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Biomedical subjects

Mine Harada

Publications and source records attributed to Mine Harada.

At least 145 records · Page 8Linked to original sources
PubMed2003

Fanconi anemia FANCG protein in mitigating radiation- and enzyme-induced DNA double-strand breaks by homologous recombination in vertebrate cells.

The rare hereditary disorder Fanconi anemia (FA) is characterized by progressive bone marrow failure, congenital skeletal abnormality, elevated susceptibility to cancer, and cellular hypersensitivity to DNA cross-linking chemicals and sometimes other DNA-damaging agents. Molecular cloning identified six causative genes (FANCA, -C, -D2, -E, -F, and -G) encoding a multiprotein complex whose precise biochemical function remains elusive. Recent studies implicate this complex in DNA damage responses that are linked to the breast cancer susceptibility proteins BRCA1 and BRCA2. Mutations in BRCA2, which participates in homologous recombination (HR), are the underlying cause in some FA patients. To elucidate the roles of FA genes in HR, we disrupted the FANCG/XRCC9 locus in the chicken B-cell line DT40. FANCG-deficient DT40 cells resemble mammalian fancg mutants in that they are sensitive to killing by cisplatin and mitomycin C (MMC) and exhibit increased MMC and radiation-induced chromosome breakage. We find that the repair of I-SceI-induced chromosomal double-strand breaks (DSBs) by HR is decreased approximately 9-fold in fancg cells compared with the parental and FANCG-complemented cells. In addition, the efficiency of gene targeting is mildly decreased in FANCG-deficient cells, but depends on the specific locus. We conclude that FANCG is required for efficient HR-mediated repair of at least some types of DSBs.

Amino Acid Sequence↗
PubMed2003

Influenza-induced rhabdomyolysis after autologous peripheral blood stem cell transplantation for malignant lymphoma.

We report influenza-induced rhabodmyolysis and congestive heart failure after high-dose therapy and hematopoietic stem cell transplantation for malignant lymphoma. Four months after autologous peripheral blood stem cell transplantation for the treatment of malignant lymphoma, a 65-year-old Japanese man developed acute congestive heart failure requiring artificial ventilation and rahbdomyolysis. Since influenza A virus was documented from his nasal cavity, he was diagnosed as rhabdomyolysis and congestive heart failure induced by influenza A infection. Neuraminidase inhibitor (oseltamivir 150 mg/ day for 5 days) was administrated, and heart failure and respiratory status were improved. Our experience suggests that early treatment with neuraminidase inhibitor may improve the clinical outcome of influenza-induced rhabdomyolysis and congestive heart failure.

Acetamides↗
PubMed2003

Successful treatment of limited disease-small cell lung cancer with multimodality treatment consisting of concurrent chemoradiotherapy, high-dose chemotherapy with autologous peripheral blood stem cell transplantation and surgical resection.

A 65-year-old man with limited disease-small cell lung cancer was treated with concurrent chemoradiotherapy which resulted in a partial response. He further received high-dose chemotherapy with autologous peripheral blood stem cell transplantation. Development of non-small cell carcinoma was, however, suspected at a site of the residual nodule in cytological examination using bronchoscopy. He then underwent lobectomy, which revealed that the nodule was composed of necrotic tissue. He has been alive without recurrence for seven years. This multimodality treatment appeared to be effective for this patient. However, further investigation is necessary to clarify the role of multimodality treatment.

Aged↗
PubMed2003

Surgical resection of malignant lymphoma in the right atrium after systemic chemotherapy.

A 74-year-old man was referred to us for evaluation of a tumor in the right atrium (RA). Transesophageal echocardiography (TEE) showed an unmovable 50x60 mm mass in the RA. Based on histological findings of subcutaneous tumors in the right abdominal wall, he was diagnosed as malignant lymphoma (ML), and treated with a THP-COP regimen. Upon completion of first THO-COP therapy, TEE showed marked regression of the mass and division into 3 masses, one of which showed marked floating movement with a small stalk. To prevent the risk of embolic events, surgical resection was performed. Resected tumors were necrotic tissues. Serial imaging of cardiac tumor and surgical resection is desirable to decrease the possibility of embolic complication.

