Faculty Profiles - FUJII Nobuharu

Serum cytokine concentrations and acute graft-versus-host disease after allogeneic peripheral blood stem cell transplantation: Concurrent measurement of ten cytokines and their respective ratios using cytometric bead array Reviewed

Other Link： http://orcid.org/0000-0003-0995-9405

N Fujii, A Hiraki, K Aoe, T Murakami, K Ikeda, K Masuda, K Matsuo, K Shinagawa, F Ishimaru, K Sugi, Z Darzynkiewicz, M Tanimoto

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 17 ( 5 ) 881 - 885 2006.5

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

Both inflammatory and anti-inflammatory cytokines have been reported to be associated with acute graft-versus-host disease (aGVHD). However, their role and possible mutual interactions during aGVHD are not well understood. Eight patients with aGVHD and eight without who had undergone allogeneic HLA-identical peripheral blood stem cell transplantation were studied. The patients had no other complications known to affect serum concentration of cytokines, including infection. Serum concentrations of IL-1B, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha and IFN-gamma were concurrently measured by a new technique, the cytometric bead array (CBA). We found that serum concentrations of IL-5, IL-6 and IL-10 were significantly higher in patients with aGVHD than in patients without it. By ratiometric analysis, the ratios of IL-5/IL-2, IL-5/IL-4, IL-6/IL-4 in patients with aGVHD were increased compared to the patients with no evidence of aGVHD. ROC analysis demonstrated that the ratio of IL-5/IL-4 was the most sensitive parameter associated with aGVHD. The second best marker of aGVHD was increased IL-5 concentration. Thus, our results indicate that the ratio of a particular cytokine/cytokine could be a potential diagnostic marker for aGVHD, more sensitive that the serum level of a given cytokine. This observation is consistent with a cross-talk among some cytokines and their possible interactions via respective receptors on cytokine-producing cells; these interactions may play an important role in pathogenesis of aGVHD. Further studies including a large number of patients and concurrent measurement of a variety of cytokines are needed to fully assess the diagnostic value of the cytokine ratiometric analysis. The CBA methodology provides a convenient and useful tool in such studies.

Activated human umbilical cord blood dendritic cells kill tumor cells without damaging normal hematological progenitor cells Reviewed

Other Link： http://orcid.org/0000-0003-1761-6314

J Shi, K Ikeda, N Fujii, E Kondo, K Shinagawa, F Ishimaru, K Kaneda, M Tanimoto, Li, X, Q Pu

CANCER SCIENCE 96 ( 2 ) 127 - 133 2005.2

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

Apart from their role as antigen presenting cells, human peripheral blood monocyte and CD34+ cell-derived dendritic cells (DC), have been demonstrated to exert cytotoxicity against some tumor cells, and their tumoricidal activity can be enhanced by some stimili. However, there have been no reports concerning the tumoricidal activity of human cord blood dendritic cells (CBDC). In this article, we report that human cord blood monocyte-derived DC acquire the ability to kill hematological tumor cells, after activation with lipopolysaccharicle (LIPS) or gamma-interferon (IFN-gamma), associated with the enhanced TNF-alpha-related apoptosis-inducing ligand (TRAIL) expression in CBDC cytoplasm. The CD14-positive cells collected from cord blood were induced to CBDC in vitro. After activation with IFN-gamma for 12 h, CBDC exhibited cytotoxicity against HL60 and Jurkat cells, while activation with LPS induced cytotoxicity against Daudi and Jurkat cells. However, both LPS- and IFN-gamma-stimulatecl CBDC showed no cytotoxic activity against normal CD14-negative cord blood mononuclear cells. The formation of umbilical cord hematopoietic progenitor colonies, identified as burst-forming unit-erythroid and colony-forming unit granulocyte-macrophage, was not inhibited by stimulated or unstimulated CBDC. IFN-gamma or LPS stimulation enhanced intracellular but not cellular surface TRAIL, and neither intracellular nor cellular surface tumor necrosing factor-alpha and Fas Ligand as analyzed by flow cytometry. Our results show that activated CBDC can serve as cytotoxic cells against hematological tumor cells without damaging the normal hematopoietic progenitor cells.

