Publications by authors named "Ryo Nakagawa"

33 Publications

Acquisition of mesenchymal-like phenotypes and overproduction of angiogenic factors in lenvatinib-resistant hepatocellular carcinoma cells.

Biochem Biophys Res Commun 2021 Apr 3;549:171-178. Epub 2021 Mar 3.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Lenvatinib-resistant HCC cell lines were established by exposure to serially escalated doses of lenvatinib over 2 months. The biological characteristics of these cells were examined by in vitro assays. To investigate the cytokine profile of lenvatinib-resistant HCC cells, the supernatant derived from lenvatinib-resistant Huh7 cells was subjected to nitrocellulose membrane-based sandwich immunoassay. Both activation of the MAPK/MEK/ERK signaling pathway and upregulation of epithelial mesenchymal transition markers were observed in lenvatinib-resistant cells. Concordant with these findings, proliferation and invasion abilities were enhanced in these cells compared with control cells. Screening of a cytokine array spotted with 105 different antibodies to human cytokines enabled us to identify 16 upregulated cytokines in lenvatinib-resistant cells. Among them, 3 angiogenic cytokines: vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and angiogenin, were increased significantly. Conditioned medium from lenvatinib-resistant cells accelerated tube formation of human umbilical vein cells. In conclusion, lenvatinib-resistant HCC cells were characterized by enhanced proliferation and invasion abilities. These findings might contribute to the establishment of new combination therapies with lenvatinib.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.097DOI Listing
April 2021

The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma.

Sci Rep 2021 Mar 5;11(1):5303. Epub 2021 Mar 5.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19 (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19 (n = 105) patients, there were no significant differences between FGF19 (n = 21) and FGF19 (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.
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http://dx.doi.org/10.1038/s41598-021-84117-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935880PMC
March 2021

BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.

Case Rep Oncol 2021 Jan-Apr;14(1):8-12. Epub 2021 Jan 11.

Department of Urology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
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http://dx.doi.org/10.1159/000511053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879257PMC
January 2021

Regional protein expression changes within the left ventricle in a mouse model of dyssynchronous and resynchronized heart failure.

ESC Heart Fail 2020 Oct 27. Epub 2020 Oct 27.

Department of Medicine, Karolinska Institutet and Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden.

Aims: The biological mechanisms conveying the salutary effects of cardiac resynchronization therapy in heart failure remain elusive. We have recently developed a mouse model of heart failure with dyssynchrony/resynchronization. The aim of this study was to characterize regional left ventricular heterogeneity in protein expression comparing early (septum) and late (lateral) activated left ventricular wall segments in synchronous (SHF), dyssynchronous (DHF), and resynchronized heart failure (RHF).

Methods And Results: Mice subjected to ischaemia/reperfusion were divided into three groups: sinus rhythm for 4 weeks (SHF), right ventricular pacing for 4 weeks (DHF), and right ventricular pacing for 2 weeks and 2 weeks of sinus rhythm (RHF). Relative concentrations of 92 proteins from septal and lateral left ventricular wall segments (n = 10 per group) were compared within each group. We also analysed the effect of DHF vs. SHF and RHF vs. DHF on protein expression pattern comparing the same left ventricular segments between the groups. Proteins with significantly differential expression between left ventricular segments were analysed for protein-protein correlations, protein-protein interactions, and biological and signalling pathways. Eight proteins were significantly down-regulated in the late activated (compared with early activated) lateral wall uniquely in RHF (P < 0.05 adjusted for a 5% false discovery rate): Erbb4, Ntf3, Pdgfb, Tnf, Notch3, Qdpr, Tpp1, and Itgb6. Protein correlation matrix showed that six of these were strongly and positively correlated and five had known protein-protein interactions. Biological pathways mainly down-regulated in late activated myocardium in RHF were MAPK signalling and hypertrophic cardiomyopathy. There were no significantly differentially expressed proteins comparing the same left ventricular segments between the DHF and SHF (range of P-values: 0.05-1.00) and RHF and DHF (range of P-values: 0.32-1.00).

Conclusions: In a mouse model of heart failure with dyssynchrony and resynchronization, we observed down-regulation of several proteins in the late activated lateral wall, compared with the septum, in resynchronized mice. These proteins display significant protein-protein correlation and share biological signalling pathways, including MAPK activation and hypertrophy signalling.
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http://dx.doi.org/10.1002/ehf2.13038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754720PMC
October 2020

Aberrant expression of a novel circular RNA in pancreatic cancer.

J Hum Genet 2021 Feb 3;66(2):181-191. Epub 2020 Sep 3.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.

Circular RNAs (circRNAs) are single-stranded, covalently closed RNA molecules that are produced from pre-mRNAs through a process known as back-splicing. Although circRNAs are expressed under specific conditions, current understanding of their comprehensive expression status is still limited. Here, we performed a large-scale circRNA profiling analysis in human pancreatic ductal adenocarcinoma (PDAC) tissues, using circular RNA-specific RNA sequencing. We identified more than 40,000 previously unknown circRNAs, some of which were upregulated in PDAC tissues, compared with normal pancreatic tissues. We determined the full-length sequence of a circRNA upregulated in PDAC, which was derived from two noncoding RNA loci on chromosome 12. The novel circRNA, named circPDAC RNA, was not expressed in normal human cells, but was expressed in PDAC and other carcinoma cells. While postulated biological functions, such as peptide production from the circPDAC RNA, were not detected, its aberrant expression was confirmed in other PDAC tissues and in serum from a PDAC patient. These results demonstrate that comprehensive studies are necessary to reveal the expression status of circRNAs and that the circPDAC RNA identified here might serve as a novel biomarker for cancers, including PDAC.
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http://dx.doi.org/10.1038/s10038-020-00826-5DOI Listing
February 2021

Interferon-γ induced PD-L1 expression and soluble PD-L1 production in gastric cancer.

