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Biomedical subjects

S Asano

Publications and source records attributed to S Asano.

At least 325 records · Page 18Linked to original sources
PubMed1993

The combined effects of all-trans retinoic acid and granulocyte colony-stimulating factor as a differentiation induction therapy for acute promyelocytic leukemia.

A 61-year-old male with acute promyelocytic leukemia (APL) had been in complete remission for the previous 15 months, but his APL relapsed with neutropenia. Although promyelocytes in bone marrow were reduced after administration of 60 mg all-trans retinoic acid (ATRA) daily, myelocytes were predominant on the myelogram and neutropenia did not recover. By adding 75 micrograms of granulocyte colony-stimulating factor (G-CSF) daily, neutrophils accounted for 35.0-55.5% of the myelogram, and the peripheral neutrophil count rose dramatically. Such morphological differentiation of myeloid series was also ascertained in terms of their functions of both neutrophil alkaline phosphatase activity and active oxygen producing capacity. This case supports the concept that G-CSF accelerates ATRA-induced neutrophilic differentiation of blast cells in APL.

Alkaline Phosphatase↗
PubMed1993

Acute myeloid leukemia possibly producing thrombopoietic factor(s).

A 75-year-old man developed a cluster of differentiation (CD)4-positive but human T-cell lymphotropic virus type I (HTLV-I)-negative T lymphoid neoplasm with overwhelming cutaneous involvement and mild thrombocytosis. Twelve courses tetrahydropyranyl adriamycin, cyclophosphamide, vincristine and prednisone (THP-COP) combination chemotherapy led him to complete remission. After four months of complete remission, however, atypical immature cells (blasts) appeared in peripheral blood and bone marrow. Surface marker analysis revealed the blasts to be CD2-, CD3-, CD4-, CD5-, CD7+, CD8-, CD10, CD13 +/-, CD19-, CD20-, CD25-, CD33+ and human leukocyte antigen-DR (HLA-DR+). Staining for myeloperoxidase, esterases, PAS and platelet peroxidase were all negative. The patient was diagnosed as having both CD7 and CD33 positive acute myeloid leukemia (AML). The relation between the T cell lymphoid neoplasm and AML was not clear. Thrombocytosis became more marked after acute leukemia occurred and the platelet count varied in parallel with the blast cell count in peripheral blood. When the leukemic cell count was high, thrombopoietic activity could be detected in the serum. In addition, conditioned medium obtained from primarily-cultured blasts had detectable thrombopoietic activity, which implied the blasts directly to produce a thrombopoietic factor(s). Analysis of the serum concentration for cytokines with associated thrombopoietic activity indicated that the blasts possibly produced a thrombopoietic factor(s) distinct from interleukin (IL)6, IL3, leukemia inhibitory factor (LIF), erythropoietin and granulocyte macrophage-colony stimulating factor. To our knowledge, this is the first reported case of an acute myeloid leukemia with marked thrombopoiesis (more than 2000 x 10(3)/microliter of maximum platelet count in peripheral blood.

Acetylcholinesterase↗
PubMed1993

Differentiation induction of human promyelocytic leukemia cells by acyclic retinoid (polyprenoic acid).

Acyclic retinoid (all-trans-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid) has a slightly different structure from all-trans retinoic acid (ATRA), while it binds cellular retinoic acid-binding protein with a similar binding affinity to that of ATRA. We studied the in vitro efficacy of acyclic retinoid for the differentiation induction of human promyelocyte-derived HL-60 cell line and primary cultured blast cells obtained from 8 patients with acute non-lymphocytic leukemia (ANLL) including 3 acute promyelocytic leukemia (APL) patients. HL-60 cells and ANLL cells were incubated with or without retinoids for 5 days. Acyclic retinoid induced the differentiation of HL-60 cells and APL cells at 10(-6) mol/l, while ATRA induced differentiation at 10(-7) mol/l. These concentrations were well below those that affected cell growth and viability. Although ATRA has an excellent capacity for differentiation induction of HL-60 and APL cells, it is also known to have severe, sometimes fatal, adverse effects, including retinoic acid syndrome. In contrast, acyclic retinoid is reported to have a much wider safety margin than that of ATRA. A clinical trial of acyclic retinoid for the differentiation induction therapy of APL may be worthwhile.

