Publications by authors named "Masaya Sato"

75 Publications

Non-mercaptalbumin is significantly associated with the coronary plaque burden and the severity of coronary artery disease.

Sci Rep 2021 Jul 9;11(1):14242. Epub 2021 Jul 9.

Department of Clinical Laboratory, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.

Human non-mercaptalbumin (HNA), oxidized form of serum albumin, has been reported as a useful marker in oxidative stress-related diseases; however, few reports have examined the association between HNA and the severity of coronary artery disease (CAD). The present study evaluated whether the HNA fraction is correlated with coronary artery stenosis in 140 patients considered to have a high risk of CAD or who were suspected of having acute coronary syndrome. The severity of CAD was defined by the number of stenotic coronary vessels and a severity score system (the Gensini score). HNA measurements were performed using our newly established high-performance liquid chromatography methodology. The results had shown that HNA was significantly increased in patients with three-vessel disease, compared with those without CAD or with single-vessel disease (p = 0.025), and was positively correlated with the Gensini score (ρ = 0.421, p < 0.001). A multivariate analysis showed that the number of stenotic vessels was an independent and significant factor associated with HNA (ρ = 1.246, p = 0.012). A logistic regression analysis showed that HNA was a strong predictor of multivessel CAD (odds ratio, 1.12; 95% confidence interval, 1.020-1.229; p = 0.017). These findings indicate that the measurement of HNA could be clinically practical for predicting the severity of coronary artery stenosis.
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http://dx.doi.org/10.1038/s41598-021-93753-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270939PMC
July 2021

Post-treatment cell-free DNA as a predictive biomarker in molecular-targeted therapy of hepatocellular carcinoma.

J Gastroenterol 2021 May 12;56(5):456-469. Epub 2021 Mar 12.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Liquid biopsies, particularly those involving circulating tumor DNA (ctDNA), are rapidly emerging as a non-invasive alternative to tumor biopsies. However, clinical applications of ctDNA analysis in hepatocellular carcinoma (HCC) have not been fully elucidated.

Methods: We measured the amount of plasma-derived cell-free DNA (cfDNA) in HCC patients before (n = 100) and a few days after treatment (n = 87), including radiofrequency ablation, transarterial chemoembolization, and molecular-targeted agents (MTAs), and prospectively analyzed their associations with clinical parameters and prognosis. TERT promoter mutations in cfDNA were analyzed using droplet digital PCR. Furthermore, we performed a comprehensive mutational analysis of post-treatment cfDNA via targeted ultra-deep sequencing (22,000× coverage) in a panel of 275 cancer-related genes in selected patients.

Results: Plasma cfDNA levels increased significantly according to HCC clinical stage, and a high cfDNA level was independently associated with a poor prognosis. TERT promoter mutations were detected in 45% of all cases but were not associated with any clinical characteristics. cfDNA levels increased significantly a few days after treatment, and a greater increase in post-treatment cfDNA levels was associated with a greater therapeutic response to MTAs. The detection rate of TERT mutations increased to 57% using post-treatment cfDNA, suggesting that the ctDNA was enriched. Targeted ultra-deep sequencing using post-treatment cfDNA after administering lenvatinib successfully detected various gene mutations and obtained promising results in lenvatinib-responsive cases.

Conclusions: Post-treatment cfDNA analysis may facilitate the construction of biomarkers for predicting MTA treatment effects.
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http://dx.doi.org/10.1007/s00535-021-01773-4DOI Listing
May 2021

Artificial intelligence in the diagnosis and management of hepatocellular carcinoma.

J Gastroenterol Hepatol 2021 Mar;36(3):551-560

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

Despite recent improvements in therapeutic interventions, hepatocellular carcinoma is still associated with a poor prognosis in patients with an advanced disease at diagnosis. Recently, significant progress has been made in image recognition through advances in the field of artificial intelligence (AI) (or machine learning), especially deep learning. AI is a multidisciplinary field that draws on the fields of computer science and mathematics for developing and implementing computer algorithms capable of maximizing the predictive accuracy from static or dynamic data sources using analytic or probabilistic models. Because of the multifactorial and complex nature of liver diseases, the machine learning approach to integrate multiple factors would appear to be an advantageous approach to improve the likelihood of making a precise diagnosis and predicting the response of treatment and prognosis of liver diseases. In this review, we attempted to summarize the potential use of AI in the diagnosis and management of liver diseases, especially hepatocellular carcinoma.
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http://dx.doi.org/10.1111/jgh.15413DOI Listing
March 2021

Radiofrequency Ablation of Liver Tumors in Patients on Antithrombotic Therapy: A Case-Control Analysis of over 10,000 Treatments.

J Vasc Interv Radiol 2021 06 6;32(6):869-877. Epub 2021 Mar 6.

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

Purpose: To evaluate the safety of radiofrequency ablation (RFA) for liver tumors in patients on antithrombotic therapy.

Materials And Methods: A total of 10,653 consecutive RFA treatments in 3,485 patients with liver tumors were analyzed. The incidence of complications was analyzed on a treatment basis. The treatments for patients who had received antithrombotic medication up to 1 week prior to RFA comprised the antithrombotic therapy group (n = 806), and the others comprised the control group (n = 9,847). Antithrombotic agents were ceased prior to RFA (aspirin, ticlopidine, clopidogrel, and prasugrel ceased 7 days before RFA; cilostazol, 2 or 3 days before RFA; warfarin, 3 days before RFA; and direct oral anticoagulants, 1 day before RFA) and resumed as soon as possible after RFA. Logistic regression analysis was performed to assess whether the antithrombotic therapy increased the risk of hemorrhagic complications.

Results: Hemorrhagic complications were diagnosed after 6 treatments (0.7%) in the antithrombotic group and 48 (0.5%) in the control group, and there was no significant difference between the groups (P = .30). In 3 treatments, hemorrhage was diagnosed on or after 8 days of RFA, all of which were in the antithrombotic group. Thrombotic complications were diagnosed after 2 treatments (0.2%) in the antithrombotic group and after 5 (0.1%) in the control group. In a multivariate analysis, receiving antithrombotic therapy was not an independent risk factor for hemorrhagic complications (adjusted odds ratio, 1.52; 95% confidence interval, 0.60-3.87; P = .38).

