論文 - 齋藤　義正

Upper gastrointestinal triple stenosis in a patient with trisomy 17p syndrome: Case report and literature review

Ando H., Mori H., Takabayashi K., Matsuura N., Masaoka T., Matsuzaki J., Saito Y., Kato M., Kosaki K., Kanai T.

DEN Open 5 （ 1 ）  2025年04月

ISSN  2692-4609

　概要を見る

Upper gastrointestinal stenosis, which can be congenital or acquired, can lead to dysphagia. The association between trisomy 17p syndrome, a rare chromosomal abnormality, and upper gastrointestinal stenosis is unclear. A 20-year-old man diagnosed with trisomy 17p syndrome was referred to our department due to recurrent vomiting. Esophagogastroduodenoscopy revealed stenotic areas in the esophagus, stomach, and duodenum. The congenital gastrointestinal stenosis present in both the duodenum and esophagus suggested that the stasis and reflux of digestive fluids exacerbated stenosis in the stomach and esophagus. Gastric acid suppression therapy and endoscopic dilation of the esophagus and duodenum effectively resolved the patient's vomiting symptoms.

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Intestinal metabolites predict treatment resistance of patients with depression and anxiety

Matsuzaki J., Kurokawa S., Iwamoto C., Miyaho K., Takamiya A., Ishii C., Hirayama A., Sanada K., Fukuda S., Mimura M., Kishimoto T., Saito Y.

Gut Pathogens 16 （ 1 ）  2024年12月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り,  ISSN  1757-4749

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Background: The impact of the gut microbiota on neuropsychiatric disorders has gained much attention in recent years; however, comprehensive data on the relationship between the gut microbiome and its metabolites and resistance to treatment for depression and anxiety is lacking. Here, we investigated intestinal metabolites in patients with depression and anxiety disorders, and their possible roles in treatment resistance. Results: We analyzed fecal metabolites and microbiomes in 34 participants with depression and anxiety disorders. Fecal samples were obtained three times for each participant during the treatment. Propensity score matching led us to analyze data from nine treatment responders and nine non-responders, and the results were validated in the residual sample sets. Using elastic net regression analysis, we identified several metabolites, including N-ε-acetyllysine; baseline levels of the former were low in responders (AUC = 0.86; 95% confidence interval, 0.69–1). In addition, fecal levels of N-ε-acetyllysine were negatively associated with the abundance of Odoribacter. N-ε-acetyllysine levels increased as symptoms improved with treatment. Conclusion: Fecal N-ε-acetyllysine levels before treatment may be a predictive biomarker of treatment-refractory depression and anxiety. Odoribacter may play a role in the homeostasis of intestinal L-lysine levels. More attention should be paid to the importance of L-lysine metabolism in those with depression and anxiety.

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Plasma extracellular vesicle microRNAs reflecting the therapeutic effect of the CBP/β-catenin inhibitor PRI-724 in patients with liver cirrhosis

Yoshida M., Matsuzaki J., Fujita K., Kimura M., Umezu T., Tokuda N., Yamaguchi T., Kuroda M., Ochiya T., Saito Y., Kimura K.

Scientific Reports 14 （ 1 ）  2024年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2045-2322

　概要を見る

There is an unmet need for antifibrotic therapies to prevent the progression of liver cirrhosis. Previously, we conducted an exploratory trial to assess the safety and antifibrotic efficacy of PRI-724, a selective CBP/β-catenin inhibitor, in patients with liver cirrhosis. PRI-724 was well tolerated and exerted a potential antifibrotic effect. Here, we investigated whether the profiles of circulating microRNAs packaged in extracellular vesicles (EV-miRNAs) are associated with responses to liver fibrosis treatments. Eighteen patients who received PRI-724 for 12 weeks in a phase 1/2a study were classified as responders (n = 10) or non-responders (n = 8) based on changes in liver stiffness. Plasma samples were obtained before and after PRI-724 administration and the levels of EV-miRNAs were analyzed. Three miRNAs (miR-6510-5p, miR-6772-5p, and miR-4261) were identified as predictors of response or non-response to PRI-724, and the levels of three other miRNAs (miR-939-3p, miR-887-3p, and miR-7112-5p) correlated with the efficacy of treatment. Expression of miR-887-3p was detected in hepatocytes and was decreased significantly in liver tissue following PRI-724 treatment. In addition, transfection of a miR-887-3p mimic activated hepatic stellate cells. Thus, decreases in the miR-887-3p level in blood may reflect recovery from liver fibroses in patients with liver cirrhosis treated with PRI-724, although further validation studies are warranted to confirm this.

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A comparative study on dietary diversity and gut microbial diversity in children with autism spectrum disorder, attention-deficit hyperactivity disorder, their neurotypical siblings, and non-related neurotypical volunteers: a cross-sectional study

Kurokawa S., Nomura K., Sanada K., Miyaho K., Ishii C., Fukuda S., Iwamoto C., Naraoka M., Yoneda S., Imafuku M., Matsuzaki J., Saito Y., Mimura M., Kishimoto T.

Journal of Child Psychology and Psychiatry and Allied Disciplines 65 （ 9 ） 1184 - 1195 2024年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00219630

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Background: Previous research has shown a significant link between gut microbiota in children with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). However, much remains unknown because of the heterogeneity of disorders and the potential confounders such as dietary patterns and control group variations. Methods: Children aged 6–12 years who had been clinically diagnosed with ASD and/or ADHD, their unaffected neurotypical siblings, and non-related neurotypical volunteers were recruited cross-sectionally. The ASD diagnosis was confirmed using the Autism Diagnostic Observation Schedule-2 (ADOS-2) in all patients, including those with ADHD. Standardized DNA extraction and sequencing methods were used to compare gut microbial alpha-diversity among the groups. Dietary diversity was calculated from a standardized dietary questionnaire form. We compared the difference in gut microbiome between patients with ASD and/or ADHD with neurotypical siblings and non-related neurotypical controls. Results: Ninety-eight subjects were included in the study (18 with ASD, 19 with ADHD, 20 with both ASD and ADHD, 13 neurotypical siblings, and 28 non-related neurotypical controls). The alpha-diversity indices, such as Chao 1 and Shannon index, showed a significant difference between the groups in a Linear mixed-effect model (F(4, 93) = 4.539, p =.02), (F(4, 93) = 3.185, p =.017), respectively. In a post-hoc pairwise comparison, patients with ASD had lower alpha-diversity compared with non-related controls after Bonferroni correction. Dietary diversity shown in Shannon index did not differ among the groups (F(4, 84) = 1.494, p =.211). Conclusions: Our study indicates disorder-specific microbiome differences in patients with ASD. In future research on gut microbiota in neurodevelopmental disorders, it is necessary to consider the impact of ASD and ADHD co-occurrence, and strictly control for background information such as diet, to elucidate the gut–microbiota interaction in ASD and ADHD for exploring the potential of therapeutic interventions.

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Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance

Calvisi D.F., Boulter L., Vaquero J., Saborowski A., Fabris L., Rodrigues P.M., Coulouarn C., Castro R.E., Segatto O., Raggi C., van der Laan L.J.W., Carpino G., Goeppert B., Roessler S., Kendall T.J., Evert M., Gonzalez-Sanchez E., Valle J.W., Vogel A., Bridgewater J., Borad M.J., Gores G.J., Roberts L.R., Marin J.J.G., Andersen J.B., Alvaro D., Forner A., Banales J.M., Cardinale V., Macias R.I.R., Vicent S., Chen X., Braconi C., Verstegen M.M.A., Fouassier L., Scheiter A., Selaru F.M., Evert K., Utpatel K., Broutier L., Cadamuro M., Huch M., Goldin R., Gradilone S.A., Saito Y.

Nature Reviews Gastroenterology and Hepatology 20 （ 7 ） 462 - 480 2023年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  17595045

　概要を見る

Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.

