Shuichi Kaneko

Kanazawa Medical University, Kanazawa, Ishikawa, Japan

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Publications (521)2403.09 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Impaired angiogenesis induced by vascular endothelial growth factor (VEGF) resistance is a hallmark of vascular complications in type 2 diabetes; however, its molecular mechanism is not fully understood. We have previously identified selenoprotein P (SeP, encoded by the SEPP1 gene in humans) as a liver-derived secretory protein that induces insulin resistance. Levels of serum SeP and hepatic expression of SEPP1 are elevated in type 2 diabetes. Here, we investigated the effects of SeP on VEGF signalling and angiogenesis.
    Diabetologia 07/2014; · 6.49 Impact Factor
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    ABSTRACT: Calcium channel blockers (CCBs) are used as antihypertensive agents and have a strong vasodilatory effect; however, the sympathetic activation mediated by baroreflex might cause adverse effects. A recently developed CCB, azelnidipine, decreases the heart rate (HR) while lowering blood pressure (BP), possibly by inhibiting sympathetic nerve activity in animal models. In this study, we evaluated whether azelnidipine inhibited sympathetic nerve activity, compared to amlodipine, in primary hypertensive patients.
    Journal of hypertension. 06/2014;
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    ABSTRACT: The prognosis in patients with idiopathic membranous nephropathy (IMN) is diverse. However, the prognosis after relapse and factors affecting relapse remain unclear.
    Clinical and Experimental Nephrology 06/2014; · 1.25 Impact Factor
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    ABSTRACT: Abstract Objective Previously, we reported that malnutrition in the advanced fibrosis stage of chronic hepatitis C (CH-C) impaired interferon (IFN) signaling by inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. However, the effect of pro-fibrotic signaling on IFN signaling was not addressed. Methods The effect of transforming growth factor (TGF)-β signaling on IFN signaling and hepatitis C virus (HCV) replication was examined in Huh-7.5 cells by evaluating the expression of forkhead box O3A (Foxo3a), suppressor of cytokine signaling 3 (Socs3), c-Jun, activating transcription factor 2, ras homolog enriched in brain, and mTORC1. The findings were confirmed in liver tissue samples obtained from 91 patients who received PEGylated-IFN and ribavirin combination therapy. Results TGF-β signaling was significantly up-regulated in the advanced fibrosis stage of CH-C. A significant positive correlation was observed between the expression of TGF-β2 and mothers against decapentaplegic homolog 2 (Smad2), Smad2 and Foxo3a, and Foxo3a and Socs3 in the liver of CH-C patients. In Huh-7.5 cells, TGF-β1 activated the Foxo3a promoter through an AP1 binding site; the transcription factor c-Jun was involved in this activation. Foxo3a activated the Socs3 promoter and increased HCV replication. TGF-β1 also inhibited mTORC1 and IFN signaling. Interestingly, c-Jun and TGF-β signaling was up-regulated in treatment-resistant IL28B minor genotype patients (TG/GG at rs8099917), especially in the early fibrosis stage. Branched chain amino acids or a TGF-β receptor inhibitor canceled these effects and showed an additive effect on the anti-HCV activity of direct-acting antiviral drugs (DAAs). Conclusions Blocking TGF-β signaling could potentiate the anti-viral efficacy of IFN- and/ or DAA-based treatment regimens and would be useful for the treatment of difficult-to-cure CH-C patients.
    Hepatology 06/2014; · 12.00 Impact Factor
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    ABSTRACT: Immunotherapy using dendritic cells (DCs) is a promising cancer therapy. The success of this therapy depends on the function of induced DCs. However, there has been no consensus on optimal conditions for DC preparation in vitro for immunotherapy of hepatocellular carcinoma (HCC) patients. To address relevant issues, we evaluated the procedures to induce DCs that efficiently function in hepatitis C virus (HCV)-related HCC.
    International immunopharmacology. 05/2014;
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    ABSTRACT: Right ventricular septal pacing is thought to be better than right ventricular apical pacing for shortening the QRS duration and for preserving left ventricular function. However, right ventricular septal pacing may not be effective in all cases. In this case report, we present a rare case in which right ventricular septal pacing induced thoroughly separated right and left ventricular excitation despite the presence of a relatively narrow QRS wave during atrium-only pacing.
    Journal of medical case reports. 05/2014; 8(1):158.