Conclusions: RFA of liver tumors in patients on antithrombotic therapy is generally safe with appropriate cessation and resumption. Late-onset hemorrhage should be noted in the patients on antithrombotic therapy.
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http://dx.doi.org/10.1016/j.jvir.2021.02.021DOI Listing
June 2021

Development of Tandem Mass Tag Labeling Method for Lipid Molecules Containing Carboxy and Phosphate Groups, and Their Stability in Human Serum.

Metabolites 2020 Dec 30;11(1). Epub 2020 Dec 30.

Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8654, Japan.

In clinical lipidomics, it is a challenge to measure a large number of samples and to reproduce the quantitative results. We expanded the range of application of the tandem mass tag (TMT) method, which is widely used in proteomics, to lipidomic fields. There are various types of lipid molecule, for example, eicosanoids have a carboxyl group and phosphatidic acid has a phosphate group. We modified these functional groups simultaneously with TMT. This approach allows for a single analysis by mixing six samples and using one of the six samples as a bridging sample; the quantitative data can be easily normalized even if the number of measurements increases. To accommodate a large number of samples, we utilize a pooled serum sample of 300 individuals as a bridging sample. The stability of these lipid molecules in serum was examined as an analytical validation for the simultaneous TMT labeling. It was found that the stability of these lipid molecules in serum differs greatly depending on the lipid species. These findings reaffirmed the importance of proper sample preparation and storage to obtain reliable data. The TMT labeling method is expected to be a useful method for lipidomics with high-throughput and reliable reproducibility.
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http://dx.doi.org/10.3390/metabo11010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824108PMC
December 2020

Analysis of vasovagal syncope in the blood collection room in patients undergoing phlebotomy.

Sci Rep 2020 10 21;10(1):17933. Epub 2020 Oct 21.

Department of Clinical Laboratory, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Vasovagal syncope (VVS) is well-known to occur in patients undergoing phlebotomy, however, there have been no large-scale studies of the incidence of VVS in the blood collection room. The aim of our present retrospective study was to investigate the conditions of phlebotomy and determine the incidence/factors predisposing to the development of VVS. We investigated 677,956 phlebotomies performed in outpatients in the blood collection room, to explore factors predisposing to the development of VVS. Our analysis revealed an overall incidence of VVS of 0.004% and suggested that use of more than 5 blood collection tubes and a waiting time of more than 15 min were associated with a higher risk of VVS. The odds ratios of these factors were 8.10 (95% CI 3.76-17.50) and 3.69 (95% CI 0.87-15.60), respectively. This is the large-scale study to analyze factors of the development of VVS in the blood collection room, and according to our results, use of a large number of blood collection tubes and a prolonged waiting time for phlebotomy may be risk factors for the development of VVS.
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http://dx.doi.org/10.1038/s41598-020-74265-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578787PMC
October 2020

Housemaid's Knee (Prepatellar Septic Bursitis).

Cureus 2020 Sep 11;12(9):e10398. Epub 2020 Sep 11.

Department of Internal Medicine, Shimane University Hospital, Izumo, JPN.

An 83-year-old Japanese tatami craftsman with underlying diabetes mellites who complained of severe pain and feeling of warmth in his right knee, with mild chills. Fluid accumulation was seen in his prepatellar bursa and was detected in his synovial fluid culture, confirming the diagnosis of prepatellar septic bursitis. Prepatellar bursitis is well known as housemaid's knee, which is caused by inflammation of the prepatellar bursa among people who spend long periods of time kneeling such as housemaids, clergy, and gardeners.
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http://dx.doi.org/10.7759/cureus.10398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549991PMC
September 2020

Engulfment of Toxic Amyloid β-protein in Neurons and Astrocytes Mediated by MEGF10.

Neuroscience 2020 09 16;443:1-7. Epub 2020 Jul 16.

Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan. Electronic address:

Amyloid-β proteins (A β), including Aβ42 and A β 43, are known pathogenesis factors of Alzheimer's disease (AD). Unwanted substances in the brain, including A β, are generally removed by microglia, astrocytes, or neurons via a phagocytosis receptor. We observed that neurons and astrocytes engulfed A β 42 and A β 43, which are more neurotoxic than A β 40. We previously showed that multiple-EGF like domains 10 (MEGF10) plays an important role in apoptotic cell elimination and is expressed in mammalian neurons and astrocytes. Therefore, we assessed whether MEGF10 is involved in A β42 and A β43 engulfment in MEGF10-expressing neurons and astrocytes. We found that MEGF10-expressing astrocytes and neurons engulfed A β42 and A β43 but not A β40. Furthermore, incubation of the neurons and astrocytes with A β42 and A β43a ugmented MEGF10 phosphorylation; however, incubation with A β40 did not have this augmenting effect. Our findings suggest that MEGF10 plays a phagocytosis receptor function for A β42 and A β43 in neurons and astrocytes.
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http://dx.doi.org/10.1016/j.neuroscience.2020.07.016DOI Listing
September 2020

Improved liver function in patients with cirrhosis due to chronic hepatitis C virus who achieve sustained virologic response is not accompanied by increased liver volume.

PLoS One 2020 20;15(4):e0231836. Epub 2020 Apr 20.

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

Background: Serum albumin level improves in patients with chronic hepatitis C virus (HCV) infection who achieve sustained virologic response (SVR) with antiviral therapy. However, it remains controversial whether liver volume increases along with SVR.

Methods: Patients with chronic HCV infection with a history of hepatocellular carcinoma (HCC) who achieved SVR with anti-HCV treatment from March 2003 to November 2017 were enrolled. Patients were followed up with periodic computed tomography (CT) scans to detect HCC recurrence. Patients who underwent treatment for HCC recurrence within 1 year after initiation of anti-HCV treatment were excluded. Laboratory data, including alanine aminotransferase (ALT) level, serum albumin level, and platelet count, were collected at baseline and timepoints after treatment initiation. Liver volume was evaluated at baseline and 24 and 48 weeks after treatment initiation using a CT volume analyzer. A linear mixed-effects model was applied to analyze the chronologic change in liver volume. The correlations between changes in ALT level, albumin level, and liver volume were also evaluated.

