[Stem cell transplantation for chronic myelogenous leukemia].
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Antineoplastic Agents↗
Biomedical subjects
S Okamoto
Publications and source records attributed to S Okamoto.
An adult patient with hypersensitivity to mosquito bites developing mantle cell lymphoma.
Hypersensitivity to mosquito bites (HMB) has been known to occur exclusively in the first 2 decades of life and is frequently associated with Epstein-Barr virus (EBV) infection and lymphoproliferative diseases. We report here the first adult patient with HMB, a 61-year-old Japanese man who developed mantle cell lymphoma. EBV was detected in the lymph node by polymerase chain reaction and by in situ hybridization. Serum levels of interleukin (IL)-4, IL-6, and IL-10 were markedly increased, and the T-helper cell (Th)1/Th2 balance determined by intracellular cytokine levels was polarized to Th2. These findings suggest that the Th1/Th2 imbalance could partly be involved in the pathogenesis of HMB.
Animals↗
Quality of life in adult patients after stem cell transplantation.
Many articles pertaining to quality of life (QOL) following stem cell transplantation have been published in the US and western Europe. However, since the actions of health insurance systems and overall cultural aspects are strongly associated with QOL, investigations into QOL should be carried out within all countries. Therefore, we have investigated the QOL of adult patients following stem cell transplantation at 31 hospitals in Japan. The survivors, who were surveyed by mail questionnaire, were 20 years or older at the time of this study. The underlying diseases were acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, myelodysplastic syndrome, and multiple myeloma. Median age at the time of the study was 36 years, and median interval after transplantation was 35.3 months. Of 383 patients surveyed, 282 (73.6%) responded to the questionnaire. One hundred and ninety-two patients were treated with an allogeneic-related transplantation, 52 with allogeneic-unrelated, and 38 with an autologous transplantation. Our data revealed that the length of time since transplantation and the diagnosis of chronic GVHD were associated with QOL. When unrelated and related transplantation recipients were compared, ratings on relief from pain, stability in weight, and confidence in dealing with daily life were lower among unrelated transplantation patients.
Adolescent↗
[Assessment of most appropriate background subtraction method for quantification of 123I-metaiodobenzylguanidine (MIBG) myocardial uptake by comparing with plasma ANP and BNP].
BACKGROUND: Quantification of 123I-metaiodobenzylguanidine (MIBG) myocardial uptake is widely accepted as a useful tool for estimating the severity of congestive heart failure. However, most reliable method has not been determined yet because of the difficulty of background (BG) subtraction. In this study, the most appropriate BG subtraction method was evaluated as compared with plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), norepinephrine (NEP) and left ventricular ejection fraction (LVEF). METHODS: Twenty-one patients with chronic heart failure were examined. After bolus injection of 123I-MIBG (111 MBq), dynamic anterior chest images were collected every second for 2 minutes. Planar anterior chest images were obtained 15 minutes (early image) and 4 hours later (delayed image) respectively. The parameters for quantification of 123I-MIBG myocardial uptake used in this study were heart to mediastinum ratio (H/M), myocardial washout rate and uptake ratio. Background was calculated using the region of interest (ROI) placed over a part of upper mediastinum, whole upper mediastinum, right lung and pericardial space respectively. The values of these parameters were calculated with and without BG subtraction and compared with plasma ANP, BNP and others. RESULTS: H/M did not correlate with ANP or BNP. Myocardial washout rate without BG subtraction showed significant correlation with ANP (p < 0.01) and BNP (p < 0.05). After BG subtraction employing ROI placed over the part of upper mediastinum and whole upper mediastinum, myocardial washout rate showed better correlation with BNP (p < 0.01). Myocardial uptake ratio did not showed any correlation with ANP or BNP without BG subtraction. However, myocardial uptake ratio showed significant correlation with BNP (p < 0.05) after subtraction of upper mediastinal BG. BG subtraction using ROI over right lung or pericardial area revealed poor results in both myocardial washout rate- and uptake ratio. CONCLUSION: BG subtraction using ROI over the upper mediastinum is likely to be suitable for quantitative analysis of 123I-MIBG myocardial scintigram.
3-Iodobenzylguanidine↗
[Idiopathic hyperammonemia following allogeneic bone marrow transplantation for refractory lymphoma].