Adolescent↗
PubMed1993

Clinical and cytogenetic findings of myelodysplastic syndromes showing hypocellular bone marrow or minimal dysplasia, in comparison with typical myelodysplastic syndromes.

Hematologic and cytogenetic data were collected on 401 myelodysplastic syndromes (MDS) patients in Japan and their clinical relevance was analyzed. More than 50% of the MDS patients with hypocellular bone marrow had > 5% marrow blasts at the time of MDS diagnosis and frequently had complex aberrations (chromosome changes at three or more regions). They showed peripheral blood findings resembling those of aplastic anemia, but progression into leukemic phase and the prognosis tended to mimic typical MDS. In MDS patients with minimal dysplasia, hematologic parameters were different from those of aplastic anemia. However, the low incidence of leukemic transformation and the favorable prognosis was similar to that of aplastic anemia. More than 90% of the patients in this group had refractory anemia and had normal karyotypes. Thus differential diagnosis from a low grade aplastic anemia is important, since this type of MDS might have a clonal nature as well. In conclusion, although some hematologic and clinical deviations are noticed in MDS with hypocellular marrow or minimal dysplasia, these MDS subtypes might constitute marginal forms of MDS.

Adult↗
PubMed1993

[A double-blind dose ranging study of weekly subcutaneous administration of rHuEPO (KRN5702) on post-phlebotomy anemia of patients scheduled for predeposit autologous blood transfusion (multicenter late PhII study)].

Preoperative blood reservation for autologous blood transfusion generally causes anemia. We performed a double blind controlled study to determine the optimal dose of subcutaneous rHuEPO (recombinant human erythropoietin, KRN5702) for preventing preoperative anemia due to blood reservation. Patients received KRN5702 subcutaneously once a week in a doses of 12000, 24000 or 36000 IU by a double blind technique. After storage of 1200 ml of their own blood right before surgery, their hemoglobin (Hb) averaged about 1 and was about 0.5 g/dl lower than the level before administration of KRN5702 in doses of 12000 and 24000 IU, respectively. This fall was significant. In patients receiving KRN5702 in a dose of 36000 IU, the level of Hb rose instead of a fall; Hb immediately before surgery was 1.1% higher than that before administration which, however, was not significant. This elevation indicates a possibility of abnormal elevation of Hb at this dose. The mean Hb value right before surgery was significantly lower in patients receiving 12000 IU KRN5702 than in patients of the other two groups. The recovery rate of Hb was an indicator to reflect improvement of anemic conditions, and increased as the dose increased after the blood reservation. The rate in the 12000 IU group was significantly lower than that in the other two groups; there was not much difference between the other two rates. We estimated that to reserve 1200 ml of autologous blood, 24000 IU of KRN5702 is adequate but not excessive. One patient receiving 24000 IU showed side effects including an elevation of body temperature, rash, and edema.

Adult↗
PubMed1993

[Clinical study of GM-CSF in patients with aplastic anemia and myelodysplastic syndrome. (CSF39-300 Study Group)].

We administered granulocyte-macrophage colony stimulating factor (GM-CSF) to patients with aplastic anemia and myelodysplastic syndrome (MDS), as a phase III trial. The GM-CSF was given by 3 hrs intravenous drip infusion daily for at least fourteen days. Twenty-five patients with aplastic anemia and nineteen patients with MDS were evaluable for efficacy. Peripheral blood granulocyte counts, especially neutrophil counts and eosinophil counts, increased markedly by the administration of GM-CSF in each disease. Fifteen patients with MDS and nineteen patients with aplastic anemia responded to the GM-CSF. Dose-related increase of granulocytes were seen in patients with MDS, but no relation was seen in patients with aplastic anemia. Adverse effects were observed in some patients and flu-like syndrome including fever, general fatigue and anorexia were seen most commonly but were transient. Our results showed that GM-CSF is a potent stimulator of hematopoiesis in patients with aplastic anemia and MDS.

