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Biomedical subjects

M Tomonaga

Publications and source records attributed to M Tomonaga.

At least 73 records · Page 4Linked to original sources
PubMed2000

[Japan Adult Leukemia Study Group (JALSG)--twelve years of activities and future direction].

The JALSG was founded in 1987 as the first large scale multi-center study group for adult leukemia in Japan. It has grown up to be an internationally-recognized national group consisting of 66 institutions. Each protocol for AML has recruited more than 300 new cases for the study period of two years, enabling randomized studies. JALSG's studies have been published in international journals and contributed much to evidence-based medicine in Japan. For administrative purposes, an Internet system has been employed with a great success for case entry and data management. Governmental research funding for cancer research has been provided to the chief doctor of JALSG, enhancing its research activity greatly. Future JALSG studies will focus on how to improve the cure rate for adult leukemia by incorporating new drugs and developing new treatment strategies.

Adult↗
PubMed2000

Recovery of hematopoietic progenitor cells in patients with severe aplastic anemia who obtained good clinical response with a combination therapy of immunosuppressive agents and recombinant human granulocyte colony-stimulating factor.

Seventeen patients with newly diagnosed acquired severe aplastic anemia were treated with a combination of immunosuppressive drugs consisting of anti-lymphocyte or anti-thymocyte globulin, cyclosporin A (CyA), methylprednisolone, and recombinant human granulocyte colony-stimulating factor (G-CSF). Fourteen (82%) of the 17 patients achieved good response (GR), and 3 (18%) had no response. Among the 14 GR patients, 5 (36%) later evolved clonal diseases, 1 developed myelodysplastic syndrome, and 4 developed paroxysmal nocturnal hemoglobinuria. The numbers of granulocyte-macrophage colony-forming units (CFU-GM) and erythrocyte burst-forming units were markedly low or absent in all cases before therapy. After therapy, those numbers in 13 patients among 14 responders recovered to the level of the normal control at the time of GR. However, the CFU-GM number substantially declined after that but gradually recovered again to reach a normal level over longer clinical courses. The positive rate for HLA-DRB1*1501 was 60% (3/5) among 5 CyA-dependent patients, which tended to be higher than the 20% (1/5) among 5 CyA-independent patients. Thus, immunosuppressive therapy combined with G-CSF provides a high rate of good hematological response accompanied by the apparent recovery of the hematopoietic progenitor compartments.

Adolescent↗
PubMed2000

Real-time polymerase chain reaction for quantification of HTLV-1 proviral load: application for analyzing aberrant integration of the proviral DNA in adult T-cell leukemia.

We describe the establishment of a real-time polymerase chain reaction (PCR) assay for the quantitative estimation of human T-cell leukemia virus type 1 (HTLV-1) proviral load using a LightCycler Technology (Roche Diagnostics, Mannheim, Germany) instrument. Proviral DNA level represents a measure of the integrated viral genome in host cells, so we applied this technique to evaluate the tumor burden in adult T-cell leukemia (ATL) patients with aberrant integration patterns of HTLV-1 detected by standard Southern blot hybridization (SBH) analysis. In 14 of our 15 ATL cases with 2 or more bands detected by SBH analysis, the ATL cells were shown to harbor multiple copies of the provirus within 1 ATL cell. This result suggests the usefulness of real-time PCR quantification for the study of the relationship between ATL pathology and HTLV-1-induced pathogenesis.

DNA, Viral↗
PubMed2000

Consensus Conference on the Treatment of Aplastic Anemia.

This article presents guidelines for the diagnosis and treatment of aplastic anemia (AA) established by a consensus panel of investigators from various countries. The panel used the scientific evidence presented during the Consensus Conference forum and found in the scientific literature to prepare guidelines categorized as immunosuppressive therapy, unrelated bone marrow transplantation in patients with AA, and myelodysplasia/acute myeloid leukemia after immunosuppressive therapy.

Anemia, Aplastic↗
PubMed1999

Fas-resistance in ATL cell lines not associated with HTLV-I or FAP-1 production.