Oncol Lett 2020 Sep 19;20(3):2161-2168. Epub 2020 Jun 19.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.

Programmed death-ligand 1 (PD-L1) plays an essential role in tumor cell escape from anti-tumor immunity in various types of cancer, including gastric cancer (GC). The present study investigated the intracellular and membrane-bound expression of PD-L1 in the GC cell lines MKN1, MKN74, KATO III and OCUM-1. Furthermore, soluble PD-L1 (sPD-L1) level in the supernatant of GC cells and the serum of patients with GC and healthy controls was determined by ELISA. Interferon (IFN)-γ treatment of cells resulted in increased cytoplasmic expression of PD-L1 in GC cells in a dose-dependent manner, except for MKN74 cells; however, there was no association between tumor necrosis factor-α treatment and enhanced PD-L1 expression. Concordant with these findings, results from flow cytometry analysis demonstrated that membrane-bound PD-L1 expression was also increased following GC cell treatment with IFN-γ in a dose-dependent manner. In addition, significant sPD-L1 overproduction was observed only in the culture supernatant of OCUM-1 cells. Serum level of sPD-L1 was significantly increased in patients with GC, in particular in stage IV patients, compared with healthy controls. In conclusion, the present study demonstrated that IFN-γ treatment increased the intracellular and membrane-bound PD-L1 expression in GC cells. In addition, sPD-L1 was detected not only in the supernatant of GC cells but also in the serum of patients with GC. Further investigation on the underlying mechanism of regulation of PD-L1 expression and sPD-L1 production is required.
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http://dx.doi.org/10.3892/ol.2020.11757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400993PMC
September 2020

A needle-type biofuel cell using enzyme/mediator/carbon nanotube composite fibers for wearable electronics.

Biosens Bioelectron 2020 Oct 12;165:112287. Epub 2020 May 12.

Graduate School of Information, Production and Systems, Waseda University, 2-7 Hibikino, Wakamatsu, Kitakyushu, Fukuoka, 808-0135, Japan. Electronic address:

To realize direct power generation from biofuels in natural organisms, we demonstrate a needle-type biofuel cell (BFC) using enzyme/mediator/carbon nanotube (CNT) composite fibers with the structure Osmium-based polymer/CNT/glucose oxidase/Os-based polymer/CNT. The composite fibers performed a high current density (10 mA/cm) in 5 mM artificial blood glucose. Owing to their hydrophilicity, they also provided sufficient ionic conductivity between the needle-type anode and the gas-diffusion cathode. When the tip of the anodic needle was inserted into natural specimens of grape, kiwifruit, and apple, the assembled BFC generated powers of 55, 44, and 33 μW from glucose, respectively. In addition, the power generated from the blood glucose in mouse heart was 16.3 μW at 0.29 V. The lifetime of the BFC was improved by coating an anti-fouling polymer 2-methacryloyloxyethyl phosphorylcholine (MPC) on the anodic electrode, and sealing the cathodic hydrogel chamber with medical tape to minimize the water evaporation without compromising the oxygen permeability.
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http://dx.doi.org/10.1016/j.bios.2020.112287DOI Listing
October 2020

Leukotriene receptor antagonists enhance HCC treatment efficacy by inhibiting ADAMs and suppressing MICA shedding.

Cancer Immunol Immunother 2021 Jan 18;70(1):203-213. Epub 2020 Jul 18.

Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan.

In our previous genome-wide association study, we demonstrated the association between MHC class I-related chain A (MICA) and hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Increasing membrane-bound MICA (mMICA) in cancer cells by reducing MICA sheddases facilitates natural killer (NK) cell-mediated cytotoxicity. Our recent study clarified that A disintegrin and metalloproteases (ADAM), including ADAM9, are MICA sheddases in HCC, and that the suppression of ADAMs increases mMICA, demonstrating the rationality of mMICA-NK targeted therapy. Furthermore, we showed that regorafenib suppresses ADAM9 transcriptionally and translationally. A library of FDA-approved drugs was screened for more efficient inhibitors of ADAM9. Flow cytometry evaluation of the expression of mMICA after treatment with various candidate drugs identified leukotriene receptor antagonists as potential ADAM9 inhibitors. Furthermore, leukotriene receptor antagonists alone or in combination with regorafenib upregulated mMICA, which was in turn downregulated by leukotriene C4 and D4 via ADAM9 function. Our study demonstrates that leukotriene receptor antagonists could be developed as novel drugs for immunological control and suppression of ADAM9 in HCC. Further, leukotriene receptor antagonists should be explored as combination therapy partners with conventional multi-kinase inhibitors for developing therapeutic strategies with enhanced efficacies for HCC management and treatment.
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http://dx.doi.org/10.1007/s00262-020-02660-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838147PMC
January 2021

A Novel Role of Interleukin 13 Receptor alpha2 in Perineural Invasion and its Association with Poor Prognosis of Patients with Pancreatic Ductal Adenocarcinoma.

Cancers (Basel) 2020 May 20;12(5). Epub 2020 May 20.

Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.

