Publications by authors named "Yoki Furuta"

11 Publications

  • Page 1 of 1

Clusterin and Related Scoring Index as Potential Early Predictors of Response to Sorafenib in Hepatocellular Carcinoma.

Hepatol Commun 2021 Nov 27. Epub 2021 Nov 27.

Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Advanced hepatocellular carcinoma (HCC) remains a highly lethal malignancy, although several systemic therapeutic options are available, including sorafenib (SFN), which has been one of the standard treatment agents for almost a decade. As early prediction of response to SFN remains challenging, biomarkers that enable early prediction using a clinically feasible method are needed. Here, we report that the serum secretory form of clusterin (sCLU) protein and its related predictive index are potential beneficial biomarkers for early prediction of SFN response. Using high-throughput screening and subsequent multivariate analysis in the derivation cohort, we found that changes in the concentrations of CLU, vascular cell adhesion molecule-1 (VCAM1), and α-fetoprotein were significantly associated with response to SFN. Furthermore, we confirmed that an increase in CLU serum level 1 month after treatment initiation was significantly associated with shorter progression-free survival. In addition, "NR-index," which comprises these proteins, was evaluated as a tool for accurately predicting the efficacy of SFN and confirmed in the validation cohort. We also established SFN-resistant HepG2 cells (HepG2-SR) and found that sCLU significantly increased in HepG2-SR cells compared with normal HepG2 cells, and confirmed that HepG2-SR cells treated with SFN were resistant to apoptosis. The mechanism underlying activation of sCLU expression in acquired SFN resistance involves aberrant signaling and expression of Akt, mammalian target of rapamycin (mTOR), and a nutrient-related transcription factor, sterol regulatory element binding protein 1c (SREBP-1c). Furthermore, the PI3K and mTOR inhibitor BEZ235 markedly decreased sCLU expression in HepG2-SR cells. Conclusion: These results suggest that measurement of sCLU serum levels and the sCLU-related NR-index are promising clinical tools for the early prediction of SFN response in HCC. Additionally, sCLU-overexpressing HCC might be susceptible to mTOR inhibition.
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http://dx.doi.org/10.1002/hep4.1872DOI Listing
November 2021

The ATP-hydrolyzing ectoenzyme E-NTPD8 attenuates colitis through modulation of P2X4 receptor-dependent metabolism in myeloid cells.

Proc Natl Acad Sci U S A 2021 09;118(39)

Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;

Extracellular adenosine triphosphate (ATP) released by mucosal immune cells and by microbiota in the intestinal lumen elicits diverse immune responses that mediate the intestinal homeostasis via P2 purinergic receptors, while overactivation of ATP signaling leads to mucosal immune system disruption, which leads to pathogenesis of intestinal inflammation. In the small intestine, hydrolysis of luminal ATP by ectonucleoside triphosphate diphosphohydrolase (E-NTPD)7 in epithelial cells is essential for control of the number of T helper 17 (Th17) cells. However, the molecular mechanism by which microbiota-derived ATP in the colon is regulated remains poorly understood. Here, we show that E-NTPD8 is highly expressed in large-intestinal epithelial cells and hydrolyzes microbiota-derived luminal ATP. Compared with wild-type mice, mice develop more severe dextran sodium sulfate-induced colitis, which can be ameliorated by either the depletion of neutrophils and monocytes by injecting with anti-Gr-1 antibody or the introduction of deficiency into hematopoietic cells. An increased level of luminal ATP in the colon of mice promotes glycolysis in neutrophils through P2x4 receptor-dependent Ca influx, which is linked to prolonged survival and elevated reactive oxygen species production in these cells. Thus, E-NTPD8 limits intestinal inflammation by controlling metabolic alteration toward glycolysis via the P2X4 receptor in myeloid cells.
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http://dx.doi.org/10.1073/pnas.2100594118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488689PMC
September 2021

Sjögren's Syndrome as an Immune-related Adverse Event of Nivolumab Treatment for Gastric Cancer.

Intern Med 2020 Oct 23;59(20):2499-2504. Epub 2020 Jun 23.

Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Japan.

Immune checkpoint inhibitors can affect any organ, including the salivary glands. A case of Sjögren's syndrome (SjS) induced by nivolumab for the treatment of gastric cancer is herein presented. Nivolumab treatment caused marked tumor shrinkage, but xerostomia developed after two cycles. It took 3 months after symptom onset to confirm the diagnosis of SjS. Prednisolone and pilocarpine hydrochloride did not relieve the symptoms. SjS is a relatively rare immune-related adverse event that might sometimes be overlooked. Since SjS can severely impair a patient's quality of life, oncologists should not miss any signs of salivary gland hypofunction and cooperate with specialists for SjS.
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http://dx.doi.org/10.2169/internalmedicine.4701-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662059PMC
October 2020

Multiple Gastric Polyps Improved After Treatment for Ulcerative Colitis.

