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ABSTRACT: A 41-year-old Japanese man complained of a left-sided visual disturbance. Imaging by magnetic resonance angiography revealed A 41-year-old Japanese man complained of a left-sided visual disturbance. Imaging by magnetic resonance angiography revealed
a narrowing of the left internal cervical artery. Thus, ticlopidine (Tc) administration was started at a daily dose of 300 a narrowing of the left internal cervical artery. Thus, ticlopidine (Tc) administration was started at a daily dose of 300
mg. However, 2 weeks later, severe thrombocytopenia, fever, nausea, and psychiatric symptoms developed; Tc was therefore discontinued. mg. However, 2 weeks later, severe thrombocytopenia, fever, nausea, and psychiatric symptoms developed; Tc was therefore discontinued.
Based on the diagnostic hallmark of 5 clinical signs, the patient’s disease was diagnosed as thrombotic thrombocytopenic purpura Based on the diagnostic hallmark of 5 clinical signs, the patient’s disease was diagnosed as thrombotic thrombocytopenic purpura
(TTP). Daily plasmapheresis was performed for the first 4 days, and the patient’s clinical signs gradually improved. Von Willebrand (TTP). Daily plasmapheresis was performed for the first 4 days, and the patient’s clinical signs gradually improved. Von Willebrand
factor-cleaving protease (vWF-CPase) activity in his plasma was less than 3% of that of the control sample at diagnosis, butthe control sample at diagnosis, but
that value recovered steadily following plasmapheresis. In addition, immunoglobulin G purified from the patient plasma inhibited that value recovered steadily following plasmapheresis. In addition, immunoglobulin G purified from the patient plasma inhibited
vWF-CPase activity in normal plasma with a specific activity of 0.8 Bethesda units/mg. No sign of TTP relapse has been noted vWF-CPase activity in normal plasma with a specific activity of 0.8 Bethesda units/mg. No sign of TTP relapse has been noted
following cessation of Tc. Thus, it was concluded that the patient developed TTP by producing an inhibitory autoantibody against following cessation of Tc. Thus, it was concluded that the patient developed TTP by producing an inhibitory autoantibody against
vWF-CPase activity that was presumably triggered by Tc administration. vWF-CPase activity that was presumably triggered by Tc administration.
International Journal of Hematology 04/2012; 74(3):347-351. · 1.27 Impact Factor
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ABSTRACT: We retrospectively analyzed 336 patients with primary chronic myelofibrosis from 203 medical institutes in Japan. Notwithstanding
their heterogeneous treatments, the median survival in 298 patients that could be evaluated was 10.0 years. Average age at
onset was 60.7 years. Men were affected 1.4 times more frequently than women. The factors associated with shorter survival
included anemia, leukocytosis/leukocytopenia, thrombocytopenia, and increased blasts in the peripheral blood, and sex (male),
age (>60), and the presence of symptoms. A new scoring system based on the peripheral blood findings (hemoglobin [Hb] level,
platelet count, and rate of blast formation) at initial diagnosis clearly correlated with survival rate. Accordingly, patients
could be categorized into 3 groups by severity grading. Through stepwise multivariate survival analysis, the significant prognostic
factors were identified as the severity grading based on the new scoring system (P = .0002), age (P = .0024), sex (P = .0153), and Hb (P = .0198). Chromosomal abnormalities were found in 58 of 154 patients (38%), although these did not influence survival.