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    ABSTRACT: Although urinary albumin is the well-known non-invasive marker for diabetic nephropathy, its sensitivity is relatively low. To select more adequate marker, we examined whether urinary tubular markers were more sensitive than albumin using spontaneous type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. The OLETF rats exhibited histopathological alterations in glomeruli and tubules at 14 weeks of age, but there were no significant differences in the urinary albumin between OLETF and control, Long-Evans Tokushima Otsuka (LETO), rats at 10-16 weeks of age. In the OLETF rats, urinary excretions of N-acetyl-β-d-glucosaminidase and neutrophil gelatinase-associated lipocalin did not increase at least until 20 weeks of age, and urinary vanin-1 transiently increased at 18 weeks of age. On the other hand, urinary kidney injury molecule-1 (Kim-1) in the OLETF rats significantly increased at 14 weeks of age, and the elevation continued up to 22 weeks of age. In a clinical study, urinary KIM-1 levels tended to be higher in type 2 diabetic patients with and without albuminuria than in control subjects. These results suggest that compared to urinary albumin, urinary Kim-1 is a more sensitive biomarker for the detection of early stage of nephropathy in these type 2 diabetic animals. Merit of urinary KIM-1 in diabetic patients remains to be determined.
    Diabetes & Vascular Disease Research 05/2014; · 2.59 Impact Factor
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    Naoki Oishi, Taro Yamashita, Shuichi Kaneko
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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. The concept of cancer stem cells (CSCs) is based primarily on the clinical and experimental observations that indicate the existence of a subpopulation of cells with the capacity to self-renew and differentiate as well as show increased resistance to radiation and chemotherapy. They are considered as the factors responsible for the cases of tumor relapse. Hepatic progenitor cells (HPCs) could form the basis of some hepatocellular carcinomas (HCC) and cholangiocarcinomas. Liver CSCs have been reported in multiple subtypes of HCC and are considered as the master regulators of HCC initiation, tumor metastasis, and progression. HPCs activators such as epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin, transforming growth factor-beta (TGF-β), Notch and Hedgehog signaling systems expedite tumorigenesis or conversely, serve as a powerful cancer-prevention tool. Recent work has also identified Sal-like protein 4 (SALL4) and some epigenetic regulations as important molecules, while several therapeutic drugs that directly control HPCs have been tested both in vivo and in vitro. However, liver CSCs clearly have a complex pathogenesis, with the potential for considerable crosstalk and redundancy in signaling pathways. Hence, the targeting of single molecules or pathways may have limited benefit for treatment. In addition to the direct control of liver CSCs, many other factors are needed for CSC maintenance including angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance. Here, we provide a brief review of molecular signaling in liver CSCs and present insights into new therapeutic strategies for their targeting.
    Liver cancer. 05/2014; 3(2):71-84.
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    ABSTRACT: Effective prophylactic therapies have not been established for hepatocellular carcinoma recurrence. Peretinoin represents one novel option for patients with hepatitis C virus-related hepatocellular carcinoma (HCV-HCC), and it was tested in a multicenter, randomized, double-blind, placebo-controlled study. Patients with curative therapy were assigned to one of the following regimens: peretinoin 600, 300 mg/day, or placebo for up to 96 weeks. The primary outcome was recurrence-free survival (RFS). Of the 401 patients initially enrolled, 377 patients were analyzed for efficacy. The RFS rates in the 600-mg group, the 300-mg group, and the placebo group were 71.9, 63.6, and 66.0 % at 1 year, and 43.7, 24.9, and 29.3 % at 3 years, respectively. The primary comparison of peretinoin (300 and 600-mg) with placebo was not significant (P = 0.434). The dose-response relationship based on the hypothesis that "efficacy begins to increase at 600 mg/day" was significant (P = 0.023, multiplicity-adjusted P = 0.048). The hazard ratios for RFS in the 600-mg group vs. the placebo group were 0.73 [95 % confidence interval (CI) 0.51-1.03] for the entire study period and 0.27 (95 % CI 0.07-0.96) after 2 years of the randomization. Common adverse events included ascites, increased blood pressure, headache, presence of urine albumin, and increased transaminases. Although the superiority of peretinoin to placebo could not be validated, 600 mg/day was shown to be the optimal dose, and treatment may possibly reduce the recurrence of HCV-HCC, particularly after 2 years. The efficacy and safety of peretinoin 600 mg/day should continue to be evaluated in further studies.