Aged↗
PubMed2003

Systemic vasculitis associated with alphal-antitrypsin deficiency.

We describe a rare case of systemic vasculitis associated with alpha1-antitrypsin (alpha1-AT) deficiency. Mutational analysis of the alpha1-AT gene in this patient revealed a homozygous alpha1-AT Mnichinan variant. Alpha1-AT possesses broad-spectrum inhibitory activity against many serine proteases, including human neutrophil elastase, to help maintaining the crucial balance between proteases and protease inhibitors. The increase in free protease activity in the context of alpha1-AT deficiency may induce exacerbation of the vasculitis. This serious genetic defect severely affects the balance between a protease and a protease inhibitor at the pathological site.

Female↗
PubMed2002

Influence of interleukin-12 receptor beta1 polymorphisms on tuberculosis.

Host genetic factors may be important determinants of susceptibility to tuberculosis, and several candidate gene polymorphisms have been shown to date. A series of recent reports concerning rare human deficiencies in the type-1 cytokine pathway suggest that more subtle variants of relevant genes may also contribute to susceptibility to tuberculosis at the general population level. To investigate whether polymorphisms in the interleukin-12 receptor (IL-12R) gene predispose individuals to tuberculosis, we studied these genes by single-strand conformational polymorphism analysis and direct sequencing. Although no common polymorphisms could be identified in the IL-12R beta 2 gene ( IL-12RB2), we confirmed four single nucleotide polymorphisms (SNPs; 641A-->G, 684C-->T, 1094T-->C, and 1132G-->C) causing three missense variants (Q214R, M365T, G378R) and one synonymous substitution in the extracellular domain of the IL-12R beta 1 gene ( IL12RB1). All SNPs were in almost perfect linkage disequilibrium (D'=0.98), and two common haplotypes of IL12RB1(allele 1: Q214-M365-G378; allele 2: R214-T365-R378) were revealed. Polymerase chain reaction/restriction fragment length polymorphism and sequence analyses were used to type IL12RB1polymorphisms in 98 patients with tuberculosis and 197 healthy controls in Japanese populations. In our case-control association study of tuberculosis, the R214-T365-R378 allele (allele 2) was over-represented in patients with tuberculosis, and homozygosity for R214-T365-R378 (the 2/2 genotype) was significantly associated with tuberculosis (odds ratio: 2.45; 95% CI: 1.20-4.99; P=0.013). In healthy subjects, homozygotes for R214-T365-R378 had lower levels of IL-12-induced signaling, according to differences in cellular responses to IL-12 between two haplotypes. These data suggest that the R214-T365-R378 allele, i.e., variation in IL12RB1, contribute to tuberculosis susceptibility in the Japanese population. This genetic variation may predispose individuals to tuberculosis infection by diminishing receptor responsiveness to IL-12 and to IL-23, leading to partial dysfunction of interferon-gamma-mediated immunity.

Adult↗
PubMed2002

Molecular bases for human complement C7 polymorphisms, C7*3 and C7*4.

Complement C7 is one of the components of membrane attack complex (MAC) generated by the terminal complement cascade. C7 protein is polymorphic and most of its polymorphisms have been identified using isoelectric focusing (IEF), which detects protein charge differences. To date, the molecular bases of the polymorphisms detected by IEF have not been determined. In this paper, we describe the structural bases of two C7 IEF-detected polymorphisms, C7*3 and C7*4, both of which are common in Asian populations. C7*3 resulted from substitution of cysteine (Cys) at amino acid residue 106 by charged arginine (Arg; C106R), while charged lysine (Lys) at amino acid residue 398 was replaced by neutral glutamine (Gln; K398Q) in C7*4. As C7*3 is hypomorphic, it is important to study its possible associations with diseases such as immunological disorders and infections. We present genetic bases for this C7 polymorphism, which we determined using polymerase chain reaction (PCR)-based genotyping, a simple and accurate method suitable for large-scale studies.