International Journal of Hematology 04/2012; 73(2):194-198. · 1.27 Impact Factor
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Tomonori Hidaka,
Kotaro Shide,
Haruko Shimoda,
Takurou Kameda,
Keiko Toyama,
Keiko Katayose,
Youko Kubuki,
Kenji Nagata,
Katsuto Takenaka,
Koichi Akashi,
Takashi Okamura, Yoshiyuki Niho,
Hideaki Mizoguchi,
Mitsuhiro Omine,
Keiya Ozawa,
Mine Harada,
Kazuya Shimoda
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ABSTRACT: Cytogenetic abnormalities were often observed in primary myelofibrosis patients. The presence of specific cytogenetic abnormalities, such as sole abnormalities of chromosome 13q-, 20q-, or -7/7q-, is reported to have the influence on the prognosis of primary myelofibrosis. We analyzed the data from the prospective survey of Japanese primary myelofibrosis patients which was conducted from 1999 to clarify the impact of cytogenetic abnormalities on the prognosis of primary myelofibrosis. A total of 202 primary myelofibrosis patients had the cytogenetic and the prognostic data. Eighty (40%) out of 202 cases had cytogenetic abnormalities, and an association was evident for platelet counts. Although the presence of an abnormal karyotype did not affect the prognosis, primary myelofibrosis patients with cytogenetic abnormalities other than 13q- and 20q- showed an inferior prognosis compared to patients with a normal karyotype or sole 13q- or 20q- abnormalities. Patients with an unfavorable cytogenetic profile (abnormal cytogenetics other than 13q- or 20q-) also had a greater tendency to transform to leukemia than patients with a favorable cytogenetic profile (normal cytogenetics, sole abnormalities of either chromosome 13q-, or 20q-). Abnormal cytogenetics other than 13q- or 20q- in primary myelofibrosis patients has the poor prognostic effect for both survival and the risk of leukemic transformation.
European Journal Of Haematology 07/2009; 83(4):328-33. · 2.61 Impact Factor
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ABSTRACT: We investigated the expression of an apoptosis associated antigen (Fas) (CD95) on hematopoietic progenitor cells. Freshly isolated CD34+ cells from bone marrow did not express Fas. However, interferon-γ (IFN-γ) and/or tumor necrosis factor-α (TNF-α) induced dose-dependent expression of both Fas mRNA and Fas protein on the surface of CD34+ cells after 48 hours of serum-free culture. TNF-α-induced Fas expression was mediated by p55-TNF-α receptor. Induced Fas was functional as it could transduce apoptotic signals in response to anti-Fas monoclonal antibody (MoAb). The Fas-defective pr mice are reported to have abnormally radio-resistant hematopoietic stem cells. Consequently, we also investigated the relation between Fas and ionizing radiation. Human CD34+ cells expressed Fas following low-dose ionizing radiation in a dose-dependent fashion. Fas induced on CD34+ cells mediated apoptosis in response to anti-Fas MoAb. We evaluated the expression of Fas and Bcl-2 on CD34+ hematopoietic progenitor cells expanded in vitro. CD34+ cells isolated from bone marrow were cultured with hematopoietic growth factors for 7 days. Approximately half of the freshly isolated CD34+ cells expressed Bcl-2. CD34+ cells cultured with hematopoietic growth factors gradually became positive for Fas and rapidly lost Bcl-2 expression. Furthermore, apoptosis was induced in the cultured CD34+ population in response to anti-Fas MoAb. Thus, functional Fas can be induced on hematopoietic progenitor cells in vitro by negative hematopoietic regulators, ionizing radiation, as well as positive hematopoietic regulators. The Fas system is thought to play an important role at the level of hematopoietic progenitor cells in both physiologic and pathologic conditions.
06/2009; 24(1-2):43-56.
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ABSTRACT: Thymosin β4 (Tβ4) was originally isolated as a thymic hormone from calf thymosin fraction 5 which exhibited both immune and endocrine functions in vivo and in vitro. Tβ4 is a ubiquitous peptide located in various tissues of mammalian species and other vertebrate classes. Recent studies on the molecular cloning and sequence analysis of rat and human Tβ4 cDNA have demonstrated that Tβ4 lacks a signal peptide which makes it unlikely that Tβ4 is a secretory peptide. The real function of Tβ4 is presently unknown, however, we focus this review on the molecular biology of Tβ4 with a special reference to the aspects of the Tβ4 gene expression in leukemic cells and cell lines during growth and differentiation.
06/2009; 6(1):7-14.
