Faculty Profiles - HANAFUSA Tadashi

Papers - HANAFUSA Tadashi

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Selective delivery of beta cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8(+) T cells in NOD mice Reviewed

Arunika Mukhopadhaya, Tadashi Hanafusa, Irene Jarchum, Yi-Guang Chen, Yoshiko Iwai, David V. Serreze, Ralph M. Steinman, Kristin V. Tarbell, Teresa P. DiLorenzo

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 105 ( 17 ) 6374 - 6379 2008.4

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Type 1 diabetes (T1D) is an autoimmune disease resulting from defects in central and peripheral tolerance and characterized by T cell-mediated destruction of islet beta cells. Cytotoxic CD8(+) T cells, reactive to beta cell antigens, are required for T1D development in the NOD mouse model of the disease, and CD8(+) T cells specific for beta cell antigens can be detected in the peripheral blood of T1D patients. It has been evident that in nonautoimmune-prone mice, dendritic cells (DCs) present model antigens in a tolerogenic manner in the steady state, e.g., in the absence of infection, and cause T cells to proliferate initially but then to be deleted or rendered unresponsive. However, this fundamental concept has not been evaluated in the setting of a spontaneous autoimmune disease. To do so, we delivered a mimotope peptide, recognized by the diabetogenic CD8(+) T cell clone A14 to DCs in NOD mice via the endocytic receptor DEC-205. Proliferation of transferred antigen-specific T cells was initially observed, but this was followed by deletion. Tolerance was achieved because rechallenge of mice with the mimotope peptide in adjuvant did not induce an immune response. Thus, targeting of DCs with P cell antigens leads to deletion of autoreactive CD8+ T cells even in the context of ongoing autoimmunity in NOD mice with known tolerance defects. Our results provide support for the development of DC targeting of self antigens for treatment of chronic T cell-mediated autoimmune diseases.

DOI： 10.1073/pnas.0802644105

Methodological Approach for Assessment of the Radioactivity Level in Dry Solid Waste Reviewed

Tomohiro Nagamatsu, Akihiro Sakoda, Katsumi Hanamoto, Ikuo Kinno, Tadashi Hanafusa, Kiyonori Yamaoka, Toshiro Ono

Radiation Safety Management 7 ( 1 ) 6 - 10 2008

Aberrant promoter methylation of insulin-like growth factor binding protein-3 gene in human cancers Reviewed

Kunitoshi Tomii, Kazunori Tsukuda, Shinichi Toyooka, Hideaki Dote, Tadashi Hanafusa, Hiroaki Asano, Minoru Naitou, Hiroyoshi Doihara, Takumi Kisimoto, Hideki Katayama, Harvery I. Pass, Hiroshi Date, Nobuyoshi Shimizu

INTERNATIONAL JOURNAL OF CANCER 120 ( 3 ) 566 - 573 2007.2

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Here, we examined the methylation status of IGFBP-3 to correlate to clinicopathological factors in human cancers. The methylation status of IGFBP-3 was determined by bisulfite DNA sequencing and was correlated with expression semi-quantified by real-time RT-PCR to develop a methylation-specific PCR (MSP) assay for IGFBP-3. Using the MSP assay, we examined the methylation status of IGFBP-3 in gastric cancer (GC), colorectal cancer (CRC), breast cancer (BC) and malignant mesothelioma (MM). IGFBP-3 methylation was detected in 6 of 13 (46%) and 16 of 24 (67%) GC cell lines and tumors, respectively; 4 of 8 (50%) and 15 of 26 (58%) CRC cell lines and tumors, respectively; 3 of 11 (27%) and 7 of 39 (18%) BC cell lines and tumors, respectively and 1 of 5 (20%) and 18 of 56 (32%) MM cell lines and tumors, respectively. Interestingly, the methylation status of MM specimens from Japanese patients (75%, 12 out of 16 patients) was significantly higher than those from the USA (15%, 6 out of 40 patients) (p < 0.0001), suggesting the presence of ethnic differences in the IGFBP-3 methylation status. We also found that IGFBP-3 methylation was preferentially present in GCs arising in the lower-third of the stomach (p = 0.079). In summary, our results showed that IGFBP-3 methylation played an important role in the silencing of its expression, suggesting that IGFBP-3 may act as a tumor suppressor gene in several human cancers examined. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/ijc.22341

