Kazuyuki Tobe

Toyama University, Тояма, Toyama, Japan

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Publications (302)1666.14 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims and background: Amrubicin monotherapy can be an effective treatment option for patients with recurrent small cell lung cancer (SCLC). We conducted this retrospective study to investigate the prognostic factors in patients with recurrent SCLC receiving amrubicin monotherapy. Methods: The associations between survival and clinical data, including the performance status, body mass index (BMI), plasma lactate dehydrogenase (LDH) level, and plasma neuron-specific enolase level, were evaluated in patients with recurrent SCLC, and a subset analysis of patients with platinum-resistant disease was conducted. Results: In all, 37 patients were evaluated. The median survival from the date of initiation of amrubicin monotherapy was 9.1 months (95% confidence interval 4.7-12.0 months). Multivariate analysis using a Cox proportional hazard model identified the plasma LDH level (p = 0.049), BMI (p = 0.031), and platinum resistance (p = 0.032) as independent factors associated with survival. The same associations were also observed in the subset of patients with platinum-resistant disease. Conclusions: Our findings suggest that the plasma LDH level and BMI may be useful prognostic factors in patients with SCLC receiving amrubicin monotherapy, including patients with platinum-resistant disease.
    10/2015; DOI:10.5301/tj.5000435
  • DrAllah Nawaz · Akiko Takikawa · Isao Usui · Kazuyuki Tobe ·

    36th Annual Meeting of the Japanese Society for the Study of Obesity, 460-0008 Naka-ku, Nagoya-shi Sakae 3-32-20 Nagoya Congress Cetnre; 10/2015
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    ABSTRACT: We present a case of acute pyelonephritis with right hydronephrosis in a middle-aged woman, who had suffered from rheumatoid arthritis and Sjögren's syndrome. She had successfully treated with antibiotics, however, ureteral stenosis sustained. She underwent ureteroscopy and stenting of right ureter. Biopsy specimen revealed submucosal amyloid deposition in the interstitium overlying a benign urothelium. Amyloid protein was positive for transthyretin (TTR) by immunohistochemistry and amyloid deposition was not demonstrated in other organs. The patient's TTR genes were wild type and she was diagnosed with wild-type ATTR (ATTR wt) amyloidosis. This is the first report about symptomatic ATTR wt amyloidosis, which was also called 'systemic senile amyloidosis (SSA)' in the ureter. We should aware that SSA can occur at younger age and cause symptomatic ureteral stenosis. Further investigation is needed to clarify the association of autoimmune diseases to develop ATTR wt amyloidosis.
    International journal of clinical and experimental pathology 09/2015; 8(7):8624-7. · 1.89 Impact Factor
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    ABSTRACT: To determine whether the creatinine/cystatin C (Cr/CysC) ratio, which is influenced by muscle mass, can be used as a predictive marker of the adverse effects of chemotherapy. This single-centre, retrospective, observational study assessed patients with lung cancer. Serum Cr and CysC levels were measured once within 1 month prior the commencement of chemotherapy. A total of 25 patients with lung cancer were enrolled in the study: 22 received first-line therapy; three received second-line therapy. A significant difference was noted regarding the Cr/CysC ratios between patients with nonsmall-cell lung cancer (NSCLC) and those with small-cell lung cancer (0.78 versus 0.92, respectively). A significant difference was also noted in the Cr/CysC ratios of patients with NSCLC with toxicity grades <3 and ≥3 (0.84 versus 0.70, respectively). Similar findings were observed in patients with NSCLC who received platinum-based combination therapy (toxicity grade < 3, 0.85; toxicity grade ≥3, 0.69). The Cr/CysC ratio could serve as a useful predictive marker for chemotherapy-related adverse effects in patients with NSCLC. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
    The Journal of international medical research 05/2015; 43(4). DOI:10.1177/0300060515579116 · 1.44 Impact Factor