Results: Of 108 enrolled patients, 78 had cirrhosis. Serum albumin level continued to increase through 48 weeks after treatment initiation. A significant increase in liver volume was observed only in patients without cirrhosis (P = 0.005). There was a significant correlation between ALT level decrease and albumin level increase (P = 0.018).

Conclusions: Improved liver albumin production with SVR was contributed by improved liver cell function rather than increased liver volume in patients with cirrhosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231836PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170262PMC
July 2020

Possible involvement of PS-PLA1 and lysophosphatidylserine receptor (LPS1) in hepatocellular carcinoma.

Sci Rep 2020 02 14;10(1):2659. Epub 2020 Feb 14.

Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.

Lysophosphatidylserine (LysoPS) is a lysophospholipid, its generating enzyme, phosphatidylserine-specific phospholipase A1 (PS-PLA1), reportedly plays roles in stomach and colon cancers. Here, we examined the potential roles of LysoPS in hepatocellular carcinoma (HCC). The ninety-seven HCC patients who underwent surgical treatment were enrolled in this study and approved by the institutional review board. Among LysoPS-related enzymes and receptors, increased PS-PLA1 or LysoPS receptor 1 (LPS1) mRNA was observed in HCC tissues compared to non-HCC tissues. PS-PLA1 mRNA in HCC was associated with no clinical parameters, while LPS1 mRNA in HCC was correlated inversely with tumor differentiation. Furthermore, higher serum PS-PLA1 was observed in HCC patients compared to healthy control and correlated with PS-PLA1 mRNA in non-HCC tissues and with serum AST or ALT. Additionally, serum levels of PS-PLA1 were higher in HCC patients with HCV-related liver injury than in those with HBV or non-HBV-, non-HCV-related liver diseases. In conclusion, among LysoPS-related enzymes and receptors, PS-PLA1 and LPS1 mRNA were increased in HCC. Based on the correlation between the serum PS-PLA1 and the mRNA level of PS-PLA1 in non-HCC tissues, the liver may be the main source of serum PS-PLA1, and serum PS-PLA1 levels may be a useful marker for liver injury.
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http://dx.doi.org/10.1038/s41598-020-59590-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021726PMC
February 2020

Quantum control of radical pair reactions by local optimization theory.

J Chem Phys 2020 Jan;152(1):014301

Department of Chemistry, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura Ward, 338-8570 Saitama, Japan.

Recently, AWG (arbitrary waveform generator) based pulse electron paramagnetic resonance and nuclear magnetic resonance have been developed in a high field regime for the improvement of sensitivity and selectivity and quantum information processing. Here, we propose the application of AWG based reaction control of radical pairs in a rather low magnetic field regime. We calculated the locally optimized radio frequency (RF) field with the control theory by Sugawara [J. Chem. Phys. 118(15), 6784-6800 (2003)]. The calculation results manifest the applicability of AWG-RF fields to reaction control (reaction yield detected magnetic resonance), stimulated nuclear polarization, magnetic isotope selection, and coherent control of the spin dynamics.
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http://dx.doi.org/10.1063/1.5131557DOI Listing
January 2020

Plant-Unique / Isomerism of Long-Chain Base Unsaturation is Selectively Required for Aluminum Tolerance Resulting from Glucosylceramide-Dependent Plasma Membrane Fluidity.

Plants (Basel) 2019 Dec 23;9(1). Epub 2019 Dec 23.

Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan.

/ isomerism of the Δ8 unsaturation of long-chain base (LCB) is found only in plant sphingolipids. This unique geometry is generated by sphingolipid LCB Δ8 desaturase SLD which produces both isomers at various ratios, resulting in diverse / ratios in plants. However, the biological significance of this isomeric diversity remains controversial. Here, we show that the plant-specific unsaturation of LCB selectively contributes to glucosylceramide (GlcCer)-dependent tolerance to aluminum toxicity. We established three transgenic rice lines with altered LCB unsaturation profiles. Overexpression of SLD from rice (OsSLD-OX), which preferentially exhibits -activity, or Arabidopsis (AtSLD-OX), showing preference for -activity, facilitated Δ8 unsaturation in different manners: a slight increase of -unsaturated glycosylinositolphosphoceramide (GIPC) in OsSLD-OX, and a drastic increase of -unsaturated GlcCer and GIPC in AtSLD-OX. Disruption of LCB Δ4 desaturase () significantly decreased the content of GlcCer. Fluorescence imaging analysis revealed that OsSLD-OX and AtSLD-OX showed increased plasma membrane fluidity, whereas had less fluidity, demonstrating that the isomers universally contributed to increasing membrane fluidity. However, the results of a hydroponic assay showed decreased aluminum tolerance in AtSLD-OX and compared to OsSLD-OX and the control plants, which did not correlate with membrane fluidity. These results suggest that -unsaturated GlcCer, not GIPC, selectively serves to maintain the membrane fluidity specifically associated with aluminum tolerance.
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http://dx.doi.org/10.3390/plants9010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020186PMC
December 2019

Utility of hepatic vein waveform and transient elastography in patients with Budd-Chiari syndrome who require angioplasty: Two case reports.

Medicine (Baltimore) 2019 Nov;98(45):e17877

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

Rationale: Budd-Chiari syndrome (BCS), which causes congestive hepatopathy and aggravates cirrhosis, is typically treated by interventional angioplasty to ameliorate blood flow. X-ray venography is useful for the evaluation of inferior vena cava (IVC) stenosis and determination of treatment timing, but it is invasive and thus unsuitable for repeated examinations. The development of a simple method for the prediction of IVC stenosis would reduce the burden on patients with BCS.

Patient Concerns: We report here our experience of 2 patients with BCS who underwent percutaneous transluminal angioplasty (PTA). The first patient was a 39-year-old male who underwent PTA to expand his stenotic IVC. The second patient was a 19-year-old male who underwent PTA 3 times due to restenosis of his IVC.