IGFBP-3 expression in hepatocellular carcinoma involves abnormalities in TGF-beta and/or Rb signaling pathways Reviewed

E Yumoto, H Nakatsukasa, T Hanafusa, Y Yumoto, K Nouso, E Matsumoto, T Onishi, Y Takuma, H Tanaka, T Fujikawa, M Suzuki, M Uemura, Y Shiratori

INTERNATIONAL JOURNAL OF ONCOLOGY 27 ( 5 ) 1223 - 1230 2005.11

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Insulin-like growth factor binding protein-3 (IGFBP-3) is a mediator of growth suppression signals and a putative tumor suppressor gene. The growth suppression mechanisms of IGFBP-3 have not been well clarified. We examined the expression of IGFBP-3 transcripts in human hepatocellular carcinoma (HCC) and the relationship between IGFBP-3 expression and the transforming growth factor-beta (TGF-beta) and/or retinoblastoma (Rb) signaling pathways. In situ hybridization revealed IGFBP-3 transcripts in cancer cells in 6 of 57 (10%) HCCs, including moderately and poorly differentiated HCCs with intrahepatic metastasis. In contrast, all lung metastatic nodules of 4 HCCs showed IGFBP-3 transcripts in cancer cells. The cDNA microarray showed that genes for the TGF-beta pathway and Rb were up-regulated in IGFBP-3-expressing HCCs. In 6 HCCs presenting IGFBP-3, immunohistochemical analyses showed abnormalities in the TGF-beta and/or Rb pathways; the loss of phosphorylated-Smad2 was observed in 2, and overexpression of phosphorylated-Rb was observed in the remaining 4 HCCs. The present study suggests that IGFBP-3 mediates growth suppression signals via the TGF-beta and/or Rb pathways in HCC.

Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinoma Reviewed

S Uematsu, T Higashi, K Nouso, K Kariyama, SI Nakamura, M Suzuki, H Nakatsukasa, Y Kobayashi, T Hanafusa, T Tsuji, Y Shiratori

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 20 ( 4 ) 583 - 588 2005.4

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Background: Advanced hepatocellular carcinoma (HCC) in humans is characterized by hypervascularity. In the present study, the expressions of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) and endostatin were analyzed in patients with chronic liver disease to clarify the effect of these major angiogenic factors.
Methods: Serum concentrations of VEGF, FGF-2 and endostatin in 24 patients with HCC, 16 patients with liver cirrhosis (LC) and 13 healthy volunteers were measured by enzyme-linked immunosorbent assay. The expression of VEGF in 21 surgically resected HCC samples was analyzed by immunohistochemistry, and that of VEGF isoforms in 15 HCC samples was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR).
Results: Serum VEGF, FGF-2 and endostatin concentrations were significantly elevated in patients with HCC compared with healthy volunteers; but there was no significant difference between patients with HCC and those with non-HCC liver disease. Immunohistochemical analysis showed that VEGF protein was strongly expressed in both well-differentiated HCC cells and non-cancerous hepatocytes, whereas in moderately and poorly differentiated HCC the expression was stronger in the endothelial cells (EC) lining intratumor vessels than in the cancer cells. On RT-PCR for VEGF isoforms it was found that VEGF-121, VEGF-165 and VEGF-189 were expressed in all but one of the HCC samples and in all corresponding non-HCC samples.
Conclusions: The results suggest that VEGF, FGF-2, and endostatin concentrations are elevated prior to the emergence of HCC and that the distribution of VEGF changes dynamically during the development of HCC. (C) 2005 Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1400-1746.2005.03726.x

Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation Reviewed

T Hanafusa, T Shinji, H Shiraha, K Nouso, Y Iwasaki, E Yumoto, T Ono, N Koide

BMC CANCER 5 2005.1

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Insulin-like growth factor binding protein (IGFBP)-3 functions as a carrier of insulin-like growth factors (IGFs) in circulation and a mediator of the growth suppression signal in cells. There are two reported p53 regulatory regions in the IGFBP3 gene; one upstream of the promoter and one intronic. We previously reported a hot spot of promoter hypermethylation of IGFBP-3 in human hepatocellular carcinomas and derivative cell lines. As the hot spot locates at the putative upstream p53 consensus sequences, these p53 consensus sequences are really functional is a question to be answered.
Methods: In this study, we examined the p53 consensus sequences upstream of the IGFBP-3 promoter for the p53 induced expression of IGFBP-3. Deletion, mutagenesis, and methylation constructs of IGFBP-3 promoter were assessed in the human hepatoblastoma cell line HepG2 for promoter activity.
Results: Deletions and mutations of these sequences completely abolished the expression of IGFBP-3 in the presence of p53 overexpression. In vitro methylation of these p53 consensus sequences also suppressed IGFBP-3 expression. In contrast, the expression of IGFBP-3 was not affected in the absence of p53 overexpression. Further, we observed by electrophoresis mobility shift assay that p53 binding to the promoter region was diminished when methylated.
Conclusion: From these observations, we conclude that four out of eleven p53 consensus sequences upstream of the IGFBP-3 promoter are essential for the p53 induced expression of IGFBP-3, and hypermethylation of these sequences selectively suppresses p53 induced IGFBP-3 expression in HepG2 cells.

DOI： 10.1186/1471-2407-5-9

Telomerase reverse transcriptase gene amplification in hepatocellular carcinoma Reviewed

Y Takuma, K Nouso, Y Kobayashi, S Nakamura, H Tanaka, E Matsumoto, T Fujikawa, M Suzuki, T Hanafusa, Y Shiratori

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 19 ( 11 ) 1300 - 1304 2004.11

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Background and Aim: Telomerase activation is essential for the immortality of cancer cells. The expression of telomerase reverse transcriptase (hTERT), the catalytic component of the telomerase complex, regulates telomerase activity in human cancers. Amplification of the hTERT gene, located at chromosome 5p, is thought to be a potential genetic event contributing to telomerase activation in sporadic tumors.
Methods: The amplification of the hTERT gene was examined in 46 surgically resected hepatocellular carcinomas (HCC) by real-time polymerase chain reaction and the status was compared with the expression of hTERT mRNA and clinicopathological parameters.
Results: Amplified hTERT genes were found in 21.7% (10/46) of HCC. The incidence of amplified hTERT genes in poorly differentiated HCC (6/12, 50%) was significantly higher than that in highly to moderately differentiated HCC (4/34, 11.8%; P = 0.012). Tumor size in those cases with hTERT gene amplification was larger compared to those cases with no amplification (P = 0.047). Amplification of the hTERT gene was not observed in non-cancerous tissues. The hTERT mRNA level did not correlate with the number of hTERT genes.
Conclusions: Based on these results, it is thought that hTERT gene amplification is a cancer-specific event, and may furthermore contribute to the dedifferentiation and development of HCC. However, hTERT gene overexpression was rarely due to an increased hTERT gene copy number in HCC. (C) 2004 Blackwell Publishing Asia Pry Ltd.

DOI： 10.1111/j.1400-1746.2004.03447.x

Decreased expression of B7 costimulatory molecules and major histocompatibility complex class-I in human hepatocellular carcinoma Reviewed

K Fujiwara, T Higashi, K Nouso, H Nakatsukasa, Y Kobayashi, M Uemura, SI Nakamura, S Sato, T Hanafusa, Y Yumoto, Naito, I, Y Shiratori

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 19 ( 10 ) 1121 - 1127 2004.10

