Biomedical subjects
Publications and source records attributed to T Tamura.
In our previous studies, uracil was identified as the active principle from Trionyx carapax. The protective effects of other nucleic acid components, and of xanthine are further investigated.
The transcription factor IRF-1 has been shown to function as a tumor suppressor. Here we report that a significant proportion of the IRF-1 mRNA detected in normal human hematopoietic cells and cultured cell lines lacks exon 2 (containing the AUG initiation codon) and 3 as a result of exon skipping. Surprisingly, when we examined the bone marrow and peripheral mononuclear cells from patients with myelodysplastic syndrome (MDS) or leukemia secondary to MDS, we could still detect the exon-skipped form but little or none of the intact IRF-1 mRNA. This appears to be the result of accelerated exon skipping since we could find no mutations within the exons and splicing junctions from these patients. The exon-skipped form of IRF-1 lacking exons 2 and 3 displayed neither DNA binding nor tumor suppressive activities. Thus this accelerated exon skipping may cause the inactivation of IRF-1 and thereby contribute to the development of human hematopoietic malignancies.
A recent approach in the treatment of limited-stage small cell lung cancer (LDSCLC) has involved a combined modality of chemotherapy and chest irradiation. In using the modality, the study of scheduling methods for combining chemotherapy and radiotherapy should lead to other trials of combined modalities against LDSCLC since it is the most basic issue to be evaluated. We have thus conducted a multicenter phase II trial of concurrent cisplatin-etoposide (PVP) chemotherapy and radiotherapy for LDSCLC to determine the effects of the concurrent administration of a PVP regimen and chest irradiation on response rate, relapse, survival and treatment toxicity. The chemotherapy regimen consisted of a four-week cycle: cisplatin (80 mg/m2, given intravenously on day 1) and etoposide (100 mg/m2, given intravenously on days 1-3). This cycle was given four to six times within six months. Chest irradiation to the primary tumors at both the hili and the mediastinum was administered in standard fractions on days 2-12 in the first cycle of chemotherapy and on days 29-47 in the second cycle, with a total dose of 40-50 Gy. Prophylactic cranial irradiation was performed among complete remission (CR) or good partial remission (PR) patients after completion of the concurrent therapy. A total of 66 patients were entered into the trial and 59 were evaluated. The concurrent therapy induced an overall response rate of 94.9% in 59 patients: 24 patients, 40.7% CR, 32 patients, 54.2% PR. The median response duration was 8.7 months, and the median survival time for all eligible patients was 14.8 months. The percentage of patients with two-year survival periods was 20. A local relapse within the irradiated area was seen in only 22% of relapse patients. Brain metastases occurred in 24% of patients. Four of 32 patients treated with prophylactic cranial irradiation had brain metastases. Toxic effects, chiefly grades 3 and 4 leukopenia, as established by the World Health Organization, were detected in all treated patients. Other toxicities, including radiation-induced esophagitis and pneumonitis, were deemed almost acceptable. We concluded concurrent treatment of a PVP regimen with chest irradiation to be a feasible and beneficial therapy with an efficacy compatible to that of other published reports. The outcome of this protocol warrants further investigation to determine the optimal type of schedule for concurrent chemoradiotherapy against LDSCLC.
The effects of sympathetic beta-agonists on blood pressure and cochlear blood flow were studied in 15 guinea pigs. Cochlear blood flow was measured by a laser Doppler flowmeter, Periflux PF2 (Perimed, Sweden). Small doses (0.01 and 0.1 microgram/kg) of isoproterenol elevated blood pressure, but larger doses (10 and 50 micrograms/kg) decreased blood pressure. Cochlear blood flow showed a biphasic pattern, in that there was an initial decrease with a subsequent increase. Dobutamine, a beta 1-agonist, elevated blood pressure and increased cochlear blood flow in a dose-dependent manner. Salbutamol, a beta 2-agonist, decreased blood pressure in a dose-dependent manner and induced a biphasic pattern of changes (i.e., an initial decrease with a subsequent increase). The effect of isoproterenol, which is a nonselective beta-agonist, is oriented more to a beta 2-agonist at larger doses. These different effects induced by isoproterenol are probably due to a balance of dominance between beta 1 action and beta 2 action at different doses.