Diagnoses: Both patients were diagnosed with BCS with severe obstruction of the IVC.

Interventions: We evaluated the hepatic vein (HV) waveform by Doppler ultrasonography and measured liver stiffness (LS) using transient elastography (TE) before and after PTA.

Outcomes: In case 1, the phasic oscillation of the HV waveform recovered and the LS value decreased after PTA. Both improvements were maintained for ∼3 years, reflecting the long-term patency of the IVC. In case 2, the HV waveform and the LS value improved temporarily after PTA, but then deteriorated gradually. Monitoring of the HV waveform and LS value allowed retreatment prior to total occlusion of the IVC and abrogated the risk of intravascular needle puncture.

Lessons: Monitoring of the HV waveform and the LS value enables safe management of patients with BCS who may require PTA.
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http://dx.doi.org/10.1097/MD.0000000000017877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855573PMC
November 2019

Clinical usefulness of human serum nonmercaptalbumin to mercaptalbumin ratio as a biomarker for diabetic complications and disability in activities of daily living in elderly patients with diabetes.

Metabolism 2020 02 29;103:153995. Epub 2019 Oct 29.

Fukuoka City Health Promotion Support Center, Fukuoka City Medical Association, Fukuoka, Japan. Electronic address:

Background: Oxidative stress may play an important role in the development of diabetic complications. The ratio of human nonmercaptalbumin (HNA; oxidized form) to human mercaptalbumin (HMA; reduced form) has attracted attention as an indicator for systemic redox states. In this study, we measured the ratio in elderly patients with diabetes and evaluated its association with diabetic complications and disability in activities of daily living (ADL disability).

Methods: One hundred twenty-six elderly patients with diabetes, aged 70 years and older, under medical care at Yukuhashi Central Hospital from April 2018 to June 2018, were continuously recruited. HNA%, defined as HNA / (HNA + HMA) × 100, was measured by a high-performance liquid chromatography method. First, multivariate regression analysis was performed to evaluate which variables were significant determinants for HNA%. Next, to evaluate the association of HNA% with ADL disability, logistic regression analysis in various models was performed. Then we plotted the receiver operating characteristic (ROC) curve and calculated the under area the curve (AUC), sensitivity, and specificity in each model.

Results: In elderly patients with diabetes, multiple regression analysis showed that serum bilirubin levels and albumin levels, both of which are major endogenous anti-oxidants, and chronic renal failure (or proliferative nephropathy) were significantly associated with HNA%, suggesting that HNA% may be a good biomarker for oxidative stress in those patients. We then evaluated the association of HNA% with ADL disability in various logistic regression models. Model using only HNA% showed that it was a significant determinant for ADL disability (OR 1.158, 95% CI 1.077-1.244, P < 0.001). Model using HNA% and age showed that both variables were significant determinants for ADL disability (OR 1.160, 95% CI 1.069-1.258, P < 0.001; OR 1.258, 95% CI 1.110-1.427, P < 0.001, respectively). ROC analysis showed that the AUC of HNA% alone was 0.765. The AUC of model using HNA% and age was further increased to 0.866.

Conclusions: HNA% was significantly associated with diabetic complications and ADL disability, thereby may be clinically useful as an oxidative stress marker in elderly patients with diabetes.
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http://dx.doi.org/10.1016/j.metabol.2019.153995DOI Listing
February 2020

Establishment of a stable sampling method to assay mercaptoalbumin/non-mercaptoalbumin and reference ranges.

Pract Lab Med 2019 Nov 12;17:e00132. Epub 2019 Sep 12.

Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.

Oxidative stress is reportedly associated with many diseases such as cancer, arteriosclerosis, diabetes and aging, but no practical biomarkers are currently available in actual clinical practice. Human mercaptoalbumin (HMA) and human non-mercaptoalbumin (HNA) are expected to become markers of oxidative stress, but the stability of HMA/HNA has been problematic. We investigated the conditions for stabilizing HMA/HNA and found that HMA/HNA was stable at room temperature for 25 h if whole blood samples were mixed with a citrate buffer so that the citric acid concentration after mixing was 70 mM or higher and the pH of the added buffer was less than pH 6.0. Whole blood samples were then collected under the above conditions, and the reference range for HNA was set at 21.8% ± 7.4% (HMA, 78.2% ± 7.4%) based on samples from 65 volunteers (28 males and 37 females; average age, 55.0 ± 13.8 years). The clinical usefulness of HMA/HNA as an oxidative stress marker should be clarified for specific pathological conditions using the previously reported, highly accurate measurement method under the conditions required for HMA/HNA stability.
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http://dx.doi.org/10.1016/j.plabm.2019.e00132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804495PMC
November 2019

Hepatic FATP5 expression is associated with histological progression and loss of hepatic fat in NAFLD patients.

J Gastroenterol 2020 Feb 10;55(2):227-243. Epub 2019 Oct 10.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are characterized by the accumulation of excess hepatic fat. However, in the progression from NASH to cirrhosis, hepatic fat is often lost. Our aim was to elucidate the mechanism underlying hepatic fat loss during NASH progression.

Methods: Liver biopsies were performed at The University of Tokyo Hospital between November 2011 and March 2016 on 146 patients with NAFLD and 14 patients with cryptogenic cirrhosis who were not being treated with any diabetes or dyslipidemia drugs. Among them, 70 patients underwent liver biopsy after an overnight fast, and 90 patients were biopsied 5 h after an oral glucose tolerance test. Expression differences in genes encoding several fatty acid metabolism-related factors were examined and correlated with hepatic histological changes based on NAFLD activity scores. Prospective patient follow-up continued until June 2018.

Results: The level of fatty acid transport protein 5 (FATP5), which is associated with free fatty acid intake, was significantly and inversely correlated with features of histological progression, including ballooning and fibrosis. This was confirmed by immunohistochemical analysis. Transcript levels of genes encoding fatty acid metabolism-related proteins were comparable between NASH with severe fibrosis and cryptogenic cirrhosis. Furthermore, a prospective cohort study demonstrated that low FATP5 expression was the most significant risk factor for hepatic fat loss.