Adolescent↗
PubMed1993

Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders.

The hematological and immunological findings and clinical courses of 33 patients (13 male, 20 female; median age at presentation, 60 years) with granular lymphocyte-proliferative disorders (GLPD) are presented. Based on the surface phenotypes of peripheral blood granular lymphocytes (GL), the GLPD were divided into CD3+ T cell-lineage GLPD (T-GLPD) and CD3- CD16+ natural killer (NK) cell-lineage GLPD (NK-GLPD). Twenty-one patients had T-GLPD, and 12 had NK-GLPD. One patient with T-GLPD and two patients with NK-GLPD had progressive clinical courses and died of the disease despite receiving combination chemotherapy. Twelve patients with T-GLPD were found to have severe anemia at presentation or during the course of the disease; four of them fulfilled the diagnostic criteria of pure red cell aplasia, and the others had closely related conditions. Six of these 12 patients were treated with cyclophosphamide, and all responded to the treatment. In 16 patients, the clinical course was stable, and spontaneous regression was observed in two patients. Since some of the patients with NK-GLPD had stable clinical courses while some had progressive clinical courses, clinical findings in these two groups were compared. We found, taking into consideration our cases and those reviewed in the literature, that age less than 40 years, fever, lymph node swelling, hepatosplenomegaly, and GL with CD16(Leu-11)-CD56+CD57- phenotype and low or absent antibody-dependent cellular cytotoxicity seemed to be predictors of a progressive clinical course.

Adult↗
PubMed1993

MLLT3 gene on 9p22 involved in t(9;11) leukemia encodes a serine/proline rich protein homologous to MLLT1 on 19p13.

Recently, the MLL gene at 11q23 was found to be involved in a subset of leukemias with an 11q23 abnormality. In the present study, we isolated chimeric cDNAs between the MLL and a gene designated MLLT3 at 9p22 from a cDNA library of an IMS-M1 cell line with a t(9;11)(p22;q23) translocation, a representative karyotypic abnormality seen in acute monocytic leukemia. We also isolated a normal MLLT3 cDNA and found an open reading frame encoding at least 318 amino acids with high serine/proline content (24.8%). The chimeric mRNAs were demonstrated to be fused to MLL in frame, as found in t(11;19) and t(4;11) leukemias. The predicted MLLT3 protein demonstrated a significant homology to that of the MLLT1 gene at 19p13 involved in t(11;19) leukemia. The highest homology, up to 74.1%, was found in 86 amino acids of the C-terminus, suggesting that this region is of particular importance for leukemogenesis in t(9;11) leukemia. Northern blot analysis with the MLLT3 cDNA probe against normal tissues revealed multiple transcripts in lymphoid organs. A survey of hematopoietic cell lines demonstrated relatively stronger signals in cells belonging to megakaryocytic and erythroid lineages. As previously found in t(11;19) leukemia, heterogeneous MLL-MLLT3 chimeric mRNAs could be detected by the reverse transcriptase-polymerase chain reaction (RT-PCR) in t(9;11) leukemia samples.

Adult↗
PubMed1993

[Gene therapy].

Recent progress of gene manipulation techniques enables us to insert foreign gene into human cells. This approach, so called gene therapy, is very attractive to treat molecular disease including congenital disorders or cancer. There have already been started 15 clinical protocols regarding gene therapy as well as gene-marking mainly in U.S.A., In this reviewing article, we introduce the public opinion about the gene therapy in Japan comparing with that in western countries. We then introduce the current clinical protocols about gene therapy and gene marking. We also discuss the future prospects of gene therapy. The progress in this field may cast a new light on the treatment of congenital disorders as well as cancers.