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Exploring the Role of C19MC on the Differentiation Status of IHCC Organoids by Inducible CRISPR/dCas9

Ye, ZX; Matsuzaki, J; Oikawa, C; Saito, Y

CANCER SCIENCE 114   129 - 129 2023年02月

ISSN  1347-9032

Tracking phenotypical changes provided by driver gene mutations of pancreatic cancer

Oikawa, C; Matsuzaki, J; Ochiya, T; Saito, Y

CANCER SCIENCE 114   1574 - 1574 2023年02月

ISSN  1347-9032

Tracking phenotypical changes provided by driver gene mutations of pancreatic cancer

Oikawa, C; Matsuzaki, J; Ochiya, T; Saito, Y

CANCER SCIENCE 114   1893 - 1893 2023年02月

ISSN  1347-9032

Exploring the Role of C19MC on the Differentiation Status of IHCC Organoids by Inducible CRISPR/dCas9

Ye, ZX; Matsuzaki, J; Oikawa, C; Saito, Y

CANCER SCIENCE 114   606 - 606 2023年02月

ISSN  1347-9032

Efficacy and safety of low-dose rifabutin-based 7-day triple therapy as a third- or later-line Helicobacter pylori eradication regimen

Inokuchi K., Mori H., Matsuzaki J., Hirata K., Harada Y., Saito Y., Suzuki H., Kanai T., Masaoka T.

Helicobacter （Helicobacter）  27 （ 4 ）  2022年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  10834389

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Background: Rifabutin-based regimens are used as rescue therapy for refractory Helicobacter pylori infection; however, the duration for which treatment is required and side effects are concerning. This study assessed the efficacy and safety of 7-day rifabutin, amoxicillin, and vonoprazan triple therapy as third- or later-line treatment for H. pylori infection. Materials and Methods: Patients who did not respond to second-line therapy were enrolled. After H. pylori infection was confirmed with the culture method, the patients received rifabutin-containing triple therapy (20 mg vonoprazan b.i.d., 500 mg amoxicillin q.i.d., and 150 mg rifabutin q.d.) for 7 days. Twelve weeks after the eradication therapy, successful eradication was confirmed using a 13C urea breath test or the H. pylori stool antigen test. The results obtained from our previous study that reported a 10-day or 14-day esomeprazole based rifabutin-containing triple therapy as a third- or fourth-line rescue therapy treated patients were used as historical control. We determined the minimum inhibitory concentrations of amoxicillin and rifabutin. We also evaluated whether the patients were positive for the mutation of the rpoB gene. Results: Intention-to-treat and per-protocol analyses showed that our regimen resulted in a high eradication rate (91.2%, 95% CI: 84%–99% and 92.7%, 95% CI: 86%–100%, respectively). Adverse events occurred in 31.6% of the patients, and two patients discontinued the therapy. Conclusions: This is the first study to evaluate the efficacy and safety of a 7-day low-dose rifabutin-based triple therapy with vonoprazan and amoxicillin. Our results suggest that our regimen was effective and safe as a third- or later-line H. pylori eradication regimen. To clarify what component in this regimen are critical, subsequent studies using a factorial design (comparing vonoprazan-amoxicillin dual therapy vs. vonoprazan-rifabutin triple therapy) will be needed.

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Hepatobiliary tumor organoids for personalized medicine: a multicenter view on establishment, limitations, and future directions Comment

van Tienderen Gilles S., Li Ling, Broutier Laura, Saito Yoshimasa, Inacio Patricia, Huch Meritxell, Selaru Florin M., van der Laan Luc J. W., Verstegen Monique M. A.

CANCER CELL （Cancer Cell）  40 （ 3 ） 226 - 230 2022年03月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り,  ISSN  1535-6108

　概要を見る

Reliable establishment of tumor organoids is paramount to advance applications of organoid technology for personalized medicine. Here, we share our multi-center experience on initiation and tumorigenic confirmation of hepatobiliary cancer organoids. We discuss current concerns, propose potential solutions, and provide future perspectives for improvements in hepatobiliary cancer organoid establishment.

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Challenges for better diagnosis and management of pancreatic and biliary tract cancers focusing on blood biomarkers: A systematic review

Tominaga H., Matsuzaki J., Oikawa C., Toyoshima K., Manabe H., Ozawa E., Shimamura A., Yokoyama R., Serizawa Y., Ochiya T., Saito Y.

Cancers 13 （ 16 ）  2021年08月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り

　概要を見る

Background: pancreatic cancer (PCa) and biliary tract cancer (BTC) are cancers with a poor prognosis and few effective treatments. One of the reasons for this is late detection. Many researchers are tackling to develop non-invasive biomarkers for cancer, but few are specific for PCa or BTC. In addition, genetic abnormalities occur in cancer tissues, which ultimately affect the expression of various molecules. Therefore, it is important to identify molecules that are altered in PCa and BTC. For this systematic review, a systematic review of Medline and Embase to select biomarker studies of PCa and BTC patients was conducted. Results: after reviewing 72 studies, 79 biomarker candidates were identified, including 22 nucleic acids, 43 proteins, and 14 immune cell types. Of the 72 studies, 61 examined PCa, and 11 examined BTC. Conclusion: PCa and BTC are characterized by nucleic acid, protein, and immune cell profiles that are markedly different from those of healthy subjects. These altered molecules and cell subsets may serve as cancer-specific biomarkers, particularly in blood. Further studies are needed to better understand the diagnosis and prognosis of PCa and BTC.

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Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids

Marsee A., Roos F.J.M., Verstegen M.M.A., Roos F., Verstegen M., Clevers H., Vallier L., Takebe T., Huch M., Peng W.C., Forbes S., Lemaigre F., de Koning E., Gehart H., van der Laan L.J.W., Spee B., Boj S., Baptista P., Schneeberger K., Soroka C., Heim M., Nuciforo S., Zaret K., Saito Y., Lutolf M., Cardinale V., Simons B., van IJzendoorn S., Kamiya A., Chikada H., Wang S., Mun S.J., Son M.J., Onder T.T., Boyer J., Sato T., Georgakopoulos N., Meneses A., Broutier L., Boulter L., Grün D., IJzermans J., Artegiani B., van Boxtel R., Kuijk E., Carpino G., Peltz G., Banales J., Man N., Aloia L., LaRusso N., George G., Rimland C., Yeoh G., Grappin-Botton A., Stange D., Prior N., Tirnitz-Parker J.E.E., Andersson E., Braconi C., Hannan N., Lu W.Y., Strom S., Sancho-Bru P., Ogawa S., Corbo V., Lancaster M., Hu H., Fuchs S., Hendriks D., Forbes S.J.

Cell Stem Cell （Cell Stem Cell）  28 （ 5 ） 816 - 832 2021年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  19345909

　概要を見る

Hepatic, pancreatic, and biliary (HPB) organoids are powerful tools for studying development, disease, and regeneration. As organoid research expands, the need for clear definitions and nomenclature describing these systems also grows. To facilitate scientific communication and consistent interpretation, we revisit the concept of an organoid and introduce an intuitive classification system and nomenclature for describing these 3D structures through the consensus of experts in the field. To promote the standardization and validation of HPB organoids, we propose guidelines for establishing, characterizing, and benchmarking future systems. Finally, we address some of the major challenges to the clinical application of organoids.

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The effects of continuous and withdrawal voluntary wheel running exercise on the expression of senescence-related genes in the visceral adipose tissue of young mice

Kimura M., Suzuki S., Moriya A., Nogami K., Uchida R., Saito Y., Saito H.