Perineural invasion (PNI) is one of the major pathological characteristics of pancreatic ductal adeno-carcinoma (PDAC), which is mediated by invading cancer cells into nerve cells. Herein, we identify the overexpression of Interleukin-13 Receptor alpha2 (IL-13Rα2) in the PNI from 236 PDAC samples by studying its expression at the protein levels by immunohistochemistry (IHC) and the RNA level by in situ hybridization (ISH). We observe that ≥75% samples overexpressed IL-13Rα2 by IHC and ISH in grade 2 and 3 tumors, while ≥64% stage II and III tumors overexpressed IL-13Rα2 (≥2+). Interestingly, ≥36 % peripancreatic neural plexus (PL) and ≥70% nerve endings (Ne) among PNI in PDAC samples showed higher levels of IL-13Rα2 (≥2+). IL-13Rα2 +ve PL and Ne subjects survived significantly less than IL-13Rα2 -ve subjects, suggesting that IL-13Rα2 may have a unique role as a biomarker of PNI-aggressiveness. Importantly, IL-13Rα2 may be a therapeutic target for intervention, which might not only prolong patient survival but also help alleviate pain attributed to perineural invasion. Our study uncovers a novel role of IL-13Rα2 in PNI as a key factor of the disease severity, thus revealing a therapeutically targetable option for PDAC and to facilitate PNI-associated pain management.
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http://dx.doi.org/10.3390/cancers12051294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281570PMC
May 2020

A Simple and Robust Functionalization of Graphene for Advanced Energy Devices.

ACS Appl Mater Interfaces 2020 Mar 6;12(11):12736-12742. Epub 2020 Mar 6.

Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.

Efficient and selective methods for graphene functionalization are needed because they allow tuning of the graphene surface and electronic properties. To date, graphene has been functionalized using ionic bonds, π-π interactions, and covalent bonds. Graphene derivatives based on these methods have been used in various applications, but a new functionalization strategy that improves the properties of graphene is still needed. Herein, a new concept for graphene functionalization using halogenated graphene has been developed, in which brominated graphene is successfully functionalized by heteroatom-containing molecules to form onium bonds, such as pyridinium or ammonium. The counterion bromide is replaced with other anions, such as sulfate, by treating with sulfuric acid while retaining the molecules, which demonstrates the durable properties of onium bonding. To emphasize the advantages of this strategy for graphene functionalization, the performance for energy-related applications, such as biofuel cells, supercapacitors, and Li-ion batteries, is evaluated after introducing redox-active moieties onto graphene through onium bonding. This new graphene functionalization concept will provide a new approach to the design of tailor-made materials with targeted functions.
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http://dx.doi.org/10.1021/acsami.9b21082DOI Listing
March 2020

Serum fibroblast growth factor 19 serves as a potential novel biomarker for hepatocellular carcinoma.

BMC Cancer 2019 Nov 12;19(1):1088. Epub 2019 Nov 12.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background: Abnormal autocrine fibroblast growth factor 19 (FGF19) production has been observed in several types of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the potential of serum FGF19 as a novel tumor marker of HCC based on a sandwich enzyme-linked immunosorbent assay (ELISA).

Methods: The serum FGF19 levels of 304 patients with HCC was measured by ELISA. The serum levels of existing markers, including alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) were determined by chemiluminescence enzyme immunoassay. Both diagnostic value of FGF19 and its changes after curative ablation therapy was further examined.

Results: The median FGF19 levels in controls, chronic liver disease patients, and primary HCC patients, were 78.8 pg/mL, 100.1 pg/mL, and 214.5 pg/mL, respectively. The subsequent receiver operating characteristic curves (ROC) successfully determined an optimal cut-off value of 200.0 pg/mL. The area under the ROC curve (AUC) of FGF19 for HCC detection was comparable to those of AFP and DCP. Of importance, FGF19 showed higher sensitivity for the detection of small HCC (solitary cancer with diameter < 20 mm) than those of existing markers. In addition, 43 out of 79 cases (54.4%) with normal AFP and DCP (so-called "double negative HCC") exhibited serum FGF19 level ≥ 200 pg/mL. In 45 HCC patients treated with curative ablation therapy, serum FGF19 levels changed from 257.4 pg/mL to 112.0 pg/mL after the treatment.

Conclusion: Our findings reveal that FGF19 can be a potential novel biomarker for HCC. Although FGF19 is not necessarily a substitute for existing markers, it may help improve the prognosis in HCC patients owing to its resourceful use in various aspects of HCC management and treatment.
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http://dx.doi.org/10.1186/s12885-019-6322-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849282PMC
November 2019

Successful treatment of neonatal idiopathic ventricular tachycardia with landiolol hydrochloride.

Pediatr Int 2019 Oct 16;61(10):1048-1050. Epub 2019 Oct 16.

Department of Pediatrics, Toyama Prefectural Central Hospital, Toyama, Japan.

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http://dx.doi.org/10.1111/ped.13969DOI Listing
October 2019

Long QT syndrome with a de novo CALM2 mutation in a 4-year-old boy.

Pediatr Int 2019 Sep;61(9):852-858

Department of Pediatrics, Toyama Prefectural Central Hospital, Toyama, Japan.

Background: Human calmodulin (CALM) gene mutation has been reported to be related to inherited arrhythmia syndromes, but the genotype-phenotype relationship remains unclear.