Idiopathic hyperammonemia (IHA) is a rare but serious complication of stem cell transplantation. We report a patient with immunoblastic lymphoadenopathy-like T-cell lymphoma who developed IHA 10 days after allogeneic bone marrow transplantation from an HLA-matched unrelated donor. Despite intensive supportive care, the patient died due to this metabolic disorder two days later. Being mindful of the possibility of IHA in patients who develop confusion and respiratory alkalosis soon after stem cell transplantation would allow earlier treatment and might improve the chance of survival.
Bone Marrow Transplantation↗
Absence of binding activity of neuron-restrictive silencer factor is necessary, but not sufficient for transcription of NMDA receptor subunit type 1 in neuronal cells.
Neuron-restrictive silencer factor (NRSF, also termed REST) has been proposed to restrict expression of a set of genes to neurons by blocking their transcription in nonneuronal cells. The N-methyl-D-aspartate (NMDA) receptor subunit type I (NR1) gene contains a consensus sequence for the NRSF/REST binding site (NRSE/RE1). In this study, we evaluated the contribution of NRSF/REST to neuronal specificity of the NR1 gene. NR1 mRNA expression correlates with the absence of NRSF/REST binding activity, rather than expression of NRSF/REST protein, in several cell lines, suggesting that the absence of NRSF/REST-binding activity is necessary for the expression of the NR1 gene. HeLa cells, which do not express the NR1 gene, have NRSF/REST binding activity to the NR1 NRSE/RE1, resulting in inhibition of NR1 promoter activity. However, we also found that two nonneuronal cell lines (C6 glioma and P19 embryonal carcinoma) that lack NRSF/REST-binding activity, manifest only small amounts of NR1 mRNA compared to neuronal cell lines (PC12 pheochromocytoma and neuronally differentiated P19 cells). The enhancement of NR1 mRNA levels during neuronal differentiation of P19 cells is accompanied by an increase in NR1 promoter activity in an NRSF/REST-binding independent manner. Our results suggest therefore that the absence of NRSF/REST-binding activity is necessary but not sufficient for robust NR1 transcription in neuronal cells.
Animals↗
Cancer gene therapy with HSV-tk/GCV system depends on T-cell-mediated immune responses and causes apoptotic death of tumor cells in vivo.
To examine the immunological mechanisms involved in cancer gene therapy using the herpes simplex virus thymidine kinase (HSV-tk) gene and ganciclovir (GCV), murine hepatocellular carcinoma (HCC) cells, BNL1ME A.7R.1, were transduced retrovirally with the HSV-tk gene. HSV-tk-transduced cells exhibited a more than 2,000-fold higher sensitivity to GCV compared with untransduced parental cells. When HSV-tk-transduced HCC cells were mixed with parental cells at a 50% ratio and implanted subcutaneously into immunocompetent syngeneic mice, complete inhibition of tumor formation was achieved by GCV treatment. Conversely, no significant inhibitory effects on tumor formation were observed in athymic nude mice. When established solid tumors in immunocompetent mice containing HSV-tk-transduced cells at an only 5% ratio were treated with GCV, marked infiltration by lymphocytes including CD4(+) and CD8(+) ones, and apoptotic death of tumor cells were induced, and significant reduction or even complete regression of tumors was achieved. Furthermore, such cured mice rejected rechallenge with parental HCC cells into the contraflank regions. Our results indicate that cancer gene therapy with the HSV-tk/GCV system can indeed induce efficient antitumor effects and protective immunity in immunocompetent mice but not in nude mice, indicating that T-cell-mediated immune responses may be a critical factor for achieving successful gene therapy against cancer using the HSV-tk/GCV system.
Animals↗
Experimental analysis of recently transposed insertion sequences in the cyanobacterium Synechocystis sp. PCC 6803.