International Journal of Molecular Sciences （International Journal of Molecular Sciences）  22 （ 1 ） 1 - 12 2021年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  16616596

　概要を見る

© 2020 by the authors. Obesity has become a global medical problem. The upregulation of senescence-related markers in adipose tissue may cause impairment of adipose tissue and disorders of systemic me-tabolism. Weight control through diet has been found to ameliorate senescence in the adipose tissue. Exercise is also important in maintaining a healthy lifestyle, however, very few researchers have examined the relationship between senescence-related markers in adipose tissue. Dietary restriction is also reported to have a legacy effect, wherein the effects are maintained for some periods after the termination of the intervention. However, very few researchers have examined the relationship between exercise and senescence-related markers in adipose tissue. Besides, there is no study on the long-term effects of exercise. Hence, we investigated whether the exercise could change the expression of senescence-related genes in the visceral adipose tissue of young mice and whether there was a legacy effect of exercise for 10 weeks after the termination of exercise. Four-week-old male ICR mice were assigned to one of the three groups: 20 weeks of sedentary condition, 20 weeks of voluntary wheel running exercise, or 10 weeks of exercise followed by 10 weeks of sedentary condition. The mice showed decreased expression in genes related to senescence and senescence-associated secretory phenotype, such as p53, p16, and IL-6, in the visceral adipose tissue in response to exercise. These effects were maintained for 10 weeks after the mice stopped exercising. Our study is the first report that exercise reduces the expression of senescence-related genes in the visceral adipose tissue of young mice, and that exercise causes the legacy effect.

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An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping

Kawasaki K., Toshimitsu K., Matano M., Fujita M., Fujii M., Togasaki K., Ebisudani T., Shimokawa M., Takano A., Takahashi S., Ohta Y., Nanki K., Igarashi R., Ishimaru K., Ishida H., Sukawa Y., Sugimoto S., Saito Y., Maejima K., Sasagawa S., Lee H., Kim H.G., Ha K., Hamamoto J., Fukunaga K., Maekawa A., Tanabe M., Ishihara S., Hamamoto Y., Yasuda H., Sekine S., Kudo A., Kitagawa Y., Kanai T., Nakagawa H., Sato T.

Cell 183 （ 5 ） 1420 - 1435.e21 2020年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00928674

　概要を見る

© 2020 Elsevier Inc. Gastroenteropancreatic (GEP) neuroendocrine neoplasm (NEN) that consists of neuroendocrine tumor and neuroendocrine carcinoma (NEC) is a lethal but under-investigated disease owing to its rarity. To fill the scarcity of clinically relevant models of GEP-NEN, we here established 25 lines of NEN organoids and performed their comprehensive molecular characterization. GEP-NEN organoids recapitulated pathohistological and functional phenotypes of the original tumors. Whole-genome sequencing revealed frequent genetic alterations in TP53 and RB1 in GEP-NECs, and characteristic chromosome-wide loss of heterozygosity in GEP-NENs. Transcriptome analysis identified molecular subtypes that are distinguished by the expression of distinct transcription factors. GEP-NEN organoids gained independence from the stem cell niche irrespective of genetic mutations. Compound knockout of TP53 and RB1, together with overexpression of key transcription factors, conferred on the normal colonic epithelium phenotypes that are compatible with GEP-NEN biology. Altogether, our study not only provides genetic understanding of GEP-NEN, but also connects its genetics and biological phenotypes. Gastroenteropancreatic neuroendocrine neoplasms are a rare but lethal cancer with a scarcity of clinically relevant models. Kawasaki et al. establish and characterize 25 organoid lines to identify molecular subtypes with genotype-phenotype mapping.

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Establishment and Long-Term Culture of Organoids Derived from Human Biliary Tract Carcinoma

Saito Y., Muramatsu T., Saito H.

STAR Protocols 1 （ 1 ） 100009 2020年06月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り

　概要を見る

This protocol is a procedure for establishment and culture of cancer and non-cancer organoids using tissues from biliary tract carcinoma (BTC) patients. These BTC organoids can be used for various biological analyses and drug screening. One challenge in establishing and culturing BTC organoids is non-cancer cells contaminating surgically resected tumor tissues form organoids concurrently with cancer organoids. Careful validation that the established organoids are cancer-derived is important. For complete details on the use and generation of this protocol, please refer to Saito et al. (2019) in the journal Cell Reports.

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Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging

Uchida R., Saito Y., Nogami K., Kajiyama Y., Suzuki Y., Kawase Y., Nakaoka T., Muramatsu T., Kimura M., Saito H.

npj Aging and Mechanisms of Disease 5 （ 1 ）  2019年12月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© 2018, The Author(s). To understand the molecular features underlying stem cell aging, we established intestinal epithelial organoids derived from both young and aged mice and investigated alterations in their senescence and epigenetic status. Senescence-related changes including accumulation of senescence-associated β-galactosidase and up-regulation of Cdkn1a (p21) by DNA demethylation were observed in intestinal epithelial organoids derived from aged mice. We also demonstrated that the important stem cell marker Lgr5 was epigenetically silenced by trimethylation of histone H3 lysine 27, inducing suppression of Wnt signaling and a decrease of cell proliferation in organoids from aged mice. We further treated intestinal epithelial organoids from aged mice with nicotinamide mononucleotide (NMN), a key NAD + intermediate. As a result, the organoids showed a higher NAD + level, increased cell proliferative ability, activation of Lgr5 and suppression of senescence-associated genes, indicating that treatment with NMN could ameliorate senescence-related changes in intestinal epithelia. These findings suggest that organoids derived from aged animals could be a powerful research tool for investigating the molecular mechanisms underlying stem cell aging and for development of some form of anti-aging intervention, thus contributing to prolongation of healthy life expectancy.

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Glucose depletion enhances the stem cell phenotype and gemcitabine resistance of cholangiocarcinoma organoids through AKT phosphorylation and reactive oxygen species

Yoshikawa N., Saito Y., Manabe H., Nakaoka T., Uchida R., Furukawa R., Muramatsu T., Sugiyama Y., Kimura M., Saito H.

Cancers 11 （ 12 ）  2019年12月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Cancer cells are strongly dependent on the glycolytic pathway for generation of energy even under aerobic condition through a phenomenon known as the Warburg effect. Rapid proliferation of cancer cells is often accompanied by high glucose consumption and abnormal angiogenesis, which may lead to glucose depletion. In the present study, we investigated how cholangiocarcinoma cells adapt to glucose depletion using a 3D organoid culture system. We cultured organoids derived from cholangiocarcinoma under glucose-free condition and investigated cell proliferation, expression of stem cell markers and resistance to gemcitabine. Cholangiocarcinoma organoids cultured under glucose-free condition showed reduced proliferation but were able to survive. We also observed an increase in the expression of stem cell markers including LGR5 and enhancement of stem cell phenotypic characteristics such as resistance to gemcitabine through AKT phosphorylation and reactive oxygen species. These findings indicate that cholangiocarcinoma cells are able to adapt to glucose depletion through enhancement of their stem cell phenotype in response to changes in microenvironmental conditions.

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Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets

Lau D.K., Mouradov D., Wasenang W., Luk I.Y., Scott C.M., Williams D.S., Yeung Y.H., Limpaiboon T., Iatropoulos G.F., Jenkins L.J., Reehorst C.M., Chionh F., Nikfarjam M., Croagh D., Dhillon A.S., Weickhardt A.J., Muramatsu T., Saito Y., Tebbutt N.C., Sieber O.M., Mariadason J.M.

iScience 21   624 - 637 2019年11月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© 2019 The Author(s) Biological Sciences; Genetics; Genomics; Cancer

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Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes

Katsuda T., Matsuzaki J., Yamaguchi T., Yamada Y., Prieto-Vila M., Hosaka K., Takeuchi A., Saito Y., Ochiya T.

eLife 8 2019年08月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© Katsuda et al. Hepatocytes are regarded as the only effective cell source for cell transplantation to treat liver diseases; however, their availability is limited due to a donor shortage. Thus, a novel cell source must be developed. We recently reported that mature rodent hepatocytes can be reprogrammed into progenitor-like cells with a repopulative capacity using small molecule inhibitors. Here, we demonstrate that hepatic progenitor cells can be obtained from human infant hepatocytes using the same strategy. These cells, named human chemically induced liver progenitors (hCLiPs), had a significant repopulative capacity in injured mouse livers following transplantation. hCLiPs redifferentiated into mature hepatocytes in vitro upon treatment with hepatic maturation-inducing factors. These redifferentiated cells exhibited cytochrome P450 (CYP) enzymatic activities in response to CYP-inducing molecules and these activities were comparable with those in primary human hepatocytes. These findings will facilitate liver cell transplantation therapy and drug discovery studies.