DOI： 10.1111/j.1349-7006.2005.00017.x

Other Link： http://orcid.org/0000-0003-0995-9405

Expression of SOCS3 mRNA in bone marrow cells from CML patients associated with cytogenetic response to IFN-alpha. Reviewed International journal

Kazuto Takeuchi, Ikuya Sakai, Hirosi Narumi, Masaki Yasukawa, Kensuke Kojima, Yoko Minamoto, Tomoaki Fujisaki, Kazushi Tanimoto, Masamichi Hara, Akihiko Numata, Hisashi Gondo, Masuhiro Takahashi, Nobuharu Fujii, Kozo Masuda, Shigeru Fujita

Leukemia research 29 ( 2 ) 173 - 8 2005.2

Language：English Publishing type：Research paper (scientific journal)

Previously, we have demonstrated that constitutive expression of suppressor of cytokine signaling-3 (SOCS3) affects the sensitivity of chronic myelogenous leukemia (CML) cell lines to interferon-alpha (IFN-alpha). In the present study, we analyzed the expression of SOCS3 mRNA in bone marrow cells from patients with CML at diagnosis, with the aid of real-time polymerase chain reaction. SOCS3 mRNA expression in bone marrow cells from CML patients who responded well to IFN-alpha therapy was significantly lower than that in cells from healthy volunteers and patients who were resistant to IFN-alpha therapy. Methylation of SOCS3 promoter was absent in bone marrow cells from all CML patients examined. These results indicate that the expression of SOCS3 mRNA is inversely associated with the sensitivity to IFN-alpha both in vitro and in vivo and that differences in SOCS3 mRNA expression are not due to the methylation status of SOCS3 promoters.

High frequency of allele-specific rown-regulation of HLA class I expression in lung cancer cell lines Reviewed

Akio Hiraki, Nobuharu Fujii, Tomoyuki Murakami, Katsuyuki Kiura, Keisuke Aoe, Hiromichi Yamane, Kozo Masuda, Tadashi Maeda, Kazuro Sugi, Zbigniew Darzynkiewicz, Mitsune Tanimoto, Mine Harada

Anticancer Research 24 ( 3 A ) 1525 - 1528 2004.5

Language：English Publishing type：Research paper (scientific journal)

Loss or down-regulation of HLA expression has been demonstrated in various types of solid tumors and is considered to be one of the mechanisms of tumor immunoescape. The effectiveness of immunotherapy using tumor-specific antigens (TSA) largely depends on the expression of the appropriate HLA class I alleles on the tumor cells. We analyzed the allele-specific HLA class I surface expression of six lung cancer cell lines using a broad panel of allele-specific monoclonal antibodies, as well as the effect of IFN-γ on HLA expression. Flow cytometric analysis displayed a wide range, from minimal to a high degree of expression of monomorphic HLA class I among the studied cell lines. Allele-specific loss or down-regulation of HLA also was observed in 5 out of 6 cell lines. Our results suggest that lung cancer patients considered for specific immunotherapy should be examined with respect to the expression of specific HLA class I allele binding the TSA.

好中球減少時の発熱に対するCefozopranの有効性に関する検討.

齋藤崇、原雅道、品川克至、名和由一郎、中瀬浩一、竹内誠、宮田明、福田俊一、角南一貴、今城健二、矢野朋文、小島研介、豊嶋崇徳、藤井伸治、石丸文彦、池田和真、原田実根、谷本光音

癌と化学療法 2004.4

Peripheral blood circulating immature cell counts predict CD34+ cell yields in G-CSF-induced PBPC mobilization in healthy donors

Kozuka T, Ikeda K, Teshima T, Yoshida C, Shinagawa K, Kojima K, Matsuo K, Bessho A, Sunami K, Hiramatsu Y, Maeda Y, Noguchi T, Yamamoto K, Fujii N, Imai T, et.al

Transfusion 2004.4

FLJ10849, a septin family gene, fuses MLL in a novel leukemia cell line CNLBC1 derived from chronic neutrophilic leukemia in transformation with t(4;11)(q21;q23) Reviewed

KOJIMA K

Leukemia 18 998 - 1005 2004.4

Peripheral blood circulating immature cell counts predict CD34+ cell yields in G-CSF-induced PBPC mobilization in healthy donors. Reviewed International journal

Teruhiko Kozuka, Kazuma Ikeda, Takanori Teshima, Chikamasa Yoshida, Katsuji Shinagawa, Kensuke Kojima, Keitaro Matsuo, Akihiro Bessho, Kazutaka Sunami, Yasushi Hiramatsu, Yoshinobu Maeda, Toshio Noguchi, Kazuhiko Yamamoto, Nobuharu Fujii, Toshi Imai, Kinuyo Kaneda Kusumoto, Kozo Masuda, Katsuto Takenaka, Fumihiko Ishimaru, Kenji Niiya, Norio Koide, Mitsune Tanimoto, Mine Harada