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Background and Aim: We analyzed the expression of antigen-processing and antigen-presenting molecules in surgically resected fresh samples of human hepatocellular carcinoma (HCC) tissue to elucidate a mechanism of immune escape. We also examined the expression of interleukin (IL)-10 protein, which might act to downregulate expression of antigen-processing and antigen-presenting molecules.
Methods: Twenty-eight HCC samples obtained by surgical resection were analyzed for the expression of beta2-microglobulin, heat-shock protein (HSP)-70, human leukocyte antigen (HLA) class-I, CD80 (B7-1), CD86 (B7-2) and IL-10 by immunostaining.
Results beta2-Microglobulin and HSP-70 were preserved in all samples. In contrast, the expression of HLA class-I molecules was significantly reduced according to lowering in the histological grading of tumor differentiation (P = 0.024). Furthermore, B7-1 and B7-2 expression was reduced in tumor cells compared with corresponding areas of liver tissue without malignant involvement irrespective of the histological grading of tumors (21% and 36%, respectively). Although IL-10 protein was expressed in 54% of HCC, no relationship between the expression of IL-10 and downregulation of B7-1, B7-2, and HLA class-I was evident.
Conclusion: These findings suggest the potential role of B7 co-stimulatory molecules and HLA class-I molecules in facilitating HCC escape from immune surveillance without the involvement of IL-10. (C) 2004 Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1400-1746.2004.03467.x

Cellular distribution of telomerase reverse transcriptase in human hepatocellular carcinoma Reviewed

T Onishi, K Nouso, T Higashi, N Toshikuni, H Nakatsukasa, Y Kobayashi, M Uemura, E Yumoto, K Fujiwara, S Sato, S Nakamura, J Yokoyama, T Hanafusa, Y Shiratori

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 18 ( 10 ) 1168 - 1174 2003.10

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Background and Aim: Telomerase is the enzyme that synthesizes telomeric DNA, and the activation of telomerase is closely related to cellular immortality. Telomerase activity has been reported in many human cancer tissues and is regulated by the expression of human telomerase reverse transcriptase ( hTERT). The aim of the present study was to identify hTERT-expressing cells in human liver tissues and evaluate the feasibility of the hTERT promoter for gene therapy of hepatocellular carcinoma (HCC).
Methods: The authors examined the cellular distribution of hTERT transcripts in surgically resected HCC by in situ hybridization.
Results: Among 20 samples, hTERT expression was observed in 15 HCC. Transcripts of hTERT were homogenously distributed in the cytoplasm of HCC cells in nine of 15 cases; six of 15 cases displayed a heterogeneous staining pattern. All poorly differentiated HCC that expressed hTERT showed a homogenous pattern of staining. None of the non-cancerous hepatocytes were positive for the transcripts, but infiltrating lymphocytes were faintly stained. The homogenous expression of hTERT was also observed in the vascular invasion of HCC.
Conclusions: The results indicate that most HCC cells express hTERT RNA and that the promoter is a good candidate as a target for gene therapy. However, careful consideration must be taken concerning the potential effects on lymphocytes. (C) 2003 Blackwell Publishing Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.2003.03137.x

Identification of the antigens predominantly reacted with serum from patients with hepatocellular carcinoma Reviewed

M Uemura, K Nouso, Y Kobayashi, H Tanaka, S Nakamura, T Higashi, T Ono, E Nakayama, T Hanafusa, Y Shiratori

CANCER 97 ( 10 ) 2474 - 2479 2003.5

Language：English Publishing type：Research paper (scientific journal) Publisher：JOHN WILEY & SONS INC

BACKGROUND. To identify antigens specifically recognized by the immune surveillance system in patients with hepatocellular carcinoma (HCC), the authors examined two complementary DNA (cDNA) libraries of moderately differentiated HCC by serologic analysis of recombinant cDNA expression libraries (SEREX).
METHODS. The libraries were screened with autologous patients' sera, and sequences of the reacted clones were determined. To study the immunoreactivity of the antigens, sera from 20 patients with HCC, from 20 healthy volunteers, and from 16 patients with chronic viral hepatitis were examined.
RESULTS. Twenty-seven antigens were identified. They included SART1, p57Kip2, ROCK-1, gamma-catenin, and heat shock proteins, which are classified as tumor-associated genes. Three of 27 antigens-Tat-binding protein-1 (TBP-1), beta4 integrin-binding protein (p27[BBP]), and ribosomal protein L30 (rpL30)-were reacted predominantly with sera from patients with HCC (55% of patients, 45% of patients, and 20% of patients, respectively). Patients in the control group had no antibodies against these three antigens. Seventy percent of patients with HCC had the antibody against at least one of these antigens.
CONCLUSIONS. Disease specific humoral immune response against TBP-1, p27(BBP), and rpL30 was induced in patients with HCC, and the antibodies against these antigens also may be used as tumor markers. (C) 2003 American Cancer Society.