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    ABSTRACT: Chronic inflammation is a pathophysiology of insulin resistance in metabolic diseases, such as obesity and type 2 diabetes. Adipose tissue macrophages (ATMs) play important roles in this inflammatory process. SIRT1 is implicated in the regulation of glucose metabolism in some metabolic tissues, such as liver or skeletal muscle. This study was performed to investigate whether SIRT1 in macrophages played any roles in the regulation of inflammation and glucose metabolism. Myeloid cell-specific SIRT1-knockout mice were originally generated and analyzed under chow-fed and high-fat-fed conditions. Myeloid cell-specific SIRT1 deletion impaired insulin sensitivity and glucose tolerance assessed by the glucose- or insulin-tolerance test, which was associated with the enhanced expression of inflammation-related genes in epididymal adipose tissue of high-fat-fed mice. Interestingly, the M1 ATMs from the SIRT1-knockout mice showed more hypoxic and inflammatory phenotypes than those from control mice. The expressions of some inflammatory genes, such as Il1b and Nos2, which were induced by in vitro hypoxia treatment, were further enhanced by SIRT1 deletion along with the increased acetylation of HIF-1α in cultured macrophages. These results suggest that deletion of SIRT1 in myeloid cells impairs glucose metabolism by enhancing the hypoxia and inflammatory responses in ATMs, thereby possibly representing a novel therapeutic target for metabolic diseases, such as type 2 diabetes.
    Diabetology International 05/2015; DOI:10.1007/s13340-015-0213-3

  • 58th Japan Diabetes Society Annual Scientific Meeting, Kaikyo Messe Shimonoseki, Fukuoka Daido Seimei Bldg 7F. 12-33, Nishi Nakasu, Chuo-ku Fukuoka 810-0002 JAPAN; 05/2015
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    ABSTRACT: Conflicting findings have been reported regarding the role of adiponectin in asthma. The aim of this study was to evaluate the association of adiponectin with pulmonary functions and asthma in the Japanese population. First, among a general population that participated in a previous study (group 1), we selected 329 subjects after excluding those with asthma, chronic obstructive pulmonary disease, and a smoking history and examined the associations of the serum total adiponectin levels with pulmonary functions. In a second cohort (group 2) consisting of 61 asthmatic patients and 175 control non-asthmatic subjects, we examined the associations between asthma and the levels of total, high (HMW), middle (MMW) and low (LMW) molecular weight adiponectin isoforms as well as the ratio of each isoform to total adiponectin level. Although the total adiponectin levels were not significantly different between the asthmatic and control subjects in group 2, the levels were significantly and positively associated with the forced expiratory volume in 1 s after adjustments for confounding factors (P < 0.05) in women in group 1. In group 2, the LMW adiponectin level was significantly higher and the MMW/total adiponectin ratio was significantly lower among the asthmatic subjects than among the control subjects after adjustments for confounding factors in both sexes (P < 0.05). The present study showed that a low total adiponectin level may lead to airway narrowing compatible with asthmatic airways in women, and higher LMW adiponectin levels and lower MMW/total adiponectin ratio are significantly associated with current asthma in both sexes.
    Endocrine Journal 05/2015; 62(8). DOI:10.1507/endocrj.EJ14-0626 · 2.00 Impact Factor
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    ABSTRACT: Determination of the presence of epidermal growth factor receptor (EGFR) gene mutation is useful for predicting the efficacy of gefitinib. However, the survival rate following the initiation of treatment with gefitinib varies among individuals. A retrospective study was conducted to investigate the associations of the pretreatment serum pro-gastrin-releasing peptide (pro-GRP) and plasma neuron-specific enolase (NSE) levels to the patient survival rate following initiation of treatment with gefitinib in non-small cell lung cancer (NSCLC) patients receiving gefitinib treatment. Patients with NSCLC harboring EGFR gene mutations who received gefitinib therapy between 2004 and 2012 were included in the study. Data from a total of 41 patients were analyzed. The serum pro-GRP level was measured in 31 patients and the plasma NSE in 22 patients. The progression-free survival (PFS) (P=0.013) and overall survival (OS) (P=0.014, log-rank test) rates decreased as the plasma NSE level increased. Statistical analysis using a Cox proportional hazards regression model adjusted for age, gender, performance status (PS) and disease stage showed that higher NSE levels were associated with shorter PFS (P=0.021) and OS (P=0.0024). By contrast, no association was detected between the serum level of pro-GRP and survival rate. The results suggest that pretreatment NSE measurement could be clinically useful in patients with NSCLC scheduled to receive gefitinib treatment.