Base Sequence↗
PubMed2002

Cutting edge: tyk2 is required for the induction and nuclear translocation of Daxx which regulates IFN-alpha-induced suppression of B lymphocyte formation.

IFN-alpha inhibits B lymphocyte development, and the nuclear protein Daxx has been reported to be essential for this biological activity. We show in this study that IFN-alpha inhibits the clonal proliferation of B lymphocyte progenitors in response to IL-7 in wild-type, but not in tyk2-deficient, mice. In addition, the IFN-alpha-induced up-regulation and nuclear translocation of Daxx are completely abrogated in the absence of tyk2. Therefore, tyk2 is directly involved in IFN-alpha signaling for the induction and translocation of Daxx, which may result in B lymphocyte growth arrest and/or apoptosis.

Active Transport, Cell Nucleus↗
PubMed2002

Parathyroid hormone-related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia.

BACKGROUND: Parathyroid hormone-related protein (PTH-rP) is a major cause of tumor-induced hypercalcemia (TIH) and frequently is found to be elevated in serum of patients with TIH. In the current study, the authors examined the usefulness of PTH-rP measurement at the time of first presentation in the follow-up of lung carcinoma patients with TIH. METHODS: The authors retrospectively studied 23 of 1149 lung carcinoma patients who were found to have TIH at the time of first presentation for the correlation between serum PTH-rP and the development of bone metastases and survival compared with lung carcinoma patients without TIH who were matched by gender, age, Eastern Cooperative Oncology Group performance status, histological type of tumor, and stage of the disease. RESULTS: Twenty-three lung carcinoma patients with TIH demonstrated significantly increased serum levels of PTH-rP (mean +/- standard error [SE], 84.1 +/- 16.5 pmol/L) compared with control patients without TIH (mean +/- SE, 36.2 +/- 2.0 pmol/L) at the time of first presentation, (P < 0.001). In these hypercalcemic patients, patients whose serum PTH-rP was > 150 pmol/L (n = 16) were found to have a significantly increased rate of bone metastases (71.4% vs. 12.5%; P = 0.01) and decreased survival (median survival of 1.4 months vs. 5.4 months; P < 0.015) compared with patients whose serum PTH-rP was < 150 pmol/L (n = 7). CONCLUSIONS: The data from the current study suggest that serum PTH-rP as determined at the time of first presentation is a useful indicator of not only hypercalcemia but also bone metastasis and eventual survival in patients with lung carcinoma.

Adult↗
PubMed2002

Efficient generation of antigen-specific cytotoxic T cells using retrovirally transduced CD40-activated B cells.

The development of rapid, efficient, and safe methods for generating Ag-specific T cells is necessary for the clinical application of adoptive immunotherapy. We show that B cells stimulated with CD40 ligand and IL-4 (CD40-B cells) can be efficiently transduced with retroviral vectors encoding a model Ag, CMV tegument protein pp65 gene, and maintain high levels of costimulatory molecules after gene transfer. CTL lines specific for pp65 were readily generated in all four healthy CMV-seropositive donors by stimulating autologous CD8(+) T cells with these transduced CD40-B cells, both of which were derived from 10 ml peripheral blood. ELISPOT assays revealed that the CTL lines used multiple HLA alleles as restricting elements. Thus, CD40-B cells transduced retrovirally with Ag-encoding cDNA can be potent APC and facilitate to generate Ag-specific CTL in vitro.

Alleles↗
PubMed2002

Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade.