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ABSTRACT: We differentially screened 5,000 clones from a cDNA library of acute myelogenous leukemia (AML) cell line HL60 using cDNA probes derived from normal granulocytes or from acute myelomonocytic leukemia cells, the objective being to identify genes preferentially expressed in myeloid lineage leukemic cells. One clone, corresponding to a mitochondrial DNA fragment, including NADH dehydrogenase subunit 2 (ND2) gene, was selected for use as a probe. We examined expression of the ND2 gene in various leukemic cell populations and in normal peripheral blood cells. DNA-RNA hybridization studies revealed that ND2 messenger RNA (mRNA) was more markedly expressed in AML cells than in other leukemic cells and normal peripheral blood granulocytes. The expression of ND2 mRNA decreased in HL60 cells several hours after treatment with phorbol myristate acetate (PMA), or dimethyl sulfoxide (DMSO). However, the ND2 gene expression did not depend on the growth-state of HL60 cells because the steady-state level of its expression was observed during transitions of growth. These results suggest that ND2 mRNA is involved in the maturation of myeloid cells and in cellular differentiation, in a lineage-preferential manner. A comparison of the nucleotide sequence of this clone with the documented human mitochondrial DNA sequence revealed several single-base substitutions, insertions and a 39-bases insertion.
06/2009; 5(5-6):397-406.
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ABSTRACT: The proto-oncogene c-kit encodes the receptor for a stem cell factor (c-kit molecule). Expression of the c-kit molecule on the gated leukemic blast cells from newly diagnosed patients with leukemia was analysed by flow cytometry using the monoclonal antibody (17F11). Among 35 myeloid leukemia cases examined, significant c-kit-positive blast cells were detected in 24 cases (69%), even though the percentage of positive cells was widely variable. The correlation between the percentage of cells positive for the c-kit molecule and the percentage of cells positive for CD34 was found to be statistically significant (rs = 0.36, p < 0.05). Fifteen cases of myeloid leukemia were positive for lymphoid markers. The mean percentage of the cells expressing c-kit molecule among the lymphoid marker-positive cases was significantly larger than that among the lymphoid marker-negative cases (p < 0.05). All 19 lymphoid leukemia cases were c-kit-negative, including 8 cases which were positive for some myeloid markers. Stem cell factor enhanced the colony growth in five out of six acute myeloblasts leukemia cases expressing the c-kit molecule. On the other hand, SCF did not stimulate colony growth in any of the four cases which were not positive for the c-kit molecule. These findings indicated that the distribution of flow cytometrically detectable c-kit molecules on leukemic cells is related to the morphologic and immunologic classification of these leukemic cells and to the expression of the CD34 cell surface molecule on some myeloid leukemic cells. On such cells, expression of the c-kit molecule may have a functional role and be related to the maturation process.
06/2009; 14(5-6):421-428.
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Koichi Akashi,
Shin Hayashi,
Hisashi Gondo,
Shin-ichi Mizuno,
Mine Harada,
Kazuo Tamura,
Kazuo Yamasaki,
Tsunefumi Shibuya,
Naokuni Uike,
Takashi Okamura,
Toshihiro Miyamoto, Yoshiyuki Niho
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ABSTRACT: Summary We investigated the role of monocyte/macrophage-activating cytokines in pathogenesis of haemophagocytic lymphohistiocytosis (HLH) in 21 adult patients. Sera from patients with active HLH contained extremely high levels of macrophage colony-stimulating factor (M-CSF) and of interferon-γ (IFN-γ). These levels returned to almost normal during remission. Neither interleukin-4 nor granulocyte/macrophage colony-stimulating factor could be detected. Active HLH sera also contained high concentrations of inflammatory monokines, such as interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). Serum concentrations of soluble CD8 and soluble interleukin-2 receptor were extremely high during active HLH, and returned to virtually normal levels during remission. Circulating CD2+ T-cells obtained from patients with active HLH spontaneously secreted M-CSF and IFN-γin vitro, whereas circulating monocytes did not produce detectable levels of both M-CSF and IFN-γ, but produced high levels of IL-6 and TNF-α. These findings suggest that IFN-γ and M-CSF at least partly from T-cells, such as CD8+ T-cells, might contribute to activation of monocytes or histiocytes, resulting in the up-regulated monokine production and haemophago-cytosis in HLH.
