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Tsuneyuki Shimada,
Tomoya Maeda,
Maho Ishikawa,
Daisuke Okamura,
Yoshihiro Ito, Naoki Wakimoto,
Yuichi Nakamura,
Nobutaka Kawai,
Hirohide Ino,
Itsuro Jinnai,
Shigehisa Mori,
Akira Matsuda,
Masami Bessho
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ABSTRACT: A 37-year-old female who presented with pancytopenia in April 2008 was diagnosed with aplastic anemia stage 2 with a normal karyotype. She had a PNH phenotype in her red blood cells (RBC) and granulocytes, and HLA DR15. Her aplastic anemia was deteriorated from stage 2 to stage 3, and she required periodic RBC transfusions. Four months after cyclosporine therapy, the pancytopenia improved and she did not need RBC transfusion. However, three months thereafter, she again required RBC transfusions after developing severe ulcerative colitis. Although mesalazine and steroid pulse therapy improved her ulcerative colitis, her transfusion dependency persisted. Eleven months after the diagnosis of aplastic anemia, equine anti-thymocyte globulin (ATG) and cyclosporine were administered, but no hematological improvement was obtained. Six months after the administration of ATG and cyclosporine, transformation to refractory cytopenia with multilineage dysplasia (RCMD) with 7-monosomy was observed. An allogeneic bone marrow transplant (BMT) from a HLA-identical sibling was performed 23 months after the diagnosis of aplastic anemia. Complete remission of both the aplastic anemia and ulcerative colitis was obtained without medication. Although the relationship between aplastic anemia and ulcerative colitis remains unclear, immunological abnormalities might be involved in the pathogenesis of both disorders because she had PNH phenotype in RBC and HLA DR15 and because allogeneic BMT improved both disorders.
[Rinshō ketsueki] The Japanese journal of clinical hematology 02/2012; 53(2):224-8.
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ABSTRACT: 19-nor-14-epi-23-yne-1,25(OH)(2) D(3) (inecalcitol) is a unique vitamin D(3) analog. We evaluated the activity of inecalcitol in a human prostate cancer model system. The analog was 11-fold more potent than 1,25(OH)(2) D(3) in causing 50% clonal growth inhibition of androgen-sensitive human prostate cancer LNCaP cells. Inecalcitol, more than 1,25(OH)(2) D(3) , reduced in a dose-dependent manner the expression levels of the transcription factor ETS variant 1 and the serine/threonine protein kinase Pim-1, both of which are upregulated in prostate cancer. Remarkably, dose challenge experiments revealed that inecalcitol maximal tolerated dose (MTD) by intraperitoneal (i.p.) administration was 30 μg/mouse (1,300 μg/kg) three times per week, while we previously found that the MTD of 1,25(OH)(2) D(3) is 0.0625 μg/mouse; therefore, inecalcitol is 480 times less hypercalcemic than 1,25(OH)(2) D(3) . Pharmacokinetic studies showed that plasma half-life of inecalcitol were 18.3 min in mice. A xenograft model of LNCaP cells was developed in immunodeficient mice treated with inecalcitol. The tumors of the diluent-treated control mice increased in size but those in the inecalcitol treatment group did not grow. Our data suggest that inecalcitol inhibits androgen-responsive prostate cancer growth in vivo and should be examined either alone or with other chemotherapy in clinical trials in individuals with rising serum prostate-specific antigen after receiving either surgery or irradiation therapy with curative intent.
International Journal of Cancer 07/2011; 130(10):2464-73. · 5.44 Impact Factor
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ABSTRACT: A 71-year-old Japanese male patient infected with HCV was diagnosed with thrombocytopenia. Histological examination of the bone marrow aspirate showed numerous lymphoid aggregates with Russell bodies. Immunohistochemistry and flow cytometric analysis demonstrated clonal expansion of CD5+ CD23+ B cells. Russell bodies were positive for IgM and lambda immunoglobulin light chain. The patient also underwent gastric biopsy, which revealed Helicobacter pylori (HP) infection. Subsequent eradication of the bacteria resulted in improvement of his thrombocytopenia. The clinical course remained uneventful at 15-month follow-up, consistent with monoclonal B-cell lymphocytosis. The observed clonal expansion with plasmacytic differentiation may have occurred under the influence of HCV with HP infection.