Caspase-8 (Fas-associating protein with death domain-like interleukin-1beta- converting enzyme [FLICE]/MACH/Mch5) belongs to a family of cysteine proteases presumed to be the apex of the apoptotic signaling pathways. We recently reported the presence of a novel isoform of caspase-8, named caspase-8L, generated by the alternative splicing of human caspase-8 gene, from human peripheral blood lymphocytes by reverse transcriptase-polymerase chain reaction. We herein report a functional analysis of caspase-8L in the Fas-mediated apoptotic pathway. Caspase-8L is missing the catalytic site of caspase-8 but retains 2 N-terminal repeats of the death-effector domain. The caspase-8L messenger RNA was detected in various tissues but not in any cell lines examined. In human peripheral blood lymphocytes, caspase-8L was strongly suggested to be expressed at the protein level. In MCF-7 cells, caspase-8L transfection itself did not affect cell viability but instead inhibited the apoptosis induced by the cotransfection of caspase-8 in a dominant negative manner. Moreover, Fas-mediated apoptosis was inhibited in caspase-8L-transfected Jurkat cells, which were associated with a reduction in the caspase-8 catalytic activity. In vitro binding assays demonstrated that caspase-8L bound to FADD (Fas-associating protein with death domain) and caspase-8a and blocked the binding of caspase-8 to FADD. In in vivo binding assays, transfected caspase-8L bound to endogenous FADD. Thus, caspase-8L acts as an inhibitor of caspase-8 by interfering with the binding of caspase-8 to FADD and is involved in the regulation of Fas-mediated apoptosis.

Amino Acid Sequence↗
PubMed2002

Expression of minor histocompatibility antigen, HA-1, in solid tumor cells.

BACKGROUND: Minor histocompatibility antigen (mHag) induces and mounts graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Among several mHags, HA-1 is one that acts alone and is the most studied. It is suggested that HA-1 may be one of the immunodominant antigens inducing not only graft-versus-host disease but also graft-versus-malignancy effects. There are some reports that mHag HA-1-specific cytotoxic T lymphocytes generated from an HA-1-negative donor can lyse HA-1-positive leukemic cells. However, the tissue distribution of HA-1 has been described as restricted to the cells of the hematopoietic lineage. METHODS: We examined the HA-1 expression in peripheral blood mononuclear cells (PBMNC), leukemia/lymphoma cell lines, solid tumor cell lines, and paired samples of tumor and normal tissues from individual cancer patients by quantitative reverse-transcription polymerase chain reaction. RESULTS: We found that mRNA of HA-1 is expressed in all leukemia/lymphoma cell lines and PBMNC. Most of the leukemia/lymphoma cell lines have the same levels of HA-1 expression as a leukemia/lymphoma cell line, Raji. The expression levels of human PBMNC were 14- to 19-fold higher than those of Raji. Among 32 solid tumor cell lines, 7 showed >50% expression levels compared with Raji. CONCLUSIONS: HA-1 expression in the mRNA level is higher in cells of hematopoietic origin, but this tissue distribution is not strictly restricted. Some solid tumor cells and tissues express HA-1 gene equal to hematopoietic cells.

Base Sequence↗
PubMed2002

Partial impairment of interleukin-12 (IL-12) and IL-18 signaling in Tyk2-deficient mice.

Tyk2 is activated in response to interleukin-12 (IL-12) and is essential for IL-12-induced T-cell function, including interferon-gamma (IFN-gamma) production and Th1 cell differentiation. Because IL-12 is a stimulatory factor for natural killer (NK) cell-mediated cytotoxicity, we examined whether tyk2 is required for IL-12-induced NK cell activity. IL-12-induced NK cell activity in cells from tyk2-deficient mice was drastically reduced compared to that in cells from wild-type mice. IL-18 shares its biologic functions with IL-12. However, the molecular mechanism of IL-18 signaling, which activates an IL-1 receptor-associated kinase and nuclear translocation of nuclear factor-kappaB, is different from that of IL-12. We next examined whether biologic functions induced by IL-18 are affected by the absence of tyk2. NK cell activity and IFN-gamma production induced by IL-18 were reduced by the absence of tyk2. Moreover, the synergistic effect of IL-12 and IL-18 for the production of IFN-gamma was also abrogated by the absence of tyk2. This was partially due to the absence of any up-regulation of the IL-18 receptor treated with IL-12, and it might suggest the presence of the cross-talk between Jak-Stat and mitogen-activated protein kinase pathways in cytokine signaling.