British Journal of Haematology 03/2008; 87(2):243 - 250. · 4.94 Impact Factor
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Hisashi Gondo,
Toshio Minematsu,
Mine Harada,
Koichi Akashi,
Shin Hayashi,
Shuichi Taniguchi,
Kazuo Yamasaki,
Tsunefumi Shibuya,
Yasushi Takamatsu,
Takanori Teshima,
Tetsuya Eto,
Koji Nagafuji,
Shin-ichi Mizuno,
Kenji Hosoda,
Ryoichi Mori,
Yoichi Minamishima, Yoshiyuki Niho
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ABSTRACT: A technique for the rapid detection of cytomegalovirus (CMV) antigen-positive blood leucocytes (CMV antigenaemia) was evaluated in 15 marrow transplant patients as a means of diagnosis and for monitoring CMV-associated disease. CMV antigenaemia was determined by direct immunoperoxidase staining of leucocytes with a peroxidase-labelled monoclonal antibody, HRP-C7, which binds an immediate-early antigen of human CMV.CMV antigenaemia occurred in 7/15 marrow transplant patients (47%) and was initially detected between 4 and 6 weeks after transplantation. CMV-associated diseases developed in 3/15 patients (20%). All patients with CMV-associated disease had a relatively large number of CMV antigen-positive leucocytes, exceeding 10 per 50000 white blood cells (WBCs). In the remaining 12 patients, CMV antigen-positive leucocytes were less than 10 per 50000 WBCs or were undetectable. CMV-associated disease did not develop in these patients during the period of monitoring. CMV antigen-positive leucocytes were detected more frequently in patients who developed acute graft-versus-host disease (GVHD) or haemorrhagic cystitis than in those without such complications. CMV antigens were detectable from 1 to 4 weeks before the onset of CMV-associated disease which allowed initiation of ganciclovir treatment at an early stage. The degree of CMV antigenaemia paralleled the clinical symptoms and signs, higher degrees of antigenaemia being associated with more significant disease. Thus, the detection of CMV antigen-positive blood leucocytes is useful for the diagnosis and monitoring of CMV-associated disease following bone marrow transplantation.
British Journal of Haematology 03/2008; 86(1):130 - 137. · 4.94 Impact Factor
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Etsushi Kounoue,
Ken-ichi Izumi,
Shuichiro Ogawa,
Shiori Kondo,
Hitoshi Katsuta,
Tomoyuki Akashi, Yoshiyuki Niho,
Mine Harada,
Sadafumi Tamiya,
Hironori Kurisaki,
Seiho Nagafuchi
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ABSTRACT: In order to clarify the significance of protective mechanisms against encephalomyocarditis (EMC) virus-induced diabetes in mice, we studied the relative importance of T cells, B cells, antibodies and macrophages in the prevention of virus-induced diabetes. Neither T cell-deficient athymic nude mice nor B cell-deficient microMT/microMT mice showed an enhanced clinical course of EMC-D virus-induced diabetes, indicating that neither T cells nor B cells played a major role in the protection against EMC-D-virus-induced diabetes. Transfer of a large amount of antiserum to EMC-D-virus-infected mice protected the development of diabetes only when transferred within 36 h of infection, the timing of which was earlier than that for the production of natural neutralizing antibodied. Since pretreatment of mice with the macrophage-activating immunopotentiator Corynebacterium parvum (CP) completely prevented the development of diabetes, we studied the clinical outcome of EMC-D-virus-infected mice pretreated with CP. Mice treated with CP showed reduced proliferation of EMC-D virus in the affected organs, including the pancreas, while the levels of development of neutralizing antibody and serum interferon were not enhanced compared with the controls. Finally, we studied the macrophages derived from mice pretreated with CP and found that they inhibited the growth of EMC-D virus in vitro more than those derived from non-treated and thioglycolate-treated mice. Taken together, it can be suggested that neither T cells nor B cells, which have to do with adaptive immunity, play a significant role in the pathogenesis of EMC-D-virus-induced diabetes, while innate immunity, which is dependent on activated macrophages, contributes to in vivo resistance against EMC-D-virus-induced diabetes.