Attitude to Health↗
PubMed1993

Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan.

It is well known that cytogenetic analysis in patients with myelodysplastic syndrome (MDS) provides information useful in determining their prognosis. Based on the chromosomal results obtained from 401 MDS patients by a multicentric study in Japan, we studied correlations between chromosomal findings and prognosis or leukemic transformation in MDS patients. Patients with complex aberrations (cytogenetic abnormalities at more than three chromosomes), of any subtype, had a poor prognosis; for example, > 60% of patients with refractory anemia (RA) showing complex aberrations died within one year, but only 11% of them developed leukemia. In patients with RA with ringed sideroblasts (RARS), > 70% of those with complex aberrations evolved into the leukemic phase and survived for less than one year, suggesting a biologic heterogeneity in RARS patients. By contrast, about 5% of patients with RA or RARS exhibiting chromosomal findings other than -7/7q-, +8, two aberrations, and complex aberrations, developed leukemia and had a favorable prognosis. Therefore, the presence of chromosome abnormalities alone in patients with RA or RARS is not a factor in predicting leukemic transformation or poor prognosis. In patients with refractory anemia with an excess of blasts (RAEB), the presence of chromosome aberrations at MDS diagnosis affected the occurrence of leukemic transformation (24% versus 43%), however, no particular difference was noted in patients with RAEB in transformation with regard to whether they had chromosome changes or not, and about 60% of them evolved into leukemia. The poor prognosis related to complex aberrations was consistently noted in all MDS subtypes or age-matched groups, indicating that this cytogenetic anomaly is an independent risk factor for a poor prognosis in MDS patients. The duration between MDS diagnosis and development of the leukemic phase and that between the latter and death were significantly shorter in patients with complex aberrations than those without this change. Although the clinical significance of certain chromosomal abnormalities differs among subtypes of MDS, a new scoring system for predicting prognosis by cytogenetic changes, in combination with hematologic parameters, was proposed.

Adolescent↗
PubMed1993

[A basic study on bradycardiac dysrhythmias following atrial surgery].

Various dysrhythmias often developing atrial surgery can be lethal, although the precise mechanism remains unknown. An experimental study was conducted to elucidate the influence of internodal tract injury and sinoatrial node (SAN) artery blockade on bradycardiac arrhythmias, using 40 adult mongrel dogs. Changes in rhythm, SAN tissue flow rate, SAN function and His bundle electrocardiogram were evaluated in those with complete division of the internodal tract (INT) and/or artery blockade under cardiopulmonary bypass. The results were as follows: 1) Junctional rhythm (JR) or ectopic atrial rhythm (ER) occurred in 87.5% of those subjected to anterior INT (AINT) division+SAN artery blockade, whereas such arrhythmias developed in none of those with division of any single INT alone, and appeared in only 18% of those with SAN artery blockade alone; 2) The SAN tissue flow rate was reduced to 29 +/- 17% of the control level by AINT division+SAN artery blockade, while it was reduced to only 91 +/- 16%, 84 +/- 12% and 90 +/- 18% by division of AINT, MINT and PINT, respectively, and 55 +/- 16% by SAN artery blockade (The former was significantly lower than the latter two (p < 0.01)); 3) None of those with the SAN tissue flow rate of less than 10 Laser Doppler Flowmeter unit (LDF unit) by laser Doppler flowmeter output were capable of maintaining sinus rhythm (SR) with its minimum requirement that was assumed to be more than 10 LDF unit; 4) Immediately before shifting to JR, corrected sinus recovery time (CSRT) was elongated, indicating a hypofunction of the SAN; 5) The A-H interval was more significantly prolonged by AINT division than by either of the other two divisions (p < 0.01). Division of the AINT brought about prolongation of the A-H interval, and AINT division+SAN artery blockade caused a marked SAN hypofunction. It was inferred that preservation of both the AINT and the SAN artery should be of vital importance in preventing surgical bradycardiac arrhythmias.