    Journal of Gastroenterology 04/2014; · 3.79 Impact Factor
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    ABSTRACT: To investigate histological and immunohistochemical differences in hepatitis between autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) with AIH features. Liver needle biopsies of 41 PBC with AIH features and 43 AIH patients were examined. The activity of periportal and lobular inflammation was scored 0 (none or minimal activity) to 4 (severe), and the degree of hepatitic rosette formation and emperipolesis was semiquantatively scored 0-3. The infiltration of mononuclear cells positive for CD20, CD38, CD3, CD4, and CD8 and positive for immunoglobulins (IgG, IgM, and IgA) at the periportal areas (interface hepatitis) and in the hepatic lobules (lobular hepatitis) were semiquantitatively scored in immunostained liver sections (score 0-6). Serum aspartate aminotransferase (AST), immunoglobulins, and autoantibodies at the time of liver biopsy were correlated with the histological and immunohistochemical scores of individual lesions. Lobular hepatitis, hepatitic rosette formation, and emperipolesis were more extensive and frequent in AIH than in PBC. CD3+, CD4+, and CD8+ cell infiltration scores were higher in the hepatic lobules and at the interface in AIH but were also found in PBC. The degree of mononuclear cell infiltration correlated well with the degree of interface and lobular hepatitis in PBC, but to a lesser degree in AIH. CD20+ cells were mainly found in the portal tracts and, occasionally, at the interface in both diseases. Elevated AST correlated well with the hepatocyte necroinflammation and mononuclear cell infiltration, specifically CD38+ cells in PBC. No correlation existed between autoantibodies and inflammatory cell infiltration in PBC or AIH. While most AIH cases were IgG-predominant at the interface, PBC cases were divided into IgM-predominant, IgM/IgG-equal, and IgG-predominant types, with the latter sharing several features with AIH. These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with interface hepatitis may not be identical.
    World Journal of Gastroenterology 04/2014; 20(13):3597-608. · 2.55 Impact Factor
  • Taro Yamashita, Shuichi Kaneko
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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the world's most aggressive diseases and carries a poor prognosis for patients. Recent evidence suggests that HCC is organized by cancer stem cells (CSCs), which are a subset of cells with stem cell-like features. CSCs are considered a pivotal target for the eradication of cancer, and liver CSCs have been investigated using various stem cell markers. Several hepatic stem/progenitor markers have been shown to be useful for isolating putative CSCs from HCC, although the expression patterns and phenotypic diversity of CSCs purified by these markers remain obscure. Recently, we found that liver CSCs defined by different markers show unique features of tumorigenicity and metastasis, with phenotypes closely associated with committed liver lineages. Furthermore, our data suggest that these distinct CSCs collaborate to orchestrate the tumorigenicity and metastasis of HCC. In this review article, we summarize the recent advances in understanding the pathogenesis and heterogeneity of liver CSCs.
    Journal of Gastroenterology 03/2014; · 3.79 Impact Factor
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    ABSTRACT: Cancer vaccine therapy is one of the most attractive therapies as a new treatment procedure for pancreatic adenocarcinoma. Recent technical advances have enabled the identification of cytotoxic T lymphocyte (CTL) epitopes in various tumor-associated antigens (TAAs). However, little is known about which TAA and its epitope are the most immunogenic and useful for a cancer vaccine for pancreatic adenocarcinoma. We examined the expression of 17 kinds of TAA in 9 pancreatic cancer cell lines and 12 pancreatic cancer tissues. CTL responses to 23 epitopes derived from these TAAs were analyzed using enzyme-linked immunospot (ELISPOT), CTL, and tetramer assays in 41 patients, and factors affecting the immune responses were investigated. All TAAs were frequently expressed in pancreatic adenocarcinoma cells, except for adenocarcinoma antigens recognized by T cells 1, melanoma-associated antigen (MAGE)-A1, and MAGE-A3. Among the epitopes recognized by CTLs in more than two patients in the ELISPOT assay, 6 epitopes derived from 5 TAAs, namely, MAGE-A3, p53, human telomerase reverse transcriptase (hTERT), Wilms tumor (WT)-1, and vascular endothelial growth factor receptor (VEGFR)2, could induce specific CTLs that showed cytotoxicity against pancreatic cancer cell lines. The frequency of lymphocyte subsets correlated well with TAA-specific immune response. Overall survival was significantly longer in patients with TAA-specific CTL responses than in those without. P53, hTERT, WT-1, and VEGFR2 were shown to be attractive targets for immunotherapy in patients with pancreatic adenocarcinoma, and the induction of TAA-specific CTLs may improve the prognosis of these patients.