Transfusion 44 ( 4 ) 526 - 32 2004.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: It has been previously reported that the number of circulating immature cells (CIC) in peripheral blood (PB) estimates the number of CD34+ cells collected in G-CSF plus chemotherapy-induced PBPC mobilization. The correlation of CIC counts in PB with CD34+ cell yield and its usefulness was evaluated in G-CSF-induced PBPC mobilization for healthy donors. STUDY DESIGN AND METHODS: CIC counts in PB and CD34+ cell counts in the apheresis product from 122 collections were assessed, and the relationship between these two variables was evaluated with the Pearson rank correlation analysis, the chi-squared test, and the U-test. RESULTS: CIC counts were correlated weakly with the number of CD34+ cells per L of blood processed in the apheresis product (Pearson rank correlation analysis; r=0.357, p<0.0001). When a level of 1.7 x 10(9) CICs per L was selected as a cutoff value, the sensitivity and specificity for collecting more than 20 x 10(6) CD34+ cells per L of blood processed were 63.6 and 77.5 percent, respectively. CONCLUSION: The present study suggests that the number of CICs in PB may estimate the number of CD34+ cells collected. The data indicate that CIC counts above 1.7 x 10(9) per L can be used as a good predictor for PBPC collections containing more than 20 x 10(6) CD34+ cells per L of blood processed in a single apheresis procedure.

[Clinical evaluation of cefozopran as treatment for febrile neutropenia].

Takashi Saito, Masamichi Hara, Katsuji Shinagawa, Yuichiro Nawa, Koichi Nakase, Makoto Takeuchi, Akira Miyata, Shunnichi Fukuda, Kazutaka Sunami, Kenji Imajoh, Tomofumi Yano, Kensuke Kojima, Takanori Teshima, Nobuharu Fujii, Fumihiko Ishimaru, Kazuma Ikeda, Mine Harada, Mitsune Tanimoto

Gan to kagaku ryoho. Cancer & chemotherapy 31 ( 1 ) 61 - 5 2004.1

Language：Japanese Publishing type：Research paper (scientific journal)

Clinical effects and safety of cefozopran (CZOP) were evaluated by the Okayama Bone Marrow Transplantation Group. Twenty-five patients expected to experience febrile neutropenia during induction chemotherapy or consolidation chemotherapy of acute leukemia were enrolled between July 2000 and November 2002. CZOP was administrated by drip infusion at 4g/day bid for a minimum of 3 days. The clinical effects and safety were evaluated in 20 patients with fever of 37.5 degrees C or more from a clinically suspected infection. The underlying disease was acute myeloid leukemia in 17 patients, acute lymphoid leukemia in 1 and acute promyelogeneous leukemia in 1. The complicating infections were sepsis and suspected sepsis. Clinical efficacy was excellent in 11 patients, good in 1, fair in 2 and poor in 6, with an efficacy rate of 60.0%. The efficacy rate in patients whose albumin levels before therapy were less than 3.8 g/dl was 37.5%, whereas the rate in patients whose albumin levels before therapy were between 3.8 g/dl and 5.3 g/dl was 80.0%. The efficacy rate in patients whose neutrophil counts before therapy were less than 100/microliter was 50.0%, whereas the rate in patients whose neutrophil counts after therapy were less than 100/microliter was 53.8%. The efficacy rate in patients whose neutrophil counts both before and after therapy were less than 100/microliter was 37.5%. Side effect of exanthema was observed in 1 patient. These results indicate that CZOP is an effective and safe antibiotic for the treatment of febrile neutropenia in patients with hematological malignancies.

Cyclic thrombocytopenia and polycythemia vera

KOJIMA K

Ann Hematol. 82 61 - 63 2003.4

Plasma stromal cell-derived factor-1 during granulocyte colony-stimulating factor-induced peripheral blood stem cell mobilization.

Kozuka T, Ishimaru F, Fujii K, Masuda K, Kaneda K, Imai T, Fujii N, Ishikura H, Hongo S, Watanabe T, Shinagawa K, Ikeda K, Niiya K, Harada M, Tanimoto M

Bone Marrow Transplant 2003.4

Human herpes virus-8-negative primary effusion lymphoma in a patient with common variable immunodeficiency.

Hisamoto A, Yamane H, Hiraki A, Maeda Y, Fujii N, Sasaki K, Miyake T, Sasaki T, Nakamura T, Kiura K, Tanimoto M, Kamei H

Leuk Lymphoma 2003.4

成人B細胞性急性リンパ性白血病(ALL L3)における長期予後の改善.

石丸文彦, 近藤英生, 藤井伸治, 豊嶋崇徳, 品川克至, 池田和眞, 谷本光音

内科専門医会誌 2003.4

Potential limitations in using minor histocompatibility antigen-specific cytotoxic T cells for targeting solid tumor cells

MIYAZAKI M

Clin Immunol. 107 198 - 201 2003.4

Successful treatment with cyclosporin A of myelodysplastic syndrome with erythroid hypoplasia associated with t(6;8) (q15;q22)

TAKATA S

Cancer Genet Cytogenet 140 167 - 169 2003.4

A novel fusion variant of the MORF and CBP genes detected in therapy-related myelodysplastic syndrome with t(10;16)(q22;p13) Reviewed