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Generation of functional human hepatocytes in vitro: Current status and future prospects

Yamaguchi T., Matsuzaki J., Katsuda T., Saito Y., Saito H., Ochiya T.

Inflammation and Regeneration 39 （ 1 ）  2019年07月

研究論文（学術雑誌）, 共著, 査読有り

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© 2019 The Author(s). Liver and hepatocyte transplantation are the only effective therapies for late-stage liver diseases, in which the liver loses its regenerative capacity. However, there is a shortage of donors. As a potential alternative approach, functional hepatocytes were recently generated from various cell sources. Analysis of drug metabolism in the human liver is important for drug development. Consequently, cells that metabolize drugs similar to human primary hepatocytes are required. This review discusses the current challenges and future perspectives concerning hepatocytes and hepatic progenitor cells that have been reprogrammed from various cell types, focusing on their functions in transplantation models and their ability to metabolize drugs.

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Circulating microRNA-1246 as a possible biomarker for early tumor recurrence of hepatocellular carcinoma

Chuma M., Toyoda H., Matsuzaki J., Saito Y., Kumada T., Tada T., Kaneoka Y., Maeda A., Yokoo H., Ogawa K., Kamiyama T., Taketomi A., Matsuno Y., Yazawa K., Takeda K., Kunisaki C., Ogushi K., Moriya S., Hara K., Nozaki A., Kondo M., Fukuda H., Numata K., Tanaka K., Maeda S., Sakamoto N.

Hepatology Research 49 （ 7 ） 810 - 822 2019年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13866346

　概要を見る

© 2019 The Japan Society of Hepatology Aims: Early tumor recurrence (ETR) after hepatic resection is a crucial predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify clinically significant serum microRNAs (miRNAs) involved in the ETR of HCC. Methods: We compared expression profiles of circulating miRNAs from serum samples between five HCC patients with ETR (recurrence within 12 months after hepatectomy) and five HCC patients without recurrence using microarray analysis of miRNA. The identified miRNA associated with ETR was further verified in 121 HCC patients, 73 liver disease patients, and 15 health controls by real-time quantitative reverse transcription–polymerase chain reaction (PCR). Results: Of the approximately 2000 miRNAs analyzed, we identified 15 miRNAs for which expression levels correlated significantly with ETR. Of these miRNAs, we further investigated expression of miRNA-1246 (miR-1246). Quantitative PCR confirmed that miR-1246 was upregulated in HCC with ETR, compared to the level in HCC without ETR (P < 0.001). Serum miR-1246 showed a receiver operating characteristic curve area of 0.762, with 77.4% specificity and 54.1% sensitivity in discriminating HCC patients with ETR from HCC patients without ETR. Altered expression of miR-1246 was associated with aggressive tumor characteristics, including tumor–node–metastasis classification (P = 0.0413), tumor differentiation (P = 0.0419), and portal vein invasion (P = 0.0394). Moreover, multivariate Cox regression analysis identified serum miR-1246 level as an independent risk factor for overall survival (hazard ratio, 2.784; 95% confidence interval, 1.528–5.071; P = 0.0008). Conclusion: Circulating miR-1246 in serum has strong potential as a novel ETR and prognostic biomarker for HCC.

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Establishment of Patient-Derived Organoids and Drug Screening for Biliary Tract Carcinoma

Saito Y., Muramatsu T., Kanai Y., Ojima H., Sukeda A., Hiraoka N., Arai E., Sugiyama Y., Matsuzaki J., Uchida R., Yoshikawa N., Furukawa R., Saito H.

Cell Reports 27 （ 4 ） 1265 - 1276.e4 2019年04月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り

　概要を見る

© 2019 The Author(s) Biliary tract carcinomas (BTCs) are among the most aggressive malignancies and have a poor prognosis. Here, we successfully established organoid lines derived from intrahepatic cholangiocarcinoma, gallbladder cancer, and neuroendocrine carcinoma of the ampulla of Vater. These organoids derived from BTCs were cultured stably for >1 year and closely recapitulated the histopathology, gene expression, and genetic alterations evident in the primary tumors. Gene expression profiling of the organoids revealed that SOX2 could be a potential prognostic biomarker for patients with BTC. We screened a compound library consisting of drugs used clinically for their ability to suppress organoids derived from BTCs and found that the antifungal drugs amorolfine and fenticonazole significantly suppressed the growth of organoids derived from BTCs with minimal toxicity to normal biliary epithelial cells. Patient-derived organoids may be a powerful research tool for the clarification of molecular pathogenesis and the discovery of biomarkers and therapeutic drugs for refractory cancers.

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CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy

Tsugawa H., Mori H., Matsuzaki J., Sato A., Saito Y., Imoto M., Suematsu M., Suzuki H.

Autophagy 15 （ 2 ） 242 - 258 2019年02月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  15548627

　概要を見る

© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Helicobacter pylori-derived CagA, a type IV secretion system effector, plays a role as an oncogenic driver in gastric epithelial cells. However, upon delivery into gastric epithelial cells, CagA is usually degraded by macroautophagy/autophagy. Hence, the induction of autophagy in H. pylori-infected epithelial cells is an important host-protective ability against gastric carcinogenesis. However, the mechanisms by which autophagosome-lysosome fusion is regulated, are unknown. Here, we report that enhancement of LAMP1 (lysosomal associated membrane protein 1) expression is necessary for autolysosome formation. LAMP1 expression is induced by nuclear translocated LRP1 (LDL receptor related protein 1) intracellular domain (LRP1-ICD) binding to the proximal LAMP1 promoter region. Nuclear translocation of LRP1-ICD is enhanced by H. pylori infection. In contrast, CAPZA1 (capping actin protein of muscle Z-line alpha subunit 1) inhibits LAMP1 expression via binding to LRP1-ICD in the nuclei. The binding of CAPZA1 to LRP1-ICD prevents LRP1-ICD binding to the LAMP1 proximal promoter. Thus, in CAPZA1-overexpressing gastric epithelial cells infected with H. pylori, autolysosome formation is inhibited and CagA escapes autophagic degradation. These findings identify CAPZA1 as a novel negative regulator of autolysosome formation and suggest that deregulation of CAPZA1 expression leads to increased risk of gastric carcinogenesis. Abbreviations: CagA: cytotoxin-associated gene A; CAPZA1: capping actin protein of muscle Z-line alpha subunit 1; ChIP: chromatin immunoprecipitation; GTF2I: general transcription factor IIi; HDAC: histone deacetylase; LAMP1: lysosomal associated membrane protein 1; LRP1: LDL receptor related protein 1; LRP1-ICD: CagA intracellular domain; qPCR: quantitative polymerase chain reaction; VacA: vacuolating cytotoxin.

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Vonoprazan-based third-line therapy has a higher eradication rate against sitafloxacin-resistant Helicobacter pylori

Saito Y., Konno K., Sato M., Nakano M., Kato Y., Saito H., Serizawa H.