Bacteriological and clinical studies were carried out on staggered intensive chemotherapy regimen for methicillin-resistant Staphylococcus aureus (MRSA) infections combined with Gram-negative opportunistic pathogens as polymicrobial infections. The regimen consisted of administering ceftazidime (CAZ) 30 minutes after infusion of arbekacin (ABK) and a bolus injection of fosfomycin (FOM). The combination of these drugs strongly inhibited the growth of MRSA and Pseudomonas aeruginosa. By this combination treatment, both of MRSA and P. aeruginosa in mixed culture became more susceptible to killing by macrophages. We evaluated the clinical efficacy and safety of combination of ABK, FOM and CAZ in the treatment of 15 patients with MRSA infections. The total efficacy rate was 80.0% and the bacterial eradication rate of MRSA was 60.0%. It is considered that staggered intensive chemotherapy with ABK, FOM and CAZ is useful for such polymicrobial infections involving MRSA.
We examined the vitreous change after the retina was destroyed by photocoagulation. Multiple photocoagulation with continuous-wave xenon or diode laser was used to create coagulated spots with 5 disc diameters near the optic disc in 26 eyes of 13 pigmented rabbits aged four weeks. After clinical observation, the eyes were enucleated at 2 weeks and 3, 4, and 14 months after photocoagulation. The vitreous was stained with fluorescein and examined by slitlamp while immersed in water. The vitreous remained unchanged in 2 eyes at 2 weeks after photocoagulation. A liquefied lacuna of the vitreous had formed anterior to the retinal scar in 20 eyes (83%) at 3, 4, and 14 months after photocoagulation. The liquefied lacuna assumed a columnar shape with its bottom corresponding to the retinal scar in 2 eyes at 14 months after photocoagulation. These results show that localized liquefaction in the posterior vitreous can be induced by fundus photocoagulation. It appeared that the presence of a normal retina is one of the prerequisites of integrity of the vitreous in young rabbit eyes.
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We describe a case of cold agglutinin disease (CAD) following allogeneic bone marrow transplantation. This 36-year-old male developed CAD 3 weeks after allogeneic bone marrow transplantation for chronic myelogenous leukemia. Cyclosporin A and methotrexate had been administered to prevent graft-versus-host disease. Other agents administered included cytomegalovirus hyperimmune globulin and recombinant human G-CSF. Pericarditis preceded the development of CAD. The characterization of cold agglutinin (CA) was monoclonal IgM-kappa with anti-Pr antigen specificity, probably derived from the engrafted donor lymphocytes. The administration of prednisolone led to transient improvement. The CA titer decreased without further treatment 12 weeks after transplant.
Autopsy findings of pulmonary arteriovenous fistula (PAVF) was initially described by Churton in 1897. Since then, several hundreds of cases have been reported in Europe and the United States. In Japan, there has recently been an increase in case reports of PAVF. PAVF seems to be no longer a rare disorder in Japan. Several morphological classifications of PAVF have been reported. One of these classifies PAVF into 1) solitary types 2) multiple types and 3) diffuse telangiectasia. Another, for example, classifies the disorder into the following 3 types: 1) multiple telangiectasia 2) pulmonary arterial aneurysm and 3) pulmonary artery-left atrial communications. Many other classifications have been proposed. In the solitary type (PA aneurysmal type), fistulas are located at the relatively large, central vessels. Here we report a case of PAVF which presented not as a solitary aneurysm but rather as a distended and tortuous anomalous vessel.
