研究者詳細 - 金井　隆典

論文 - 金井　隆典

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Redox-dependent PPARγ/Tnpo1 complex formation enhances PPARγ nuclear localization and signaling

Teratani T., Tomita K., Toma-Fukai S., Nakamura Y., Itoh T., Shimizu H., Shiraishi Y., Sugihara N., Higashiyama M., Shimizu T., Inoue I., Takenaka Y., Hokari R., Adachi T., Shimizu T., Miura S., Kanai T.

Free Radical Biology and Medicine （Free Radical Biology and Medicine） 156 45 - 56 2020年08月

ISSN 08915849

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ has been implicated in the pathogenesis of various human diseases including fatty liver. Although nuclear translocation of PPARγ plays an important role in PPARγ signaling, details of the translocation mechanisms have not been elucidated. Here we demonstrate that PPARγ2 translocates to the nucleus and activates signal transduction through H2O2-dependent formation of a PPARγ2 and transportin (Tnpo)1 complex via redox-sensitive disulfide bonds between cysteine (Cys)176 and Cys180 of the former and Cys512 of the latter. Using hepatocyte cultures and mouse models, we show that cytosolic H2O2/Tnpo1-dependent nuclear translocation enhances the amount of DNA-bound PPARγ and downstream signaling, leading to triglyceride accumulation in hepatocytes and liver. These findings expand our understanding of the mechanism underlying the nuclear translocation of PPARγ, and suggest that the PPARγ and Tnpo1 complex and surrounding redox environment are potential therapeutic targets in the treatment of PPARγ-related diseases.

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A significant association of non-obese non-alcoholic fatty liver disease with sarcopenic obesity

Kashiwagi K., Takayama M., Fukuhara K., Shimizu-Hirota R., Chu P.S., Nakamoto N., Inoue N., Iwao Y., Kanai T.

Clinical Nutrition ESPEN （Clinical Nutrition ESPEN） 38 86 - 93 2020年08月

ISSN 24054577

Background & aims: Non-alcoholic fatty liver disease (NAFLD) is significantly related to sarcopenia as well as obesity and its associated comorbidities. This cross-sectional study aims to examine the association between four body composition phenotypes (standard, obesity alone, sarcopenia alone, sarcopenic obesity) and non-obese NAFLD, or obese NAFLD. Methods: Reduced muscle mass and high percentage of body fat mass was measured by dual-energy x-ray absorptiometry, and body composition phenotypes were determined, according to Asian criteria for sarcopenia. Based on body mass index (BMI) cut-off point (25 kg/m2) and hepatic steatosis on ultrasound, 748 subjects who underwent a health checkup were enrolled and divided into three groups: non-obese NAFLD, obese NAFLD, and no steatosis. Results: Of 563 subjects (64.1 ± 13.0 years) without secondary causes for steatosis, the overall prevalence of non-obese NAFLD and obese NAFLD were 17% and 16%, respectively. The former prevalence remained relatively constant at around 20% from the 50s to 80's, while the proportion of sarcopenic obesity in all subjects increased gradually with age, reaching 18% in the 80's. Multivariate analysis demonstrated a significant association between sarcopenic obesity and non-obese NAFLD after adjusting for confounders (odds ratio = 2.367, 95% confidence interval = 1.317–4.254, P = 0.004). On the other hand, no significant association was found between obesity alone and obese NAFLD, when BMI and visceral adipose tissue were added as confounders, although 91% of obese NAFLD was included in obesity alone phenotype. Conclusion: Non-obese NAFLD had a significant association with sarcopenic obesity, independent of metabolic confounders. Early treatment intervention for non-obese NAFLD could suppress the deterioration of sarcopenic obesity because non-obese NAFLD might be a risk factor for sarcopenic obesity.

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Development of a Scalable Coculture System for Gut Anaerobes and Human Colon Epithelium

Sasaki N., Miyamoto K., Maslowski K.M., Ohno H., Kanai T., Sato T.