Methods And Results: We report here a 4-year-old boy who had cardiac arrest while playing in a kindergarten playground. Cardiopulmonary resuscitation was initiated immediately. Eleven minutes after the cardiac arrest, ambulance crews arrived and an automated external defibrillator was attached. His heart rhythm, which was ventricular fibrillation (VF), was returned to sinus rhythm after only one shock delivery. The boy was brought to hospital by air ambulance. During transfer, electrocardiogram (ECG) showed transient VF. On arrival, chest radiograph showed a cardiothoracic ratio of 55% without pulmonary congestion. A 12-lead ECG showed a normal sinus rhythm, biphasic T wave, and prolongation of the corrected QT interval. On ECG, VF was preceded by torsade de pointes or frequent polymorphic premature ventricular contractions (PVC). Echocardiography showed a normal heart structure with decreased cardiac function. On the second day of hospitalization, ECG showed remarkable QT prolongation, T-wave alternans, and frequent PVC. Thereafter, propranolol was started. The ECG showed rapid improvement of QT prolongation and T-wave abnormality. Genetic test indicated a CALM2 mutation, and he was diagnosed with long QT syndrome-15 (LQT15).

Conclusions: CALM mutations cause long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) and idiopathic VF. This patient with a CALM2 p.N98S mutation had both phenotypes of LQTS and CPVT.
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http://dx.doi.org/10.1111/ped.13959DOI Listing
September 2019

Significance of urinary albumin excretion in patients with cast nephropathy
.

Clin Nephrol 2019 Aug;92(2):81-88

Background: This study was performed to determine whether the urinary albumin excretion rate (%UAE) could distinguish myeloma cast nephropathy (MCN) without glomerular amyloid deposition from MCN with glomerular amyloid deposition.

Materials And Methods: We retrospectively reviewed clinicopathological data on 16 patients with MCN diagnosed by renal biopsy at Toranomon Hospital from 2004 to 2014.

Results: A total of 10 patients had pure MCN without glomerular amyloid deposition (group 1), and 6 patients had MCN with glomerular amyloid deposition (group 2). In all 10 patients from group 1, the underlying disease was multiple myeloma (MM), while 4 patients had MM, and 2 patients had lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) in group 2. Total protein did not show a significant difference between the two groups, but serum albumin was significantly higher in group 1 than group 2 (p = 0.0101). Serum-adjusted calcium did not show a significant difference between the groups, while serum creatinine (Cre) was significantly higher in group 1 than group 2 (p = 0.0343). Although urinary protein excretion did not differ significantly between the groups, the %UAE was significantly lower in group 1 than group 2 (p = 0.00198). In group 2, 3 of the 4 patients with MM died within 15 months of diagnosis, but the 2 patients with LPL/WM are alive after 32 months. In group 1, only 1 patient died (of unknown causes) within 15 months after diagnosis.

Conclusion: In patients with MCN, %UAE may be a useful marker for the detection of coexistence of glomerular lesions, such as amyloidosis, which are associated with a poor outcome.
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http://dx.doi.org/10.5414/CN109630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637393PMC
August 2019

Preemptive therapy for cytomegalovirus reactivation after daratumumab-containing treatment in patients with relapsed and refractory multiple myeloma.

Ann Hematol 2019 Aug 1;98(8):1999-2001. Epub 2019 Mar 1.

Department Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.

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http://dx.doi.org/10.1007/s00277-019-03645-7DOI Listing
August 2019

Chronic Atrial and Ventricular Pacing in the Mouse.

Circ Heart Fail 2019 02;12(2):e005655

Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (M.S., R.N., D.B., G.Z., B.L.L., A.S., D.I.L., D.A.K.).

Background: The mouse is the most widely used mammal in experimental biology. Although many clinically relevant in vivo cardiac stressors are used, one that has eluded translation is long-term cardiac pacing. Here, we present the first method to chronically simulate and simultaneously record cardiac electrical activity in conscious mobile mice. We then apply it to study right ventricular pacing induced electromechanical dyssynchrony and its reversal (resynchronization).

Methods And Results: The method includes a custom implantable bipolar stimulation and recording lead and flexible external conduit and electrical micro-commutator linked to a pulse generator/recorder. This achieved continuous pacing for at least 1 month in 77% of implants. Mice were then subjected to cardiac ischemia/reperfusion injury to depress heart function, followed by 4 weeks pacing at the right ventricle (dyssynchrony), right atrium (synchrony), or for 2 weeks right ventricle and then 2 weeks normal sinus (resynchronization). Right ventricular pacing-induced dyssynchrony substantially reduced heart and myocyte function compared with the other groups, increased gene expression heterogeneity (>10 fold) comparing septum to lateral walls, and enhanced growth and metabolic kinase activity in the late-contracting lateral wall. This was ameliorated by restoring contractile synchronization.

Conclusions: The new method to chronically pace conscious mice yields stable atrial and ventricular capture and a means to dissect basic mechanisms of electromechanical physiology and therapy. The data on dyssynchrony and resynchronization in ischemia/reperfusion hearts is the most comprehensive to date in ischemic heart disease, and its similarities to nonischemic canine results support the translational utility of the mouse.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.118.005655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513021PMC
February 2019

CD4 T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T-cell receptor repertoires.

Hepatol Res 2019 Jun 26;49(6):653-662. Epub 2019 Feb 26.

Division of Advanced Genome Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

Aim: Primary biliary cholangitis (PBC) is an autoimmune liver disease with unknown pathogenesis. In PBC, activation of T-cell receptor (TCR) signaling is associated with inflammatory cytokine production through N-Ras upregulation. Although the CD4 T cell TCR repertoire could be associated with PBC pathogenesis, it has not been evaluated. Thus, we analyzed the PBC-CD4 T cell TCR repertoire using next generation sequencing (NGS).

Methods: Four PBC patients (one treatment-naïve and three receiving ursodeoxycholic acid) and three healthy individuals were enrolled. NRAS expression in CD4 T cells was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). N-Ras dynamics in CD4 T cells were assessed by qRT-PCR and GTP-N-Ras activation assay. The TCR α- (TRA) and β-chain (TRB) repertoires on CD4 T cells were analyzed by NGS and profiled using hierarchical analysis. Motif analysis was undertaken to elucidate the structure of PBC-specific TCRs.