A feasibility study on the vibratory perception threshold (VPT) in normal volunteers was conducted to detect anti-cancer drug induced peripheral neuropathy. The VPT was found to increase with age. The mean VPT in the main hand in 25 normal volunteers was significantly higher than in the other hand. No variation of VPT was observed in one day or one week. Variation of VPT in the lower extremities was detected between two examiners. In conclusion, the measurement of VPT was expected to be useful for the detection of anti-cancer drug induced peripheral neuropathy, if there is one examiner and the examined hand is specified.
The nucleotide sequence of a cDNA that encodes a new subunit, named RC10-II, of the 20S proteasome of rat embryonic brain has been determined. The polypeptide predicted from the open reading frame consists of 205 amino acid residues with a calculated molecular weight of 22,965 and isoelectric point of 6.15. Computer analysis showed that RC10-II belongs to the beta-type subgroup of proteasomes, differing clearly from alpha-type subunits of the proteasome gene family. The primary structure of RC10-II was found to contain the partial amino acid sequences of several fragments of subunit 13, which has a cysteinyl residue critical for the trypsin-like catalytic activity, as reported by L. R. Dick et al. [Biochemistry 31, 7347-7355, 1992], suggesting that RC10-II is a proteasomal subunit necessary for the expression of tryptic activity.
It has been reported that soluble interleukin (IL)-6 receptor (sIL-6R) is detected in the serum of healthy individuals and its level is increased in patients with multiple myeloma and human immunodeficiency virus infection. Although several reports have suggested that sIL-6R potentiates IL-6 action, its physiological role remains unclear. In this study, we examined the role of sIL-6R on osteoclast formation by IL-6, using a coculture of mouse osteoblasts and bone marrow cells. Neither recombinant mouse IL-6 (mIL-6) nor mouse sIL-6R (smIL-6R) induced osteoclast-like multinucleated cell (MNC) formation when they were added separately. In contrast, simultaneous treatment with mIL-6 and smIL-6R strikingly induced MNC formation. These MNCs satisfied major criteria of authentic osteoclasts, such as tartrate-resistant acid phosphatase (TRAP) activity, calcitonin receptors, and pit formation on dentine slices. The MNC formation induced by mIL-6 and smIL-6R was dose-dependently inhibited by adding monoclonal anti-mouse IL-6R antibody (MR16-1). It is likely that osteoblasts and osteoclast progenitors are capable of transducing a signal from a complex of IL-6 and sIL-6R through gp130, even though they may have no or a very small number of IL-6Rs. Factors such as IL-11, oncostatin M, and leukemia inhibitory factor, which are known to exert their functions through gp130 (the signal-transducing chain of IL-6R), also induced MNC formation in our coculture system. These results suggest that increased circulating or locally produced sIL-6R induces osteoclast formation in the presence of IL-6 mediated by a mechanism involving gp130. This may play an important physiological or pathological role in conditions associated with increased osteoclastic bone resorption.
To elucidate Th2 cell clone activation mechanism through TCR-CD3 complex, we examined the reactivity of Th2 cell clones to soluble anti-CD3 in the absence of accessory cells or costimulator. The soluble anti-CD3 stimulated IL-4 production of Th2 cell clones as efficiently as specific Ag. IL-4 production of Th2 cell clones was consistent with the elevation of intracellular free Ca2+ concentration ([Ca2+]i). The elevation was slow and sustained but occurred consistently after the anti-CD3 stimulation in all Th2 cell clones tested. The [Ca2+]i elevation appeared to depend on Ca2+ influx because it could not be observed in Ca(2+)-free medium. Several chemicals such as cholera toxin, neomycin, and herbimycin A, which have been shown to block phosphatidylinositol-4,5-bisphosphate (PIP2) breakdown pathway or protein tyrosine kinase activation, exerted no effect on the IL-4 production. In accordance with these findings, neither PIP2 breakdown nor protein tyrosine phosphorylation was observed in Th2 cell clones stimulated with anti-CD3. The inclusion of anti-CD4 in culture and the depletion of protein kinase C (PKC) did not affect IL-4 production of Th2 cell clones either. These findings support a hypothesis that Th2 cell clones use a signaling pathway for IL-4 production that is independent of protein tyrosine kinase, PIP2 breakdown or PKC, and that the [Ca2+]i elevation is the only pathway common to an IL-2 production of Th1 cell subset.