A preventive role for human T-cell leukemia virus type-I (HTLV-I) and Fas-associated phosphatase-1 (FAP-1) in Fas-mediated apoptosis has been reported in HTLV-I-infected cells. In the present study, we examined whether these molecules increased during the acquisition of Fas-resistance in adult T-cell leukemia (ATL) cell lines. SO4, ST1 and KK1 are Fas-sensitive ATL cell lines, and produce small amounts of HTLV-I in vitro. Although their subclones RSO4 and RST1 are completely Fas-resistant, they produced an equivalent amount of HTLV-I to SO4 and ST1. Moreover, FAP-1 mRNA was not detected in these cell lines irrespective of Fas sensitivity. Thus, Fas resistance in ATL cells was not directly associated with the increased production of HTLV-I or FAP-1.

Antibodies, Monoclonal↗
PubMed1999

Expression of human inducible nitric oxide synthase gene in T-cell lines infected with human T-cell leukemia virus type-I and primary adult T-cell leukemia cells.

We examined the expression of messenger RNA (mRNA) of the human inducible nitric oxide synthase (hiNOS) gene in a panel of human T-cell lines. Reverse transcriptase-polymerase chain reaction showed that human T-cell leukemia virus type-I (HTLV-I)-infected T-cell lines (MT-1, SLB-1, and C5/MJ) expressed mRNA for the hiNOS, but TL-Om1 or uninfected Jurkat, H9, and CCRF-CEM did not. The MT-1, SLB-1, and C5/MJ cell lines are infected with HTLV-I and express the viral transactivator Tax, whereas TL-Om1 cells, although derived from adult T-cell leukemia (ATL) leukemic cells, do not express Tax. There was, thus, a correlation between Tax and hiNOS mRNA expression. The transcriptional regulatory region of the hiNOS gene was activated by Tax in Jurkat, in which endogenous hiNOS is induced by Tax. Deletion analysis showed that the region of hiNOS encompassing nucleotides -159 to -111 contained the minimum Tax-responsive elements. Mutations in the NF-kappaB element at position -115 and -106 bp in the hiNOS promoter were still activated by Tax, and a Tax mutant defective for activation of the NF-kappaB pathway retained the ability to activate the hiNOS promoter. In addition, overexpression of the dominant-negative mutants of IkappaBalpha and I kappaBbeta failed to reduce Tax-induced activation of hiNOS gene. Furthermore, hiNOS mRNA was detected in leukemic cells from ATL patients. Our results show that the hiNOS promoter contains a minimum Tax-responsive element located between nucleotides -159 and -111, and imply that the expression of the hiNOS gene is involved in the pathogenesis of HTLV-I-associated diseases.

Adult↗
PubMed1999

Adult T-cell leukemia cells over-express the multidrug-resistance-protein (MRP) and lung-resistance-protein (LRP) genes.

Adult T-cell leukemia (ATL) is a T-cell malignancy caused by human T-cell-leukemia-virus-I (HTLV-I) infection. ATL comprises 4 clinical forms: acute, chronic, smoldering and lymphoma types. ATL is usually resistant to conventional chemotherapy and has a relatively poor prognosis; however, the resistance mechanisms remain undetermined. To explore the multidrug-resistance (MDR) mechanisms of ATL, we examined the expression and functional activity of MDR-related genes in peripheral-blood mononuclear cells (PBMC) from ATL patients by semi-quantitative RT-PCR and FACScan with calcein-AM. PBMC from ATL patients expressed similar or higher levels of MRP, LRP and cMOAT mRNAs, as compared with normal PBMC. In normal controls and ATL patients, MDR1 mRNA expression was undetectable in this study. PBMC from acute and chronic ATL patients expressed significantly higher levels of MRP and LRP mRNA than did normal PBMC (p < 0.01 and p < 0.05 respectively). In chronic ATL, positive correlations were apparent between levels of MRP and LRP mRNA expression (r = 0.759, p = 0.018), and between each mRNA level and the absolute number of abnormal lymphocytes in peripheral blood. Probenecid, an inhibitor of the MRP pump, significantly increased the accumulation of calcein in PBMC from 3 chronic ATL patients. Our findings suggest that the MRP and LRP genes in ATL are often activated by HTLV-I infection and may confer MDR of ATL cells in vivo. Combined chemotherapy with inhibitors of these MDR genes may be promising in the treatment of ATL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Concurrent three dimensional neuroendoscopy: initial descriptions of application to clinical practice.