Archives of Virology 02/2008; 153(7):1223-31. · 2.11 Impact Factor
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Kazuya Shimoda,
Kotaro Shide,
Kenjirou Kamezaki,
Takashi Okamura,
Naoki Harada,
Naoko Kinukawa,
Kazuma Ohyashiki, Yoshiyuki Niho,
Hideaki Mizoguchi,
Mitsuhiro Omine,
Keiya Ozawa,
Mine Haradaa
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ABSTRACT: Between 1999 and 2005, 285 patients received new diagnoses of myelofibrosis with myeloid metaplasia (MMM) in Japan. Anemic symptoms were present in 162 patients, and hemoglobin (Hb) concentrations were <10 g/dL in 197 patients. Fifty-five MMM patients were treated with anabolic steroids, and their effect on anemia during MMM was evaluated in 39 patients. A "good" response was defined as an Hb increase of >or=1.5 g/dL, cessation of transfusion dependence, and an Hb concentration of >10 g/dL maintained for at least 8 weeks. A "minimum" response was defined as an Hb increase of >or=1.5 g/dL and transfusion independence for at least 8 weeks. Both good and minimum responses were considered "favorable." Favorable responses were achieved in 17 patients (44%, 8 good and 9 minimum responses). None of the pretreatment variables, such as the lack of transfusion dependence, a higher Hb concentration at the start of treatment, or the absence of cytogenetic abnormalities, were associated with a response to anabolic steroid therapy. Adverse events associated with anabolic steroid therapy were moderate and transient. Two patients required definitive withdrawal of treatment. Thus, anabolic steroids are well tolerated and effective for the treatment of anemia in a subset of MMM patients.
International Journal of Hematology 06/2007; 85(4):338-43. · 1.27 Impact Factor
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ABSTRACT: The E-cadherin/catenin complex (alpha-catenin, beta-catenin, and E-cadherin) plays a crucial role in cell-cell adhesion and tissue remodeling, and abnormalities in these molecules have been suggested to participate in the proliferation and invasive and metastatic potentials of several human carcinomas. However, in human lung adenocarcinomas, its importance has not yet been sufficiently investigated. We immunohistochemically examined the expressions of E-cadherin/catenin complex in 35 primary lung adenocarinomas, and evaluated their expressions in a semiquantitative manner. Correlations between these expression levels, MIB-1 and nuclear p53 indices, and clinicopathological factors were analyzed by subdividing the cases into high- and low-expression groups for each protein. The reduction in membranous E-cadherin/catenin complex expression correlated significantly with low-grade histological differentiation and with high MIB-1 index. Survival analyses were also performed to clarify which factors potentially affected the prognosis of lung adenocarcinoma patients. The low expression of beta-catenin and the high MIB-1 index had a significantly unfavorable influence on the patients' survival. Moreover, the immunohistochemical expression of beta-catenin by cancer cells and MIB-1 index are considered useful prognostic factors for lung adenocarcinoma.