Cancers 11 （ 1 ）  2019年01月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Eradication of Helicobacter pylori (H. pylori) is an effective strategy for preventing various gastrointestinal diseases such as gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. However, the eradication success rate is decreasing because of a recent increase in drug-resistant strains of H. pylori. Here, we evaluated the success rate of eradication therapy with vonoprazan (VPZ), a new potassium-competitive acid blocker, against drug-resistant H. pylori. In total, 793 patients who received H. pylori eradication therapy were investigated retrospectively. All underwent esomeprazole (EPZ)-based triple therapy (n = 386) or VPZ-based triple therapy (n = 407) for first-, second- and third-line H. pylori eradication for 7 days. The overall success rates of first- and third-line H. pylori eradication were significantly higher for VPZ-based triple therapy (88.4% and 93.0%, respectively, per protocol (PP)) than for EPZ-based triple therapy (69.5% and 56.5%, respectively, PP). Moreover, the success rates of first- and third-line eradication of clarithromycin (CLR)- and sitafloxacin (STFX)-resistant H. pylori were significantly higher for VPZ-based triple therapy (72.0% and 91.7%, PP) than for EPZ-based triple therapy (38.5% and 20.0%, PP). In addition, patient age did not affect the eradication rate of VPZ-based first-line therapy, whereas the success rate of EPZ-based therapy was lower in patients under 65 years of age. Our results clearly demonstrated that VPZ-based therapy achieved a higher eradication rate even against CLR- and STFX-resistant H. pylori, and that patient age did not affect the eradication rate of VPZ-based therapy. These findings suggest that dual therapy using VPZ and amoxicillin may be sufficient for standard H. pylori eradication, and may thus also be beneficial for avoiding antibiotic misuse.

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Establishment of an organoid bank of biliary tract and pancreatic cancers and its application for personalized therapy and future treatment

Saito Y.

Journal of Gastroenterology and Hepatology 34 （ 11 ） 1906 - 1910 2019年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  08159319

　概要を見る

© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd Biliary tract cancers and pancreatic cancers are aggressive malignancies that are difficult to diagnose early and have a poor prognosis. Patients with inoperable biliary tract and pancreatic cancers generally receive chemotherapy regimens including gemcitabine. However, the effects of these drugs are limited, and the 5-year survival rates of patients are very low. The newly developed three-dimensional culture system known as “organoid culture” allows long-term expansion of stem cells into cyst-like structures (organoids) with properties resembling those of the original tissues. We and other groups have successfully established long-term in vitro cultures of organoids derived from biliary tract and pancreatic cancers. Organoids derived from biliary tract and pancreatic cancers closely recapitulate the properties of the original tumors including genetic alterations, gene expression profiles, and histopathological structures. These patient-derived cancer organoids can be applied for drug sensitivity testing, drug screening, epigenetic therapy, and differentiation-inducing therapy to identify therapeutic agents optimal for each patient. We intend to further establish organoids derived from various cancer cases and construct an organoid bank of biliary tract and pancreatic cancers. These powerful in vitro preclinical models of refractory cancers may bridge the gap between basic research and clinical trials and allow personalized therapy for patients.

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Anticancer Drug Prescription Patterns in Japan: Future Directions in Cancer Therapy

Shibata S., Matsushita M., Saito Y., Suzuki T.

Therapeutic Innovation and Regulatory Science 52 （ 6 ） 718 - 723 2018年11月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  21684790

　概要を見る

© The Author(s) 2018. Background: Despite their benefits, the rapid development of new cancer treatments has been a significant driver of increasing health care expenditures in the face of limited health care budgets. In this study, we analyzed the prescribing trends for anticancer drugs from 2010 through 2016 in Japan and sought to identify unique trends that could provide a basis for future medical economic research aiming to develop more efficacious and cost-effective cancer therapies. Methods: We used publicly available marketing data for anticancer drugs in Japan for 2010-2016. The drugs selected for this research were categorized according to the Anatomical Therapeutic Chemical Classification System. We investigated the overall anticancer drug market size, the number of anticancer drugs, the top 30 selling anticancer categories, sales and prescription volumes, and changes in sales and prescription volumes between 2010 and 2016 in the country. Results: The anticancer agent market expanded each year from 2010 to 2016, with sales exceeding 1 trillion yen in 2015. The proportion of molecular targeted drugs (antineoplastic mAbs and protein kinase inhibitors) among the top 30 selling anticancer categories has continued to increase, and both the sales and prescription volumes of these drugs exceeded those of drugs in other categories, suggesting that these treatments play a dominant role in cancer pharmacotherapy. Conclusion: The availability and increasing use of innovative but more expensive targeted therapies were major drivers of increases in pharmaceutical expenditures for cancer treatment in Japan. Therefore, the effective use of genetic testing can mitigate these rising costs.

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Nrf2mediated antioxidant effects contribute to suppression of nonalcoholic steatohepatitis associated hepatocellular carcinoma in murine model

Yamada S., Kimura M., Saito Y., Saito H.

Journal of Clinical Biochemistry and Nutrition （Journal of Clinical Biochemistry and Nutrition）  63 （ 2 ） 123 - 128 2018年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09120009

　概要を見る

©2018 JCBN. The exact mechanisms of hepatocellular carcinoma development in nonalcoholic steatohepatitis remain unclear. In this study, we used a new class of highfat diet, which could induce hepatocellular carcinoma development without the use of general chemical carcinogens or knockout mice. We investigated the correlation between hepatocellular carcinoma and oxidative stress/anti oxidant effects after depletion of the gut microbiota by treatment with antibiotics. Mice fed with the steatohepatitisinducing high fat diet (STHD01) for 41 weeks developed hepatocellular carci noma. Antibiotictreatment in mice fed with STHD01 significantly depleted the gut microbiota and significantly ameliorated liver injury/histology. The tumor numbers of hepatocellular carcinoma were dramatically decreased by the antibioticstreatment. We analyzed the factors involved in oxidative stress and antioxidant effects. Oxidative stress was elevated in mice fed with STHD01, whereas some antioxidant factors were significantly elevated after antibiotics treatment. These results suggest that the gut microbiota is a key factor in improving oxidative stress induced by STHD01 feeding.

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Optimal Anti-cancer Drug Profiles for Effective Penetration of the Anti-cancer Drug Market by Generic Drugs in Japan

Shibata S., Matsushita M., Saito Y., Suzuki T.

Therapeutic Innovation and Regulatory Science 52 （ 4 ） 442 - 448 2018年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  21684790

　概要を見る

© The Author(s) 2017. Background: The increased use of generic drugs is a good indicator of the need to reduce the increasing costs of prescription drugs. Since there are more expensive drugs compared with other therapeutic areas, “oncology” is an important one for generic drugs. The primary objective of this article was to quantify the extent to which generic drugs in Japan occupy each level of the Anatomical Therapeutic Chemical (ATC) classification system. Methods: The dataset used in this study was created from publicly available information obtained from the IMS Japan Pharmaceutical Market database. Data on the total amount of sales and number of prescriptions for anti-cancer drugs between 2010 and 2016 in Japan were selected. The data were categorized according to the third level of the ATC classification system. Results: All categories of the ATC classification system had increased market shares in Japan between 2010 and 2016. The barriers to market entry were relatively low in L01F (platinum anti-neoplastics), L01C (plant-based neoplastics), L02B (cytostatic hormone antagonists), and L01D (anti-neoplastic antibiotics) but were high in L02A (cytostatic hormones), L01H (protein kinase inhibitors), and L01B (anti-metabolites). Conclusions: Generic cancer drugs could bring savings to Japanese health care systems. Therefore, their development should be directed toward niche markets, such as L02A, L01H, and L01B, and not competitive markets.

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Dual effects of the Nrf2 inhibitor for inhibition of hepatitis C virus and hepatic cancer cells

Murakami Y., Sugiyama K., Ebinuma H., Nakamoto N., Ojiro K., Chu P., Taniki N., Saito Y., Teratani T., Koda Y., Suzuki T., Saito K., Fukasawa M., Ikeda M., Kato N., Kanai T., Saito H.

