Biomedical subjects
Publications and source records attributed to M Mori.
We isolated a plant homologue of Tcp-1 (t complex polypeptide 1) cDNA from Arabidopsis thaliana. It encodes a 545-amino acid (aa) protein, which has extensive aa and nucleotide sequence homology to the corresponding proteins of mouse, yeast, fruit fly and archaebacteria.
BACKGROUND: DNA content of malignant tumors has been considered a significant prognostic factor, but intratumor variations in DNA content and differences in DNA content between primary and metastatic lesions have been found in various tumors. METHODS: DNA indexes of multiple samples obtained from different sites in each tumor were determined by flow cytometry (FCM) in 27 esophageal squamous cell carcinomas. RESULTS: Intratumor variation in DNA indexes in primary lesions was found in 10 (37%) of the 27 specimens. Of the rest, all DNA indexes were diploid in 5 and all identically aneuploid in 12 samples. A DNA index differing from that of the metastatic lesion was found in four (50%) of eight primary lesions; however, a component of the DNA index identical to that of metastatic lesion was found in seven (88%) of eight primary lesions. CONCLUSIONS: Recurrence after a "curative" operation was frequent in patients with a tumor that had an aneuploid DNA index, with or without a variation in DNA indexes. There was no recurrence in the five patients with tumors that had only a diploid DNA index. These results suggest that differences in DNA content between primary and metastatic lesions reflect intratumor variation in DNA content in the primary lesions. The presence of a tumor cell population with an aneuploid DNA content, even when the DNA content varied in the primary lesion, may indicate an aggressive clinical course in patients with esophageal squamous cell carcinoma.
The effects of dexamethasone on the modulation of insulin secretion by recombinant human interleukin-1 beta (IL-1) were examined in HIT-T 15 cells. The addition of IL-1 from 1.2 x 10(-8) to 10(-10) M increased insulin secretion in the 0-4-h period after IL-1 administration and prostaglandin E2 (PGE2) production was suppressed by IL-1 from 1.2 x 10(-8) to 10(-12) M. At all doses used, IL-1 inhibited insulin secretion in the 4-24-h period after IL-1 administration and PGE2 levels were increased in the culture medium. In the second experiment, the addition of 10(-7) M dexamethasone prevented the inhibitory effects of IL-1 on insulin secretion. In the third experiment, dexamethasone at 10(-7) M attenuated both the short-term stimulation of insulin release and the long-term suppression of insulin release caused by IL-1. It also prevented the effects of IL-1 on PGE2 production. The present studies suggest that dexamethasone may have a suppressive action on the effects of IL-1 on in vitro insulin secretion.
Interleukin-1 beta (IL-1), a cytokine released from inflammatory cells, is thought to be involved in the anorexia associated with severe infection. To assess a possible role of the amino acid sequence found in the supposed IL-1 receptor binding sites, we determined the antagonistic effects of alpha-melanocyte-stimulating hormone (MSH) and the carboxyl-terminal tripeptide of alpha-MSH-(11-13) (alpha-MSH-(11-13)) on the anorexia induced by intracerebroventricular (i.c.v.) administration of 0.5 pmol IL-1. The parent alpha-MSH molecule completely prevented the induction of anorexia by IL-1 at both doses tested, 0.5 and 5.0 pmol. In contrast, alpha-MSH-(11-13) prevented the IL-1-induced anorexia only at 5.0 pmol, but not at 0.5 pmol. Intracerebroventricular injection of 5 pmol of the parent alpha-MSH molecule alone temporarily decreased food consumption at 1-2 h; 5.0 pmol of alpha-MSH-(11-13) alone did not affect food consumption. These data indicate that alpha-MSH can antagonize the anorexic effects of IL-1. The carboxyl-terminal tripeptide portion of alpha-MSH may be important for the antagonistic action of alpha-MSH on the anorexia induced by IL-1.
BACKGROUND: The biologic behavior of poorly differentiated medullary carcinoma of the stomach is unclear. METHODS: A clinicopathologic study on 74 poorly differentiated medullary carcinomas (PMC) and 73 nonmedullary carcinomas (NMC) of the stomach was done. PMC were defined as gastric carcinomas in which more than 50% of the tumor area contained poorly differentiated adenocarcinoma with no fibrous stroma. RESULTS: They were characterized by a location in the upper 33% of the stomach (49%), grossly expansive growth (69%), frequent vascular permeation (57%), and simultaneous liver metastasis (15%). Although the 5-year survival rate was similar for PMC and NMC, death of PMC was related more frequently to liver metastasis (47%) and less frequently to peritoneal dissemination (12%). The outcome of patients with PMC was influenced by frequent vascular permeation, extended lymph node metastasis, and simultaneous liver metastasis. CONCLUSIONS: These results indicate that PMC are characterized by expansive growth of the tumor and simultaneous or recurrent metastasis to the liver. Therefore, the biologic behavior of poorly differentiated medullary carcinoma is similar to that of well-differentiated carcinoma of the stomach.