The genome DNA of the cyanobacterium Synechocystis sp. PCC 6803 carries a number of insertion sequences (Kaneko, T. et al. 1996, DNA Res., 3, 109-136). We analyzed one of the abundant ISs (ISY203 group of IS4 family) in the common three substrains of Synechocystis and found that the four ISs with identical nucleotide sequences were present only in the "Kazusa" strain, whose complete genome sequence had been determined, while absent in ancestral strains (the original strain from Pasteur Culture Collection and its glucose-tolerant derivative). Three of these ISs were found in the genomic sequence as transposase genes of sll1474, sll1780 and slr1635. The fourth was on the plasmid, pSYSM. On the other hand, all three strains had a novel IS (denoted ISY203x), of which the nucleotide sequence was totally identical to the four ISs found only in the Kazusa strain. Since the flanking regions of ISY203x did not match any part of the genome or of the known plasmids of Synechocystis, it is presumably located on a yet uncharacterized plasmid. These suggest that the four ISs in Kazusa strain were recently transposed from ISY203x. Apparently, the transposition inactivated four preexisting genes, of which modified forms are presented as putative genes (sll1473, sll1475, slr1862, slr1863, slr1635 and ssl2982) in the list of the complete genome (CyanoBase: http://www.kazusa.or.jp/cyano/cyano.html). The possible effects of transposition of ISs in Synechocystis are discussed in relation to phenotypic mutations and microevolution.
Amino Acid Sequence↗
Cellular source(s) of platelet-activating-factor acetylhydrolase activity in plasma.
Platelet activating factor (PAF) is immediately degraded and inactivated in the bloodstream by plasma PAF acetylhydrolase (PAF-AH). Although plasma PAF-AH-like activity was secreted in vitro from various cell types such as macrophages and hepatocytes, the exact cellular source(s) of this enzyme activity in vivo remains unclear. There is a naturally-occurring missense mutation (V279F) in the plasma PAF-AH gene in the Japanese population which results in complete loss of the enzyme activity. We analyzed 52 Japanese who had received an allogeneic bone marrow transplant and maintained donor-derived hematopoiesis. Ten recipients had chimeric plasma PAF-AH genotypes between the donor-derived peripheral blood leukocytes and the recipient-derived epithelial cells of buccal mucosa. Multiple regression analysis demonstrated that PAF-AH activity in plasma depended on the donor's genotype (standardized regression coefficient = 0.68, P < 0.0001), but not on the recipient's genotype (p = 0.48). One recipient who was a V279F homozygote in leukocytes and wild type homozygote in buccal mucosa had undetectable PAF-AH activity in plasma. We conclude that most of the PAF-AH activity in human plasma originates from hematopoietic lineage cells.
1-Alkyl-2-acetylglycerophosphocholine Esterase↗
Overexpression of Fas ligand does not confer immune privilege to a pancreatic beta tumor cell line (betaTC-3).
BACKGROUND: Fas ligand (Fas-L) is thought to provide immune privilege to specific tissues and tumors by inducing an apoptotic signal of cytotoxic T cells expressing its Fas receptor. Purpose. The purpose of this work was to evaluate whether an immortalized insulin-secreting cell line (betaTC-3) gains immune privilege by inducing overexpression of Fas-L. METHODS: A lipofection technique was used to transfect a betaTC-3 tumor cell line with a plasmid (pcDNA3.1/Zeo) carrying the Fas-L gene and a zeocin resistance gene. Insertion of Fas-L into betaTC was characterized by reverse transcription polymerase chain reaction (RT-PCR) and the ability of transfectants (betaTC-3/Fas-L) to induce apoptosis of Fas-sensitive T cells. Transfectants and control cells were tested for insulin secretion following which 1 x 10(6) insulin-secreting betaTC-3 and betaTC-3/Fas-L cells were subcutaneously implanted into syngeneic, allogeneic, and Fas mutant (lpr) syngeneic mice. Survival of the insulin-secreting cells was then determined by monitoring serum glucose levels in recipients. RESULTS: Successful transfection of vector resistance gene was achieved in the transfected betaTC-3 cells, which was confirmed by zeocin resistance. RT-PCR in resistant Fas-L clones confirmed the transcription of Fas-L, which was absent in controls. Fas-L transfectants induced 20 +/- 4.2% apoptosis of Fas-sensitive T cells, while controls induced 3.47 +/- 2.3% by flow cytometry (P = 0.04, n = 3). Insulin secretion was equivalent in both betaTC-3 and betaTC-3/Fas-L cells. Syngeneic mice implanted with control betaTC-3 cells died within 3 weeks from hypoglycemia due to overgrowth of betaTC-3 tumor. Implanted Fas-L transfected betaTC-3 cells were killed and had no effect on glycemic status except in Fas mutant hosts, where tumors formed in two of three mice. CONCLUSIONS: Despite the ability of transfected betaTC-3 cells to induce apoptosis of T cells in vitro, expression of Fas-L provided no immune privilege to these cells in vivo, but paradoxically induced killing of betaTC-3 cells even in syngeneic hosts.