Conclusions: Decreased hepatic FATP5 expression in NAFLD is linked to histological progression, and may be associated with hepatic fat loss during NASH progression to cirrhosis.
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http://dx.doi.org/10.1007/s00535-019-01633-2DOI Listing
February 2020

A Novel Non-invasive Method for Predicting Liver Fibrosis by Quantifying the Hepatic Vein Waveform.

Ultrasound Med Biol 2019 09 12;45(9):2363-2371. Epub 2019 Jul 12.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

The hepatic vein (HV) waveform by Doppler ultrasound reflects the severity of liver fibrosis. We conducted a proof-of-concept study of a new method for quantifying the HV waveform. We calculated the coefficient of variation (CV) of the HV flow velocity and created a new index "q-HV" (quantified HV) and analyzed its performance for predicting histologic liver fibrosis in 114 patients with chronic liver disease. The CV of the HV flow velocity was well associated with flattening of the waveform and the q-HV significantly increased with the progression of liver fibrosis. The areas under the curve for the prediction of fibrosis stage were 0.732 for F2, 0.772 for F3 and 0.805 for F4. Combined q-HV and FIB-4 index (widely used liver fibrosis score) increased the diagnostic accuracy for liver fibrosis. The q-HV showed good accuracy for predicting liver fibrosis; thus, q-HV is feasible and acceptable as a non-invasive tool for predicting liver fibrosis.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2019.05.028DOI Listing
September 2019

In-hospital mortality associated with transcatheter arterial embolization for treatment of hepatocellular carcinoma in patients on hemodialysis for end stage renal disease: a matched-pair cohort study using a nationwide database.

BJR Open 2019 12;1(1):20190004. Epub 2019 Jun 12.

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

Objectives: No previous study has evaluated the risks associated with transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma in patients on hemodialysis (HD) for end stage renal disease (ESRD), because invasive treatment is rarely performed for such patients. We used a nationwide database to investigate in-hospital mortality and complication rates following TACE in patients on HD for ESRD.

Methods: Using the Japanese Diagnosis Procedure Combination database, we enrolled patients on HD for ESRD who underwent TACE for hepatocellular carcinoma. For each patient, we randomly selected up to four non-dialyzed patients using a matched-pair sampling method based on the patient's age, sex, treatment hospital, and treatment year. In-hospital mortality and complication rates were compared between dialyzed and non-dialyzed patients following TACE.

Results: We compared matched pairs of 1551 dialyzed and 5585 non-dialyzed patients. Although the complication rate did not differ between the dialyzed and non-dialyzed ESRD patients [5.7% 5.8%, respectively; odds ratio, 0.99; 95% confidence interval (0.79-1.23); = 0.90], the in-hospital mortality rate was significantly higher in dialyzed ESRD patients than in non-dialyzed patients [2.2% 0.97%, respectively; odds ratio, 2.21; 95% confidence interval (1.44-3.40); < 0.001]. Among the dialyzed patients, the mortality rate was not significantly associated with sex, age, Charlson comorbidity index, or hospital volume.

Conclusions: The in-hospital mortality rate following TACE was 2.2 % and was significantly higher in dialyzed than in non-dialyzed ESRD patients. The indications for TACE in HD-dependent patients should be considered carefully with respect to the therapeutic benefits risks.

Advances In Knowledge: In hospital mortality rate following TACE in dialyzed patients was more than twice compared to non-dialyzed patients. Post-procedural complication following TAE in ESRD onHD patients was 5.7%, and did not differ from that in non dialyzed patients.
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http://dx.doi.org/10.1259/bjro.20190004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592431PMC
June 2019

Machine-learning Approach for the Development of a Novel Predictive Model for the Diagnosis of Hepatocellular Carcinoma.

Sci Rep 2019 05 30;9(1):7704. Epub 2019 May 30.

Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Because of its multifactorial nature, predicting the presence of cancer using a single biomarker is difficult. We aimed to establish a novel machine-learning model for predicting hepatocellular carcinoma (HCC) using real-world data obtained during clinical practice. To establish a predictive model, we developed a machine-learning framework which developed optimized classifiers and their respective hyperparameter, depending on the nature of the data, using a grid-search method. We applied the current framework to 539 and 1043 patients with and without HCC to develop a predictive model for the diagnosis of HCC. Using the optimal hyperparameter, gradient boosting provided the highest predictive accuracy for the presence of HCC (87.34%) and produced an area under the curve (AUC) of 0.940. Using cut-offs of 200 ng/mL for AFP, 40 mAu/mL for DCP, and 15% for AFP-L3, the accuracies of AFP, DCP, and AFP-L3 for predicting HCC were 70.67% (AUC, 0.766), 74.91% (AUC, 0.644), and 71.05% (AUC, 0.683), respectively. A novel predictive model using a machine-learning approach reduced the misclassification rate by about half compared with a single tumor marker. The framework used in the current study can be applied to various kinds of data, thus potentially become a translational mechanism between academic research and clinical practice.
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http://dx.doi.org/10.1038/s41598-019-44022-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543030PMC
May 2019

Functional Segments on Intrinsically Disordered Regions in Disease-Related Proteins.

Biomolecules 2019 03 5;9(3). Epub 2019 Mar 5.

Department of Life Science and Informatics, Faculty of Engineering, Maebashi Institute of Technology, 460-1, Kamisadori, Maebashi, Gunma 371-0816, Japan.

One of the unique characteristics of intrinsically disordered proteins (IPDs) is the existence of functional segments in intrinsically disordered regions (IDRs). A typical function of these segments is binding to partner molecules, such as proteins and DNAs. These segments play important roles in signaling pathways and transcriptional regulation. We conducted bioinformatics analysis to search these functional segments based on IDR predictions and database annotations. We found more than a thousand potential functional IDR segments in disease-related proteins. Large fractions of proteins related to cancers, congenital disorders, digestive system diseases, and reproductive system diseases have these functional IDRs. Some proteins in nervous system diseases have long functional segments in IDRs. The detailed analysis of some of these regions showed that the functional segments are located on experimentally verified IDRs. The proteins with functional IDR segments generally tend to come and go between the cytoplasm and the nucleus. Proteins involved in multiple diseases tend to have more protein-protein interactors, suggesting that hub proteins in the protein-protein interaction networks can have multiple impacts on human diseases.
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http://dx.doi.org/10.3390/biom9030088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468909PMC
March 2019

Ischemic complications after percutaneous radiofrequency ablation of liver tumors: Liver volume loss and recovery.