Animals↗
PubMed1992

Acquisition of interleukin-3 independence in FDC-P2 cells after transfection with the activated c-H-ras gene using a bovine papillomavirus-based plasmid vector.

Since the ras family of proto-oncogenes is supposed to be involved in leukemogenesis by point-mutational activation, we studied the effect of the activated ras gene on the growth of a murine interleukin-3 (IL-3)-dependent cell line, FDC-P2. The human activated c-H-ras gene was transfected into FDC-P2 cells by electroporation using a high-level expression vector, BMGhph, which contains a partial DNA sequence from bovine papillomavirus (BPV) and a hygromycin B (hmB)-resistant gene as a selectable marker. The transformed FDC-P2 cells showed a high incidence of IL-3-independent growth and tumorigenicity in nude mice. These clones did not express or secrete IL-3, suggesting the acquisition of IL-3 independence by a nonautocrine mechanism. The high incidence of autonomous growth may be due to the use of the BMG vector, because (1) the activated ras gene in pBR322 vector (pHs-49) was not so efficient in the induction of IL-3 independence, (2) the c-H-ras genome copies per cell increased in number up to about 50 copies by using the BMG vector, and (3) cotransfection with the activated ras gene and the BPV gene in separate plasmids partly enhanced the incidence of autonomous growth without increasing the copy number of the ras gene compared with transfection with the activated ras gene alone. The present study supports the idea that the activation of ras gene is an important step in malignant transformation of hematopoietic cells and suggests that the BPV gene products may cooperate with ras gene activation probably by affecting the cellular genes that may be involved in multistep leukemogenesis. The BMG vector may be useful to test the transforming ability of oncogenes whose oncogenic potential is relatively low.

Animals↗
PubMed1992

Deletion mutagenesis of stem cell factor defines the C-terminal sequences essential for its biological activity.

We constructed a series of murine stem cell factor (mSCF) cDNAs which were sequentially truncated at the 3' termini. The resultant six mutant cDNA encode N-terminal 183, 179, 162, 149, 142 and 133 amino acid residues of the mature mSCF protein fused to the heterogeneous C-terminal peptides derived from the linker sequences. Each mutant cDNA was transiently expressed in COS cells, and the cultured supernatant was assayed for its ability to support the growth of a human factor-dependent cell line, TF-1 and to enhance colony formation by murine hematopoietic progenitor cells. The results showed that as few as N-terminal 142 but not 133 amino acid residues of mSCF remained biologically active in vitro, suggesting that the region of 9 amino acids from Asp134 to Ser142 containing a Cys138-mediated disulfide bond may contribute to the C-terminal end of the active subdomain of mSCF.

Amino Acid Sequence↗
PubMed1992

Tumor necrosis factor and interleukin-1 induce activin A gene expression in a human bone marrow stromal cell line.

Activin A, a homodimer of the beta A chain, regulates hematopoiesis. In a human bone marrow-derived stromal cell line, KM-102, phorbol myristate acetate, tumor necrosis factor-alpha and interleukin-1 beta induced great increases in beta A chain mRNA levels and production of activin A activities. The phorbol ester-induced beta A chain gene expression was inhibited by cycloheximide and down regulation of protein kinase C, whereas the cytokine-induced expression was little affected by these treatments. These results indicate that the inflammatory cytokines directly stimulate beta A chain gene expression via protein kinase C-independent pathways.

Activins↗
PubMed1992

Affinity of a highly repetitive bent DNA for nuclear scaffold proteins from rat liver.