BMC Cancer 18 （ 1 ）  2018年06月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© 2018 The Author(s). Background: We previously showed that knockdown of nuclear factor E2-related factor 2 (Nrf2) resulted in suppression of hepatitis C virus (HCV) infection. In this study, whether brusatol, an Nrf2 inhibitor, has dual anti-HCV and anticancer effects was explored. Methods: The anti-HCV effect of brusatol was investigated by analyzing HCV RNA and proteins in a hepatic cell line persistently-infected with HCV, HPI cells, and by analyzing HCV replication in a replicon-replicating hepatic cell line, OR6 cells. Then, dual anti-HCV and anticancer effects of brusatol and enhancement of the effects by the combination of brusatol with anticancer drugs including sorafenib, which has been reported to have the dual effects, were then investigated. Results: Brusatol suppressed the persistent HCV infection at both the RNA and protein levels in association with a reduction in Nrf2 protein in the HPI cells. Analysis of the OR6 cells treated with brusatol indicated that brusatol inhibited HCV persistence by inhibiting HCV replication. Combination of brusatol with an anticancer drug not only enhanced the anticancer effect but also, in the case of the combination with sorafenib, strongly suppressed HCV infection. Conclusions: Brusatol has dual anti-HCV and anticancer effects and can enhance the comparable effects of sorafenib. There is therefore the potential for combination therapy of brusatol and sorafenib for HCV-related hepatocellular carcinoma.

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Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice

Yamada S., Takashina Y., Watanabe M., Nagamine R., Saito Y., Kamada N., Saito H.

Oncotarget 9 （ 11 ） 9925 - 9939 2018年06月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© Yamada et al. Gut microbiota plays a significant role in the development of hepatocellular carcinoma (HCC) in non-alcoholic steatohepatitis (NASH). However, understanding of the precise mechanism of this process remains incomplete. A new class steatohepatitis-inducing high-fat diet (HFD), namely STHD-01, can promote the development of HCC without the administration of chemical carcinogens. Using this diet, we comprehensively analyzed changes in the gut microbiota and its metabolic functions during the development of HCC in NASH. Mice fed the STHD-01 developed NASH within 9 weeks. NASH further progressed into HCC by 41 weeks. Treatment with antibiotics significantly attenuated liver pathology and suppressed tumor development, indicating the critical role of the gut microbiota in tumor development in this model. Accumulation of cholesterol and bile acids in the liver and feces increased after feeding the mice with STHD-01. Treatment with antibiotics did not reverse these phenotypes. In contrast, accumulation of secondary bile acids was dramatically reduced after the treatment with antibiotics, suggesting the critical role of the gut microbiota in the conversion of primary bile acids to secondary bile acids. Secondary bile acids such as deoxycholic acid activated the mTOR, pathway in hepatocytes. Activation of mTOR was observed in the liver of mice fed STHD-01, and the activation was reduced when mice were treated with antibiotics. Collectively, bile acid metabolism by the gut microbiota promotes HCC development in STHD-01- induced NASH.

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機能性食品とアンチエイジング　消化機能低下の予防

齋藤 義正、齋藤 英胤

モダンフィジシャン （新興医学出版社）  38 （ 4 ） 357 - 359 2018年04月

研究論文（学術雑誌）, 共著

Induction of differentiation of intrahepatic cholangiocarcinoma cells to functional hepatocytes using an organoid culture system

Saito Y., Nakaoka T., Muramatsu T., Ojima H., Sukeda A., Sugiyama Y., Uchida R., Furukawa R., Kitahara A., Sato T., Kanai Y., Saito H.

Scientific Reports 8 （ 1 ） 2821 2018年02月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

© 2018 The Author(s). Intrahepatic cholangiocarcinoma (IHCC) is a highly aggressive malignancy with a poor prognosis. It is thought to originate from cholangiocytes, which are the component cells of intrahepatic bile ducts. However, as patients with viral hepatitis often develop IHCC, it has been suggested that transformed hepatocytes may play a role in IHCC development. To investigate whether IHCC cells can be converted to functional hepatocytes, we established organoids derived from human IHCC and cultured them under conditions suitable for hepatocyte differentiation. IHCC organoids after hepatocyte differentiation acquired functions of mature hepatocytes such as albumin secretion, bile acid production and increased CYP3A4 activity. Studies using a mouse model of IHCC indicate that Wnt3a derived from macrophages recruited upon inflammation in the liver may promote the malignant transformation of hepatocytes to IHCC cells. The results of the present study support the recently proposed hypothesis that IHCC cells are derived from hepatocytes.

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Gut microbiota-mediated generation of saturated fatty acids elicits inflammation in the liver in murine high-fat diet-induced steatohepatitis.

Yamada S, Kamada N, Amiya T, Nakamoto N, Nakaoka T, Kimura M, Saito Y, Ejima C, Kanai T, Saito H

BMC Gastroenterol. 17 （ 1 ） 136 2017年11月

研究論文（学術雑誌）, 共著

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Aberrant DNA Methylation as a Biomarker and a Therapeutic Target of Cholangiocarcinoma.

Nakaoka T, Saito Y, Saito H.

Int J Mol Sci. 18 （ 6 ） E1111 2017年05月

共著, 査読有り

Cluster microRNAs miR-194 and miR-215 suppress the tumorigenicity of intestinal tumor organoids.

Nakaoka T, Saito Y, Shimamoto Y, Muramatsu T, Kimura M, Kanai Y, Saito H.

Cancer Sci. 108 （ 4 ） 678 - 684 2017年04月

共著, 査読有り

A New Molecular Mechanism Underlying the Antitumor Effect of DNA Methylation Inhibitors via an Antiviral Immune Response.

Saito Y, Nakaoka T, Saito H.

Advances in Protein Chemistry and Structural Biology 106   227 - 242 2017年01月

研究論文（学術雑誌）, 共著, 査読有り

microRNA-mediated resistance to hypoglycemia in the HepG2 human hepatoma cell line.

Ueki S, Murakami Y, Yamada S, Kimura M, Saito Y, Saito H.

BMC Cancer 16 （ 1 ） 732 - 744 2016年

研究論文（学術雑誌）

Inhibition of DNA methylation suppresses intestinal Tumor Organoids by inducing an Anti-Viral response.

Saito Y, Nakaoka T, Sakai K, Muramatsu T, Toshimitsu K, Kimua M, Kanai T, Sato T, Saito H.

Sci Rep 6   25311 2016年

研究論文（学術雑誌）, 共著

First-line eradication for Helicobacter pylori-positive gastritis by esomeprazole-based triple therapy is influenced by CYP2C19 genotype.

Saito Y, Serizawa H, Kato Y, Nakano M, Nakamura M, Saito H, Suzuki H, Kanai T.

World J Gastroenterol. 21(48)   13548 - 13554 2015年12月

研究論文（学術雑誌）, 共著, 査読有り

マイクロRNAの発現異常は肝発癌にどのようにかかわっているのか？

齋藤 義正, 齋藤 英胤, 金井 弥栄

分子消化器病 12(4)   371 - 377 2015年12月

研究論文（学術雑誌）

microRNA-34a as a Therapeutic Agent against Human Cancer.

Saito Y, Nakaoka T, Saito H

Journal of Clinical Medicine 4(11)   1951 - 1959 2015年11月

研究論文（学術雑誌）, 共著, 査読有り

No contsibution of the ABCB11 p.444A Polymorphism in Japanese patients with drug-induced cholestasis.

Kagawa T, Hirose S, Arase Y, Oka A, Anzai K, Tsuruya K, Shiraishi K, Orii R, Ieda S, Nakazawa T, Tomita K, Hokari R, Miura S, Ebinuma H, Saito H, Kitamura T, Horie Y, Okuse C, Wasada M, Inoko H, Tohkin M, Saito Y, Maekawa K, Takikawa H, Mine T.

Drug Metab Dispos 43 （ (5) ） 691 - 697 2015年05月

研究論文（学術雑誌）, 共著

Astaxanthin supplementation effects on adipocyte size and lipid profile in OLETF rats with hyperphagia and visceral fat accumulation.