Animals↗
PubMed2002

Expression of AIRE gene in peripheral monocyte/dendritic cell lineage.

The responsible gene for autoimmune polyglandular syndrome type 1, known as autoimmune regulator (AIRE), was identified by positional cloning. The AIRE gene was reported to be expressed in the thymus medulla and lymph nodes. However, an expression of the AIRE gene in peripheral blood cells has not yet been reported. In the present study, we found that the AIRE gene was restrictively expressed in peripheral CD14-positive monocytes but not in CD4-positive T cells nor polymorphonuclear cells, as assessed by RT-PCR. Moreover, immunocytochemical study revealed the expression of the AIRE protein not only in CD14-positive monocytes but also in differentiated dendritic cells, cultured in RPMI1640 medium containing 800 U/ml GM-CSF, 1000 U/ml IL-4 and 100 U/ml TNF-alpha. Thus, it was concluded that the AIRE gene is restrictively expressed in the peripheral monocyte/dendritic cell lineage.

Cell Lineage↗
PubMed2002

Cellular processing of a multibranched lysine core with tumor antigen peptides and presentation of peptide epitopes recognized by cytotoxic T lymphocytes on antigen-presenting cells.

We showed that pRL1a multiple antigen peptide (MAP)-sensitized dendritic cell (DC) and P815 cell lysis by pRL1a-specific B-24 CTL was blocked by incubating target cells at 4 degrees C during sensitization. The finding suggested that pRL1a MAP was mostly internalized in DC and P815 cells and produced pRL1a peptide epitopes for presentation with H-2L(d). Furthermore, we showed that sensitization with pRL1a MAP was inhibited by the addition of chloroquine, cycloheximide, and brefeldin A to the culture, but not by the addition of inhibitors for lysosomal proteases or proteasome. Inhibition of sensitization by the addition of chloroquine to the culture suggested the requirement of acidification of the endosomal compartment for pRL1a MAP processing. Inhibition of sensitization by the addition of cycloheximide and brefeldin A to the culture indicated the requirement of newly generated MHC class I antigen molecules and the involvement of transport of the peptide MHC class I complex from the endoplasmic reticulum to the Golgi. The findings suggested that pRL1a MAP in the endosomal compartment leaked to the cytosol, and degraded, and the pRL1a peptide produced was presented by the MHC class I pathway.

Animals↗
PubMed2002

Multiple sclerosis associated with interferon-alpha therapy for chronic myelogenous leukemia.

We report a chronic myelogenous leukemia (CML) patient in chronic phase (CP) who developed multiple sclerosis (MS) in association with interferon-alpha (IFN-alpha) administration. In our patient, recombinant IFN-alpha2b therapy induced hematologically complete and cytogenetically major partial response for CML first, and sequential central nervous system dysfunction evolved, which subsided shortly after the cessation of its administration. Restarting IFN-alpha therapy by changing to a natural type of IFN-alpha resulted in rapid exacerbation of MS. The patient's neurological symptoms progressed gradually, but partial hematologic response persisted without any IFN-alpha derivatives or anti-cancer agents until a matched unrelated donor transplant procedure was performed. Myeloablative therapy led to lasting stable state of MS and finally to complete cytogenetic remission of CML. This patient's presenting clinical course and laboratory data suggest that both exertion of anti-leukemic activity and autoimmune process of MS might be mediated by mutual mechanisms, such as enhancement of specific cellular immunity induced by IFN-alpha.

Adult↗