Pathology - Research and Practice 02/2006; 202(9):639-50. · 1.21 Impact Factor
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ABSTRACT: The levels and types of immune responses are determined dependent on the extent of pathogen invasion, reactions to antigens mediated by macrophage-dendritic cells, T cells and antibodies. Recently, accumulating evidence suggests that B cells also play an important role in the regulation of immune responses. Here we have made a review to present a role of B cells in determining the level of immune responses and discussed about the clinical significance of B cell-targeted therapy in patients with autoimmune diseases. Type 1 diabetes is a T cell-mediated autoimmune disease characterized by the destruction of insulin-producing pancreatic beta cells. We and other groups have elucidated that B cells play a critical role in the development of insulitis and diabetes, as B-cell-deficient NOD mice are protected from developing type 1 diabetes. B cells are essential for the T cell receptor clonotype spreading of islet-infiltrating T cells, indicating that B cells may play a role in determining the level of immune responses by antigen presentation to antigen specific T cells. There are now numerous case reports and small series of clinical trials regarding rituximab therapy in autoimmune diseases, such as refractory autoimmune hemolytic anemia, IgM antibody-associated polyneuropathy, systemic lupus erythematosus and rheumatoid arthritis. Rituximab is a genetically engineered chimeric anti-CD 20 monoclonal antibody that is approved for the treatment of lymphoma. CD20 is a B-cell surface antigen that is expressed only on pre- B and mature B cells. Thus, rituximab causes a selective transient depletion of the CD20+ B -cell subpopulation. Rationale and strategy for targeting B cells in the treatment of autoimmune diseases consist of the inhibition of antigen-presentation and co-stimulation that induces T cell expansion and activation. Further careful mechanistic studies are required to develop therapies in patients with autoimmune diseases.
Fukuoka igaku zasshi = Hukuoka acta medica 05/2005; 96(4):86-92.
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Mayumi Mori,
Kiyoshi Kitamura,
Michihiko Masuda,
Tomomitsu Hotta,
Tamotsu Miyazaki,
Akira B Miura,
Hideaki Mizoguchi,
Akira Shibata,
Hidehiko Saito,
Tamotsu Matsuda,
Toru Masaoka,
Mine Harada, Yoshiyuki Niho,
Fumimaro Takaku
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ABSTRACT: In treating elderly non-Hodgkin's lymphoma (NHL) patients, it is particularly important to use drugs that have a low incidence of adverse events and high efficacy. In this multicenter study, THP (pirarubicin)-COP (cyclophosphamide, vincristine, and prednisolone) was compared to two thirds dosage of full CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen with regard to both adverse events and efficacy. For a third group, etoposide (E) was added to the THP-COP regimen (THP-COPE) in order to achieve high dose-intensity. Subjects were 486 previously untreated patients, aged 65 or older (range, 65-92 years; median, 74 years), with NHL. Subjects were randomly assigned to receive THP-COP, two thirds CHOP, or THP-COPE. Four hundred and forty-three patients were assessed for response and followed for 8 years after the last subject registered. The complete remission rates for the THP-COP, CHOP, and THP-COPE groups were 42.5%, 41.4%, and 48.0%, respectively. There was no difference in overall survival or progression-free survival among these 3 groups. In aggressive lymphoma, there was also no difference in complete response (CR) rate (45.3% in THP-COP, 44.9% in CHOP, 48.0% in THP-COPE), overall survival, and progression-free survival among these groups. The 5- and 8-year survival rates for all patients were 29.4% and 18.7%, respectively. The 5- and 8-year survival rates for patients with aggressive lymphoma were 27.4% and 17.4%, respectively. Although long-term survival for patients with aggressive lymphoma on our regimens was not worse compared to previous reports, the CR rate was lower. Because severe adverse events were not observed, higher dose chemotherapy may be directed to achieve better CR rates. In patients with T-cell-type lymphoma, the CR rate was greater after treatment with THP-COP (51.4%) or THP-COPE (57.7%) compared to treatment with CHOP (19.4%). Pirarubicin may be more useful for T-cell lymphoma than doxorubicin. Because adverse cardiac events were reported only in CHOP, adverse cardiac events might be low in the THP group.