    Cancer Immunology and Immunotherapy 03/2014; · 3.64 Impact Factor
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    ABSTRACT: Background Sorafenib is the sole molecular-targeted agent showing a survival benefit in patients with advanced hepatocellular carcinoma (HCC). We evaluated the tolerability and effectiveness of a combination of S-1 with sorafenib in patients with advanced HCC. Methods S-1 was administered during days 1-14 and sorafenib was administered every day. This treatment was repeated every 21 days. In phase I, we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). The dose of each drug was planned as follows: cohort 1: S-1 48 mg/m(2)/day and sorafenib 400 mg/day, cohort 2a: S-1 48 mg/m(2)/day and sorafenib 800 mg/day, cohort 2b: S-1 64 mg/m(2)/day and sorafenib 400 mg/day, cohort 3: S-1 64 mg/m(2)/day and sorafenib 800 mg/day, and cohort 4: S-1 80 mg/m(2)/day and sorafenib 800 mg/day. In phase II, the patients were treated at the MTD to evaluate safety and efficacy. Results Nineteen patients were enrolled in phase I. One of the six patients in cohort 1 and one of the six patients in cohort 3 experienced DLT. None of the three patients in cohort 2a experienced DLT and three of the four patients in cohort 4 experienced DLT. Therefore, cohort 3 was considered the MTD. Subsequently, 26 patients were enrolled in phase II. The most common grade 3/4 toxicities were an increase of aspartate aminotransferase (38.5 %), thrombocytopenia (23.1 %), neutropenia (19.2 %), hyperbilirubinemia (15.4 %), an increase of alanine aminotransferase (15.4 %), hyponatremia (11.5 %), rash (11.5 %), and hypophosphatemia (11.5 %). Sudden death occurred in one patient (3.8 %). A patient (3.8 %) had a partial response, 15 (57.7 %) had stable disease, and 10 (38.5 %) had progressive disease. The median times to progression and overall survival were 2.4 and 10.5 months, respectively. Conclusion The MTD of S-1 and sorafenib in patients with advanced HCC was 64 mg/m(2)/day and 800 mg/day, respectively. This dose/regimen demonstrated substantial clinical activity among patients with advanced HCC.
    Investigational New Drugs 03/2014; · 3.50 Impact Factor
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    ABSTRACT: The survival of patients with hepatocellular carcinoma (HCC) is often individually different even after surgery for early-stage tumors. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) has been introduced recently to evaluate hepatic lesions with regard to vascularity and the activity of the organic anion transporter OATP1B3. Here, we report that Gd-EOB-DTPA-enhanced MRI (EOB-MRI) in combination with serum alpha-fetoprotein (AFP) status reflects the stem/maturational status of HCC with distinct biology and prognostic information. Gd-EOB-DTPA uptake in the hepatobiliary phase was observed in approximately 15% of HCCs. This uptake correlated with low serum AFP levels, maintenance of hepatocyte function with the up-regulation of OATP1B3 and HNF4A expression, and good prognosis. By contrast, HCC showing reduced Gd-EOB-DTPA uptake with high serum AFP levels was associated with poor prognosis and the activation of the oncogene FOXM1. Knockdown of HNF4A in HCC cells showing Gd-EOB-DTPA uptake resulted in the increased expression of AFP and FOXM1 and the loss of OATP1B3 expression accompanied by morphological changes, enhanced tumorigenesis, and loss of Gd-EOB-DTPA uptake in vivo. HCC classification based on EOB-MRI and serum AFP levels predicted overall survival in a single-institution cohort (n = 70), and its prognostic utility was validated independently in a multi-institution cohort of early-stage HCCs (n = 109). Conclusion: This non-invasive classification system is molecularly based on the stem/maturation status of HCCs and can be incorporated into current staging practices to improve management algorithms, especially in the early stage of disease. (Hepatology 2014;).