Animals↗
Expression of galectin-3 in fine-needle aspirates as a diagnostic marker differentiating benign from malignant thyroid neoplasms.
BACKGROUND: Galectin-3 is a beta-galactoside-binding protein that has been reported to be expressed preferentially in thyroid malignancies. The current study was designed to substantiate this finding further and to establish a presurgical diagnostic modality of differentiating between benign and malignant thyroid neoplasms by analyzing galectin-3 expression in fine-needle aspirates. METHODS: The expression of galectin-3 was examined immunohistochemically in total of 172 specimens: 45 primary and 20 metastatic papillary carcinomas, 8 primary and 2 metastatic follicular carcinomas, 5 primary and 3 metastatic anaplastic carcinomas, 3 primary medullary carcinomas, 25 follicular adenomas, 3 goiters, and 58 adjacent normal thyroid tissue. Alternatively, epithelial cells were isolated from the fine- needle aspirates of 14 thyroid nodules and subjected to immunoblotting analysis of galectin-3. RESULTS: Immunohistochemical analysis revealed that all thyroid malignancies of follicular cell origin (including papillary, follicular, and anaplastic carcinomas) showed high and diffuse expression of galectin-3, whereas one of the three medullary carcinomas of parafollicular cell origin displayed weaker and focal expression of galectin-3. In contrast, neither benign thyroid adenomas, goiters, nor normal thyroid tissues expressed galectin-3. Immunoblot analysis of the isolated epithelial cells detected galectin-3 in nine thyroid nodules that were proven histologically to be malignant ( eight papillary carcinomas and one follicular carcinoma) after surgical intervention, whereas galectin-3 was not detected in five nodules proven to be benign follicular adenomas. CONCLUSIONS: Galectin-3 serves as a marker of thyroid malignancy of follicular cell origin. Analysis of galectin-3 expression in fine-needle aspirates enhances the differential diagnostic accuracy between benign and malignant thyroid neoplasms.
Antigens, Differentiation↗
Complete DNA sequence and characterization of a 330-kb VNTR-rich region on chromosome 6q27 that is commonly deleted in ovarian cancer.
We report the complete genomic DNA sequence and the characterization of a 330-kb region on chromosome 6q27 that is often deleted in ovarian cancers. Using computer programs to predict exonic sequences, we isolated four novel genes, HGC6.1-4, as well as the known AF-6 gene. None of the deduced products of the novel genes exhibited significant homology to previously known proteins. We also identified ten microsatellites and 12 different VNTR sequences within the target region. HGC6.3 contained a VNTR within a coding exon, each repeat consisting of 42 nucleotides; the predicted 14-amino-acid consensus unit is MTPTVFSSQHTAGG. At least nine different sizes of this VNTR locus were detected among 20 unrelated DNA samples from caucasians. The polymorphic markers and the transcript map documented here may contribute to identification of novel genes or allelic aberrations associated with the development of ovarian cancers.
Amino Acid Sequence↗
Activation of Xenopus eggs by proteases: possible involvement of a sperm protease in fertilization.
Egg activation in cross-fertilization between Xenopus eggs and Cynops sperm may be caused by a protease activity against Boc-Gly-Arg-Arg-MCA in the sperm acrosome. To determine the role of the sperm protease in fertilization, the protease was purified from Cynops sperm using several chromatographic techniques. We found that purified sperm protease readily hydrolyzes Boc-Gly-Arg-Arg-MCA and Z-Arg-Arg-MCA, that protease activity was inhibited by the trypsin inhibitors aprotinin and leupeptin, and that not only the purified protease, but also cathepsin B, induces activation in Xenopus eggs. We inseminated unfertilized Xenopus eggs with homologous sperm in the presence of various peptidyl MCA substrates or protease inhibitors and demonstrated that trypsin inhibitors or MCA substrates containing Arg-Arg-MCA reversibly inhibited fertilization of both fully jellied and denuded eggs. Sperm motility was not affected by the reagents. An extract obtained from Xenopus sperm showed hydrolytic activity against Boc-Gly-Arg-Arg-MCA, Z-Arg-Arg-MCA, and Arg-MCA. These results suggest that the tryptic protease in Xenopus sperm is involved in fertilization, most likely by participating in egg activation.