Gastroenterology （Gastroenterology） 159 （ 1 ） 388 - 390.e5 2020年07月

ISSN 00165085

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Landscape and function of multiple mutations within individual oncogenes

Saito Y., Koya J., Araki M., Kogure Y., Shingaki S., Tabata M., McClure M.B., Yoshifuji K., Matsumoto S., Isaka Y., Tanaka H., Kanai T., Miyano S., Shiraishi Y., Okuno Y., Kataoka K.

Nature （Nature） 582 （ 7810 ） 95 - 99 2020年06月

ISSN 00280836

Sporadic reports have described cancer cases in which multiple driver mutations (MMs) occur in the same oncogene1,2. However, the overall landscape and relevance of MMs remain elusive. Here we carried out a pan-cancer analysis of 60,954 cancer samples, and identified 14 pan-cancer and 6 cancer-type-specific oncogenes in which MMs occur more frequently than expected: 9% of samples with at least one mutation in these genes harboured MMs. In various oncogenes, MMs are preferentially present in cis and show markedly different mutational patterns compared with single mutations in terms of type (missense mutations versus in-frame indels), position and amino-acid substitution, suggesting a cis-acting effect on mutational selection. MMs show an overrepresentation of functionally weak, infrequent mutations, which confer enhanced oncogenicity in combination. Cells with MMs in the PIK3CA and NOTCH1 genes exhibit stronger dependencies on the mutated genes themselves, enhanced downstream signalling activation and/or greater sensitivity to inhibitory drugs than those with single mutations. Together oncogenic MMs are a relatively common driver event, providing the underlying mechanism for clonal selection of suboptimal mutations that are individually rare but collectively account for a substantial proportion of oncogenic mutations.

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Efficacy and safety of immediate oral intake in patients with mild acute pancreatitis: A randomized controlled trial

Horibe M., Iwasaki E., Nakagawa A., Matsuzaki J., Minami K., Machida Y., Tamagawa H., Takimoto Y., Ueda M., Katayama T., Kawasaki S., Matsushita M., Seino T., Fukuhara S., Kanai T.

Nutrition （Nutrition） 74 2020年06月

ISSN 08999007

Objectives: Early enteral nutrition is recommended for patients with severe acute pancreatitis (AP); however, nutritional management strategies for patients with mild AP have not been established. The aim of this study was to evaluate the benefits and safety of immediate oral intake of low-fat solid food in patients with mild AP who were allowed to take opioid analgesics. Methods: In this single-center randomized study, the immediate feeding (IMF) group was permitted immediate oral intake of low-fat (15 g/d) solid food. In the standard food (STF) group, patients received gradually increasing amounts of dietary fat. Twenty-six patients were randomized, with 13 allocated to each group. The primary outcome was the period between diagnosis and recovery from AP. The cost and rate of progression to severe disease were evaluated as secondary outcomes. Results: The IMF group (mean recovery days: 2 ± 1) recovered significantly earlier (mean difference in recovery days: 6.3; 95% confidence interval [CI], 4.8–7.9; P < 0.001) than the STF group (mean recovery days: 8.3 ± 2.3), with a lower overall treatment cost (mean difference in costs: −$460; 95% CI, −$880 to –$40; P = 0.034). The IMF group showed a lower rate of progression to severe AP (IMF, 0%; STF, 15.3%; P = 0.48). Conclusion: The initial treatment strategy for mild AP should be altered from the gradual introduction of oral feeding upon the absence of pain to immediate oral nutrition with opioid analgesics, to improve treatment efficacy and reduce treatment cost.

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Significance of Conducting 2 Types of Fecal Tests in Patients With Ulcerative Colitis

Naganuma M., Kobayashi T., Nasuno M., Motoya S., Kato S., Matsuoka K., Hokari R., Watanabe C., Sakamoto H., Yamamoto H., Sasaki M., Watanabe K., Iijima H., Endo Y., Ichikawa H., Ozeki K., Tanida S., Ueno N., Fujiya M., Sako M., Takeuchi K., Sugimoto S., Abe T., Hibi T., Suzuki Y., Kanai T.