Bone marrow research. 01/2011; 2011:814372.
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ABSTRACT: We report a patient with hairy cell leukemia Japanese variant (HCL-Jv) that developed after radiotherapy for orbital adnexal MALT lymphoma. A 78-year-old man was diagnosed as having MALT lymphoma in the left conjunctiva in December 2003. The patient was treated by local radiotherapy and the tumor disappeared. Thereafter, he gradually developed leukocytosis and mild splenomegaly. In May 2009, the leukocyte count was 34,300 with 80% lymphoid cells. A diagnosis of HCL-Jv was made since the lymphoid cells showed a hairy morphology with round nuclei and indistinct nucleoli. These cells expressed CD11c, CD19, CD20, CD103 and showed weak reaction for tartrate-resistant acid phosphatase (TRAP). Bone marrow was infiltrated by atypical cells with an intrasinusoidal pattern. No treatment was needed as the patient was asymptomatic without anemia, thrombocytopenia or lymphadenopathy. Results of the immunoglobulin light chain expression and the heavy chain rearrangement in the tumor cells indicated that the two mature B-lymphoid neoplasms, MALT lymphoma and HCL-Jv, in this patient were derived from independent clones. This appears to be the first reported case of HCL-Jv associated with other lymphoid tumor. Further analysis is needed to clarify the risk of secondary malignancy in HCL-Jv.
[Rinshō ketsueki] The Japanese journal of clinical hematology 11/2010; 51(11):1674-9.
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Naoki Wakimoto
Nippon rinsho. Japanese journal of clinical medicine 07/2010; 68 Suppl 7:50-2.
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ABSTRACT: Studies have conjectured that nonsteroidal anti-inflammatory drugs (NSAID) inhibit growth of various malignancies by inhibiting cyclooxygenase-2 (COX-2) enzyme activity. Yet, several lines of evidence indicate that a COX-2-independent mechanism may also be involved in their antitumor effects. Here, we report that NSAIDs may inhibit the growth of glioblastoma multiforme (GBM) cells through COX-2-independent mechanisms, including up-regulation of both 15-hydroxyprostaglandin dehydrogenase (15-PGDH, the key prostaglandin catabolic enzyme) and the cell cycle inhibitor p21. Using Western blot and real-time PCR analysis in various GBM cell lines, we observed up-regulation of 15-PGDH and p21 after NSAIDs treatment. To elucidate the role of 15-PGDH in GBM, transfection assays were conducted using the T98G GBM cell line. Overexpression of 15-PGDH suppressed cell growth and was associated with increased expression of p21. In an attempt to investigate the roles of COX-2, 15-PGDH, and p21 in the inhibition of growth of GBM, small interfering RNA (siRNA) against each of these proteins was transfected into T98G cells. Inhibition of growth mediated by NSAIDs was partially reversed after knockdown of either 15-PGDH or p21, but not after COX-2 knockdown. Moreover, expression level of p21 was not affected in COX-2 siRNA transfected cells. Our studies provide evidence that the up-regulation of 15-PGDH induced by NSAIDs has the potential to inhibit growth of GBM, in part, by up-regulation of p21 possibly independent from COX-2 enzymatic function.