Hepatol Res 2019 Apr 6;49(4):453-461. Epub 2019 Feb 6.

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

Aim: The liver regrows after acute liver injury and liver resection. However, it is not clear whether the liver regenerates in advanced cirrhosis. This study aimed to evaluate the clinical course of, and liver volume change after, ischemic liver complications caused by radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC).

Methods: We enrolled 35 patients with ischemic complications after RFA. Ischemic complications were defined as rapid elevation of aspartate aminotransferase (AST) to over 500 U/L, with typical radiological findings. Patient characteristics and the ischemic liver volume were investigated. Long-term liver volume changes at 3-8 months after ischemic complications were also assessed in 32 patients. We also assessed the overall survival rate after ischemic complications.

Results: The median value of peak AST was 798 U/L (range, 531-4096 U/L). The median ischemic liver volume relative to the functional liver volume before RFA was 13% (range, 3.1-46.5%). There was a strong correlation between the peak AST value and the ischemic liver volume (r = 0.84, P < 0.001). The liver volume recovered to some extent in 18 of 32 (56%) patients after ischemic complications. The survival rate after ischemic complications was 45.7% at 5 years and correlated with the functional liver volume after ischemic complications (P = 0.02).

Conclusions: Ischemic complications after RFA can lead to massive liver parenchymal loss. Although the liver volume recovered to some extent in the majority of our patients, ischemic liver complications after RFA should be avoided to improve the overall survival rate.
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http://dx.doi.org/10.1111/hepr.13302DOI Listing
April 2019

Liver stiffness measurements in chronic hepatitis C: Treatment evaluation and risk assessment.

J Gastroenterol Hepatol 2019 May 7;34(5):921-928. Epub 2018 Dec 7.

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

Background And Aim: Liver stiffness (LS), measured by transient elastography, has been validated as a non-invasive surrogate for liver fibrosis.

Methods: We investigated the long-term predictive ability of LS for hepatocellular carcinoma (HCC) development and overall survival in 1146 patients with chronic hepatitis C by using LS value at enrollment. We also investigated chronological changes in LS based on antiviral therapy and its outcome in 752 patients.

Results: During the mean follow-up period of 6.6 years, 190 patients developed HCC. Cumulative HCC incidence rates at 5 years were clearly stratified as 1.7% in the ≤ 5 kPa, 3.3% in 5.1-10 kPa, 16.7% in 10.1-15 kPa, 24.4% in 15.1-20 kPa, 36.3% in 20.1-25 kPa, and 43.7% in > 25 kPa subgroups (P < 0.001). Overall survival was also stratified: 10-year survival rates were 99.3% in the ≤ 5 kPa, 95.4% in 5.1-10 kPa, 81.4% in 10.1-15 kPa, 79.5% in 15.1-20 kPa, 66.1% in 20.1-25 kPa, and 49.1% in > 25 kPa subgroups (P < 0.001). LS decreased at a rate of 8.1% per year in those who achieved sustained virological responses, but increased at 0.1% per year in those who could not achieve sustained virological response instead of antiviral therapy, and increased at 3.7% per year in those who did not undergo antiviral therapy.

Conclusions: Liver stiffness measurements can be useful in the prediction of HCC development and overall survival and in the evaluation of chronological changes in liver fibrosis grade during and after antiviral therapy.
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http://dx.doi.org/10.1111/jgh.14530DOI Listing
May 2019

Impact of direct-acting antivirals on early recurrence of HCV-related HCC: Comparison with interferon-based therapy.

J Hepatol 2019 01 16;70(1):78-86. Epub 2018 Oct 16.

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

Background & Aims: It remains controversial whether direct-acting antivirals (DAAs) accelerate the recurrence of hepatitis C-related hepatocellular carcinoma (HCC) after curative therapy. This study aimed to evaluate HCC recurrence after DAA treatment of chronic hepatitis C.

Methods: We enrolled patients with a history of successful radiofrequency ablation treatment for hepatitis C-related HCC who received antiviral therapy with DAAs (DAA group: 147 patients) or with interferon (IFN)-based therapy (IFN group: 156 patients). We assessed HCC recurrence rates from the initiation of antiviral therapy using the Kaplan-Meier method and evaluated risk factors for HCC recurrence by multivariate Cox proportional hazard regression analysis. The recurrence pattern was categorized as follows: intrahepatic recurrence with a single tumor <2 cm (stage 0), a single tumor or up to 3 tumors ≤3 cm (stage A), multinodular (stage B), and extrahepatic metastasis or macrovascular invasion (stage C).

Results: The recurrence rates at 1 and 2 years were 39% and 61% in the IFN group and 39% and 60% in the DAA group, respectively (p = 0.43). Multivariate analysis identified higher lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, a history of multiple HCC treatments, and a shorter interval between HCC treatment and initiation of antiviral therapy as independent risk factors for HCC recurrence. HCC recurrence in stage 0, A, B, and C was found in 56 (41%), 60 (44%), 19 (14%), and 1 (0.7%) patients in the IFN group and 35 (44%), 32 (40%), 11 (14%), and 2 (2.5%) patients in the DAA group, respectively (p = 0.70).

Conclusions: HCC recurrence rates and patterns after initiation of antiviral therapy did not differ between patients who received IFN-based therapy and DAA therapy.

Lay Summary: We detected no significant difference in early hepatocellular carcinoma (HCC) recurrence rates and patterns between patients who received interferon-based and direct-acting antiviral therapy after HCC treatment. High lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, short recurrence-free period, and a history of multiple HCC treatments were independent risk factors for early HCC recurrence after the initiation of antiviral therapy.
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http://dx.doi.org/10.1016/j.jhep.2018.09.029DOI Listing
January 2019

Identification of liver fibrosis using the hepatic vein waveform in patients with Fontan circulation.