Clinical Gastroenterology and Hepatology （Clinical Gastroenterology and Hepatology） 18 （ 5 ） 1102 - 1111.e5 2020年05月

ISSN 15423565

Background & Aims: We compared the diagnostic accuracy of the fecal calprotectin (FCP) test vs the fecal immunochemical blood test (FIT) in determining the endoscopic severity and predicting outcomes of patients with ulcerative colitis (UC). Methods: We performed a nationwide study of 879 patients with UC, enrolled at medical centers across Japan, from March 2015 to March 2017. We collected data on fecal biomarkers, endoscopic severities, and other clinical indices from Cohort 1 (n = 427) and assessed the diagnostic accuracy of FCP measurement and FIT results in determining clinical severity, based on Mayo score, and endoscopic remission, based on Mayo endoscopic sub-score (MES) or UC endoscopic index of severity. We also followed 452 patients in clinical remission from UC (Cohort 2) for 12 months and evaluated the associations of FCP levels and FIT results with clinical recurrence. Results: The levels of FCP and FIT each correlated with the MES and UC endoscopic index of severity. There were no significant differences in the areas under the curve of FCP vs FIT in distinguishing patients with MES≤1 from those with MES≥2 (P = .394) or in distinguishing patients with MES=0 from those with MES≥1 (P = .178). Among 405 patients in clinical remission at baseline, 38 (9.4%) had UC recurrences within 3 months and 90 (22.2%) had recurrences within 12 months. FCP≥146 mg/kg (hazard ratio [HR], 4.83; 95% confidence interval [CI], 2.80-8.33) and FIT≥77 ng/mL (HR, 2.92; 95% CI, 1.76-4.83) were independently associated with clinical recurrence within 12 months. UC recurred within 12 months in 69% of patients with levels of FCP≥146 mg/kg and FIT ≥77 ng/mL; this value was significantly higher than the rate of recurrence in patients with levels of FCP≥146 mg/kg and FIT <77 ng/mL (31.5%, P < .001) or patients with levels of FCP<146 mg/kg and FIT ≥77 ng/mL (30.0%, P < .001). Conclusion: In a nationwide study of patients with UC in Japan, we found that the level of FCP and FIT could each identify patients with endoscopic markers of disease severity (MES≥2). The combination of FCP and FIT results can identify patients in remission who are at risk for disease recurrence. Clinical Trials Registry no: UMIN000017650 (http://www.umin.ac.jp/ctr/)

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ラジオ波焼灼療法により良好な病勢制御が得られたトロトラスト沈着症による肝内胆管癌の一例

谷木信仁, 中本伸宏, 吉田文, ちょ柏松, 伊倉顕彦, 山高果林, 森川麗, 志波俊輔, 山口晃弘, 碓井真吾, 尾城啓輔, 海老沼浩利, 斎藤英胤, 久保田直人, 眞杉洋平, 坂元亨宇, 金井隆典

肝臓（(一社)日本肝臓学会） 61 （ 5 ） 262 - 269 2020年05月

ISSN 0451-4203

症例は87歳男性。検診で増大する肝腫瘤を指摘され当科紹介受診となった。画像所見から肝内胆管癌を含む肝原発悪性腫瘍が疑われたが、胆管浸潤を示唆する所見はなく、高齢で基礎疾患を多数有するため、ラジオ波焼灼療法(RFA:radiofrequency ablation)を行なった。治療時に施行した腫瘍生検の結果、肝内胆管癌と診断されたが、同時に採取された背景肝に1930-50年にかけて使用された造影剤であるトロトラストの沈着が疑われた。再発病変に対して2度RFAを施行し、初回治療後約3年間病勢が制御されている。今回我々は、RFAにより良好な病勢制御が得られたトロトラスト沈着症による肝内胆管癌の一例を経験した。トロトラスト晩発障害による発癌症例は肝内多中心性の発癌様式を示すため、本症例のように高齢で耐術能の低い胆管細胞癌症例においては、RFAなどの局所療法が有用な治療選択肢となりうると考えられた。(著者抄録)

Efficacy of apheresis as maintenance therapy for patients with ulcerative colitis in an open-label prospective multicenter randomised controlled trial

Naganuma M., Yokoyama Y., Motoya S., Watanabe K., Sawada K., Hirai F., Yamamoto T., Hanai H., Omori T., Kanai T., Hibi T., Naganuma M., Sugimoto S., Nanki K., Mizuno S., Ogata H., Nagase K., Nakamura S., Tanaka H., Nasuno M., Miyagawa M., Shimoyama T., Ikeya K., Itoh A., Yokoyama K., Mitsuyama K., Yamazaki H., Sakata Y., Yoshimura N., Shirai T., Suzuki Y., Matsuura M., Tanaka S., Hayashi K., Ueno Y., Sakemi R., Ishiguro Y., Yoshida A., Endo Y., Yamagami H., Sakurai T., Iwabuchi M., Sugimura M., Iizuka M., Nagino K., Kobayashi T., Ohnishi K., Yoshino T., Ohmori T., Teramoto T.