Applications of endoscopic technique neurosurgery are becoming increasingly popular as greater evidence of the safety and efficacy of these techniques is reported. Nevertheless, significant technical limitations need to be solved before neuroendoscopy can achieve widespread popularity. One limitation is the surgeon's difficulties in becoming anatomically oriented in a two-dimensional (2-D) environment. The lack of appropriate visual cues to orient oneself in three-dimensional (3-D) space makes relatively simple anatomical regions difficult to navigate. The authors describe an endoscopy system that allows for stereoscopic visualization during minimally invasive procedures and that acts as an adjunct to conventional open craniotomies. Four cases are described in which stereoendoscopy was used as either a primary means of visualization or as an adjunct to the operating microscope in conventional open neurosurgical procedures. The authors believe that stereoendoscopic vision is a significant advance in endoscope technology and will play a large role in the popularization of minimally invasive techniques in neurosurgery.

Journal Article↗
PubMed1999

Fas gene mutation in the progression of adult T cell leukemia.

Fas antigen (Apo-1/CD95) is an apoptosis-signaling cell surface receptor belonging to the tumor necrosis factor receptor superfamily. Adult T cell leukemia (ATL) cells express Fas antigen and show apoptosis after treatment with an anti-Fas monoclonal antibody. We established the ATL cell line KOB, which showed resistance to Fas-mediated apoptosis, and found that KOB expressed two forms of Fas mRNA, the normal form and a truncated form. The truncated transcript lacked 20 base pairs at exon 9, resulting in a frame shift and the generation of a premature stop codon at amino acid 239. The same mutation was detected in primary ascitic cells and peripheral blood cells. The mutation was not detected in lymph node cells, however, although all of the primary ATL cells were of the same clonal origin. A retroviral-mediated gene transfer of the truncated Fas to Jurkat cells rendered the cells resistant to Fas-mediated apoptosis, suggesting a dominant negative interference mechanism. These results indicate that an ATL subclone acquires a Fas mutation in the lymph nodes, enabling the subclone to escape from apoptosis mediated by the Fas/Fas ligand system and proliferate in the body. Mutation of the Fas gene may be one of the mechanisms underlying the progression of ATL.

Aged↗
PubMed1999

Constitutive activation of NF-kappaB in primary adult T-cell leukemia cells.

Human T-cell leukemia virus type I (HTLV-I) is an etiologic agent of adult T-cell leukemia (ATL). The viral protein Tax induces the activation and nuclear translocalization of transcription factor NF-kappaB, which is proposed to play a crucial role in the transformation of T cells by HTLV-I. However, the HTLV-I genes including Tax are not expressed significantly in primary leukemic cells from ATL patients. In this study, we examined the basis for NF-kappaB activation in freshly isolated leukemic cells from ATL patients. We found that leukemic cells from ATL patients, like HTLV-I-infected T-cell lines, display constitutive NF-kappaB DNA binding activity and increased degradation of IkappaBalpha (an inhibitor of NF-kappaB). Whereas the NF-kappaB binding activity in Tax-expressing T-cell lines consisted mostly of p50/c-Rel, fresh ATL samples contained p50/p50 and p50/p65 heterodimers. One T-cell line derived from ATL leukemic cells, TL-Om1, displayed constitutive NF-kappaB activity, as well as enhanced degradation of IkappaBalpha, despite the lack of detectable Tax expression. Interestingly, the NF-kappaB in TL-Om1 consists of p50/p50 and p50/p65 like that in fresh primary leukemic cells. Our results suggest that activation of NF-kappaB occurs through a Tax-independent mechanism in leukemic cells of ATL patients, possibly due to differential NF-kappaB subunit activation.

DNA, Neoplasm↗
PubMed1999

Detailed deletion mapping of the long arm of chromosome 6 in adult T-cell leukemia.