Hepatol Res 2019 Mar 27;49(3):304-313. Epub 2018 Sep 27.

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

Aim: Liver fibrosis caused by congestive hepatopathy has emerged as an important complication after Fontan procedure. We evaluated the utility of the hepatic vein (HV) waveform using Doppler ultrasound for identification of liver fibrosis in Fontan patients.

Methods: We investigated the HV waveforms in 41 Fontan patients and assessed correlations with clinical parameters, liver fibrosis markers, and hemodynamic data.

Results: Based on our preliminary analysis of 64 adult patients with chronic liver disease who underwent liver biopsy, we classified HV waveforms into five types with reference to the degree of flattening (from type 1, normal triphasic waveform; to type 5, a monophasic waveform indicating cirrhosis), and confirmed a significant correlation between waveform pattern and fibrosis stage. Notably, we detected HV waveforms in all of the Fontan patients and classified them into five types. The HV waveform pattern positively correlated with γ-glutamyl transferase and hyaluronic acid levels, and negatively correlated with albumin level and platelet count, but did not correlate with central venous pressure or brain natriuretic peptide level, suggesting that HV waveform could reflect pathophysiological changes in the liver without being affected by hepatic congestion. The highest area under the receiver operating characteristic curve of the HV waveform for detecting advanced liver fibrosis, as defined by ultrasonic findings and clinical features, was 0.829 (81.8% sensitivity, 73.3% specificity), which was higher than that of other non-invasive fibrosis markers.

Conclusions: Hepatic vein waveforms change in accordance with liver fibrosis progression in Fontan patients, and can be a useful indicator of liver fibrosis after the Fontan procedure.
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http://dx.doi.org/10.1111/hepr.13248DOI Listing
March 2019

Effects of l-Carnitine Supplementation, Botulinum Neurotoxin Injection, and Rehabilitation for a Chronic Stroke Patient.

J Stroke Cerebrovasc Dis 2018 Nov 1;27(11):3342-3344. Epub 2018 Sep 1.

Department of Rehabilitation, Tokyo Metropolitan Health and Medical TreatmentCorporation Ebara Hospital, Tokyo, Japan.

Botulinum neurotoxin injection therapy and rehabilitation have been conducted for stroke patients to reduce the spasticity of their affected limbs and improve their walking ability and daily living. Furthermore, their disability was reported to be related to muscle wasting. Supplementation of l-carnitine was reported to improve physical endurance and was used to treat sarcopenia in, for example, patients with cancer. Here, we report a case of chronic stroke with muscle wasting in a patient with improved walking endurance by l-carnitine supplementation, botulinum neurotoxin injection, and rehabilitation. A 58-year-old woman had a left putamen hemorrhage 9years before, and right spastic hemiplegia and walking disability. She could walk no more than 20m. Botulinum neurotoxin injection and rehabilitation were performed 6times every 3 months. The first time, walking speed and continuous walking distance increased as her spasticity decreased. However, the improvement declined after the second and third treatments. She had right leg pain during walking, accompanied by muscle wasting. The l-carnitine prescription contributed to the attenuation of her leg pain during walking and rapid improvement of her continuous walking distance. Walking speed and endurance further improved. In addition, the withdrawal of l-carnitine did not decrease her walking ability or induce a recurrence of her leg pain. Interestingly, creatine phosphokinase increased after l-carnitine was stopped, indicating that l-carnitine had helped to reduce muscle damage during rehabilitation. This case suggests that chronic stroke patients with muscle wasting have an abnormality in the mitochondrial energy metabolism of their muscles.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.07.033DOI Listing
November 2018

Serum levels of ferritin do not affect the prognosis of patients with hepatocellular carcinoma undergoing radiofrequency ablation.

PLoS One 2018 25;13(7):e0200943. Epub 2018 Jul 25.

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

Background & Aims: Hepatic iron accumulation can accelerate liver injury in patients with various chronic liver diseases and lead to hepatocarcinogenesis. We elucidated the impact of serum levels of ferritin on the prognosis of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) in a large cohort.

Methods: We retrospectively analyzed 578 treatment-naïve HCC patients who underwent RFA. We divided our cohort into four groups by the quartile points of serum ferritin level: G1 (≤55 ng/mL, n = 148), G2 (56-130 ng/mL, n = 142), G3 (131-243 ng/mL, n = 144) and G4 (≥244 ng/mL, n = 144). We analyzed the recurrence and survival of patients using the Kaplan-Meier method. We also evaluated pathological iron deposition among patients with a solitary tumor smaller than 2 cm.

Results: The cumulative rates of overall recurrence and survival at 5 years were 81.6% and 66.3%, respectively. The serum levels of ferritin were correlated with pathological iron deposition. There were no significant differences in recurrence and survival rates according to serum levels of ferritin and pathological hepatic iron deposition.

Conclusions: Serum levels of ferritin do not affect the prognosis of HCC patients undergoing RFA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200943PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059486PMC
January 2019

A Novel Morphological Marker for the Analysis of Molecular Activities at the Single-cell Level.

Cell Struct Funct 2018 Aug 29;43(2):129-140. Epub 2018 Jun 29.

Research Center for Dynamic Living Systems, Graduate School of Biostudies, Kyoto University.