Cancer Research 10/2008; 68(17):6978-86. · 7.86 Impact Factor
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ABSTRACT: Cucurbitacins are a group of diverse triterpenoid substances isolated from plants with medicinal properties. One particularly potent family member is cucurbitacin B (CuB). The antiproliferative effects of CuB against human breast cancer cells were tested. Six human breast cancer cell lines were examined because they represent a diverse mix of breast cancer subtypes varying in expression of estrogen receptor (ER), Her2/neu, and p53 mutation. The antiproliferative effect of CuB were also studied in vivo. The effective dose inhibiting 50% growth (ED(50)) was between 10(-8) M and 10(-7) M for this collection of breast cancer cell lines. These cells underwent rapid morphologic changes after 15-20 min exposure to CuB (5 x 10(-7) M), which was associated with disruption of the microtubules and F-actin, as observed by confocal microscopy. Human MDA-MB-231 (ER-, p53 mutated) breast cancer cells were orthotopically implanted into the breasts of nude mice who intraperitoneally received either CuB 1.0 mg/kg or vehicle. Tumor volume was reduced by 55% in the group that received CuB for 6 weeks compared with vehicle controls. No apparent organ tissue damage was observed by pathological assessment. Interestingly, the experimental mice had lower serum glucose levels, consistent with use of CuB as an antidiabetic drug in China. This drug appears to be a third in a family of drugs targeting the microtubules (taxanes [e.g. taxol], vinca alkaloid [e.g. vincristine], and now CuB). Our in vitro and in vivo results suggest that CuB may be an effective, new approach for the treatment of ER-, Her2/neu amplified, and p53 mutant breast cancers.
Cancer Science 09/2008; 99(9):1793-7. · 3.33 Impact Factor
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ABSTRACT: Glioblastoma Multiforme (GBM) is almost inevitably a fatal tumor of the brain with most individuals dying within 1 year of diagnosis. It is the most frequent brain tumor in adults. Dose-response studies showed that Cucurbitacin B inhibited 50% growth (ED(50)) of 5 human GBM cell lines in liquid culture at approximately 10(-7) M. Soft-gel assays demonstrated that nearly all of the GBM clonogenic cells were inhibited at 10(-8) M of Cucurbitacin B. FACS analysis found that the compound (10(-7) M, 24 hr) caused G2/M arrest. The GBM cells underwent profound morphologic changes within 15-30 min after exposure to Cucurbitacin B (10(-7) M), rounding up and losing their pseudopodia associated with disruption of actin and microtubules, as observed by immunoflourescence. Cucurbitacin B (10(-7) M) caused prominent multinucleation of the cells after they were pulse-exposed (48 hr) to the drug, washed and cultured in normal medium for an additional 2 days. The drug (10(-7) M, 3-24 hr) increased levels of p-p38, p-JNK and p-JUN in U87 and T98G GBM cell lines as seen by Western blot. Interestingly, alterations in cell morphology caused by Cucurbitacin B (10(-7) M) were blocked by the JNK inhibitor SP600125. In summary, Cucurbitacin B has a prominent anti-proliferative activity on GBM cells; and at least in part, the mode of action is by affecting the cytoskeleton, as well as, the JNK pathway. Clinical trails of this drug should be pursued in GBM.
International Journal of Cancer 07/2008; 123(6):1364-75. · 5.44 Impact Factor
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ABSTRACT: Tumor suppressor genes are often silenced in human cancer; this can occur by transcriptional repression by deacetylation in the promoter regions, mediated by histone deacetylase (HDAC). HDAC inhibitors can block cancer cell growth by restoring expression of tumor suppressor genes. In this study, we investigated the effects of a HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) on pancreatic cancer cells. SAHA inhibited the growth of 6 pancreatic cancer cell lines in a dose-dependent manner as measured by MTT and clonogenic assays (ED(50) approximately 10(-6) M) associated with induction of apoptosis, G2 cell cycle arrest and also induced differentiation as indicated by morphology and increased expression of cytokeratin 7. It increased expression of p21(WAF1) (independent of the mutational status of p53), C/EBPalpha, RARalpha and E-cadherin; these genes have been associated with decreased proliferation in other cancers. SAHA decreased cyclin B1 expression; this cyclin normally promotes progression through G2 of the cell cycle. SAHA mediated acetylation of histone H3 globally, as well as, associated with the p21(WAF1) promoter, as measured by chromatin immunoprecipitation. SAHA also decreased levels of c-myc and cyclin D1, independent of an active beta-catenin pathway. In further studies, the combination of SAHA and an inhibitor of DNA methylation, 5-Aza-2'-deoxycytidine, had an enhanced antiproliferative effect on pancreatic cancer cells. In summary, SAHA inhibited the growth of human pancreatic cancer cells by inducing apoptosis, differentiation and cell cycle arrest, as well as increase in the expression of several tumor suppressor genes. SAHA is a novel, promising therapeutic agent for human pancreatic cancers.