Inflamm Bowel Dis 2020 10;26(11):e144-e145

Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

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http://dx.doi.org/10.1093/ibd/izaa159DOI Listing
October 2020

Cytomegalovirus Enterocolitis in a Patient with Refractory Immune-Related Colitis.

Case Rep Gastroenterol 2020 Jan-Apr;14(1):103-109. Epub 2020 Feb 25.

Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Although most immune-related adverse events (irAEs) secondary to immune checkpoint inhibitors can be managed with immunosuppressive therapies; they can induce reactivation of infectious diseases, including cytomegalovirus (CMV). Here, we show a case of CMV enterocolitis during steroid therapy for an irAE. A 77-year-old man with unresectable malignant melanoma was treated with ipilimumab. He suffered from immune-related colitis (irColitis) and was treated with methylprednisolone. Although corticosteroids initially improved his symptoms, CMV reactivation occurred and colitis was exacerbated. Antiviral therapy improved his symptoms without augmenting the immunosuppressive therapy. CMV colitis should be considered when a patient with irColitis shows resistance to immunosuppressive therapy.
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http://dx.doi.org/10.1159/000506186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098339PMC
February 2020

Primary mucosa-associated lymphoid tissue (MALT) lymphoma of the gallbladder and review of the literature.

BMJ Case Rep 2017 May 27;2017. Epub 2017 May 27.

Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Mucosa-associated lymphoid tissue (MALT) lymphoma is rarely observed in the gallbladder, and its diagnosis before surgery is difficult. This report describes a case of primary MALT lymphoma of the gallbladder in an 80-year-old man. Imaging studies revealed a protruding lesion on the inside of the gallbladder, which led us to diagnose gallbladder carcinoma prior to the patient undergoing extended cholecystectomy. Microscopic examination of the resected specimen of the gallbladder demonstrated lymphoid follicles with atypical lymphocytes and the formation of lymphoepithelial lesions. These findings led to a final pathological diagnosis of primary MALT lymphoma of the gallbladder. The patient has been free of recurrence for 39 months after the surgery. Although precise diagnosis before the surgery was difficult in this case, preoperative examinations revealed a submucosal tumour-like lesion. MALT lymphomas should be considered when imaging findings are atypical for gallbladder carcinoma.
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http://dx.doi.org/10.1136/bcr-2017-220161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747624PMC
May 2017

Fungal ITS1 Deep-Sequencing Strategies to Reconstruct the Composition of a 26-Species Community and Evaluation of the Gut Mycobiota of Healthy Japanese Individuals.

Front Microbiol 2017 15;8:238. Epub 2017 Feb 15.

Department of Infection Metagenomics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University Suita, Japan.

The study of mycobiota remains relatively unexplored due to the lack of sufficient available reference strains and databases compared to those of bacterial microbiome studies. Deep sequencing of Internal Transcribed Spacer (ITS) regions is the standard for fungal diversity analysis. However, results are often biased because of the wide variety of sequence lengths in the ITS regions and the complexity of high-throughput sequencing (HTS) technologies. In this study, a curated ITS database, ntF-ITS1, was constructed. This database can be utilized for the taxonomic assignment of fungal community members. We evaluated the efficacy of strategies for mycobiome analysis by using this database and characterizing a mock fungal community consisting of 26 species representing 15 genera using ITS1 sequencing with three HTS platforms: Illumina MiSeq (MiSeq), Ion Torrent Personal Genome Machine (IonPGM), and Pacific Biosciences (PacBio). Our evaluation demonstrated that PacBio's circular consensus sequencing with greater than 8 full-passes most accurately reconstructed the composition of the mock community. Using this strategy for deep-sequencing analysis of the gut mycobiota in healthy Japanese individuals revealed two major mycobiota types: a single-species type composed of or and a multi-species type. In this study, we proposed the best possible processing strategies for the three sequencing platforms, of which, the PacBio platform allowed for the most accurate estimation of the fungal community. The database and methodology described here provide critical tools for the emerging field of mycobiome studies.
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http://dx.doi.org/10.3389/fmicb.2017.00238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309391PMC
February 2017

E-NPP3 controls plasmacytoid dendritic cell numbers in the small intestine.

PLoS One 2017 22;12(2):e0172509. Epub 2017 Feb 22.

Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.

Extracellular adenosine 5'-triphosphate (ATP) performs multiple functions including activation and induction of apoptosis of many cell types. The ATP-hydrolyzing ectoenzyme ecto-nucleotide pyrophosphatase/phosphodiesterase 3 (E-NPP3) regulates ATP-dependent chronic allergic responses by mast cells and basophils. However, E-NPP3 is also highly expressed on epithelial cells of the small intestine. In this study, we showed that E-NPP3 controls plasmacytoid dendritic cell (pDC) numbers in the intestine through regulation of intestinal extracellular ATP. In Enpp3-/- mice, ATP concentrations were increased in the intestinal lumen. pDC numbers were remarkably decreased in the small intestinal lamina propria and Peyer's patches. Intestinal pDCs of Enpp3-/- mice showed enhanced cell death as characterized by increases in annexin V binding and expression of cleaved caspase-3. pDCs were highly sensitive to ATP-induced cell death compared with conventional DCs. ATP-induced cell death was abrogated in P2rx7-/- pDCs. Accordingly, the number of intestinal pDCs was restored in Enpp3-/- P2rx7-/- mice. These findings demonstrate that E-NPP3 regulates ATP concentration and thereby prevents the decrease of pDCs in the small intestine.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172509PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321438PMC
August 2017

Dysbiosis Contributes to Arthritis Development via Activation of Autoreactive T Cells in the Intestine.