    Hepatology 02/2014; · 12.00 Impact Factor
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    ABSTRACT: -Muscle-specific RING finger protein-1 (MuRF1) is an E3 ligase that inhibits cardiac hypertrophy. However, how MuRF1 regulates cardiac hypertrophy and function during pressure overload (PO) remains poorly understood. We investigated the role of endogenous MuRF1 in regulating cardiac hypertrophy in response to PO in vivo. -Transverse aortic constriction (TAC) for 4 weeks significantly reduced expression of MuRF1 in the mouse heart. After 2 and 4 weeks of TAC, MuRF1 knockout (Murf1(-/-)) mice exhibited enhanced cardiac hypertrophy and left ventricular (LV) dysfunction compared to non-transgenic (NTg) mice. Histological analyses showed that Murf1(-/-) mice exhibited more severe fibrosis and apoptosis than NTg mice after TAC. TAC-induced increases in the activity of a nuclear factor of activated T cells (NFAT) luciferase reporter were significantly greater in Murf1(-/-) than in NTg mice. TAC-induced increases in calcineurin A (CnA) expression were also significantly enhanced in Murf1(-/-) compared to in NTg mice. Co-immunoprecipitation assays showed that endogenous MuRF1 and CnA interact with one another. Polyubiquitination of CnA was attenuated in Murf1(-/-) mouse hearts at baseline and in response to TAC, and the protein stability of CnA was enhanced in cardiomyocytes in which MuRF1 was downregulated in vitro. Furthermore, MuRF1 directly ubiquitinated CnA in vitro. Cardiac-specific overexpression of ZAKI-4β, an endogenous inhibitor of CnA, significantly suppressed the enhancement of TAC-induced cardiac hypertrophy and dysfunction, as well as increases in cardiac fibrosis and apoptosis, in Murf1(-/-) mice. - Endogenous MuRF1 negatively regulates cardiac hypertrophy and dysfunction in response to PO through inhibition of the calcineurin-NFAT pathway.
    Circulation Heart Failure 02/2014; · 6.68 Impact Factor
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    ABSTRACT: Recent papers have reported an association between fatty liver disease and systemic insulin resistance in humans, but the causal relationship remains unclear. The liver may contribute to muscle insulin resistance by releasing secretory proteins, termed hepatokines. Here, we demonstrate that leukocyte cell-derived chemotaxin 2 (LECT2), as an energy-sensing hepatokine, is a link between obesity and skeletal muscle insulin resistance. Circulating LECT2 positively correlated with the severity of both obesity and insulin resistance in humans. LECT2 expression was negatively regulated by starvation-sensing kinase adenosine monophosphate-activated protein kinase (AMPK) in H4IIEC hepatocytes. Genetic deletion of LECT2 in mice increased insulin sensitivity in the skeletal muscle. Treatment with recombinant LECT2 protein impaired insulin signaling via phosphorylation of JNK in C2C12 myocytes. These results demonstrate the involvement of LECT2 in glucose metabolism, and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance.
    Diabetes 01/2014; · 7.90 Impact Factor
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    ABSTRACT: The cholesterol absorption inhibitor ezetimibe has been shown to ameliorate non-alcoholic fatty liver disease (NAFLD) pathology in a single-armed clinical study and in experimental animal models. In this study, we investigated the efficacy of ezetimibe on NAFLD pathology in an open-label randomised controlled clinical trial. We had planned to enrol 80 patients in the trial, as we had estimated that, with this sample size, the study would have 90% power. The study intervention and enrolment were discontinued because of the higher proportion of adverse events (significant elevation in HbA1c) in the ezetimibe group than in the control group. Thirty-two patients with NAFLD were enrolled and randomised (allocation by computer program). Ezetimibe (10 mg/day) was given to 17 patients with NAFLD for 6 months. The primary endpoint was change in serum aminotransferase level. Secondary outcomes were change in liver histology (12 control and 16 ezetimibe patients), insulin sensitivity including a hyperinsulinaemic-euglycaemic clamp study (ten control and 13 ezetimibe patients) and hepatic fatty acid composition (six control and nine ezetimibe patients). Hepatic gene expression profiling was completed in 15 patients using an Affymetrix gene chip. Patients and the physician in charge knew to which group the patient had been allocated, but people carrying out measurements or examinations were blinded to group. Serum total cholesterol was significantly decreased in the ezetimibe group. The fibrosis stage and ballooning score were also significantly improved with ezetimibe treatment. However, ezetimibe treatment significantly increased HbA1c and was associated with a significant increase in hepatic long-chain fatty acids. Hepatic gene expression analysis showed coordinate downregulation of genes involved in skeletal muscle development and cell adhesion molecules in the ezetimibe treatment group, suggesting a suppression of stellate cell development into myofibroblasts. Genes involved in the L-carnitine pathway were coordinately downregulated by ezetimibe treatment and those in the steroid metabolism pathway upregulated, suggestive of impaired oxidation of long-chain fatty acids. Ezetimibe improved hepatic fibrosis but increased hepatic long-chain fatty acids and HbA1c in patients with NAFLD. These findings shed light on previously unrecognised actions of ezetimibe that should be examined further in future studies. Trial registration University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000005250. Funding The study was funded by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and research grants from MSD.