Results: NRAS was upregulated in PBC relative to control CD4 T cells (P < 0.05), and N-Ras enhanced T cell activation in CD4 T cells. Among 2668 TRAs and 841 TRBs, 20 and 11, respectively, were differentially expressed in PBC compared to that in controls (P < 0.05, fold-change >2). Among them, TRAV29/J22, TRBV6-5/J2-6, and TRBV10-1/J2-1 were expressed in PBC but the expression was negligible in the controls, with more mature and longer forms observed in PBC-CD4 T cells.

Conclusions: N-Ras was upregulated in PBC-CD4 T cells, and it enhanced TCR activation, indicating that PBC-CD4 T cells were activated by N-Ras upregulation with differentially expressed TCR repertoires on their surfaces.
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http://dx.doi.org/10.1111/hepr.13318DOI Listing
June 2019

Catecholaminergic polymorphic ventricular tachycardia managed as orthostatic dysregulation and epilepsy in 11- and 15-year-old sisters.

Pediatr Int 2018 Nov;60(11):998-1001

Department of Pediatrics, Toyama Prefectural Central Hospital, Toyama, Japan.

Background: In pediatric patients, syncope commonly occurs as vasovagal syncope, or in epilepsy or orthostatic dysregulation. Cardiogenic syncope is rare but it is lethal, and needs to be promptly diagnosed and treated.

Methods And Results: We describe the cases of 11- and 15-year-old sisters with frequent syncope during exercise and emotional stress since the age of 10 and 12, respectively. There were no abnormalities on 12-lead electrocardiogram (ECG) at rest. They were first diagnosed with orthostatic dysregulation and epilepsy. Because of recurrent exercise-induced syncope, cardiac examinations were performed. On treadmill exercise stress test, bidirectional ventricular tachycardia was induced in the 11-year-old girl, which degenerated into ventricular fibrillation; frequent polymorphic premature ventricular contractions were induced in her elder sister. They were diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) and started on oral beta-blockers and exercise restriction.

Conclusions: It is important to suspect CPVT in pediatric exercise-induced syncope, and to recognize that CPVT does not show ECG abnormalities at rest.
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http://dx.doi.org/10.1111/ped.13688DOI Listing
November 2018

Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition.

Circulation 2018 10;138(18):1974-1987

Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (T.H., G.E.K., R.S.T., T.A., S.H., R.N., G.Z., D.I.L., D.A.K.).

Background: Phosphodiesterase type-1 (PDE1) hydrolyzes cAMP and cGMP and is constitutively expressed in the heart, although cardiac effects from its acute inhibition in vivo are largely unknown. Existing data are limited to rodents expressing mostly the cGMP-favoring PDE1A isoform. Human heart predominantly expresses PDE1C with balanced selectivity for cAMP and cGMP. Here, we determined the acute effects of PDE1 inhibition in PDE1C-expressing mammals, dogs, and rabbits, in normal and failing hearts, and explored its regulatory pathways.

Methods: Conscious dogs chronically instrumented for pressure-volume relations were studied before and after tachypacing-induced heart failure (HF). A selective PDE1 inhibitor (ITI-214) was administered orally or intravenously±dobutamine. Pressure-volume analysis in anesthetized rabbits tested the role of β-adrenergic and adenosine receptor signaling on ITI-214 effects. Sarcomere and calcium dynamics were studied in rabbit left ventricular myocytes.

Results: In normal and HF dogs, ITI-214 increased load-independent contractility, improved relaxation, and reduced systemic arterial resistance, raising cardiac output without altering systolic blood pressure. Heart rate increased, but less so in HF dogs. ITI-214 effects were additive to β-adrenergic receptor agonism (dobutamine). Dobutamine but not ITI-214 increased plasma cAMP. ITI-214 induced similar cardiovascular effects in rabbits, whereas mice displayed only mild vasodilation and no contractility effects. In rabbits, β-adrenergic receptor blockade (esmolol) prevented ITI-214-mediated chronotropy, but inotropy and vasodilation remained unchanged. By contrast, adenosine A-receptor blockade (MRS-1754) suppressed ITI-214 cardiovascular effects. Adding fixed-rate atrial pacing did not alter the findings. ITI-214 alone did not affect sarcomere or whole-cell calcium dynamics, whereas β-adrenergic receptor agonism (isoproterenol) or PDE3 inhibition (cilostamide) increased both. Unlike cilostamide, which further enhanced shortening and peak calcium when combined with isoproterenol, ITI-214 had no impact on these responses. Both PDE1 and PDE3 inhibitors increased shortening and accelerated calcium decay when combined with forskolin, yet only cilostamide increased calcium transients.

Conclusions: PDE1 inhibition by ITI-214 in vivo confers acute inotropic, lusitropic, and arterial vasodilatory effects in PDE1C-expressing mammals with and without HF. The effects appear related to cAMP signaling that is different from that provided via β-adrenergic receptors or PDE3 modulation. ITI-214, which has completed phase I trials, may provide a novel therapy for HF.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.030490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205901PMC
October 2018

Enzymatic inhibition of MICA sheddase ADAM17 by lomofungin in hepatocellular carcinoma cells.

Int J Cancer 2018 11 22;143(10):2575-2583. Epub 2018 Sep 22.

Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

In our previous study on hepatocellular carcinoma (HCC) susceptibility genes in chronic hepatitis patients, we identified the MHC class I polypeptide-related sequence A (MICA). Natural killer cells eliminate various cancer cells, including HCC, by suppressing MICA shedding. Therefore, we investigated MICA sheddases and inhibitors for HCC immunotherapy. In this study, HepG2, PLC/PRF/5, and Hep3B were treated with the siRNA of a disintegrin and metalloproteases (ADAMs) and matrix metalloproteases to measure the concentration of soluble MICA (sMICA) by ELISA to detect the therapeutic target. Furthermore, an FDA-approved drug library was tested for the enzymatic inhibition of the targeted enzyme in an in vitro drug screening assay system. ADAM17 knockdown reduced sMICA levels and increased membrane-bound MICA (mMICA) expression in HCC cells. In an in vitro drug screen using an FDA-approved drug library, lomofungin, an antifungal drug, was found to strongly decrease ADAM17 activity. In HCC cells, mMICA expression was induced and sMICA production was inhibited in a dose-dependent manner. These effects were cancelled upon ADAM17 knockdown, suggesting that lomofungin targeted ADAM17. Analysis of lomofungin analogs revealed the responsible functional groups. In summary, we suggest lomofungin to be an attractive agent for the immunological control of HCC, via the suppression of ADAM17.
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http://dx.doi.org/10.1002/ijc.31615DOI Listing
November 2018

Predominance of regorafenib over sorafenib: Restoration of membrane-bound MICA in hepatocellular carcinoma cells.

J Gastroenterol Hepatol 2018 May 6;33(5):1075-1081. Epub 2018 Feb 6.

Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Background And Aim: The multi-kinase inhibitor regorafenib (REG) was recently demonstrated to be effective in patients with sorafenib (SOR)-resistant hepatocellular carcinoma (HCC). Interestingly, SOR is known to enhance the accumulation of membrane-bound MHC class I polypeptide-related sequence A (mMICA) in HCC cells and to block the production of soluble MICA (sMICA), an immunological decoy. In addition, MICA is associated with HCC in patients with chronic hepatitis C. We have now compared the impact of REG and SOR on MICA in HCC cells, as well as the immunotherapeutic implications thereof.

Methods: HepG2 and PLC/PRF/5 cells were exposed to REG and SOR, and levels of sMICA and mMICA were measured by ELISA and flow cytometry, respectively. The drugs were also tested in vitro for inhibitory activity against recombinant human A disintegrin and metalloprotease 9 (ADAM9), a sheddase that releases MICA from the membrane.

Results: To a greater extent than SOR, but without marked difference in cytotoxicity, REG significantly suppressed mRNA and protein expression of ADAM9 and ADAM10, thereby decreasing production of sMICA and boosting accumulation of mMICA. Accumulation of mMICA in response to REG was reversed by siRNA against ADAM9. However, the drugs did not inhibit the enzymatic activity of ADAM9 in vitro.

Conclusions: The clinical superiority of REG over SOR is partially attributable to reduced MICA shedding via transcriptional suppression of ADAM9 and ADAM10.
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http://dx.doi.org/10.1111/jgh.14029DOI Listing
May 2018

Cefepime-induced encephalopathy in end-stage renal disease patients.

J Neurol Sci 2017 May 16;376:123-128. Epub 2017 Mar 16.

Department of Neurology, Toranomon Hospital, Tokyo, Japan; Okinaka Memorial Institute for Medical Research, Tokyo, Japan.

Objectives: Impaired renal function is a risk factor for cefepime (CFPM)-induced encephalopathy (CFPMIE) in patients treated with CFPM; dose-titration to renal function is recommended to prevent CFPMIE. However, available evidence on the incidence of CFPMIE or preventive efficacy of dose adjustment against CFPMIE in end-stage renal disease (ESRD) patients is limited.

Methods: Single-centre, retrospective observational study. We reviewed consecutive in-hospital adult patients treated with adjusted-dose of CFPM in the period between September 2012 and September 2016, and assessed the CFPMIE in ESRD patients treated with adjusted-dose of CFPM.

Results: Out of 422 eligible patients, 6 patients (1.4%) were diagnosed with CFPMIE. The incidence of CFPMIE in ESRD patients was 7.5% (5/67). Among ESRD patients, pre-existing central nervous system (CNS) morbidity was significantly associated with the risk of CFPMIE. CFPMIE occurred in ESRD patients regardless of daily dose, and even with 0.5g/day of CFPM.

Conclusions: Pre-existing CNS morbidity may be associated with an increased risk of CFPMIE in ESRD patients. No significant association was observed between CFPM dose and incidence of CFPMIE in ESRD patients, and future investigation on the safer dose-adjustment strategy in ESRD patients is required for achieving balance between successful infectious treatment and reducing CFPMIE.
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http://dx.doi.org/10.1016/j.jns.2017.03.018DOI Listing
May 2017

miR-425 regulates inflammatory cytokine production in CD4 T cells via N-Ras upregulation in primary biliary cholangitis.

J Hepatol 2017 06 10;66(6):1223-1230. Epub 2017 Feb 10.

Department of Gastroenterology and Hepatology, The Jikei University School of Medicine, Tokyo, Japan; Sanno Medical Center, Sanno Hospital, International University of Health and Welfare, Tokyo, Japan.

Background & Aims: Primary biliary cholangitis (PBC) is an autoimmune liver disease of unknown pathogenesis. Consequently, therapeutic targets for PBC have yet to be identified. CD4 T cells play a pivotal role in immunological dysfunction observed in PBC, and therefore, microRNA (miRNA) and mRNA expression were analysed in CD4 T cells, to investigate PBC pathogenesis and identify novel therapeutic targets.