Journal of Gastroenterology （Journal of Gastroenterology） 55 （ 4 ） 390 - 400 2020年04月

ISSN 09441174

Background: Apheresis therapy involves the selective removal of leukocytes and is used to induce remission in ulcerative colitis (UC) patients. The aim of this study was to demonstrate the efficacy and safety of apheresis therapy for maintaining UC remission. Methods: We conducted a multicenter, prospective, randomised-control trial of patients with remitting UC induced by granulocyte and monocyte adsorption apheresis or leukocytapheresis. Patients were randomly assigned to the apheresis group (twice per month for 12 months) or the control group (no apheresis treatment) using a 1:1 allocation ratio. The primary endpoint was the rate of cumulative clinical remission (Mayo score ≤ 2) at 12 months. The secondary endpoints were the rates of clinical remission, endoscopic remission, and complete endoscopic remission at 12 months. Results: Between March 2013 and March 2017, 164 patients were enrolled. The cumulative remission rate at 12 months was 46.6% in the apheresis group and 36.4% in the control group (p = 0.1621). The rate of endoscopic remission at 12 months was significantly higher in the apheresis group than in the control group (42.5% vs. 25.9%) p = 0.0480). The rate of clinical remission (47.5% vs.32.1%, p = 0.0540) and complete endoscopic remission (33.8% vs.19.8%, p = 0.0513) tended to be higher in the apheresis than in the control group; however, the difference was not significant. No severe adverse events were observed in either group. Conclusions: Apheresis was well tolerated as maintenance therapy for UC although the cumulative clinical remission rate at 12 months was comparable between the apheresis and control groups.

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Etiology and mortality in severe acute pancreatitis: A multicenter study in Japan

Yasuda H., Horibe M., Sanui M., Sasaki M., Suzuki N., Sawano H., Goto T., Ikeura T., Takeda T., Oda T., Ogura Y., Miyazaki D., Kitamura K., Chiba N., Ozaki T., Yamashita T., Koinuma T., Oshima T., Yamamoto T., Hirota M., Sato M., Miyamoto K., Mine T., Misumi T., Takeda Y., Iwasaki E., Kanai T., Mayumi T.

Pancreatology （Pancreatology） 20 （ 3 ） 307 - 317 2020年04月

ISSN 14243903

Background/Objectives: Severe acute pancreatitis (SAP) has a high mortality rate despite ongoing attempts to improve prognosis through a various therapeutic modalities. This study aimed to delineate etiology-based routes that may guide clinical decisions for the treatment of SAP. Methods: Using data from a recent retrospective multicenter study in Japan, we analyzed the association between clinical outcomes, mainly in-hospital mortality and pancreatic infection, and various etiologies while considering confounding factors. We performed additional multivariate analyses and built decision tree models. Results: The 1097 participating patients were classified into the following groups by etiology: alcohol (n = 436, 39.7%); cholelithiasis (n = 230, 21.0%); idiopathic (n = 227, 20.7%); and others (n = 204, 18.6%). Mortality at hospital discharge was 8.4%, 12.2%, 16.7%, and 16.2% in the alcohol, cholelithiasis, idiopathic, and others groups, respectively. According to multivariable analysis, early enteral nutrition (EN) was significantly associated with reduced in-hospital mortality only in the cholelithiasis group. However, there was a consistent association between age and the need for mechanical ventilation and increased mortality, regardless of etiology. Our decision tree models presented different contributing factors depending on the etiology and patient background. Interaction analysis showed that EN and the use of prophylactic antibiotics may influence these results differently according to etiology. Conclusions: No study has yet used comprehensive models to investigate etiology-related prognostic factors for SAP; our results can, therefore, be used as a reference for improving clinical decisions.