A highly repetitive component in rat nuclear DNA was isolated by HindIII digestion and cloned. A self-ligated tandem dimer of the 370-bp cloned component was digested with each of DraI, HindIII and XmnI. The resulting 370-bp restriction fragments exhibited anomalously slow gel electrophoretic mobilities. Of them, the XmnI fragment had the slowest mobility. This suggested that sequence-directed bending of the helix axis is the strongest in this fragment. Moreover, the 370-bp restriction fragments had selective affinities for the nuclear scaffold proteins, P123 and P130. The affinity levels of XmnI fragment were higher than those of DraI or HindIII fragment. These results implied that the affinity of a highly repetitive component for the nuclear scaffold proteins depends on the degree of sequence-directed bending of the helix axis.

Animals↗
PubMed1992

K(+)-site-directed pyridine derivative, AU-1421, activates hydrolysis of the K(+)-sensitive phosphoenzyme of sarcoplasmic reticulum Ca(2+)-ATPase and inactivates that of K(+)-transporting ATPases.

(Z)-5-Methyl-2-[2-(1-naphthyl)ethenyl]-4-piperidinopyridine, AU-1421, interacted at 0 degree C with the K(+)-sensitive phosphoenzymes of three transport ATPases, Ca(2+)-, H+/K(+)- and Na+/K(+)-ATPase. In the case of Ca(2+)-ATPase, AU-1421 at about 80 microM stimulated 6-fold the rate of splitting of the phosphoenzyme, on which K+ simply functions as an accelerator from one side of the membrane. Probably AU-1421 also simply interacts with the K(+)-binding site of the phosphoenzyme that is easily accessible from the aqueous phase. In the cases of H(+)/K(+)- and Na(+)/K(+)-ATPases, AU-1421 stabilized the phosphoenzymes which accept K+ as the translocating ion. The rate constants of dephosphorylation for H(+)/K(+)-ATPase and Na(+)/K(+)-ATPase were decreased to half by AU-1421 at about 5 and 10 microM, respectively. Presumably after binding of AU-1421 to a K(+)-recognition site of the phosphoenzyme, local motion of the peptide region near the binding site that serves to move the bound ion into the ion-transport pathway (occlusion center) might be inhibited. Thus AU-1421 may be able to distinguish two modes of K+ action on the K(+)-sensitive phosphoenzymes.

Adenosine Triphosphatases↗
PubMed1992

The energy transduction mechanism is different among P-type ion-transporting ATPases. Acetyl phosphate causes uncoupling between hydrolysis and ion transport in H+,K(+)-ATPase.

H+,K(+)-ATPase, Na+,K(+)-ATPase, and Ca(2+)-ATPase belong to the P-type ATPase group. Their molecular mechanisms of energy transduction have been thought to be similar until now. Ca(2+)-ATPase and Na+,K(+)-ATPase are phosphorylated from both ATP and acetyl phosphate (ACP) and dephosphorylated, resulting in active ion transport. However, we found that H+,K(+)-ATPase did not transport proton nor K+ when ACP was used as a substrate, resulting in uncoupling between energy and ion transport. ACP bound competitively to the ATP-binding site of H+,K(+)-ATPase. The hydrolysis of ACP by H+,K(+)-ATPase was stimulated by cytosolic K+, the half-maximal stimulating K+ concentration (K0.5) being 2.5 mM, whereas the hydrolysis of ATP was stimulated by luminal K+, the K0.5 being 0.2 mM. Furthermore, during the phosphorylation from ACP in the absence of K+, the fluorescence intensity of H+,K(+)-ATPase labeled with fluorescein isothiocyanate increased, but those of Na+,K(+)-ATPase and Ca(2+)-ATPase decreased. These results indicate that phosphorylated intermediates of H+,K(+)-ATPase formed from ACP are not rich in energy and that there is a striking difference(s) in the mechanism of energy transduction between H+,K(+)-ATPase and other cation-transporting ATPases.

Adenosine Triphosphatases↗