International Journal of Cancer 09/2007; 121(3):656-65. · 5.44 Impact Factor
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ABSTRACT: Tumor suppressor genes are often silenced in human cancer; this can occur by transcriptional repression by deacetylation in the promoter regions, mediated by histone deacetylase (HDAC). HDAC inhibitors can block cancer cell growth by restoring expression of tumor suppressor genes. In this study, we investigated the effects of a HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) on pancreatic cancer cells. SAHA inhibited the growth of 6 pancreatic cancer cell lines in a dose-dependent manner as measured by MTT and clonogenic assays (ED50 ≈10−6 M) associated with induction of apoptosis, G2 cell cycle arrest and also induced differentiation as indicated by morphology and increased expression of cytokeratin 7. It increased expression of p21WAF1 (independent of the mutational status of p53), C/EBPα, RARα and E-cadherin; these genes have been associated with decreased proliferation in other cancers. SAHA decreased cyclin B1 expression; this cyclin normally promotes progression through G2 of the cell cycle. SAHA mediated acetylation of histone H3 globally, as well as, associated with the p21WAF1 promoter, as measured by chromatin immunoprecipitation. SAHA also decreased levels of c-myc and cyclin D1, independent of an active β-catenin pathway. In further studies, the combination of SAHA and an inhibitor of DNA methylation, 5-Aza-2′-deoxycytidine, had an enhanced antiproliferative effect on pancreatic cancer cells. In summary, SAHA inhibited the growth of human pancreatic cancer cells by inducing apoptosis, differentiation and cell cycle arrest, as well as increase in the expression of several tumor suppressor genes. SAHA is a novel, promising therapeutic agent for human pancreatic cancers. © 2007 Wiley-Liss, Inc.
International Journal of Cancer 07/2007; 121(3):656 - 665. · 5.44 Impact Factor
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ABSTRACT: Honokiol (HNK), a naturally occurring biphenyl, possesses potent antineoplastic and antiangiogenic properties. We investigated the in vitro and in vivo activity of HNK against breast cancer. HNK exhibited potent anti-proliferative activity against breast cancer cell lines and enhanced the activity of other drugs used for the treatment of breast cancer. In vivo, HNK was highly effective against breast cancer in nude mice. We identified two different effects of HNK on breast cancer cells: cell cycle inhibition, observed at lower doses of HNK, and induction of apoptosis, observed at higher doses of the compound. Our data suggest that HNK is a systemically available, non-toxic inhibitor of breast cancer growth and should be examined for clinical applications.
International Journal of Oncology 07/2007; 30(6):1529-37. · 2.40 Impact Factor
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Naoki Wakimoto,
Motohiro Misumi,
Tomoya Maeda,
Tsuneyuki Shimada,
Daisuke Wakao,
Yasutaka Sato,
Naoki Takahashi,
Yuichi Sugahara,
Katsuhiko Yoshida,
Fumiharu Yagasaki,
Yoshihiro Ito,
Yuichi Nakamura,
Nobutaka Kawai,
Akira Matsuda,
Itsuro Jinnai,
Masami Bessho
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ABSTRACT: A 61-year-old man with primary macroglobulinemia (PMG) had been followed without any treatment as he had no apparent manifestations. After 1 year and 3 months, he was admitted to our hospital with a fever. No signs or symptoms of infection and no progressive increase of serum IgM levels was observed. Non-Hodgkin's lymphoma was not additionally found. Fever without infection, elevated serum LDH level and further enlargement of the spleen compelled us to diagnose his condition as deterioration of the PMG. An immediate fall in his temperature and serum IgM levels was observed after CHOP therapy. Effective therapy must be discussed in the deterioration of this type of disease.