    Molecular and Clinical Oncology 05/2015; 3(4). DOI:10.3892/mco.2015.568
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    ABSTRACT: We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and 7 susceptibility loci originally identified by European genome-wide association study (GWAS) in 2012: ZMIZ1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, and BCAR1. We also examined the association of 3 additional loci: CCND2 and GIPR, identified in sex-differentiated analyses, and LAMA1, which was shown to be associated with non-obese European type 2 diabetes. We genotyped 6,972 Japanese participants (4,280 type 2 diabetes patients and 2,692 controls) for each of the 10 single nucleotide polymorphisms (SNPs): rs12571751 in ZMIZ1, rs10842994 near KLHDC5, rs2796441 near TLE1, rs459193 near ANKRD55, rs10401969 in CILP2, rs12970134 near MC4R, rs7202877 near BCAR1, rs11063069 near CCND2, rs8108269 near GIPR, and rs8090011 in LAMA1 using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using a logistic regression analysis. All SNPs examined in this study had the same direction of effect (odds ratio > 1.0, p = 9.77 × 10-4, binomial test), as in the original reports. Among them, rs12571751 in ZMIZ1 was significantly associated with type 2 diabetes [p = 0.0041, odds ratio = 1.123, 95% confidence interval 1.037-1.215, adjusted for sex, age and body mass index (BMI)], but we did not observe significant association of the remaining 9 SNP loci with type 2 diabetes in the present Japanese population (p ≥ 0.005). A genetic risk score, constructed from the sum of risk alleles for the 7 SNP loci identified by un-stratified analyses in the European GWAS meta-analysis were associated with type 2 diabetes in the present Japanese population (p = 2.3 × 10-4, adjusted for sex, age and BMI). ZMIZ1 locus has a significant effect on conferring susceptibility to type 2 diabetes also in the Japanese population.
    PLoS ONE 05/2015; 10(5):e0126363. DOI:10.1371/journal.pone.0126363 · 3.23 Impact Factor
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    ABSTRACT: Nicotinamide phosphoribosyltransferase (NAMPT), the key NAD(+) biosynthetic enzyme, has two different forms, intra- and extracellular (iNAMPT and eNAMPT), in mammals. However, the significance of eNAMPT secretion remains unclear. Here we demonstrate that deacetylation of iNAMPT by the mammalian NAD(+)-dependent deacetylase SIRT1 predisposes the protein to secretion in adipocytes. NAMPT mutants reveal that SIRT1 deacetylates lysine 53 (K53) and enhances eNAMPT activity and secretion. Adipose tissue-specific Nampt knockout and knockin (ANKO and ANKI) mice show reciprocal changes in circulating eNAMPT, affecting hypothalamic NAD(+)/SIRT1 signaling and physical activity accordingly. The defect in physical activity observed in ANKO mice is ameliorated by nicotinamide mononucleotide (NMN). Furthermore, administration of a NAMPT-neutralizing antibody decreases hypothalamic NAD(+) production, and treating ex vivo hypothalamic explants with purified eNAMPT enhances NAD(+), SIRT1 activity, and neural activation. Thus, our findings indicate a critical role of adipose tissue as a modulator for the regulation of NAD(+) biosynthesis at a systemic level. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 04/2015; 21(5). DOI:10.1016/j.cmet.2015.04.002 · 17.57 Impact Factor
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    ABSTRACT: To investigate the reactivity of monoclonal anti-citrullinated protein antibody (ACPA) obtained from peripheral blood B cells of RA patients to human autoantigens as well as environmental proteins by determining the essential epitope for the ACPA. A human monoclonal ACPA (CCP-Ab1) was obtained by screening peripheral blood lymphocytes of 31 patients with rheumatoid arthritis (RA) using a novel monoclonal antibody-secreting cell (ASC) screening system, the immunospot-array assay on a chip (ISAAC). The essential epitope for CCP-Ab1was determined using epitope