DOI： 10.1002/cncr.11374

Quantitative analysis of p40/p46 and p69/p71 forms of 2 ',5 '-oligoadenylate synthetase mRNA by competitive PCR and its clinical application Reviewed

A Takahashi, Y Iwasaki, J Miyaike, H Taniguchi, H Shimomura, T Hanafusa, Y Yumoto, A Moriya, N Koide, T Tsuji

CLINICAL CHEMISTRY 48 ( 9 ) 1551 - 1559 2002.9

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CLINICAL CHEMISTRY

Background: 2',5.-Oligoadenylate synthetases (2-5AS) are type I interferon (IFN)-induced proteins with antiviral capacity. Three major forms of 2-5AS with distinct enzymatic activities have been described in IFN-treated human cells. We. measured, distinct forms of 2-5AS MRNA to analze the relationship with its enzymatic activity and response to IFN therapy in chronic hepatitis C.
Methods: We established a method to quantify p40/p46 and p69/p71 forms of 2-5AS mRNA by use of reverse transcription followed by competitive PCR. The 2-5AS mRNA concentrations, were measured in peripheral blood mononuclear cells from 40 patients with chronic hepatitis C and 28 control individuals.
Results: Reconstitution experiments and comparison with Northern blot analyses revealed that our method accurately. and linearly quantified 2-5AS mRNA. 2-5AS mRNA concentrations and 2-5AS enzymatic activity were correlated (P <0.03). Our data demonstrated a correlation in 2-5AS mRNA between p40/p46 and p69/p71 (P <0.02), indicating a. similar regulation of the expression of these genes. Our data also demonstrated that pretreatment concentrations of 2-5AS mRNA correlated with responses to IFN therapy in chronic hepatitis C.
Conclusions: Our method for measuring 2-5AS mRNA concentrations could provide art important marker for selecting patients for IFN therapy and may be useful for the development of more effective therapeutic strategies for chronic hepatitis C. (C) 2002 American Association for Clinical Chemistry.

Genome aberrations observed by restriction landmark genome scanning analysis of chromosomal DNA in various types of primary hepatocellular carcinoma Reviewed

T Hanafusa, Y Yumoto, T Mimura, T Shinji, H Hada, N Koide, T Tsuji

HEPATO-GASTROENTEROLOGY 49 ( 44 ) 482 - 486 2002.3

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：H G E UPDATE MEDICAL PUBLISHING S A

Background/Aims: The genes responsible for hepatocellular carcinoma have not been identified. To identify the relevant genes of hepatocellular carcinoma, detailed and comprehensive information of genomic aberrations must be obtained. To reveal the chromosomal aberrations in hepatocellular carcinoma, we carried out a restriction landmark genome scanning analysis of various types of hepatocellular carcinoma.
Methodology: Samples of various types of hepatocellular carcinoma, including two with multinodular-hepatocellular carcinomas, one hepatocellular carcinoma showing nodules in a nodule pattern, one hepatocellular carcinoma metastasized to different tissues, three small (<2.0 cm) hepatocellular carcinomas and four large (>5.0 cm) hepatocellular carcinomas were examined by the restriction landmark genome scanning method with corresponding nonhepatocellular carcinoma tissues. Restriction enzyme (N) under bar(o) under bar(t) under bar I was used as a landmark enzyme, (E) under bar(c) under bar(o) under bar RV was used as a fragmentation enzyme, and (H) under bar(i) under bar(n) under bar fI was used as a digestion enzyme in the gel for two-dimensional electorophoresis.
Results: We observed spot aberrations with different origins. Frequently observed spot aberrations originated from the change in the methylation status of repetitive sequences. No clear correlation between the pathological grade and the number or type of spot aberrations was observed.
Conclusions: We demonstrated that major aberrations of restriction landmark genome scanning spots originated from the change of methylation status in hepatocellular carcinoma.

