Biomedical subjects
Publications and source records attributed to M Hino.
The synthesis and biological properties of a novel water-soluble echinocandin-like lipopeptide, FR131535, are described. This compound displayed potent in vitro and in vivo antifungal activities. The hemolytic activity of FR901379 was reduced by replacing the acyl side chain. This compound showed good water-solubility, comparable to the natural product FR901379.
Transcript levels of hexokinase (HK) isozymes and glucose transporter (GLUT) isoforms in RNA samples of AH130 cells obtained from dish cultures and ascites were evaluated in a quantitative manner. In AH130 cells cultured in dishes, HKI and HKII were expressed at a similar level, but HKIII and HKIV were not. GLUT1 and GLUT3 were also expressed, and messages of these two isoforms represented 27% and 71%, respectively, of the total GLUT messages. A faint signal of GLUT2 was also observed. On the contrary, in cells grown as ascites, the transcript of HKII was dominant, and its level was about 15-fold over that of dish-cultured AH130 cells. Transcript levels of GLUT1 and GLUT3 were 4.5- and 2-fold, respectively, higher than those in dish-cultured cells. Thus, GLUT1 was more susceptible to changes in culture conditions than GLUT3. Based on these results, we concluded that the change in growth conditions caused synchronized changes in the transcript levels of HKII and GLUT1 in AH130 cells. However, such marked changes in the transcript levels of HKII and GLUT1 were not observed when AH130 cells were cultured in dishes under a hypoxic condition, indicating that the observed changes were not solely attributable to the difference in oxygen concentration between the ascites and cell culture conditions. Accordingly, other factors such as growth factors may be responsible for this difference in levels of HKII and GLUT1 between the two growth conditions.
Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) are major signaling molecules activated in human neutrophils stimulated by cytokines. Both molecules were cleaved at the N-terminal portion in neutrophils undergoing apoptosis induced by in vitro culture alone or treatment with TNF and/or cycloheximide. The cleavage of both molecules was inhibited by G-CSF and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, a caspase inhibitor, both of which can inhibit neutrophil apoptosis. In a cell-free system, ERK and p38 MAPK were not cleaved by recombinant caspase-3 or caspase-8 while gelsolin was cleaved by caspase-3 under the same condition. The cleavage of both molecules appears to be specific to mature neutrophils, since it was not detected in immature cells (HL-60 and Jurkat) undergoing apoptosis, indicating that proteases responsible for the cleavage of both molecules may develop during differentiation into mature neutrophils. Concomitant with the cleavage of ERK and p38 MAPK, GM-CSF- and TNF-induced superoxide release, adherence, and phosphorylation of ERK and p38 MAPK were decreased in neutrophils undergoing apoptosis. In addition, GM-CSF- and TNF-induced superoxide release and adherence were inhibited by PD98059 MAPK/ERK kinase inhibitor) as well as SB203580 (p38 MAPK inhibitor), suggesting possible involvement of ERK and p38 MAPK in superoxide release and adherence induced by these cytokines. These findings indicate that ERK and p38 MAPK are cleaved and degraded in neutrophils undergoing apoptosis in a caspase-dependent manner and the cleavage of both molecules may be partly responsible for decreased functional responsiveness to inflammatory cytokines.
A 26-year-old woman with idiopathic thrombocytopenic purpura (ITP) was admitted to our hospital because of fever and rash. Blood tests revealed thrombocytopenia, liver dysfunction, coagulopathy, and hyperferritinemia. Bone marrow examination revealed many atypical lymphocytes and some histiocytes with hemophagocytosis. On admission she was diagnosed with rubella virus-associated hemophagocytic syndrome (VHAS), but on laboratory examination, she was seropositive for varicella-zoster virus (VZV)-IgM as well as rubella virus-IgM. She was therefore diagnosed with dual infection by rubella virus and VZV. Her simultaneous rubella virus and VZV infection may have been related to the VAHS pathogenesis. She was treated with prednisolone and gamma globulin therapy and recovered completely.
A 64-year-old woman with adult T cell leukemia (ATL) was admitted to our hospital with severe hypercalcemia. The serum calcium level was elevated to 14.9 mg/dl. Biochemical parameters for bone formation including serum osteocalcin (bone Gla protein, BGP) and alkaline phosphatase (ALP) were normal. The serum levels of tartrate-resistant acid phosphatase (TRAP), a parameter for bone resorption, were increased (4.6 KAU). The serum level of parathyroid hormone-related protein (PTHrP) was elevated (343 pmol/l). The cytokines with stimulatory effects on bone resorption, such as interleukin (IL)-1alpha, IL-1beta, IL-6, and tumor necrosis factor-alpha, were not detected. Serum Ca levels, PTHrP levels, and TRAP levels decreased with the decrease in ATL cells after chemotherapy, while serum BGP levels and ALP levels increased. On the 29th hospital day, ATL cells began to increase again. Then serum PTHrP levels, Ca levels, and TRAP levels increased, while serum BGP levels and ALP levels decreased. A marked excessive bone resorption with suppressed bone formation (uncoupling) occurred in this patient. The ATL cells produced not only PTHrP but also IL-1alpha and IL-1beta. These results suggest that PTHrP may act as a humoral factor and IL-1 may act as a local factor in bone metabolism of ATL patients.