The nucleotide sequence of a cDNA that encodes a new subunit, named RC7-I, of the 20 S proteasome of rat hepatoma cells has been determined. The polypeptide predicted from the open reading frame consists of 201 amino acid residues with a calculated molecular weight of 22,912 and isoelectric point of 7.25. Approximately 80% of the partial amino acid sequences of several fragments of RC7-I, determined by protein chemical analyses, were found to be in excellent accordance with those deduced from the cDNA sequence. Computer analysis showed that RC7-I belongs to the beta-type subgroup of proteasomes with similarity to the beta-subunit of the archaebacterial proteasome, differing clearing from alpha-type subunits of the proteasome gene family. The overall structure of RC7-I was found to be homologous to that of yeast PRE1, which is necessary for chymotryptic activity.
A series of spirooxazolidine-2,4-dione derivatives related to the putative M1 agonist 2-ethyl-8-methyl-2,8-diazaspiro[4.5]decane-1,3-dione (RS86; 1) were synthesized. The compounds were evaluated as cholinergic agents in in vitro binding assays and in in vivo pharmacological tests including antiamnesic effects using scopolamine-treated mice, hypothermia, and salivation in mice. Four compounds (5a,c,f and 17a) exhibited affinity for cortical M1 receptors and reversed scopolamine-induced impairment of mouse passive avoidance tasks, as did 1. Among these compounds, only 5a exhibited M1-receptor stimulating activity in pithed rats. Structural requirements for muscarinic activity in this series of spirooxazolidine-2,4-dione derivatives were as strict as those reported for spirosuccinimide derivatives including 1. The antiamnesic dose of 3-ethyl-8-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2,4-dione (5a) was 2 orders of magnitude lower than the doses inducing hypothermia and salivation, in contrast to 1 for which the former dose was only 5-10-fold lower than the latter. These results suggest that the 8-azaspiro[4.5]decane skeleton represents a useful template for designing new muscarinic agonists as antidementia drugs.
Mos, the c-mos proto-oncogene product, is a key regulator of cell cycle progression. Recently, rapid turnover of Mos in an early stage of meiotic maturation of Xenopus oocytes was found to be mediated by the ubiquitin pathway, but the protease responsible for its breakdown was not identified. In the present study, we found that 35S-labeled Mos synthesized in an in vitro transcription/translation system was degraded ATP- and time-dependently by the 26S proteasome, but not by the 20S proteasome, in the presence of a ubiquitin-ligation system. The 26S proteasome did not degrade a mutant Mos in which Ser3 was replaced by Asp3 that is metabolically stable in oocytes, indicating a similarity in the proteolytic events in vivo to those observed in vitro in the present work. This is the first demonstration that the proteasome catalyzes the ATP-dependent degradation of a naturally occurring, short-lived oncoprotein by the ubiquitin pathway. This finding suggests that the proteasome may regulate the intracellular stability of various oncoproteins.
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In order to clarify the effects of estrogen on cholinergic basal forebrain neurons, a cholinergic neuron in the diagonal band nucleus of the female fetal rat was implanted into the anterior eye chamber of the female adult rat. Some host rats were treated with 2mg estradiol valerate (E2v) injected every 3 days after ovariectomy while others were not 2 and 4 weeks after transplantation, the growth of cholinergic neurons in the graft was studied using acethylcholinesterase (AChE) histochemistry. At 2 weeks after transplantation, AChE positive neurons and fibers were densely distributed in the grafts of E2v treated rats. Also in grafts without E2v treatment, AChE positive neurons and fibers were found in all the grafts although their density was low. At 4 weeks, AChE staining was dense staining observed in both groups. These results indicate that neurotrophic effect of estrogen on the cholinergic basal forebrain neurons.