Animals↗
Stimulation side-dependent asymmetrical secretion of poly I:poly C-induced interferon-beta from polarized epithelial cell lines.
Mode of secretion of poly I:poly C-induced IFN was examined using epithelial cell lines in a bicameral culture system. Although the cell lines formed a tight cell sheet and produced IFN-beta following poly I:poly C treatment in spite of its application to the upper or lower compartment, IFN secretion differed between the apical and basolateral cell membranes. When poly I:poly C was applied to the upper compartment, IFN was secreted predominantly from the apical membrane. Inversely, poly I:poly C applied to the lower compartment caused preferential IFN secretion from the basolateral membrane. These results suggest that in epithelial cells poly I:poly C stimulation induces intracellular membrane traffic toward the stimulation side.
Animals↗
Tense blisters after bone marrow transplantation.
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Biopsy↗
Development of plasma kallikrein selective inhibitors.
During the course of the development of active center-directed plasmin inhibitors, it was found that N-(trans-4-aminomethylcyclohexanecarbonyl)-lysine-4-methoxycarb onylanilide inhibited plasma kallikrein more potently than other enzymes such as plasmin, urokinase, and thrombin, although the inhibitory activity was not as potent and enzyme selectivity not as high. Based on studies of structure-activity relationship, we designed and synthesized the plasma kallikrein selective inhibitor, N-(trans-4-aminomethylcyclohexanecarbonyl)-phenylalanine-4-carboxy methyl- anilide (Tra-Phe-APAA). Tra-Phe-APAA inhibited plasma kallikrein with a Ki value of 0.81 microM, while it inhibited glandular kallikrein, plasmin, urokinase, tissue plasminogen activator, factor Xa, factor XIIa, and thrombin with Ki values of > 500, 390, 200, > 500, > 500 > 500, and > 500 microM, respectively. We designated Tra-Phe-APAA as PKSI-527. Using PKSI-527 as an affinity ligand, we synthesized a new affinity gel (PKSI-Toyopearl) and employed it for the rapid purification of plasma kallikrein from human plasma. Human plasma activated with kaolin after acid treatment was applied to a PKSI-527-Toyopearl column. Adsorbed protein was eluted with 50 mM glycinehydrochloric acid buffer (pH 3.0). Plasma kallikrein was purified 181-fold with a yield of 85% from the kaolin-activated plasma.
Binding Sites↗
Antimicrobial triterpenes from Ilex integra and the mechanism of antifungal action.
Antimicrobial triterpenes were isolated from the fruits of Ilex integra. Their structures were elucidated by spectral data and identified as rotundic acid (1), ulsolic acid (2) and peduncloside (3). Triterpene 1 showed significantly broad antimicrobial activity against bacteria, yeast and filamentous fungi. The antifungal activity of 1 was reversed by fatty acids. Cellular constituents leaked from Candida albicans cells incubated with triterpene 1. These results suggest that the antimicrobial activity of triterpenes in I. integra is due to a change of membrane permeability arising from membrane lipid alteration.
Antifungal Agents↗
A synthetic mimetic of CD4 is able to suppress disease in a rodent model of immune colitis.
CD4+ mucosal T cells mediate the intestinal inflammation in Crohn's disease and may serve as an important target for immune intervention. Here we assessed the therapeutic effect of a synthetic mimetic of CD4 designed to mimic both the sequence and conformation of the complementarity-determining region 3 of murine CD4 V1 domain (rD-mPGPtide) in a mouse colitis model using immunization with 2,4,6-trinitrobenzene sulfonic acid (TNB). i.v. administration of the rD-mPGPtide but not control scrambled peptide could suppress severe inflammation in the chronic colitis mouse model. After treatment with the rD-mPGPtide, a striking improvement of diarrhea and acute wasting disease was observed with decreased mortality. Serum anti-TNB antibody titers, CD45RBlowCD4+ T cells in the lamina propria and IFN-gamma mRNA expression in the mucosa were significantly decreased with the rD-mPGPtide treatment. Anti-CD4 antibody also suppressed disease by depletion of CD45RBhighCD4+ T cells in the colonic mucosa. The observation that the synthetically engineered analogue of murine CD4 inhibits inflammation in a rodent disease model by different mechanisms than anti-CD4 antibody suggests that a human version of this peptide has potential therapeutic utility in CD4+ mucosal T cell-mediated intestinal inflammation in Crohn's disease.
Animals↗