Previously, we have found that the loss of heterozygosity (LOH) was frequently observed on chromosome 6q in acute/lymphoma-type adult T-cell leukemia (ATL), suggesting a putative tumor-suppressor gene for ATL may be present on chromosome 6q. To further define a region containing this gene, we performed fine-scale deletional mapping of chromosome 6q in 22 acute/lymphomatous ATL samples using 24 highly informative microsatellite markers. LOH was found in 9 samples (40. 9%) at 1 or more of the loci examined. Of the 9 samples, 8 shared the same smallest commonly deleted region flanked by D6S1652 and D6S1644 (6q15-21). The genetic distance between these two loci is approximately 4 cM. These results suggest that a putative tumor-suppressor gene on chromosome 6q15-21 probably plays a very important role in the evolution of acute/lymphomatous ATL. Our map provides key information toward cloning the gene.

Chromosome Mapping↗
PubMed1999

Brain abscess caused by Streptococcus intermedius: two case reports.

BACKGROUND: Although Streptococcus intermedius has been recognized as an important pathogen for abscess formation outside the central nervous System, the Streptococcus milleri group, of which it is a member, has not been recognized as a specific pathogen for brain abscess, often thought to be caused by Streptococcus viridans, which includes other streptococcal species. CASE DESCRIPTION: Two cases of brain abscess in the left frontal lobe caused by S. intermedius, which responded well to antimicrobial treatment combined with needle aspiration, are presented. In the first patient, the predisposing disease was paranasal sinusitis of the frontal and ethmoid sinuses. In the second patient, the source of the pathogen was not detected despite extensive examination. The patients underwent aspiration of pus under ultrasound guidance in the first patient, and via a computed tomography-guided stereotactic procedure in the second patient. They subsequently received appropriate antimicrobial therapy against S. intermedius isolated from the pus culture. Both patients were discharged without any neurological deficits. CONCLUSION: It is important to recognize S. intermedius as a pathogen of brain abscess, and to be aware of its predisposing factors, i.e., mucosal disturbance and liver abscess.

Adolescent↗
PubMed1999

Giant fusiform aneurysm of the basilar artery: consideration of its pathogenesis.

BACKGROUND: We tried to determine the pathogenesis of a fusiform aneurysm of the basilar artery based on the findings of two patients who had pontine infarctions due to thrombosis within the aneurysm. CASE REPORT: The patients were female, aged 75 and 62 years. At autopsy of the first case, the dilated basilar artery was filled with fresh and old thrombus. The wall was extremely thin on the left side, where a fresh red thrombus was evident, and thick on the right side, where an old white thrombus appeared. The thick wall had a thickened and hyalinized intima, and a deposition of atheromatous plaque disrupted both the internal elastic lamina and muscle layer. The left vertebral artery was atherosclerotic and its lumen was severely compromised, but the right vertebral artery was hypoplastic. On angiogram of the second case, the dilated basilar artery presumably was filled with thrombus on the left side, contralateral to the dilated and tortuous vertebral artery. The left vertebral artery was hypoplastic. CONCLUSION: Atherosclerosis may be the essential factor in the pathogenesis of a fusiform aneurysm of the basilar artery in elderly patients. The disrupted internal elastic lamina and muscle layer may be susceptible to mechanical injury by hemodynamic strain, causing progressive attenuation of the arterial wall. Stenosis of the vertebral artery on the dominant side probably produces a jet stream within the basilar artery on the stenotic side and a stagnant zone on the opposite side, promoting the initial thrombus formation.

Aged↗
PubMed1999

Qualitative and quantitative characterization of Fas (APO-1/CD95) on leukemic cells derived from patients with B-cell neoplasms.

Expression density and function of Fas (APO-1/CD95) on malignant B-cells, an antigen thought responsible for abnormal tumor biology, remains to be fully understood. Fifty-five cases with B-cell neoplasms of acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), B-cell malignant lymphoma (ML), and myeloma (MM) were studied for qualitative and quantitative expression and function of Fas using flow cytometry and annexin-V staining methods. Fas expression was flow cytometrically unimodal with heterogeneous density and showed quantitatively characteristic features among different diseases; weak in ALL, faint in CLL, moderate in HCL, and strong in ML, respectively. Not only full-length but also alternatively spliced truncated mRNAs were detected even in leukemic B-cells with qualitatively faint or negative Fas, and then band density of the former transcripts by RT-PCR was correlated to the Fas protein expression level. Short-term culture of freshly isolated cells gave rise to increases of Fas density and susceptibility for apoptosis, suggesting that the mRNA and inducible Fas are functional at least in vitro. These results show that Fas is a biological marker for characterizing B-cell neoplasms reflecting various stages of B-cell ontogeny and may have clinical utility as a therapeutic strategy.