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Clinical implications with tolvaptan on monitored bioimpedance-defined fluid status in patients with cirrhotic ascites: An observational study

Shiba S., Chu P.S., Nakamoto N., Yamataka K., Taniki N., Ojiro K., Yamaguchi A., Morikawa R., Yoshida A., Ikura A., Ebinuma H., Saito H., Kanai T.

BMC Gastroenterology （BMC Gastroenterology） 20 （ 1 ） 2020年03月

Background: Prognostic value or clinical implications of fluid status monitoring in liver cirrhosis are not fully elucidated. Tolvaptan, an orally available, selective vasopressin V2-receptor antagonist approved for hyponatremia in the United States and European Union. It is also used for cirrhotic ascites at a relatively low dose (3.75 mg to 7.5 mg) in Japan, exerts its diuretic function by excreting electrolyte-free water. We hypothesized that bioimpedance-defined dynamic changes in fluid status allow prediction of response of V2 antagonism and survival in cirrhotic patients. Methods: In this prospective observational study, 30 patients with decompensated liver cirrhosis who were unresponsive to conventional diuretics were enrolled. Detailed serial changes of body composition that were assessed by using non-invasive bioimpedance analysis (BIA) devices, along with biochemical studies, were monitored at 5 time points. Results: Sixteen patients were classified as short-term responders (53%). Rapid and early decrease of BIA-defined intracellular water, as soon as 6 h after the first dose (ΔICWBIA%-6 h), significantly discriminated responders from non-responders (AUC = 0.97, P < 0.0001). ΔICWBIA%-6 h was highly correlated with the change of BIA-derived phase angle of trunk, e.g. reduced body reactance operated at 50 kHz after 24 h of the first dose of tolvaptan. Lower baseline blood urea nitrogen and lower serum aldosterone were predictive of a rapid and early decrease of ICWBIA. A rapid and early decrease of ICWBIA in response to tolvaptan was also predictive of a better transplant-free survival. Conclusions: BIA-defined water compartment monitoring may help predict short-term efficacy and survival in decompensated cirrhotic patients treated with tolvaptan.

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Effects of vedolizumab in Japanese patients with Crohn’s disease: a prospective, multicenter, randomized, placebo-controlled Phase 3 trial with exploratory analyses

Watanabe K., Motoya S., Ogata H., Kanai T., Matsui T., Suzuki Y., Shikamura M., Sugiura K., Oda K., Hori T., Araki T., Watanabe M., Hibi T.

Journal of Gastroenterology （Journal of Gastroenterology） 55 （ 3 ） 291 - 306 2020年03月

ISSN 09441174

Background: Vedolizumab is a gut-selective humanized antibody that binds the α4β7 integrin. We evaluated efficacy and safety of vedolizumab in Japanese patients with moderate-to-severe Crohn’s disease (CD). Methods: In this Phase 3, double-blind study (NCT02038920), 157 patients were randomized to receive intravenous vedolizumab 300 mg (n = 79) or placebo (n = 78) at Weeks 0, 2, and 6 (induction phase). Patients with CD activity index (CDAI)-70 response at Week 10 were randomized to receive vedolizumab 300 mg (n = 12) or placebo (n = 12) at Week 14, then every 8 weeks until Week 54 (maintenance phase). Primary endpoints were ≥ 100-point reduction in CDAI (CDAI-100 response) at Week 10 for induction, and clinical remission (CR: CDAI ≤ 150) at Week 60 for maintenance. Results: At Week 10, 26.6% of patients who received vedolizumab and 16.7% who received placebo achieved CDAI-100 response (odds ratio [OR] [95% confidence interval (CI)] 1.80 [0.82–3.96]; p = 0.145). At Week 60, 41.7% of vedolizumab-treated patients and 16.7% of placebo-treated patients achieved CR (OR [95% CI] 3.57 [0.53–23.95]; p = 0.178). The incidence of adverse events was similar in both treatment groups in both induction and maintenance phases. In patients without prior anti-TNFα exposure or with inadequate response to anti-TNFα, vedolizumab showed improved outcomes over placebo in the induction phase. Age might be a possible predictive factor of CR for future research. Conclusion: Vedolizumab showed a numerically greater efficacy versus placebo as induction therapy, but the difference was not statistically significant. Vedolizumab also showed a numerically greater efficacy in maintenance therapy, and was well tolerated.