mapping. Then, human, microbial, and plant proteins that share the identified essential epitope were searched using BLAST. Finally the representative searched proteins were produced in vitro and their reactivity to CCP-Ab1 was examined. CCP-Ab1 bound cyclic citrullinated peptide (CCP) in citrulline-indispensable manner. In CCP, the six amino acid residues were found to be required for CCP-Ab1 binding. In the BLAST search, 38 human, 56 viral, 1383 fungal, 547 bacterial, and 1072 plant proteins were found to share the essential epitope, andCCP-Ab1 reacted with all the recombinant citrullinated proteins tested, which included the various environmental factors, such as various plant proteins for the daily diet. A monoclonal ACPA (CCP-Ab1) derived from RA patients was demonstrated for the first time to cross-react not only with various autoantigens but also with numerous plant and microbial proteins. We propose that countless environmental factors, including microbes and diet, may trigger the generation of ACPAs that then cross-react with various citrullinated human autoantigens through molecular mimicry to induce RA. This article is protected by copyright. All rights reserved. © 2015 American College of Rheumatology.
    Arthritis and Rheumatology 04/2015; 67(8). DOI:10.1002/art.39161
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    ABSTRACT: Aim/hypothesis Lowering the body weight set point is a prerequisite for the maintenance of reduced body weight. In this context, obesity is known to be strongly linked to leptin resistance, and it remains to be clarified whether recovery from leptin resistance might lower the body weight set point to allow sustained body weight loss. Methods Obese IRS-2 knockout (IRS-2 −/−) mice were subjected to calorie restriction (CR) or β3-adrenergic receptor (AR) agonist treatment. The physiological effects of leptin, hypothalamic leptin signaling, and alterations of the body weight set point were evaluated. Results In the CR mice, recovery from acquired leptin resistance was observed, as shown by the restoration of the suppressive effects of leptin on food intake and weight gain, as well as the recovery of signal transducer and activator of transcription 3 (STAT3) phosphorylation. Nevertheless, the body weight quickly rebounded to the original body weight after cessation of the CR, suggesting that CR failed to overcome the primary defect in IRS-2/phosphatidylinositol 3-kinase (PI3K) signaling. On the other hand, after 2 weeks β3-AR agonist treatment, the mice began to lose body weight, indicating that the treatment was able to overcome the primary defect in IRS-2/PI3K signaling and lower the body weight set point. Conclusions/interpretation Recovery of acquired leptin resistance does not lead to a resetting of the body weight set point in obese IRS-2/PI3K-defective mice. β3-AR agonist treatment may act on some pathways distal to or independent of PI3K and/or STAT3, inducing resetting of the body weight set point.
    Diabetology International 02/2015; DOI:10.1007/s13340-015-0205-3
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    ABSTRACT: Background: Few medical education programs provide hands-on classes using electronic medical charts for a large number of students. Methods: To simulate medical interview, the third- and sixth-year medical students viewed the electronic medical chart samples on screen, created by FileMaker and discussed the management of them. Following this, they underwent a questionnaire survey. Results: A total of 63.1 and 76.3% of the third- and sixth-year students responded to the questionnaire, and 87.1 and 78.9% of the responders became interested in the class, respectively, because it focused on hands-on, practical training. A total of 5.6% third-year students stated that the class was difficult to master but they hoped to continue learning. Discussion: The adoption of hands-on class using electronic medical charts interested even junior medical students.