International Journal of Hematology 05/2005; 81(3):246-54. · 1.27 Impact Factor
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ABSTRACT: We investigated the origin of leukemic progenitors in a case of the simultaneous occurrence of myelomonocytic leukemia and multiple myeloma (IgG-K). At presentation, myeloperoxidase and nonspecific esterase-positive myelomono-cytic cells had proliferated up to 12.2 x 109/liter in the peripheral blood. Bone marrow cell differentials revealed the coexistence of myelomonocytic cells (30%) and atypical plasmacytoid cells (26%). Myelomonocytic cells in peripheral blood expressed both myeloid antigens (CD11b, CD13, CD14, CD15, CD33) and T/B-lymphoid antigens (CD2, CD4, CD5, CD7, CD10, PCA-1). Bone marrow mononuclear cells (BMMC) could be divided into PCA-1 strongly positive and PCA-1 weakly positive populations, which were considered to represent myeloma cells and myelomonocytic cells, respectively; the former were CD2-positive (CD2+), CD14−, and CD15−, whereas the latter were CD2+, CD14+, and CD15+. Immunohistochemical analysis revealed that, in addition to plasmacy-toid cells, a minority of myelomonocytic cells showed a positive reaction for IgG staining, and production of IgG was observed in the culture supernatant of CD14+ myelomonocytic cells in peripheral blood. Southern blot analysis revealed the presence of two identical rearrangement bands of immunoglobulin heavy chain gene in both BMMC containing myeloma cells and myelomonocytic cells and CD14+ myelomonocytic cells in peripheral blood. In a long-term methylcellulose assay, peripheral blood mononuclear cells produced large compact colonies consisting of macrophages and IgG+ plasmacytoid cells (Mϕ/P colonies), while BMMC produced a different type of colonies consisting of CD14+ myelomono-blasts, macrophages, and IgG+ plasma cells (Mb/Mϕ/P colonies) in addition to Mϕ/P colonies. Recloning experiments showed that primary Mb/Mϕ/P colonies gave rise to both secondary Mϕ/P and Mb/Mϕ/P colonies. These observations strongly suggest that common leukemic progenitors provide both myeloma and myelomonocytic leukemia cells, and the mechanism of “lineage infidelity” is probably involved in the development of their “bilineal” differentiation.
Journal of Cellular Physiology 02/2005; 148(3):446 - 456. · 3.87 Impact Factor
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ABSTRACT: A chimeric toxin in which the cell-surface binding domain of Pseudomonas exotoxin A was replaced with mature human granulocyte colony-stimulating factor (G-CSF) was produced in Escherichia coli, purified and tested for its biological activity on the human G-CSF-responsive myeloid leukemia cell line, UT7/GR. This fusion protein, termed G-CSF-PE40, showed potent cytotoxicity in the cell line in a dose-dependent manner. G-CSF-PE40 displaced binding of biotinylated G-CSF to its receptor, and the cytotoxicity of G-CSF-PE40 was neutralized by an excess of wild-type G-CSF, indicating the receptor-mediated effects of this chimeric toxin. When G-CSF-PE40 was injected into normal mice, they showed transient neutropenia but no significant changes in the numbers of red blood cells or platelets. Furthermore, G-CSF-PE40 prolonged the survival of mice transplanted with syngeneic myeloid leukemia cells. These observations suggest that G-CSF-PE40 may be useful in targeted therapy of myeloid leukemia cells expressing G-CSF receptors.