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Giant mesocaval shunt formed by recurrent ileal intussusception

Takabayashi K., Hosoe N., Ogata H., Kanai T.

Internal Medicine （Internal Medicine） 59 （ 5 ） 747 - 748 2020年03月

ISSN 09182918

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A Phase II Study of Regorafenib With a Lower Starting Dose in Patients With Metastatic Colorectal Cancer: Exposure–Toxicity Analysis of Unbound Regorafenib and Its Active Metabolites (RESET Trial)

Suzuki T., Sukawa Y., Imamura C.K., Masuishi T., Satake H., Kumekawa Y., Funakoshi S., Kotaka M., Horie Y., Kawai S., Okuda H., Terazawa T., Kondoh C., Kato K., Yoshimura K., Ishikawa H., Hamamoto Y., Boku N., Takaishi H., Kanai T.

Clinical Colorectal Cancer （Clinical Colorectal Cancer） 19 （ 1 ） 13 - 21.e3 2020年03月

ISSN 15330028

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Clinical and endoscopic characteristics of pyogenic granuloma in the small intestine: A case series with literature review

Hayashi Y., Dr N.H., Takabayashi K., Limpias Kamiya K.J.L., Mutaguchi M., Miyanaga R., Hirata K., Fukuhara S., Mikami Y., Sujino T., Masugi Y., Naganuma M., Ogata H., Kanai T.

Internal Medicine （Internal Medicine） 59 （ 4 ） 501 - 505 2020年02月

ISSN 09182918

Pyogenic granuloma (PG) generally appears in the skin or oral cavity, but rarely occurs in the small intestine, where it can cause bleeding. To date, only 35 cases of small intestinal PG have been reported in the English literature. We retrospectively collected information from the clinical records of seven cases of small intestinal PG that were managed in our hospital and summarized the characteristics. Further information on the clinical characteristics was obtained from the literature. Capsule endoscopy, useful for identifying the source of hemorrhage in obscure gastrointestinal bleeding, can detect PGs. Treatment can often be accomplished with endoscopic mucosal resection.

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Previous Helicobacter pylori infection–induced atrophic gastritis: A distinct disease entity in an understudied population without a history of eradication

Kishikawa H., Ojiro K., Nakamura K., Katayama T., Arahata K., Takarabe S., Miura S., Kanai T., Nishida J.

Helicobacter （Helicobacter） 25 （ 1 ） 2020年02月

ISSN 10834389

Individuals with chronic atrophic gastritis who are negative for active H. pylori infection with no history of eradication therapy have been identified in clinical practice. By excluding false-negative and autoimmune gastritis cases, it can be surmised that most of these patients have experienced unintentional eradication of H. pylori after antibiotic treatment for other infectious disease, unreported successful eradication, or H. pylori that spontaneously disappeared. These patients are considered to have previous H. pylori infection–induced atrophic gastritis. In this work, we define these cases based on the following criteria: absence of previous H. pylori eradication; atrophic changes on endoscopy or histologic confirmation of glandular atrophy; negative for a current H. pylori infection diagnosed in the absence of proton-pump inhibitors or antibiotics; and absence of localized corpus atrophy, positivity for autoantibodies, or characteristic histologic findings suggestive of autoimmune gastritis. The risk of developing gastric cancer depends on the atrophic grade. The reported rate of developing gastric cancer is 0.31%-0.62% per year for successfully eradicated severely atrophic cases (pathophysiologically equal to unintentionally eradicated cases and unreported eradicated cases), and 0.53%-0.87% per year for spontaneously resolved cases due to severe atrophy. Therefore, for previous H. pylori infection–induced atrophic gastritis cases, we recommend endoscopic surveillance every 3 years for high-risk patients, including those with endoscopically severe atrophy or intestinal metaplasia. Because of the difficulty involved in the endoscopic diagnosis of gastric cancer in cases of previous infection, appropriate monitoring of the high-risk subgroup of this understudied population is especially important.