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    ABSTRACT: Aims To evaluate the association of rs7578597 in THADA, rs10886471 in GRK5, rs7403531 in RASGRP1, and rs6723108 in TMEM163 with type 2 diabetes among the Japanese we performed a replication study of the association of these single nucleotide polymorphism (SNP) loci. Methods We genotyped these 4 SNPs for 10,287 Japanese participants (7,478 type 2 diabetes, 2,809 controls) and used logistic regression analysis to examine the association of these SNPs with type 2 diabetes. Results Rs6723108 was not polymorphic in our control group, and was excluded from the analysis. Rs7578597 was nominally associated with type 2 diabetes (p = 0.0186, odds ratio = 0.55, 95 % confidence interval = 0.33-0.90 adjusted for age, sex, and body mass index); however this association was not significant after Bonferroni correction (p ≥ 0.0125) and the effect direction was not consistent with that in the original report. There was significant heterogeneity in the allele frequency of rs7578597 among our control groups, and the nominal association was no longer observed (p = 0.58) after excluding a control collection in which the risk allele frequency was significantly higher than those in the other control collections. The remaining 2 SNP loci were not associated with type 2 diabetes in this Japanese population (p ≥ 0.05). We did not observe a significant association between the 3 SNPs and glycemic traits. Conclusions The 4 loci have no significant effect on susceptibility to type 2 diabetes among the Japanese, although further evaluation with larger cohorts is necessary, especially for rs7578597 in THADA.
    Diabetology International 01/2015; DOI:10.1007/s13340-015-0202-6
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    ABSTRACT: Cortisol plays an important role in the physical status of patients with end-stage lung cancer, but the association of urine cortisol levels with TNM stage/performance status (PS) is unclear in patients with advanced lung cancer receiving chemotherapy. The objective of this study was to examine this association. In this single-center, retrospective, observational study, cortisol concentrations in 24-h pooled urine from 22 patients with advanced lung cancer were measured over 2 days. The mean concentration in each patient was compared with PS, TNM stage, and serum sodium and potassium ion levels. The 24-h urine cortisol levels were higher in PS2 or PS3 cases compared to PS1 (p < 0.05) and increased proportionally with PS. Urine cortisol also increased in N2 or N3 cases compared to N1 (p < 0.01) and also increased in M1 cases (p < 0.05). Urine cortisol levels were negatively correlated with serum sodium (R = -0.49, p < 0.05) and had a tendency for a positive correlation with serum potassium (R = 0.40, p = 0.06). The 24-h urine cortisol level increased in patients with advanced lung cancer undergoing chemotherapy. Low serum levels of potassium and high levels of sodium may indicate relative adrenal insufficiency.
    Supportive Care Cancer 12/2014; 23(7). DOI:10.1007/s00520-014-2585-5 · 2.36 Impact Factor

  • Revue du Rhumatisme 12/2014; 81(6). DOI:10.1016/j.rhum.2014.08.001
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    ABSTRACT: Recent studies have highlighted the renoprotective effect of sirtuin1 (SIRT1), a deacetylase that contributes to cellular regulation. However, the pathophysiologic role of SIRT1 in podocytes remains unclear. Here, we investigated the function of SIRT1 in podocytes. We first established podocyte-specific Sirt1 knockout (SIRT1(pod-/-)) mice. We then induced glomerular disease by nephrotoxic serum injection. The increase in urinary albumin excretion and BUN and the severity of glomerular injury were all significantly greater in SIRT1(pod-/-) mice than in wild-type mice. Western blot analysis and immunofluorescence showed a significant decrease in podocyte-specific proteins in SIRT1(pod-/-) mice, and electron microscopy showed marked exacerbation of podocyte injury, including actin cytoskeleton derangement in SIRT1(pod-/-) mice compared with wild-type mice. Protamine sulfate-induced podocyte injury was also exacerbated by podocyte-specific SIRT1 deficiency. In vitro, actin cytoskeleton derangement in H2O2-treated podocytes became prominent when the cells were pretreated with SIRT1 inhibitors. Conversely, this H2O2-induced derangement was ameliorated by SIRT1 activation. Furthermore, SIRT1 activation deacetylated the actin-binding and -polymerizing protein cortactin in the nucleus and facilitated deacetylated cortactin localization in the cytoplasm. Cortactin knockdown or inhibition of the nuclear export of cortactin induced actin cytoskeleton derangement and dissociation of cortactin from F-actin, suggesting the necessity of cytoplasmic cortactin for maintenance of the actin cytoskeleton. Taken together, these findings indicate that SIRT1 protects podocytes and prevents glomerular injury by deacetylating cortactin and thereby, maintaining actin cytoskeleton integrity. Copyright © 2014 by the American Society of Nephrology.