Biochemical and Biophysical Research Communications 07/2004; 319(2):582-9. · 2.48 Impact Factor
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Takashi Shimamoto,
Kaoru Tohyama,
Takahiro Okamoto,
Takashi Uchiyama,
Hiroyuki Mori,
Masao Tomonaga,
Yoshinobu Asano, Yoshiyuki Niho,
Masanao Teramura,
Hideaki Mizoguchi,
Mitsuhiro Omine,
Kazuma Ohyashiki
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ABSTRACT: We examined the efficacy of cyclosporin A (CsA) in 50 patients with myelodysplastic syndrome (MDS) consisting from 47 of RA, 1 of RARS, and 2 of RAEB. These patients showed various marrow cell types including hypo-, normo-, and hypercellularity. Patients belonged to the following International Prognostic Scoring System (IPSS) risk groups: 4 of low, 41 of intermediate-1, and 5 of intermediate-2. The median CsA dose was 4.58mg/kg, and treatment responses were classified according to the International Working Group (IWG) criteria. Hematological improvement (HI) was observed in 30 (60%) patients, and all of them were belonged to RA. In the patients with RARS or RAEB, no efficacy was observed. Four (8%) of the responders achieved partial remission (PR) with granulocytes > or = 1500microl(-1), Hb>11g/dl and platelets > or = 100,000microl(-1). Higher response rate (53%) was shown in erythroid lineage (HI-E) compared to platelet (HI-P, 36%) or neutrophil lineage (HI-N, 35%). When we analyzed the correlation between the response to CsA therapy and the karyotype or HLA type, there were significantly more responders with good karyotype or DRB1*1501 than with intermediate/poor karyotypes or with other HLA types. These results indicate the usefulness of CsA therapy for MDS patients with any marrow cellularity, especially for erythroid lineage and patients with good karyotype or DRB1*1501.
Leukemia Research 09/2003; 27(9):783-8. · 2.92 Impact Factor
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ABSTRACT: The in vitro effect of bestatin on Philadelphia (Ph) chromosome positive chronic myeloid leukemia (CML) was investigated using mature clonogenic cells and primitive stem cells derived from long-term culture-initiating cells (LTC-ICs). Individual colonies were grown in methycellulose culture (clonogenic cells) and after 5 weeks, LTC (colonies derived from LTC-ICs) were individually isolated. DNA isolated from these clonogenic colonies was studied by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis to detect BCR/ABL mRNA transcripts b3a2 and b2a2. At the mature hematopoietic progenitor cell level, almost all (20/21) colonies, including both erythroid and myeloid progenitors, were leukemic, i.e. BCR/ABL mRNA positive. Although normal progenitors were able to grow in the presence of bestatin, even at the most primitive progenitor cell level (LTC-ICs), the number of leukemic clones gradually decreased. Furthermore, bestatin suppressed the outgrowth of leukemic clones more frequently than control LTC without any effect on the growth of normal clones. These results indicate that bestatin, at levels that can be obtained by per os administration clinically, suppresses only Ph-positive leukemic clones without affecting normal hematopoiesis. Based on these results, we suggest that bestatin has the potential to provide another treatment for patients with CML.
International Immunopharmacology 07/2003; 3(6):901-7. · 2.38 Impact Factor
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Shigeharu Tsurumi,
Yuichi Nakamura,
Kazuhiro Maki,
Mitsuhiro Omine,
Kazuhiro Fujita,
Takashi Okamura, Yoshiyuki Niho,
Sachiko Hashimoto,
Keiko Kanno,
Kenshi Suzuki,
Akira Hangaishi,
Seishi Ogawa,
Hisamaru Hirai,
Kinuko Mitani
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ABSTRACT: Alterations of the N-ras oncogene and p53 tumor suppressor gene have been demonstrated to play an important role in pathogenesis of hematological malignancies. We simultaneously investigated genetic lesions of both genes in bone marrow cells from 64 Japanese patients with myeloproliferative disorders (MPD), including polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (MF), by direct sequencing analysis. No mutations of the N-ras gene were detected in any cases. Two patients, one with chronic neutrophilic leukemia derived from PV and one with acute mylogenous leukemia derived from ET, exhibited three mutations of the p53 gene. Among them, two were missense mutations in exon 5 or 7 and one was a deletion in exon 5. All samples in chronic phase or from MF were devoid of mutations in both genes. These data suggested that disruptions of both genes are extremely rare in MPD in chronic phase and that loss of functions in the p53 gene could be involved in progression of MPD such as PV and ET.
American Journal of Hematology 11/2002; 71(2):131-3. · 4.67 Impact Factor
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Nihon Naika Gakkai Zasshi 08/2002; 91(7):1989-93.