Methods: Integral miRNA and mRNA analysis of 14 PBC patients and ten healthy controls was carried out using microarray and quantitative real-time polymerase chain reaction (qRT-PCR), with gene set enrichment analysis. The functional analyses of miRNA were then assessed using reporter and miRNA-overexpression assays.

Results: The integral analysis of miRNA and mRNA identified four significantly downregulated miRNAs (miR-181a, -181b, -374b, and -425) related to the T cell receptor (TCR) signalling pathway in CD4 T cells of PBC. N-Ras, a regulator of the TCR signalling pathway, was found to be targeted by all four identified miRNAs. In addition, in vitro assays confirmed that decreased miR-425 strongly induced inflammatory cytokines (interleukin [IL]-2 and interferon [IFN]-γ) via N-Ras upregulation in the TCR signalling pathway.

Conclusion: The decreased expression of four miRNAs that dysregulate TCR signalling in PBC CD4 T cells was identified. miR-425 was demonstrated as an inflammatory regulator of PBC via N-Ras upregulation. Therefore, the restoration of decreased miR-425 or the suppression of N-Ras may be a promising immunotherapeutic strategy against PBC.

Lay Summary: Primary biliary cholangitis (PBC) is an autoimmune liver disease, but the causes are unknown. MicroRNAs are molecules known to regulate biological signals. In this study, four microRNAs were identified as being decreased in PBC patients, leading to activation of T cell receptor signalling pathways, involved in inflammation. One particular target, N-Ras, could be an attractive and novel immunotherapeutic option for PBC.

Transcript Profiling: Microarray data are deposited in GEO (GEO accession: GSE93172).
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http://dx.doi.org/10.1016/j.jhep.2017.02.002DOI Listing
June 2017

Clinical usefulness of ursodeoxycholic acid for Japanese patients with autoimmune hepatitis.

World J Hepatol 2017 Jan;9(1):57-63

Yuichi Torisu, Masanori Nakano, Keiko Takano, Ryo Nakagawa, Chisato Saeki, Atsushi Hokari, Tomohisa Ishikawa, Masayuki Saruta, Division of Gastroenterology and Hepatology, Department of Internal Medicine, the Jikei University School of Medicine, Tokyo 105-8461, Japan.

Aim: To evaluate the therapeutic effects of ursodeoxycholic acid (UDCA) on autoimmune hepatitis (AIH).

Methods: A total 136 patients who were diagnosed with AIH were included in our study. All of the patients underwent a liver biopsy, and had at least a probable diagnosis on the basis of either the revised scoring system or the simplified scores. Initial treatment included UDCA monotherapy (Group U, = 48) and prednisolone (PSL) monotherapy (Group P, = 88). Group U was further classified into two subgroups according to the effect of UDCA: Patients who had achieved remission induction with UDCA monotherapy and showed no sign of relapse (Subgroup U1, = 34) and patients who additionally received PSL during follow-up (Subgroup U2, = 14). We compared the clinical and histological findings between each groups, and investigated factors contributing to the response to UDCA monotherapy.

Results: In Group U, 34 patients (71%) achieved and maintained remission over 49 (range: 8-90) mo (Subgroup U1) and 14 patients (29%) additionally received PSL (Subgroup U2) during follow-up. Two patients in Subgroup U2 achieved remission induction once but additionally required PSL administration because of relapse (15 and 35 mo after the start of treatment). The remaining 12 patients in Subgroup U2 failed to achieve remission induction during follow-up, and PSL was added during 7 (range: 2-18) mo. Compared with Subgroup U2, Subgroup U1 had significantly lower alanine aminotransferase (ALT) levels at onset (124 IU/L 262 IU/L, = 0.023) and a significantly higher proportion of patients with mild inflammation (A1) on histological examination (70.6% 35.7%, = 0.025). When multivariate analysis was performed to identify factors contributing to the response to UDCA monotherapy, only a serum ALT level of 200 IU/L or lower was found to be associated with a significant difference ( = 0.013).

Conclusion: To prevent adverse events related to corticosteroids, UDCA monotherapy for AIH needs to be considered in patients with a serum ALT level of 200 IU/L or lower.
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http://dx.doi.org/10.4254/wjh.v9.i1.57DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220272PMC
January 2017

Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study.

Sci Rep 2016 12 2;6:38407. Epub 2016 Dec 2.

The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.

Pharmacotherapeutic options are limited for hepatocellular carcinoma (HCC). Recently, we identified the anti-tumor ligand MHC class I polypeptide-related sequence A (MICA) gene as a susceptibility gene for hepatitis C virus-induced HCC in a genome-wide association study (GWAS). To prove the concept of HCC immunotherapy based on the results of a GWAS, in the present study, we searched for drugs that could restore MICA expression. A screen of the FDA-approved drug library identified the anti-cancer agent vorinostat as the strongest hit, suggesting histone deacetylase inhibitors (HDACis) as potent candidates. Indeed, the HDACi-induced expression of MICA specific to HCC cells enhanced natural killer (NK) cell-mediated cytotoxicity in co-culture, which was further reinforced by treatment with an inhibitor of MICA sheddase. Similarly augmented anti-tumor activity of NK cells via NK group 2D was observed in vivo. Metabolomics analysis revealed HDACi-mediated alterations in energy supply and stresses for MICA induction and HCC inhibition, providing a mechanism for the chemoimmunotherapeutic actions. These data are indicative of promising strategies for selective HCC innate immunotherapy.
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http://dx.doi.org/10.1038/srep38407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133582PMC
December 2016

Repression of MicroRNA Function Mediates Inflammation-associated Colon Tumorigenesis.