    Journal of the American Society of Nephrology 11/2014; 26(8). DOI:10.1681/ASN.2014030289 · 9.34 Impact Factor

  • American Journal of Respiratory and Critical Care Medicine 11/2014; 190(9):e30-1. DOI:10.1164/rccm.201401-0086IM · 13.00 Impact Factor
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    ABSTRACT: Although phenotypically polarized macrophages are now generally classified into two major subtypes termed proinflammatory M1 and anti-inflammatory M2 macrophages, a contributory role of lung M2 macrophages in the pathophysiological features of acute lung injury is not fully understood. Herein, we show in an endotoxemic murine model that M2 macrophages serve as key anti-inflammatory cells that play a regulatory role in the severity of lung injury. To study whether M2 macrophages can modify inflammation, we depleted M2 macrophages from lungs of CD206-diphtheria toxin (DT) receptor transgenic (Tg) mice during challenge with lipopolysaccharide. The i.p. administration of DT depleted CD206-positive cells in bronchoalveolar lavage fluid. The use of M2 macrophage markers Ym1 and arginase-1 identified pulmonary CD206-positive cells as M2 macrophages. A striking increase in neutrophils in bronchoalveolar lavage fluid cell contents was found in DT-treated CD206-DT receptor Tg mice. In CD206-DT receptor Tg mice given DT, endotoxin challenge exaggerated lung inflammation, including up-regulation of proinflammatory cytokines and increased histological lung damage, but the endotoxemia-induced increase in NF-κB activity was significantly reduced, suggesting that M2 phenotype-dependent counteraction of inflammatory insult cannot be attributed to the inhibition of the NF-κB pathway. Our results indicate a critical role of CD206-positive pulmonary macrophages in triggering inflammatory cascade during endotoxemic lung inflammation.
    American Journal Of Pathology 10/2014; 185(1). DOI:10.1016/j.ajpath.2014.09.005 · 4.59 Impact Factor

Publication Stats

21k Citations
1,666.14 Total Impact Points


  • 2008-2015
    • Toyama University
      Тояма, Toyama, Japan
    • University of Toyama
      • • Department of Internal Medicine 3
      • • Faculty of Medicine
      Тояма, Toyama, Japan
  • 2010
    • Asahi General Hospital
      Asahi, Chiba, Japan
  • 1987-2009
    • The University of Tokyo
      • • Department of Diabetes and Metabolic Diseases
      • • Division of Internal Medicine
      • • School of Medicine
      白山, Tōkyō, Japan
  • 1998-2008
    • Okayama University
      • Faculty of Pharmaceutical Science
      Okayama, Okayama, Japan
    • Nara Institute of Science and Technology
      • Graduate School of Biological Sciences
      Ikuma, Nara, Japan
  • 2006
    • Japan Science and Technology Agency (JST)
      Edo, Tōkyō, Japan
  • 2002
    • Yokohama City University
      Yokohama, Kanagawa, Japan
    • Tokyo Metropolitan Hiroo Hospital
      • Department of Radiology
      Edo, Tōkyō, Japan
  • 1996
    • Kyoto University
      • Institute for Virus Research
      Kioto, Kyōto, Japan