K Kojima, K Kaneda, C Yoshida, H Dansako, N Fujii, T Yano, K Shinagawa, M Yasukawa, S Fujita, M Tanimoto

BRITISH JOURNAL OF HAEMATOLOGY 120 ( 2 ) 271 - 273 2003.1

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

We report a case of therapy-related myelodysplastic syndrome (t-MDS) with t(10;16)(q22;p13), in which novel fusion transcripts of the MORF and CBP genes were detected. In one MORF-CBP fusion transcript, exon 15 of the MORF gene was fused in frame with exon 5 of the CBP gene. In a reciprocal CBP-MORF transcript, exon 4 of the CBP gene was fused in frame with exon 16 of the MORF gene. This is the first reported case of t-MDS associated with t(10;16), and provides molecular evidence that the novel MORF-CBP and/or CBP-MORF fusion protein(s) might play an important role in the development of t-MDS.

Predictive value of circulating immature cell counts in peripheral blood for timing of peripheral blood progenitor cell collection after G-CSF plus chemotherapy-induced mobilization Reviewed

T Kozuka, K Ikeda, T Teshima, K Kojima, K Matsuo, A Bessho, K Sunami, Y Hiramatsu, Y Maeda, T Noguchi, K Yamamoto, N Fujii, T Imai, K Takenaka, K Shinagawa, F Ishimaru, K Niiya, N Koide, M Tanimoto, M Harada

TRANSFUSION 42 ( 11 ) 1514 - 1522 2002.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC BLOOD BANKS

Background: Enumeration of CD34+ cells in peripheral blood (PB) before apheresis predicts the number of CD34+ cells collected, although flow cytometric techniques used are complex and expensive. In an attempt to determine the optimal timing for peripheral blood progenitor cell (PBPC) collection, the usefulness of circulating immature cell (CIC) counts in PB was evaluated.
Study design and methods: CIC counts in PB and CD34+ cell counts in the apheresis product from 249 collections were assessed, and the relationship between these two parameters was evaluated by with the Pearson rank correlation analysis, the Fisher exact test, and the U-test.
Results: CIC counts were correlated significantly with the number of CD34+ cells per kg of patient's body weight in the apheresis product (Pearson rank correlation analysis: r=0.635, p<0.0001). When a level of 1x10(9) CICs per L was selected as a cutoff value, the sensitivity and specificity for collecting more than 1x10(6) CD34+ cells per kg of body weight were 75.7 and 85.5 percent, respectively.
Conclusion: The present study strongly suggests that the number of CICs in PB may estimate the number of CD34+ cells collected. The data indicate that CIC counts above 1x10(9) per L can be used as a good predictor for PBPC collections containing more than 1x10(6) CD34+ cells per kg of body weight in a single apheresis procedure.

Other Link： http://orcid.org/0000-0003-1761-6314

Tandem high-dose chemotherapy supported by autologous peripheral blood stem cell transplantation for recurrent soft tissue sarcoma Reviewed

Teruhiko Kozuka, Katsuyuki Kiura, Hideki Katayama, Nobuharu Fujii, Fumihiko Ishimaru, Kazuma Ikeda, Hiroshi Ueoka, Shuuji Hamasaki, Tadashi Yoshino, Yoshio Kashihara, Hiroshi Date, Mitsune Tanimoto, Mine Harada

Anticancer Research 22 ( 5 ) 2939 - 2944 2002.9

Language：English Publishing type：Research paper (scientific journal)

Background: Patients with recurrent soft tissue sarcoma (STS) are seldom curable, with 5-year survival rates of less than 10% in all large series. The role of high-dose chemotherapy (HDC) with hematopoietic stem cell support in this disease has not been established. Case Report: We report on two patients with recurrent STS who were treated with tandem HDC supported by autologous peripheral blood stem cell transplantation (PBSCT). One patient with malignant fibrous histiocytoma recurred with multiple lung metastases. This patient achieved a partial response after two cycles of induction chemotherapy consisting of ifosfamide and epirubicin. During four cycles of induction chemotherapy, peripheral blood stem cells (PBSCs) were harvested. Tandem high-dose ICE regimen (ifosfamide 3 g/m2 on days - 7 to - 3, carboplatin 400 mg/m2 on days - 7, - 5 and 3, etoposide 500 mg/m2 on days - 7, - 5 and 3) supported by autologous PBSCT gave rise to further regression of the tumors. Another patient with malignant hemangiopericytoma was treated by tandem high-dose ICE regimen supported by autologous PBSCT after the 3rd removal of abdominal tumors. Relapse-free intervals until the 1st, 2nd and 3rd relapses were 40, 19 and 22 months, respectively. Tandem high-dose ICE regimen might delay the relapse. Conclusion: These observations suggest that a tandem high-dose ICE regimen with autologous PBSCT is feasible with some clinical efficacy in the control of refractory STS.