Serum gamma-interferon-inducing factor (IL-18) and IL-10 levels in patients with acute hepatitis and fulminant hepatic failure Reviewed

E Yumoto, T Higashi, K Nouso, H Nakatsukasa, K Fujiwara, T Hanafusa, Y Yumoto, T Tanimoto, M Kurimoto, N Tanaka, T Tsuji

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 17 ( 3 ) 285 - 294 2002.3

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING ASIA

Background and Aims: The aim was to determine the role of T-helper (Th)1/Th2 cytokine responses in the clinical outcome of patients with acute liver injury.
Methods: The serum levels of the cytokines, interleukin (IL)-18, gamma-interferon (IFN-gamma), IL-10 and IL-4 were measured in 20 fulminant hepatic failure (FHF), 18 acute hepatitis (AH), 30 chronic viral hepatitis and 20 liver cirrhosis (LC) patients. Thirteen cases were from the intensive care unit (ICU) and there were 21 healthy volunteers. Immunohistochemical staining of liver biopsies for IL-18 expression was also performed.
Results: Serum IL-18 levels in patients with FHF were significantly more elevated than in patients with other liver diseases, ICU cases and healthy volunteers. Furthermore, serum IFN-gamma levels in patients with FHF were also significantly higher than in patients with chronic viral hepatitis, LC and healthy volunteers. We found a positive correlation between the levels of IL-18 and IFN-gamma. However, no relationship was observed between these and clinical outcome. In immunohistochemical staining, CD68+ macrophage cells and IL-18-positive cells were observed in portal zones. Elevated serum IL-10 levels were restricted to patients presenting with FHF, and were significantly higher in surviving cases (P < 0.01). Furthermore, serum IL-10 levels, but not IL-4 levels, were inversely correlated with serum total bilirubin concentrations (P = 0.045) and the death rate (p) outlined in Japan (P = 0.030).
Conclusion: These results suggest that IL-18 and IFN-gamma are involved in the pathogenesis of acute hepatic injury in humans, and that, in particular, elevated serum levels of IL-10 may be predictive of improved outcomes for these patients. (C) 2002 Blackwell Science Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.2002.02690.x

Reduced expression of insulin-like growth factor binding protein-3 and its promoter hypermethylation in human hepatocellular carcinoma Reviewed

T Hanafusa, Y Yumoto, K Nouso, H Nakatsukasa, T Onishi, T Fujikawa, M Taniyama, S Nakamura, M Uemura, Y Takuma, E Yumoto, T Higashi, T Tsuji

CANCER LETTERS 176 ( 2 ) 149 - 158 2002.2

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Reduced expression Of the IGFBP-3 was observed in nine out of 12 human hepatocellular carcinomas (HCC) (75%). Promoter hypermethylation of the IGFBP-3 was detected in four out of 12 HCCs (33%) although mutations were not identified. The expression of IGFBP-3 was restored by the demethylating agent 5-aza-2'-deoxycytidine in HCC cell line with promoter hypermethylation (HepG2). As IGFBP-3 functions like a tumor suppressor gene, it may be used as a therapeutic target for HCC. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0304-3835(01)00736-4

Replication of hepatitis B virus which carries foreign DNA in vitro Reviewed

Tadashi Hanafusa, Yasuhiro Yumoto, Hajime Hada, Toshiyuki Shinji, Norio Koide, Takao Tsuji

Biochemical and Biophysical Research Communications 262 ( 2 ) 530 - 533 1999.8

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Academic Press Inc.

Targeting a specific DNA sequence to the desired tissues is an important step in gene therapy. The hepatitis B virus (HBV) is the only DNA virus that has hepatocyte specificity. We attempted to construct an HBV-based vector for targeting the liver. We observed the replication and secretion of virus particles in an HBV construct that lacks X gene and carries an extra 63 bp DNA fragment in vitro. Replication was observed in the cell line HuH-7 but not HepG2. From this construct, we designed an HBV-based vector that could carry foreign DNA. HBV based vectors provide for the possibilities of generating therapeutic agents for individual patients. Our host vector system may be used to clear out the HBV from the HBV carrier or chronic hepatitis B patients by introducing a genetically engineered HBV into these patients.