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Chromosome Engineering of Human Colon-Derived Organoids to Develop a Model of Traditional Serrated Adenoma

Kawasaki K., Fujii M., Sugimoto S., Ishikawa K., Matano M., Ohta Y., Toshimitsu K., Takahashi S., Hosoe N., Sekine S., Kanai T., Sato T.

Gastroenterology （Gastroenterology） 158 （ 3 ） 638 - 651.e8 2020年02月

ISSN 00165085

Background & Aims: Traditional serrated adenomas (TSAs) are rare colorectal polyps with unique histologic features. Fusions in R-spondin genes have been found in TSAs, but it is not clear whether these are sufficient for TSA development, due to the lack of a chromosome engineering platform for human tissues. We studied the effects of fusions in R-spondin genes and other genetic alterations found in TSA using CRISPR-Cas9–mediated chromosome and genetic modification of human colonic organoids. Methods: We introduced chromosome rearrangements that involve R-spondin genes into human colonic organoids, with or without disruption of TP53, using CRISPR-Cas9 (chromosome-engineered organoids). We then knocked a mutation into BRAF encoding the V600E substitution and overexpressed the GREM1 transgene; the organoids were transplanted into colons of NOG mice and growth of xenograft tumors was measured. Colon tissues were collected and analyzed by immunohistochemistry or in situ hybridization. We also established 2 patient-derived TSA organoid lines and characterized their genetic features and phenotypes. We inserted a bicistronic cassette expressing a dimerizer-inducible suicide gene and fluorescent marker downstream of the LGR5 gene in the chromosome-engineered organoids; addition of the dimerizer eradicates LGR5+ cells. Some tumor-bearing mice were given intraperitoneal injections of the dimerizer to remove LGR5-expressing cells. Results: Chromosome engineering of organoids required disruption of TP53 or culture in medium containing IGF1 and FGF2. In colons of mice, organoids that expressed BRAFV600E and fusions in R-spondin genes formed flat serrated lesions. Patient-derived TSA organoids grew independent of exogenous R-spondin, and 1 line grew independent of Noggin. Organoids that overexpressed GREM1, in addition to BRAFV600E and fusions in R-spondin genes, formed polypoid tumors in mice that had histologic features similar to TSAs. Xenograft tumors persisted after loss of LGR5-expressing cells. Conclusions: We demonstrated efficient chromosomal engineering of human normal colon organoids. We introduced genetic and chromosome alterations into human colon organoids found in human TSAs; tumors grown from these organoids in mice had histopathology features of TSAs. This model might be used to study progression of human colorectal tumors with RSPO fusion gene and GREM1 overexpression.

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Somatic inflammatory gene mutations in human ulcerative colitis epithelium

Nanki K., Fujii M., Shimokawa M., Matano M., Nishikori S., Date S., Takano A., Toshimitsu K., Ohta Y., Takahashi S., Sugimoto S., Ishimaru K., Kawasaki K., Nagai Y., Ishii R., Yoshida K., Sasaki N., Hibi T., Ishihara S., Kanai T., Sato T.

Nature （Nature） 577 （ 7789 ） 254 - 259 2020年01月

ISSN 00280836

With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations1–7. However, whether such clonal expansion exists in the non-neoplastic intestine remains unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling—including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the pro-apoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice8–11, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis.

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Anti-MAdCAM-1 antibody (PF-00547659) for active refractory Crohn's disease in Japanese and Korean patients: The OPERA study

Saruta M., Park D.I., Kim Y.H., Yang S.K., Jang B.I., Cheon J.H., Im J.P., Kanai T., Katsuno T., Ishiguro Y., Nagaoka M., Isogawa N., Li Y., Banerjee A., Ahmad A., Hassan-Zahraee M., Clare R., Gorelick K.J., Cataldi F., Watanabe M., Hibi T.

