68, respectively). CONCLUSIONS: In patients with PDAC, detection of KRAS mutations in plasma proved independently predictive of early recurrence after surgical resection but did not correlate with PFS following chemotherapy.

DOI： 10.1080/15384047.2021.1980312

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コロナ禍における医学科1年次行動科学I〜社会におけるコミュニケーション〜の実施とアウトカム

三好智子, 小崎吉訓, 越智可奈子, 吉田登志子, 山根正修, 赤穂宗一郎, 伊野英男, 大塚愛二, 松川昭博

医学教育 52 ( Suppl. ) 122 - 122 2021年7月

医学科1年生における行動科学授業「コロナ禍での医学生生活を考える」コロナ禍での入学の現状と課題

越智可奈子, 三好智子, 小崎吉訓, 赤穂宗一郎, 吉田登志子, 山根正修, 伊野英男, 大塚愛二, 松川昭博

医学教育 52 ( Suppl. ) 147 - 147 2021年7月

Direct Effects of Lipopolysaccharide on Human Pancreatic Cancer Cells. 国際誌

Roxanne L Massoumi, Yaroslav Teper, Soichiro Ako, Linda Ye, Elena Wang, O Joe Hines, Guido Eibl

Pancreas 50 ( 4 ) 524 - 528 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Obesity, a risk factor for pancreatic adenocarcinoma (PDAC), is often accompanied by a systemic increase in lipopolysaccharide (LPS; metabolic endotoxemia), which is thought to mediate obesity-associated inflammation. However, the direct effects of LPS on PDAC cells are poorly understood. METHODS: The expression of toll-like receptor 4, the receptor for LPS, was confirmed in PDAC cell lines. AsPC-1 and PANC-1 cells were exposed to LPS, and differential gene expression was determined by RNA sequencing. The activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway by LPS in PDAC cells was assessed by Western blotting. RESULTS: The expression of toll-like receptor 4 was confirmed in all PDAC cell lines. The exposure to LPS led to differential expression of 3083 genes (426 ≥5-fold) in AsPC-1 and 2584 genes (339 ≥5-fold) in PANC-1. A top canonical pathway affected by LPS in both cell lines was PI3K/Akt/mTOR. Western blotting confirmed activation of this pathway as measured by phosphorylation of the ribosomal protein S6 and Akt. CONCLUSIONS: The exposure of PDAC cells to LPS led to differential gene expression. A top canonical pathway was PI3K/Akt/mTOR, a known oncogenic driver. Our findings provided evidence that LPS can directly induce differential gene expression in PDAC cells.

DOI： 10.1097/MPA.0000000000001790

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Evaluation of Local Recurrence of Pancreatic Cancer by KRAS Mutation Analysis Using Washes from Endoscopic Ultrasound-Guided Fine-Needle Aspiration. 国際誌

Kazuyuki Matsumoto, Hironari Kato, Kazuhiro Nouso, Soichiro Ako, Hideaki Kinugasa, Shigeru Horiguchi, Yosuke Saragai, Saimon Takada, Shuntaro Yabe, Shinichiro Muro, Daisuke Uchida, Takeshi Tomoda, Hiroyuki Okada

Digestive diseases and sciences 65 ( 10 ) 2907 - 2913 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND AIMS: The sensitivity of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for diagnosing the recurrence of pancreatic cancer is usually low because of difficulties in obtaining adequate samples for pathological examinations. We evaluated the efficacy of highly sensitive KRAS mutation analysis using EUS-FNA washes to detect cancer recurrence. METHODS: Nineteen consecutive patients with suspected pancreatic cancer recurrence after surgical resection were enrolled. All underwent EUS-FNA, and samples were obtained for pathological examination. After the first session, the inside of the FNA needle was washed with saline for DNA extraction. KRAS mutations were examined using digital droplet PCR (dPCR). RESULTS: The median needle puncture number used to obtain adequate pathological samples was two (range 1-6). In ten patients pathologically diagnosed with malignant pancreatic cancer, nine patients tested positive for a KRAS mutation. All patients who were not diagnosed with a malignant pancreatic cancer tested negative for a KRAS mutation. About half of surgically resected primary cancers (9/19) showed double KRAS mutations (G12V and G12D); however, all but one wash sample showed a single KRAS mutation, G12D. After including one patient who showed a malignant recurrence during follow-up, the sensitivities of a pathological diagnosis and KRAS analysis to detect recurrence were 90.9% and 81.8%, respectively. CONCLUSIONS: KRAS mutation analysis of needle wash samples using dPCR is a new methodology for the diagnosis of the local recurrence of pancreatic cancer. The diagnostic ability of dPCR with a one-time needle wash sample was comparable to a pathological diagnosis with multiple samplings.

DOI： 10.1007/s10620-019-06006-6

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Ballvalve syndromeを契機に診断されたGAPPS (Gastric Adenocarcinoma and Proximal Polyposis of the Stomach)一例とその家系の検討

赤穂宗一郎, 川野誠司, 岡上昇太郎, 里見拓也, 岡本雄貴, 大林由佳, 馬場雄己, 濱田健太, 榮浩行, 安部真, 神崎洋光, 岩室雅也, 河原祥朗, 田中健太, 岡田裕之

Gastroenterological Endoscopy 62 ( Suppl.2 ) 2101 - 2101 2020年10月

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