    Diabetologia 01/2014; · 6.49 Impact Factor
  • Tatsuya Yamashita, Kuniaki Arai, Shuichi Kaneko
    Nihon Naika Gakkai Zasshi 01/2014; 103(1):102-9.
  • Kuniaki Arai, Tatsuya Yamashita, Shuichi Kaneko
    Nihon Naika Gakkai Zasshi 01/2014; 103(1):37-43.
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    ABSTRACT: Radiofrequency ablation therapy (RFA) is a radical treatment for liver cancers and induces tumor antigen-specific immune responses. In the present study, we examined the antitumor effects of focal OK-432-stimulated dendritic cell (DC) transfer combined with RFA and analyzed the functional mechanisms involved using a murine model. C57BL/6 mice were injected subcutaneously with colon cancer cells (MC38) in their bilateral flanks. After the establishment of tumors, the subcutaneous tumor on one flank was treated using RFA, and then OK-432-stimulated DCs were injected locally. The antitumor effect of the treatment was evaluated by measuring the size of the tumor on the opposite flank, and the immunological responses were assessed using tumor-infiltrating lymphocytes, splenocytes and draining lymph nodes. Tumor growth was strongly inhibited in mice that exhibited efficient DC migration after RFA and OK-432-stimulated DC transfer, as compared to mice treated with RFA alone or treatment involving immature DC transfer. We also demonstrated that the antitumor effect of this treatment depended on both CD8-positive and CD4-positive cells. On the basis of our findings, we believe that combination therapy for metastatic liver cancer consisting of OK-432-stimulated DCs in combination with RFA can proceed to clinical trials, and it is anticipated to be markedly superior to RFA single therapy.
    Cancer Immunology and Immunotherapy 01/2014; · 3.64 Impact Factor

Publication Stats

9k Citations
2,403.09 Total Impact Points

Institutions

  • 1994–2014
    • Kanazawa Medical University
      • • Department of Gastroenterology
      • • Department of Radiology
      • • Department of Nephrology
      • • Department of Internal Medicine (III)
      Kanazawa, Ishikawa, Japan
  • 1989–2014
    • Kanazawa University
      • • Department of Disease Control and Homeostasis
      • • Department of Laboratory Medicine
      • • Department of Internal Medicine
      • • Division of Oncology and Molecular Biology
      • • Department of Gastroenterology
      • • School of Medicine
      Kanazawa, Ishikawa, Japan
  • 2004–2013
    • Jichi Medical University
      • Division of Clinical Pharmacology
      Totigi, Tochigi, Japan
  • 2001–2013
    • The University of Tokyo
      • • Institute of Industrial Science
      • • Faculty & Graduate School of Medicine
      • • School of Medicine
      Edo, Tōkyō, Japan
    • Kanazawa Municipal Hospital
      Kanazawa, Ishikawa, Japan
  • 2012
    • National Center for Global Health and Medicine in Japan
      Tiba, Chiba, Japan
  • 2011
    • Musashino Red Cross Hospital
      Edo, Tōkyō, Japan
  • 2008–2009
    • NEC Corporation
      Edo, Tōkyō, Japan
  • 2007
    • University Hospital Medical Information Network
      Edo, Tōkyō, Japan
  • 2006
    • Kumamoto University
      • Department of Reproductive Engineering
      Kumamoto, Kumamoto Prefecture, Japan
  • 2001–2002
    • University of Tsukuba
      • Institute of Basic Medical Sciences
      Tsukuba, Ibaraki, Japan
  • 1994–1997
    • Kanazawa Institute of Technology
      Kanazawa, Ishikawa, Japan
  • 1995
    • University of Southern California
      Los Angeles, California, United States
  • 1988–1994
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States