Arthritis Rheumatol 2016 11;68(11):2646-2661

Osaka University, Osaka, Japan, and Japan Agency for Medical Research and Development, Tokyo, Japan.

Objective: The intestinal microbiota is involved in the pathogenesis of arthritis. Altered microbiota composition has been demonstrated in patients with rheumatoid arthritis (RA). However, it remains unclear how dysbiosis contributes to the development of arthritis. The aim of this study was to investigate whether altered composition of human intestinal microbiota in RA patients contributes to the development of arthritis.

Methods: We analyzed the fecal microbiota of patients with early RA and healthy controls, using 16S ribosomal RNA-based deep sequencing. We inoculated fecal samples from RA patients and healthy controls into germ-free arthritis-prone SKG mice and evaluated the immune responses. We also analyzed whether the lymphocytes of SKG mice harboring microbiota from RA patients react with the arthritis-related autoantigen 60S ribosomal protein L23a (RPL23A).

Results: A subpopulation of patients with early RA harbored intestinal microbiota dominated by Prevotella copri; SKG mice harboring microbiota from RA patients had an increased number of intestinal Th17 cells and developed severe arthritis when treated with zymosan. Lymphocytes in regional lymph nodes and the colon, but not the spleen, of these mice showed enhanced interleukin-17 (IL-17) responses to RPL23A. Naive SKG mouse T cells cocultured with P copri-stimulated dendritic cells produced IL-17 in response to RPL23A and rapidly induced arthritis.

Conclusion: We demonstrated that dysbiosis increases sensitivity to arthritis via activation of autoreactive T cells in the intestine. Autoreactive SKG mouse T cells are activated by dysbiotic microbiota in the intestine, causing joint inflammation. Dysbiosis is an environmental factor that triggers arthritis development in genetically susceptible mice.
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http://dx.doi.org/10.1002/art.39783DOI Listing
November 2016

Regulation of intestinal homeostasis by the ulcerative colitis-associated gene RNF186.

Mucosal Immunol 2017 03 6;10(2):446-459. Epub 2016 Jul 6.

Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.

Genome-wide association studies and subsequent deep sequencing analysis have identified susceptible loci for inflammatory bowel diseases (IBDs) including ulcerative colitis (UC). A gene encoding RING finger protein 186 (RNF186) is located within UC-susceptible loci. However, it is unclear whether RNF186 is involved in IBD pathogenesis. Here, we show that RNF186 controls protein homeostasis in colonic epithelia and regulates intestinal inflammation. RNF186, which was highly expressed in colonic epithelia, acted as an E3 ligase mediating polyubiquitination of its substrates. Permeability of small organic molecules was augmented in the intestine of Rnf186 mice. Increased expression of several RNF186 substrates, such as occludin, was found in Rnf186 colonic epithelia. The disturbed protein homeostasis in Rnf186 mice correlated with enhanced endoplasmic reticulum (ER) stress in colonic epithelia and increased sensitivity to intestinal inflammation after dextran sulfate sodium (DSS) treatment. Introduction of an UC-associated Rnf186 mutation led to impaired E3 ligase activity and increased sensitivity to DSS-induced intestinal inflammation in mice. Thus, RNF186 maintains gut homeostasis by controlling ER stress in colonic epithelia.
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http://dx.doi.org/10.1038/mi.2016.58DOI Listing
March 2017

[A case of pulmonary embolism due to heparin-induced thrombocytopenia after the placement of hepatic arterial infusion catheter].

Nihon Shokakibyo Gakkai Zasshi 2012 Jun;109(6):944-51

Department of Gastroenterology, Saiseikai Kumamoto Hospital.

A 68-year-old woman developed acute pulmonary embolism after hepatic arterial infusion therapy for advanced hepatocellular carcinoma. Because the platelet count was significantly reduced, heparin-induced thrombocytopenia (HIT) due to heparin usage in hepatic arterial infusion therapy was clinically suspected. Subsequently, the patient tested positively for HIT antibodies, and a definitive diagnosis was obtained. Antithrombotic therapy with heparin was discontinued and treatment with argatroban was started. After the heparinized hydrophilic catheter was removed, the platelet count improved immediately. HIT should be considered when a decrease in platelet count and thrombosis are involved with the usage of heparin.
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June 2012
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