Intestinal Research （Intestinal Research） 18 （ 1 ） 45 - 55 2020年01月

ISSN 15989100

Background/Aims: PF-00547659 is a monoclonal antibody against human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) that prevents the binding of α4β7+ lymphocytes to MAdCAM-expressing sites in the gastrointestinal tract with high affinity and selectivity, and is being developed for the treatment of Crohn's disease (CD). Methods: OPERA is a randomized, multicenter, double-blind, placebo-controlled study to investigate the efficacy, safety, and pharmacokinetics of PF-00547659 following subcutaneous administration in subjects with active CD, a history of failure or intolerance to anti-tumor necrosis factor and/or immunosuppressants, high-sensitivity C-reactive protein >3.0 mg/L, and ulcers on colonoscopy. The primary endpoint was Crohn's Disease Activity Index-70 response at week 8 or 12. Subpopulation analyses for Asian subjects were performed as some differences are observed in genetics and clinical phenotypes in Asian CD patients compared with Western patients. Results: In this study, 265 CD subjects were randomized, with a subpopulation of 21 subjects (8 Japanese and 13 Korean) defined as the Asian population. In the overall and Asian populations; PF-00547659 was pharmacologically active as evidenced by soluble MAdCAM and circulating β7+ central memory CD4+ T-lymphocytes, although no clear evidence of efficacy was observed in any clinical endpoints; pharmacokinetics of PF-00547659 in the Asian subpopulation was generally comparable to the overall population; and the safety profile of PF-00547659 appeared acceptable up to 12 weeks of treatment. Conclusions: In the overall and Asian populations, efficacy of PF-00547659 could not be demonstrated using any clinical endpoints compared with placebo. Pharmacokinetics and safety of PF-00547659 were generally comparable. Further studies with larger numbers of patients are required to confirm our results.

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5-Aminosalicylic acid intolerance is associated with a risk of adverse clinical outcomes and dysbiosis in patients with ulcerative colitis

Mizuno S., Ono K., Mikami Y., Naganuma M., Fukuda T., Minami K., Masaoka T., Terada S., Yoshida T., Saigusa K., Hirahara N., Miyata H., Suda W., Hattori M., Kanai T.

Intestinal Research （Intestinal Research） 18 （ 1 ） 69 - 78 2020年01月

ISSN 15989100

Background/Aims: 5-Aminosalicylic acid (ASA) causes intolerance reactions in some patients. This study was performed to examine the prognosis of patients with ulcerative colitis (UC) and 5-ASA intolerance, and to evaluate the potential interaction between 5-ASA intolerance and the intestinal microbiota. Methods: We performed a retrospective cohort study of patients with UC who visited participating hospitals. The primary endpoint was to compare the incidence of hospitalization within 12 months between the 5-ASA intolerance group and the 5-ASA tolerance group. The secondary endpoint was to compare the risk of adverse clinical outcomes after the start of biologics between the 2 groups. We also assessed the correlation between 5-ASA intolerance and microbial change in an independently recruited cohort of patients with UC. Results: Of 793 patients, 59 (7.4%) were assigned to the 5-ASA intolerance group and 734 (92.5%) were assigned to the 5-ASA tolerance group. The admission rate and incidence of corticosteroid use were significantly higher in the intolerance than tolerance group (P<0.001). In 108 patients undergoing treatment with anti-tumor necrosis factor biologics, 5-ASA intolerance increased the incidence of additional induction therapy after starting biologics (P<0.001). The 5-ASA intolerance group had a greater abundance of bacteria in the genera Faecalibacterium, Streptococcus, and Clostridium than the 5-ASA tolerance group (P<0.05). Conclusions: In patients with UC, 5-ASA intolerance is associated with a risk of adverse clinical outcomes and dysbiosis. Bacterial therapeutic optimization of 5-ASA administration may be important for improving the prognosis of patients with UC.

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Clinical characteristics and outcomes of duodenal-type follicular lymphoma

Abe R., Mori T., Tanigawa T., Koda Y., Hosoe N., Sakurai M., Kikuchi T., Kato J., Shimizu T., Ogata H., Kanai T., Sasaki A., Kameyama K., Okamoto S.

Leukemia and Lymphoma （Leukemia and Lymphoma） 3266 - 3268 2020年

ISSN 10428194

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金井 隆典

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金井　隆典

論文 - 金井　隆典