Kimura M, Iida M, Yamauchi H, Suzuki M, Shibasaki T, Saito Y, Saito H.

Journal of Functional Foods 11   114 - 120 2014年11月

研究論文（学術雑誌）, 共著, 査読有り

Epigenetic alterations and microRNA misexpression in cancer and autoimmune diseases: a critical review.

Saito Y, Saito H, Liang G-N, Friedman JM.

Clinic Rev Allerg Immunol 47(2)   128 - 135 2014年10月

研究論文（学術雑誌）, 共著, 査読有り

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Silencing of microRNA-122 is an early event during hepatocarcinogenesis from non-alcoholic steatohepatitis.

Takaki Y, Saito Y, Takasugi A, Toshimitsu K, Yamada S, Muramatsu T, Kimura M, Sugiyama K, Suzuki H, Arai E, Ojima H, Kanai Y, Saito H.

Cancer Sci 105(10)   1254 - 1260 2014年08月

研究論文（学術雑誌）, 共著, 査読有り

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Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells.

Hibino S, Saito Y, Muramatsu T, Otani A, Kasai Y, Kimura M, Saito H, Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells.

Oncogenesis 3   e104 2014年05月

研究論文（学術雑誌）, 共著, 査読有り

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Prominent steatosis with hypermetabolism of the cell line permissive for years of infection with hepatitis C virus.

Sugiyama K, Ebinuma H, Nakamoto N, Sakasegawa N, Murakami Y, Chu PS, Usui S, Ishibashi Y, Wakayama Y, Taniki N, Murata H, Saito Y, Fukasawa M, Saito K, Yamagishi Y, Wakita T, Takaku H, Hibi T, Saito H, Kanai T.

PLoS One 9(4)   e94460 2014年04月

研究論文（学術雑誌）, 共著, 査読有り

Alterations of epigenetics and microRNA in hepatocellular carcinoma.

Saito Y, Hibino S, Saito H.

Hepatol Res 44(1)   31-42 2014年01月

研究論文（学術雑誌）, 共著, 査読有り

Bile acids increase levels of microRNAs 221 and 222, leading to degradation of CDX2 during esophageal carcinogenesis.

Matsuzaki J, Suzuki H, Tsugawa H, Watanabe M, Hossain S, Arai E, Saito Y, Sekine S, Akaike T, Kanai Y, Mukaisho K, Auwerx J, Hibi T.

Gastroenterology 145(6)   1300-11 2013年12月

研究論文（学術雑誌）, 共著, 査読有り

Derangement of ghrelin secretion after long-term high-fat diet feeding in rats.

Sugiishi A, KimuraM, Kamiya R, Ueki S, Yoneya M, Saito Y, Saito H.

Hepatol Res 43(10)   1105-14 2013年10月

研究論文（学術雑誌）, 共著, 査読有り

Suppressive effect of the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on hepatitis C virus replication via epigenetic changes in host cells.

Sato A, Saito Y, Sugiyama K, Sakasegawa N, Muramatsu T, Fukuda S, Yoneya M, Kimura M, Ebinuma H, Hibi T, Saito H.

J Cell Biochem 114(9)   1987-96 2013年09月

研究論文（学術雑誌）, 共著, 査読有り

The tumor suppressor microRNA-29c is downregulated and restored by celecoxib in human gastric cancer cells.

Saito Y, Suzuki H, Imaeda H, Matsuzaki J, Hirata K, Tsugawa H, Hibino S, Kanai Y, Saito H, Hibi T.

Int J Cancer 132(8)   1751-60 2013年04月

研究論文（学術雑誌）, 共著, 査読有り

Improvement of reflux symptom related quality of life after Helicobacter pylori eradication therapy.

Hirata K, Suzuki H, Matsuzaki J, Masaoka T, Saito Y, Nishizawa T, Iwasaki E, Fukuhara S, Okada S, Hibi T.

J Clin Biochem Nutr 52(2)   172-8 2013年03月

研究論文（学術雑誌）, 共著, 査読有り

Overexpression of miR-142-5p and miR-155 in gastric mucosa-associated lymphoid tissue (MALT) lymphoma resistant to Helicobacter pylori eradication.

Saito Y, Suzuki H, Tsugawa H, Imaeda H, Matsuzaki J, Hirata K, Hosoe N, Nakamura M, Mukai M, Saito H, Hibi T.

PLoS One 7(11)   e47396 2012年11月

研究論文（学術雑誌）, 共著, 査読有り

Role of CTCF in the regulation of microRNA expression.

Saito Y, Saito H.

Front Genet 3(186)   1-5 2012年09月

研究論文（学術雑誌）, 共著, 査読有り

Development of a novel microRNA promoter microarray for ChIP-on-chip assay to identify epigenetically regulated microRNAs.

Saito Y, Suzuki H, Taya T, Nishizawa M, Tsugawa H, Matsuzaki J, Hirata K, Saito H, Hibi T.

Biochem Biophys Res Commun 426(1)   33-37 2012年09月

研究論文（学術雑誌）, 共著, 査読有り

MicroRNAs in cancers and neurodegenerative disorders.

Saito Y, Saito H.

Front Genet 3(194)   1-5 2012年09月

研究論文（学術雑誌）, 共著, 査読有り

Efficacy of sitafloxacin-based rescue therapy for Helicobacter pylori after failures of first- and second-line therapies.

Matsuzaki J, Suzuki H, Nishizawa T, Hirata K, Tsugawa H, Saito Y, Okada S, Fukuhara S, Hibi T.

Antimicrob Agents Chemother 56 (3)   1643-5 2012年03月

研究論文（学術雑誌）, 共著, 査読有り

Effect of lansoprazole versus roxatidine on prevention of bleeding and promotion of ulcer healing after endoscopic submucosal dissection for superficial gastric neoplasia.

Imaeda H, Hosoe N, Suzuki H, Saito Y, Ida Y, Nakamura R, Iwao Y, Ogata H, Hibi T.

J Gastroenterol 46(11)   1267-72 2011年11月

研究論文（学術雑誌）, 共著, 査読有り

MicroRNAs in Hepatobiliary and Pancreatic Cancers.

Saito Y, Suzuki H, Matsuura M, Sato A, Kasai Y, Yamada K, Saito H, Hibi T.

Front Genet 2 (66)   1-5 2011年09月

研究論文（学術雑誌）, 共著, 査読有り

The effect of PTEN on proliferation and drug-, and radiosensitivity in malignant glioma cells.

Inaba N, Kimura M, Fujioka K, Ikeda K, Somura H, Akiyoshi K, Inoue Y, Nomura M, Saito Y, Saito H, Manome Y.

Anticancer Research 31(5)   1653-1658 2011年05月

研究論文（学術雑誌）, 共著, 査読有り

Etiological difference between ultrashort- and short-segment Barrett's esophagus.

Matsuzaki J, Suzuki H, Asakura K, Saito Y, Hirata K, Takebayashi T, Hibi T.

J Gastroenterol 46(3)   332-8 2011年03月

研究論文（学術雑誌）, 共著, 査読有り

Enhanced bacterial efflux system is the first step to the development of metronidazole resistance in Helicobacter pylori.

Tsugawa H, Suzuki H, Muraoka H, Ikeda F, Hirata K, Matsuzaki J, Saito Y, Hibi T.

Biochem Biophys Res Commun 404(2)   656-60 2011年01月

研究論文（学術雑誌）, 共著, 査読有り

Dysfunctional gastric emptying with downregulation of muscle-specific microRNAs in Helicobacter pylori-infected mice.

Saito Y, Suzuki H, Tsugawa H, Suzuki S, Matsuzaki J, Hirata K, Hibi T.

Gastroenterology 140(1)   189-198 2011年01月

研究論文（学術雑誌）, 共著, 査読有り

Two amino acids mutation of Ferric uptake regulator (Fur) determines Helicobacter pylori resistance to metronidazole.