[Rinshō ketsueki] The Japanese journal of clinical hematology 08/2005; 46(7):536-8.
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Naoki Wakimoto,
Motohiro Misumi,
Tomoya Maeda,
Tsuneyuki Shimada,
Daisuke Wakao,
Yasutaka Sato,
Naoki Takahashi,
Yuichi Sugahara,
Katsuhiko Yoshida,
Fumiharu Yagasaki,
Yuichi Nakamura,
Nobutaka Kawai,
Akira Matsuda,
Hidekazu Kayano,
Itsuro Jinnai,
Masami Bessho
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ABSTRACT: A 62-year-old woman was admitted to our hospital because of gastric mucosal bleeding. Gastroendoscopy revealed a gastric tumor which was diagnosed from the biopsied specimen as diffuse large B-cell lymphoma (DLBCL). Lymphoma cells had infiltrated the bone marrow showed morphological features resembling Burkitt lymphoma (BL). Nearly 100% of the cells in the bone marrow were positive for MIB-1 immunostaining. The chromosomal study was normal. Surface marker analysis disclosed that the cells were positive for CD10, CD19, CD20 and CD25. As lymphoma cells had infiltrated the central nervous system, combined chemotherapy was performed accompanied with intrathecal administration of anticancer drugs. Although transient improvement was observed, the patient died of the advanced disease three months after admission. As we have shown here, there are some cases of DLBCL with immunohistochemical features resembling BL. Further consideration about the appropriate chemotherapy program for this type of disease might be necessary.
[Rinshō ketsueki] The Japanese journal of clinical hematology 07/2005; 46(6):458-62.
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Daisuke Wakao,
Nobutaka Kawai,
Yoshio Kuwayama,
Motohiro Misumi,
Yasutaka Satoh,
Tsuneyuki Shimada,
Miki Akiba,
Kuniya Kishimoto,
Katsuhiko Yoshida, Naoki Wakimoto,
Naoki Takahashi,
Yuichi Sugahara,
Fumiharu Yagasaki,
Yoshihiro Itoh,
Tohru Sakata,
Toshiya Suzuki,
Akira Matsuda,
Masami Bessho
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ABSTRACT: Systemic capillary leak syndrome (SCLS) is a disorder characterized by hypotension, edema, and an increased hematocrit (Ht) due to sudden leakage of plasma into the extravascular space through some unknown mechanism, in which monoclonal gammopathy is observed. A 30-year-old man visited our emergency department because of abdominal pain, and was admitted to our hematology department because of a markedly increased hemoglobin concentration reaching 26.2 g/dl. The polycythemia was thought to be pseudo-polycythemia due to hemoconcentration, and we diagnosed the patient as having SCLS based on the triad of increased hematocrit, whole-body edema which was especially marked in the lower extremities, and monoclonal gammopathy. The patient recovered after administration of extracellular fluids and albumin, but the attacks recurred. Prophylaxis with terbutaline sulfate, theophylline and corticosteroid reduced the frequency of severe attacks. Because there is possibility that patients with SCLS may be admitted to hematology departments due to severe erythrocytosis, we report this case to increase the awareness of hematologists that SCLS is one of the important differential diagnoses of erythrocytosis.
[Rinshō ketsueki] The Japanese journal of clinical hematology 03/2002; 43(2):122-7.