Gastroenterology 2017 02 5;152(3):631-643. Epub 2016 Nov 5.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background & Aims: Little is known about the mechanisms by which chronic inflammation contributes to carcinogenesis, such as the development of colon tumors in patients with inflammatory bowel diseases. Specific microRNA (miRNAs) can function as suppressors or oncogenes, and widespread alterations in miRNA expression have been associated with tumorigenesis. We studied whether alterations in miRNA function contribute to inflammation-associated colon carcinogenesis.

Methods: We studied the effects of inflammatory cytokines, such as tumor necrosis factor, interleukin-1α (IL1A), and IL1β (IL1B), on miRNA function, measured by activity of reporter constructs containing miRNA-binding sites in their 3' untranslated regions, in human 293T embryonic kidney, Caco-2, HT29, and HCT116 colon carcinoma cells, as well as dicer and dicer, and Apobec3 and Apobec3 mouse embryonic fibroblasts. Cells were analyzed by immunoblots, immunohistochemistry, and flow cytometry. We generated transgenic mice expressing reporter constructs regulated by LET7B, MIR122, and MIR29b response elements; some mice were given injections of miRNA inhibitors (anti-MIR122 or anti-LET7B), a negative control, or tumor necrosis factor. Liver tissues were collected and analyzed by immunoblotting. Reporter mice were given azoxymethane followed by dextran sulfate sodium to induce colitis and colon tumors; some mice were given the ROCK inhibitor fasudil along with these agents (ROCK inhibitors increase miRNA function). Colon tissues were collected and analyzed by immunohistochemistry, immunoblots, and fluorescence microscopy.

Results: Incubation of cell lines with inflammatory cytokines reduced the ability of miRNAs to down-regulate expression from reporter constructs; dicer was required for this effect, so these cytokines relieve miRNA-dependent reductions in expression. The cytokines promoted degradation of APOBEC3G, which normally promotes miRNA loading into argonaute 2-related complexes. Mice with colitis had reduced miRNA function, based on increased expression of reporter genes. Administration of fasudil to mice did not reduce the severity of colitis that developed but greatly reduced the numbers of colon tumors formed (mean 2 tumors/colon in mice given fasudil vs 9 tumors/colon in mice given control agent). We made similar observations in IL10-deficient mice.

Conclusions: We found inflammatory cytokines to reduce the activities of miRNAs. In mice with colitis, activities of miRNAs are reduced; administration of an agent that increases miRNA function prevents colon tumor formation in these mice. This pathway might be targeted to prevent colon carcinogenesis in patients with inflammatory bowel diseases.
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http://dx.doi.org/10.1053/j.gastro.2016.10.043DOI Listing
February 2017

[Development status of DAA against hepatitis C].

Nihon Rinsho 2015 Dec;73 Suppl 9:262-8

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December 2015

Mechanism of aortic root dilation and cardiovascular function in tetralogy of Fallot.

Pediatr Int 2016 May;58(5):323-30

Division of Pediatric Cardiology, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan.

The aortic root dilation in tetralogy of Fallot (TOF) is a long-term clinical problem, because a severely dilated aorta can lead to aortic regurgitation, dissection, or rupture, which can be fatal, necessitating surgical intervention. The details of the mechanism of aortic root dilation, however, are unclear. We have shown that aortic stiffness is increased in patients with repaired TOF, and may mirror the histological abnormality of elastic fiber disruption and matrix expansion. This aortic stiffness is related closely to the aortic dilation, indicating that aortic stiffness may be a predictor of outcome of aortic dilation. Furthermore, the aortic volume overload is a very important determinant of aortic diameter in TOF patients before corrective surgery. In addition, a chromosomal abnormality and the transforming growth factor-β signaling pathway, a major contributor to aortic dilation in Marfan syndrome, also affect this mechanism. In this way, aortic dilation in TOF patients is suggested to be a multifactorial disorder. The aim of this review was therefore to clarify the mechanism of aortic dilation in TOF, focusing on recent research findings. Studies linking histopathology, mechanical properties, molecular/cellular physiology, and clinical manifestations of aortic dilation facilitate appropriate treatment intervention and improvement of long-term prognosis of TOF.
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http://dx.doi.org/10.1111/ped.12932DOI Listing
May 2016

Mechanism of aortic root dilation and cardiovascular function in tetralogy of Fallot.

Pediatr Int 2016 May;58(5):323-30

Division of Pediatric Cardiology, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan.

The aortic root dilation in tetralogy of Fallot (TOF) is a long-term clinical problem, because a severely dilated aorta can lead to aortic regurgitation, dissection, or rupture, which can be fatal, necessitating surgical intervention. The details of the mechanism of aortic root dilation, however, are unclear. We have shown that aortic stiffness is increased in patients with repaired TOF, and may mirror the histological abnormality of elastic fiber disruption and matrix expansion. This aortic stiffness is related closely to the aortic dilation, indicating that aortic stiffness may be a predictor of outcome of aortic dilation. Furthermore, the aortic volume overload is a very important determinant of aortic diameter in TOF patients before corrective surgery. In addition, a chromosomal abnormality and the transforming growth factor-β signaling pathway, a major contributor to aortic dilation in Marfan syndrome, also affect this mechanism. In this way, aortic dilation in TOF patients is suggested to be a multifactorial disorder. The aim of this review was therefore to clarify the mechanism of aortic dilation in TOF, focusing on recent research findings. Studies linking histopathology, mechanical properties, molecular/cellular physiology, and clinical manifestations of aortic dilation facilitate appropriate treatment intervention and improvement of long-term prognosis of TOF.
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http://dx.doi.org/10.1111/ped.12932DOI Listing
May 2016