DOI： 10.1006/bbrc.1999.1224

Expression of the midkine gene in human hepatocellular carinomas. (jointly worked) Reviewed

Koide N, Hada H, Shinji T, Ujike K, Hirasaki S, Yumoto Y, Hanafusa T, Kadomatsu K, Muramatsu H, Muramatsu T, Tsuji T

Hepato-Gastroenterology 46 ( 30 ) 3189 - 3196 1999.4

Volume reduction by the incineration of the combustible radioactive solid samples from radioisotope usase at the utilization facility : Estimation of the distribution of low energy β emitter using the imaging plate. (jointly worked) Reviewed

Yumoto Y, Hanafusa T, Nagamatsu T, Okada S

Radioisotopes 48 ( 5 ) 320 - 326 1999.4

Language：English Publisher：Japan Radioisotope Association

We want to establish a system of volume reduction by the incineration of the combustible radioactive solid wastes from radioisotope usage at the utilization facility. We have been performing experiments using an experimental incineration system to examine the distribution of radionuclides during incineration and to collect basic data. To reproduce the realistic conditions of incineration of low-level radioactive wastes in an experimental system, we adopted new incineration methods in this study. Low level radioactive samples (LLRS) were set up in a mesh container of stainless steel and incinerated at high temperature (over 800°C) generated by two sets of high calorie gas burners. Low energy β-emitters ³⁵S, ⁴⁵Ca, ³³P, and a high energy β-emitter ³²P were used for the experiment. Their translocation percentages in exhaust air and dust were estimated using the Imaging Plate. Distribution of radionuclides during the incineration was similar to that estimated by conventional methods by our study or to that reported in incineration of liquid scintillation cocktail waste. We concluded that the use of the Imaging Plates is a simple and reliable method for estimation of the distribution of low energy β-emitters in incineration gas and ash.

DOI： 10.3769/radioisotopes.48.320

Other Link： https://jlc.jst.go.jp/DN/JALC/00060829443?from=CiNii

Point mutations in the S and pre-S2 senes observed in two hepatitis B virus carriers positive for antibody to hepatitis B surface antigen. (jointly worked) Reviewed

Shinji T, Koide N, Hanafusa T, Hada H, Oka T, Takayama N, Shiraha H, Nakamura M, Ujike K,Yumoto Y, Tsuji T

Hepato Gastroenterology 45 ( 20 ) 500 - 502 1998.4

Reciprocal Gene Expression of Rat Fibro glycan and β-actin during the coruse of Regeneration after-D-Galactosamine Liver Injury (jointly worked) Reviewed

Shinji T, Koide H, Hada H, Sasaki S, Oka T, Takayama N, Shiraha H, Ujike K, Nakamura M, Hanafusa T, Yumoto Y, Tsuji T

Hepato・Gastroenterdogy 44 239 1997.4

Setting up Experimental Incineration System for Low-level Radioactive Samples and Combustion Experiments. Reviewed

YUMOTO Yasuhiro, HANAFUSA Tadashi, NAGAMATSU Tomohiro, OKADA Shigeru

RADIOISOTOPES 46 ( 7 ) 443 - 449 1997

Language：Japanese Publisher：Japan Radioisotope Association

An incineration system was constructed which were composed of a combustion furnace (AP-150R), a cyclone dust collector, radioisotope trapping and measurement apparatus and a radioisotope storage room built in the first basement of the Radioisotope Center.<BR>Low level radioactive samples (LLRS) used for the combustion experiment were composed of combustible material or semi-combustible material containing 500 kBq of ^99mTcO₄ or 23.25 kBq of ¹³¹INa. The distribution of radioisotopes both in the inside and outside of combustion furnace were estimated. We measured radioactivity of a smoke duct gas in terminal exit of the exhaust port. In case of combustion of LLRS containing ^99mTcO₄ or ¹³¹INa, concentration of radioisotopes at the exhaust port showed less than legal concentration limit of these radioisotopes. In cases of combustion of LLRS containing ^99mTcO₄ or ¹³¹INa, decontamination factors of the incineration system were 120 and 1.1, respectively.

DOI： 10.3769/radioisotopes.46.443

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