Apoptosis↗
PubMed1999

High rate of chromosomal abnormalities in HTLV-I-infected T-cell colonies derived from prodromal phase of adult T-cell leukemia: a study of IL-2-stimulated colony formation in methylcellulose.

To detect chromosomal abnormalities in prodromal phase of adult T-cell leukemia (ATL), we established a clonal culture method for human T-lymphotropic virus type I (HTLV-I) infected T-cells in methylcellulose containing recombinant human interleukin 2 (rhIL-2). We tried to analyze chromosomes of 187 colonies (4, 23, 69, 74, and 17, from HTLV-I-uninfected normal T-cells, HTLV-I-Infected normal T-cells, HTLV-I carriers, smoldering ATL, and chronic ATL, respectively), using chromosomal banding methods. In the prodromal group, 53% of colonies (84/160) (36/69, 37/74, 11/17 in HTLV-I carriers, smoldering ATLs, and chronic ATL, respectively) had chromosomal abnormal clones. In HTLV-I carriers, multiple clones with simple chromosomal abnormalities were observed. In more progressed chronic ATL, more complex chromosomal abnormalities were detected, and specific colonies were selected. Thus, colonies in the prodromal phase of ATL are characterized by cytogenetical clonal evolution and clonal changes.

Adult↗
PubMed1999

Visual texture segregation by the chimpanzee (Pan troglodytes).

One adult male chimpanzee (Pan troglodytes) was trained to detect a target area consisting of texture elements from the background texture made of the different elements from the target area. The subject was given eight different stimulus conditions. In Condition 1, segregation was based on the difference of local feature of elements but not on global similarity. Conditions 2-3 investigated the effects of the number of terminators, which was considered as 'textons' in human texture perception. The chimpanzee showed better performance when the discrimination can be based on the difference of the number of terminators. This tendency, however, was reversed when the local salient feature (length of shorter lines) was enhanced, as in Enns' [15] study with humans as subjects. The subject showed asymmetries in segregation performance when discriminating based on gap (Conditions 4-5), line length (Condition 6), and regularity of line arrangement (Condition 7). Observed asymmetries were consistent with humans and with visual search asymmetries. The performance of texture segregation by the chimpanzee was consistent with humans, and the texture segregation is one of the useful tasks for comparative study of early vision as well as visual search task.

Animals↗
PubMed1999

Fas antigen (CD95) in pure erythroid cell line AS-E2 is induced by interferon-gamma and tumor necrosis factor-alpha and potentiates apoptotic death.

We investigated the expression of Fas antigen (CD95) in the pure erythroid cell line AS-E2 in the presence and absence of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). TNF-alpha induced apoptosis in AS-E2 cells, whereas IFN-gamma did not. In culture containing no IFN-gamma or TNF-alpha, AS-E2 cells expressed little Fas antigen. However, IFN-gamma and IFN-gamma and TNF-alpha both induced expression of Fas antigen and its mRNA within 24 hours after the stimulation. When anti-Fas monoclonal antibody (IgM) was added to AS-E2 cells after the induction of Fas expression, AS-E2 cells underwent apoptosis as shown by the induction of DNA fragmentation. This apoptotic change was inhibited by an inhibitor of caspase-3-like proteases (Ac-DEVD-CHO) and an inhibitor of CED-3/ICE family proteases (Z-Asp-CH2-DCB) but not by an inhibitor of caspase-1-like proteases (Ac-YVAD-CHO), suggesting a role for caspase-3-like proteases in Fas-receptor signaling. Although AS-E2 cells expressed Fas ligand mRNA, treatment with ZB4, an antibody that inhibits Fas-mediated cell death, failed to suppress IFN-gamma- or TNF-alpha-mediated cytotoxicity. These findings suggest that the late erythroid progenitor cells are negatively regulated by IFN-gamma and TNF-alpha, both of which are capable of inducing functional Fas expression.

Antibodies, Monoclonal↗