For more than a century, hematoxylin and eosin (H&E) staining has been the de facto standard for histological studies. Consequently, the legacy of histological knowledge is largely based on H&E staining. Due to the recent advent of multi-photon excitation microscopy, the observation of live tissue is increasingly being used in many research fields. Adoption of this technique has been further accelerated by the development of genetically encoded biosensors for ions and signaling molecules. However, H&E-based histology has not yet begun to fully utilize in vivo imaging due to the lack of proper morphological markers. Here, we report a genetically encoded fluorescent marker, NuCyM (Nucleus, Cytosol, and Membrane), which is designed to recapitulate H&E staining patterns in vivo. We generated a transgenic mouse line ubiquitously expressing NuCyM by using a ROSA26 bacterial artificial chromosome (BAC) clone. NuCyM evenly marked the plasma membrane, cytoplasm and nucleus in most tissues, yielding H&E staining-like images. In the NuCyM-expressing cells, cell division of a single cell was clearly observed as five basic phases during M phase by three-dimensional imaging. We next crossed NuCyM mice with transgenic mice expressing an ERK biosensor based on the principle of Förster resonance energy transfer (FRET). Using NuCyM, ERK activity in each cell could be extracted from the FRET images. To further accelerate the image analysis, we employed machine learning-based segmentation methods, and thereby automatically quantitated ERK activity in each cell. In conclusion, NuCyM is a versatile cell morphological marker that enables us to grasp histological information as with H&E staining.Key words: in vivo imaging, histology, machine learning, molecular activity.
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http://dx.doi.org/10.1247/csf.18013DOI Listing
August 2018

Eradication of hepatitis C virus is associated with the attenuation of steatosis as evaluated using a controlled attenuation parameter.

Sci Rep 2018 05 18;8(1):7845. Epub 2018 May 18.

Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.

Chronic hepatitis C virus (HCV) infection was shown to cause hepatic steatosis or suppression of serum lipid levels. However, little is known about the changes in hepatic steatosis following HCV eradication. We aimed to evaluate this issue using the controlled attenuation parameter (CAP), which was recently shown to provide a standardized non-invasive measure of hepatic steatosis. We enrolled 70 patients with chronic HCV infections and steatosis (CAP of over 248 dB/m) who had achieved a sustained viral response at 12 weeks after discontinuation of antiviral treatment using direct-acting antivirals (DAA). We then evaluated the state of hepatic steatosis before and after HCV eradication. We also investigated the changes in serum parameters such as cholesterol and glucose levels. The median value of CAP level decreased significantly after HCV eradication from 273 dB/m to 265 dB/m (P = 0.034). Also, LDL and HDL cholesterol levels increased significantly after HCV eradication (P = 0.002 and P = 0.027, respectively). In conclusion, a decrease in hepatic steatosis after HCV eradication with DAA was revealed in chronic hepatitis C patients with significant steatosis. Cancellation of the viral effect is a possible underlying cause of hepatic steatosis improvement and increase in HDL and LDL cholesterol levels.
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http://dx.doi.org/10.1038/s41598-018-26293-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959884PMC
May 2018

Hepatic IRS1 and ß-catenin expression is associated with histological progression and overt diabetes emergence in NAFLD patients.

J Gastroenterol 2018 Dec 10;53(12):1261-1275. Epub 2018 May 10.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes. Our aim was to investigate the relationship between NAFLD and impaired glucose metabolism in terms of insulin receptor substrate 1 and 2 (IRS1 and IRS2) expression in the liver.

Methods: Liver biopsy was performed at the University of Tokyo Hospital between November 2011 and March 2016 on 146 patients with NAFLD who were not being treated with any diabetes or dyslipidemia drugs. Among them, 63 underwent liver biopsy after an overnight fast, and 83 at 5 h after an oral glucose tolerance test (OGTT). Differences in messenger RNA (mRNA) levels of several glucose metabolism-related factors were determined and correlated with hepatic histological changes assessed by NAFLD activity score. We prospectively followed up with the patients until May 2017.

Results: Hepatic necroinflammation was significantly correlated with serum insulin levels and inversely correlated with IRS1 mRNA levels. In specimens obtained after an OGTT, hepatic necroinflammation and IRS1 expression correlated significantly with both peripheral and hepatic insulin resistance. We also found that hepatic β-catenin and glucokinase mRNA levels were elevated in patients undergoing liver biopsy after an OGTT, especially in those with less hepatic necroinflammation and a lower degree of fibrosis. A prospective cohort study showed that ballooning is the most significant risk factor for developing diabetes.

Conclusions: The decreased hepatic expression of IRS1 and β-catenin in NAFLD is linked to histological progression such as ballooning, and might lead to diabetes as a result of impaired glucose metabolism.
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http://dx.doi.org/10.1007/s00535-018-1472-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244858PMC
December 2018

Evidence Suggests Sphingosine 1-Phosphate Might Be Actively Generated, Degraded, and Transported to Extracellular Spaces With Increased S1P and S1P Expression in Colon Cancer.

Clin Colorectal Cancer 2018 06 21;17(2):e171-e182. Epub 2017 Nov 21.

Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.

Background: A pivotal role of sphingosine 1-phosphate (S1P) in cancer has been suggested based on the ceramide-S1P rheostat theory that the intracellular balance between prosurvival S1P and proapoptotic ceramide determines cell fate. Upregulation of S1P-generating sphingosine kinases (SKs) and downregulation of S1P-degrading S1P lyase (SPL) might increase intracellular S1P levels to exert a prosurvival effect in cancer in general, such as colon cancer. However, we recently observed a distinct S1P metabolism in hepatocellular carcinoma tissues that increased SPL mRNA levels with reduced S1P levels. Thus, we investigated S1P metabolism in colon cancer.

Patients And Methods: We enrolled 26 consecutive colon cancer patients, who had undergone surgical treatment.

Results: Not only SK, but also SPL, mRNA levels were increased in colon cancer tissues compared with the adjacent nontumorous tissues. Furthermore, the mRNA levels of another S1P degrading enzyme, S1P phosphatase 1, S1P transporters, spinster homolog 2, adenosine triphosphate-binding cassette subfamily C member 1, and S1P receptors, S1P and S1P were also increased, but the S1P levels were not increased in the colon cancer tissues. The reduction of SPL expression by silencing led to reduced proliferation and invasion, and overexpression of SPL caused enhanced proliferation in colon cancer cell lines.

Conclusion: In human colon cancer tissues, mRNA levels of S1P-generating and S1P-degrading enzymes, transporters from inside to outside the cells, and S1P receptors, S1P and S1P were elevated, suggesting active S1P metabolism and movement. This altered S1P metabolism might play a role in colon cancer pathophysiology.
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http://dx.doi.org/10.1016/j.clcc.2017.11.004DOI Listing
June 2018
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