Tsugawa H, Suzuki H, Satoh K, Hirata K, Matsuzaki J, Saito Y, Suematsu M, Hibi T.

Antioxid Redox Signal 14(1)   15-23 2011年01月

研究論文（学術雑誌）, 共著, 査読有り

Clinical results of observation of the upper gastrointestinal tract by transgastrostomic endoscopy using an ultrathin endoscope.

Imaeda H, Hosoe N, Nakamizo H, Kashiwagi K, Suzuki H, Saito Y, Suganuma K, Ida Y, Matsuzaki J, Iwasaki E, Iwao Y, Ogata H, Hibi T.

J Gastroenterol Hepatol 25(12)   1850-4 2010年12月

研究論文（学術雑誌）, 共著, 査読有り

DNMT1 and DNMT3b silencing sensitizes human hepatoma cells to TRAIL-mediated apoptosis via up-regulation of TRAIL-R2/DR5 and caspase-8.

Kurita S, Higuchi H, Saito Y, Nakamoto N, Takaishi H, Tada S, Saito H, Gores GJ, Hibi T.

Cancer Sci 101(6)   1431-1439 2010年06月

研究論文（学術雑誌）, 共著, 査読有り

Contribution of efflux pumps to clarithromycin resistance in Helicobacter pylori.

Hirata K, Suzuki H, Nishizawa T, Tsugawa H, Muraoka H, Saito Y, Matsuzaki J, Hibi T.

J Gastroenterol Hepatol 25 Suppl 1   S75-79 2010年05月

研究論文（学術雑誌）, 共著, 査読有り

Autofluorescence videoendoscopy system using the SAFE-3000 for assessing superficial gastric neoplasia.

Imaeda H, Hosoe N, Kashiwagi K, Ida Y, Saito Y, Suzuki H, Aiura K, Ogata H, Kumai K, Hibi T.

J Gastroenterol Hepatol 25(4)   706-711 2010年04月

研究論文（学術雑誌）, 共著, 査読有り

Gallstones increase the prevalence of Barrett's esophagus.

Matsuzaki J, Suzuki H, Asakura K, Saito Y, Hirata K, Takebayashi T, Hibi T.

J Gastroenterol 45(2)   171-178 2010年02月

研究論文（学術雑誌）, 共著, 査読有り

Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells.

Saito Y, Suzuki H, Tsugawa H, Nakagawa I, Matsuzaki J, Kanai Y, Hibi T.

Oncogene 28(30)   2738-2744 2009年07月

研究論文（学術雑誌）, 共著, 査読有り

Epigenetic therapy upregulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells.

Saito Y, Friedman JM, Chihara Y, Egger G, Chuang JC, Liang G.

Biochem Biophys Res Commun 379(3)   726-731 2009年02月

研究論文（学術雑誌）, 共著, 査読有り

The role of microRNAs in gastrointestinal cancers.

Saito Y, Suzuki H, Hibi T.

J Gastroenterol 44 Suppl 19   18-22 2009年01月

研究論文（学術雑誌）, 共著, 査読有り

Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells.

Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA, Jones PA.

Cancer Cell 9(6)   435 - 443 2006年06月

研究論文（学術雑誌）, 共著, 査読有り

Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis

Saito Yoshimasa, Kanai Yae, Sakamoto Michiie, Saito Hidetsugu, Ishii Hiromasa, Hirohashi Setsuo

Proceedings of the National Academy of Sciences of the United States of America 99 （ 15 ） 10060-10065 2002年07月

研究論文（学術雑誌）, 共著

免疫複合体.　特集「肝臓と免疫」

斎藤義正，齋藤英胤

肝胆膵 45 （ 5 ） 693-699 2002年05月

研究論文（学術雑誌）, 共著

Reduction of c-myc expression by an antisense approach under Cre/ loxP switching induces apoptosis in human liver cancer cells

Ebinuma Hirotoshi, Saito Hidetsugu, Wakabayashi Kanji, Saito Yoshimasa, Takagi Tamako, Nakamoto Nobuhiro, Kurita Satoshi, Okuyama Torayuki, Ishii Hiromasa

Journal of Cellular Physiology 188 （ 1 ） 56-66 2001年07月

研究論文（学術雑誌）, 共著

Interferon-associated retinopathy in a uniform regimen of natural interferon-a therapy for chronic hepatitis C

Saito Hidetsugu, Ebinuma Hirotoshi, Nagata Hiroshi, Inagaki Yasutaka, Nakamoto Nobuhiro, Saito Yoshimasa, Wakabayashi Kanji, Takagi Tamako, Nakamura Mitsuyasu, Katsura H, Oguchi Y, Ishii Hiromasa

Liver 21 （ 3 ） 192-197 2001年06月

研究論文（学術雑誌）, 共著

Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis

Saito Yoshimasa, Kanai Yae, Sakamoto Michiie, Saito Hidetsugu, Ishii Hiromasa, Hirohashi Setsuo

Hepatology 33 （ 3 ） 561-568 2001年03月

研究論文（学術雑誌）, 共著

Interferon regulatory factor-1 promoter polymorphism and response to type 1 interferon

Saito Hidetsugu, Tada Shinichiro, Wakabayashi Kanji, Takagi Tamako, Saito Yosimasa, Nakamoto Nobuhiro, Kurita Satoshi, Ishii Hiromasa

Journal of Cellular Biochemistry 81 （ S 36 ） 191-200 2001年

研究論文（学術雑誌）, 共著

Effect of the molar ratio of branched-chain to aromatic amino acids on growth and albumin mRNA expression of human liver cancer cell lines in a serum-free medium

Saito Yoshimasa, Saito Hidetsugu, Nakamura Mitsuyasu, Wakabayashi Kanji, Takagi Tamako, Ebinuma Hirotoshi, Ishii Hiromasa

Nutrition and Cancer 39 （ 1 ） 126-131 2001年

研究論文（学術雑誌）, 共著

高齢者C型慢性肝炎におけるインターフェロン惹起性網膜症の検討

高木珠子，齋藤英胤，若林寛二，海老沼浩利，中本伸宏，齋藤義正，永田博司，稲垣恭孝，桂弘，小口芳久，石井裕正

日本高齢消化器医学会議会誌 2 （ 2 ） 17-22 2000年10月

研究論文（学術雑誌）, 共著

Bcl-2 related proteins are dramatically induced at the early stage of differentiation in human liver cancer cells by a histone deacetylase inhibitor projecting an anti-apoptotic role during this period

Wakabayshi Kanji, Saito Hidetsugu, Ebinuma Hirotoshi, Saito Yoshimasa, Takagi Tamako, Nakamura Mitsuyasu, Umezawa Akihiro, Hata Junichi, Ishii Hiromasa

Oncology Reports 7 （ 2 ） 285-288 2000年04月

研究論文（学術雑誌）, 共著

Antisense oligodeoxynucleotide against c-myc mRNA induces diffeentiation of human hepatocellular carcinoma cells

Ebinuma Hirotoshi, Saito Hidetsugu, Saito Yoshimasa, Wakabayashi Kanji, Nakamura Mitsuyasu, Kurose Iwao, Ishii Hiromasa

International Journal of Oncology 15 （ 5 ） 991-999 1999年11月

研究論文（学術雑誌）, 共著

高齢者の初発肝癌に対する肝動脈区域・亜区域塞栓術の侵襲性

斎藤義正，中村光康，若林寛二，高木珠子，齋藤英胤，石井裕正

日本高齢消化器医学会議会誌 1 （ 2 ） 203-207 1999年

研究論文（学術雑誌）, 共著

培養肝癌細胞の運動能に対する分化誘導剤の影響. Rho関連蛋白からみた変化

増田哲也，斎藤英胤，金子文彦，若林寛二，中村光康，斎藤義正，重田洋介，石井裕正

消化器癌の発生と進展 10   261-263 1998年

研究論文（学術雑誌）, 共著