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BACKGROUND AND OBJECTIVES: Anti-Nak(a), a platelet-specific antibody, occasionally causes platelet-transfusion refractoriness (PTR) together with human leucocyte antigen (HLA) antibodies. Anti-Nak(a) usually appears after frequent platelet transfusions or pregnancy. We report the first case of PTR caused by anti-Nak(a) alone. MATERIALS AND METHODS: A 19-year-old male patient with testicular tumour showed PTR when receiving his first transfusion of platelets. Screening for platelet antigens and platelet antibodies revealed that he had type I CD36 (Nak(a)) deficiency and that anti-Nak(a), but not anti-HLA, was present before he received his first transfusion. RESULTS: The transfusion of Nak(a)-negative, but HLA non-selected, platelets was effective in raising the platelet count. CONCLUSION: Clinically significant Nak(a) antibody was present as naturally occurring antibody in a platelet glycoprotein IV (CD36)-negative non-transfused male patient.
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Gamma/delta T cell lymphoma is very rare, and usually occurs as an extranodal tumor. We describe the case of a 16-year-old Japanese man with an unusual nodal gamma/delta T cell lymphoma with generalized lymphadenopathy and bone marrow involvement. No tumor involvement was observed in the liver, spleen, or nasal cavity. Examination for surface antigens on lymphoma cells revealed a unique phenotype, positive for CD3 and T cell receptor (TCR) gamma/delta, but negative for CD2. Genotypic analysis revealed the tumor to be of monoclonal origin and characterized by TCR gamma-chain gene rearrangement, but there was no rearrangement of the TCR beta-chain gene. Our patient's tumor responded to combination chemotherapy and subsequent allogeneic bone marrow transplantation from an HLA-matched unrelated donor. He has remained well and free of disease for 35 months.
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We studied apoptosis and thymidylate synthase (TS) inductions by 5-fluorouracil (5-FU) in gastric cancer cells with wild-type p53 (MKN-45 and MKN-74) and with mutated p53 (MKN-28 and KATO-III). Apoptotic inductions in MKN-45 and MKN-74 were stronger than those in MKN-28 and KATO-III, suggesting that wild-type p53 may contribute to the induction of apoptosis. After continuous exposure to 0.1 microg/ml of 5-FU for 96 h, no TS induction was obtained in KATO-III, while approximately twice the amount of TS was observed compared to non-treatment cells in MKN-45, MKN-74, and MKN-28. The results of immunohistochemical staining for TS and p53 showed no relation between these two protein expressions in endoscopic biopsy specimens of 25 patients with advanced gastric cancer. These results indicated that p53 status may not play a pivotal role in regulating TS expression. We found no significantly different effects of 5-FU between intermittent (repeat of 24-h continuous infusion and 24-h drug-free) and continuous treatments in either MKN-28 or stem cells (CD34+ hematopoietic progenitor cells) when the same area under the time-concentration curve of 5-FU was administered. The TS induction in MKN-28 cells by intermittent treatment was significantly higher than that by continuous treatment; however, most TSs in both types of 5-FU treatment cells were of the inactive form, i.e., TS bound to FdUMP, a 5-FU metabolite. Therefore, neither intermittent nor continuous treatment appears to induce 5-FU resistance related to the level of increment free TS. In conclusion, our observations suggested that p53 mutation may be associated with apoptotic induction by 5-FU; however, p53 status may not strongly affect TS induction by 5-FU. Intermittent treatment can be replaced with continuous treatment without causing 5-FU resistance.
A novel anti-influenza agent, FR198248, was isolated from the cultured broth of a fungal strain No.13830. The strain was identified as Aspergillus terreus from morphological characteristics. FR198248, a new type of hydroxyl benzaldehyde compound, showed antiinfluenza virus activity in Madin-Darby canine kidney (MDCK) cells in vitro. The mode of action of FR198248 against influenza virus A could be ascribed to an inhibitory effect on the stage of virus adsorption. Furthermore, FR198248 possessed potent in vivo anti-influenza activity in a murine model of respiratory tract infection.
Two cases of advanced and metastatic breast cancers were treated by docetaxel (TXT) in combination with intra-arterial infusion of adriamycin (ADM). Patients received 60 mg/body TXT i.v. and 30 mg/body ADM ia (AT therapy) bi-weekly. Clinical responses were observed in these two patients and the durations of responses were over 20 weeks. Critical toxicities of grade 2 leukopenia and alopecia were observed but grade 4 severe toxicities were not. Thus AT therapy can be easily and safely performed with outpatients. This therapy can improve the response rate and time to progression; therefore phase I or phase I/II clinical trials of AT therapy in Japan are recommended.
We report a case of chronic myelogenous leukemia (CML) with marked thrombocytosis. The patient was a 68-year-old woman who showed marked thrombocytosis (> 200 x 10(4)/microliter), a slightly increased leukocyte count without any immature myeloid cells in the peripheral blood, and no hepatosplenomegaly. Philadelphia chromosome (Ph) was detected by karyotype analysis and FISH. The bcr-abl transcript was detected by RT-PCR and the break point was located in the major bcr. Treatment with interferon-alpha was effective, reducing the proportion of Ph-positive cells from 56% to 7% within 21 months. Detailed study of atypical cases of CML such as the present one may provide additional information about the disease pathogenesis.