We previously obtained evidence for intrinsic aminopeptidase activity for leukotriene (LT)A4 hydrolase, an enzyme characterized to specifically catalyse the hydrolysis of LTA4 to LTB4, a chemotactic compound. From a sequence homology search between LTA4 hydrolase and several aminopeptidases, it became clear that they share a putative active site for known aminopeptidases and a zinc binding domain. Thus, Glu-297 of LTA4 hydrolase is a candidate for the active site of its aminopeptidase activity, while His-296, His-300 and Glu-319 appear to constitute a zinc binding site. To determine whether or not this putative active site is also essential to LTA4 hydrolase activity, site-directed mutagenesis experiments were carried out. Glu-297 was mutated into 4 different amino acids. The mutant E297Q (Glu changed to Gln) conserved LTA4 hydrolase activity but showed little aminopeptidase activity. Other mutants at Glu-297 (E297A, E297D and E297K) showed markedly reduced amounts of both activities. It is thus proposed that either a glutamic or glutamine moiety at 297 is required for full LTA4 hydrolase activity, while the free carboxylic acid of glutamic acid is essential for aminopeptidase.
Adenosine has dose-dependent biphasic excitatory and inhibitory effects on neurotransmission in the hippocampus. The mechanism of the excitatory action is not known although that of the inhibitory action has been well analyzed. Here we report on the mechanism of excitatory action of adenosine, using hippocampal slices. Studies of intracellular recordings of CA3 pyramidal neurons showed that the amplitude of EPSP was dramatically enhanced by application of adenosine at low concentration (0.1 microM) without changing resting membrane potentials, membrane conductance or the threshold for spike generation by injecting current pulses. On the other hand, the presence of adenosine at a concentration of 0.1 microM during electrical stimulation to the slices increased 1.7 times the release of glutamate, an excitatory neurotransmitter in the hippocampus. These results indicate that the excitatory action of adenosine at low doses is due to the increase of transmitter release.
In the asporogenic yeast Candida cylindracea, the codon CUG is read as serine instead of leucine. This is an unusual instance in which the amino acid assignment of a codon deviates from the universal code. To infer the evolutionary process of this change, the tRNA with the anticodon sequence CAG, which is complementary to and thus responsible for translation of the codon CUG, has been identified. Indeed, this tRNA translates an in-frame CUG codon in a synthetic mRNA as serine in an in vitro translation system. The gene for the tRNA is interrupted by an intron in the anticodon loop. Sequence comparisons of the tRNA and its gene suggest that a single cytidine was inserted into the anticodon loop of the gene for tRNA(Ser)IGA during evolution to produce tRNA(Ser)CAG. The tRNA(Ser)CAG may be produced from its precursor molecule containing the cytidine insertion by splicing.
An antiserum raised against an alignment of amino acid-(32-56), termed TSHRP-1, in the extracellular domain of human thyrotropin (TSH) receptor was used to identify the TSH receptor-like substance in plasma of Graves' disease. The dilution curve of plasma TSHRP-1-like immunoreactivity was observed in a manner parallel to the standard synthetic peptide curve in radioimmunoassay, and its molecular weight estimated approximately 60 kDa. The amounts of TSHRP-1-like immunoreactivity were significantly higher in Graves' plasma than those in plasma of normal and hypothyroid patients due to Hashimoto's thyroiditis. The present results indicate that human peripheral blood possesses a soluble form of the extracellular domain of TSH receptor which may contribute to the pathophysiology of Graves' disease.
Regional aortic distensibility was measured noninvasively using cine MR imaging to determine whether it correlates with aging or risk of coronary artery disease (CAD). Twenty-two patients with CAD confirmed by angiography and 33 without CAD underwent cine MR imaging. Thirty-two sequential images were obtained in one cardiac cycle. The cross sectional area of the descending thoracic aorta was measured on both diastolic (A) and systolic (A') images. Aortic distensibility (A.D.) was calculated from the following equation: A.D. = (A'-A)/A/delta P. (delta P represents pulse pressure). Results of a simple regression analysis showed that decreased regional aortic distensibility was significantly correlated with the age of the patients (r = -0.762, p less than 0.005). In addition, the parameter was lower in patients with CAD than those without CAD (p less than 0.05). In conclusion, regional aortic distensibility derived from cine MR imaging is a useful parameter to evaluate not only aging but also pathological atherosclerosis of the aorta. In addition, this parameter might have some potential to evaluate the prediction of CAD in patients with normal serum cholesterol.
Ninety-one brain tissue sections taken at autopsy from 33 elderly patients (63-100 years old) without progressive multifocal leukoencephalopathy were examined for the presence of JC virus DNA by the polymerase chain reaction and Southern hybridization analysis after DNA extraction. JC virus DNA was detected in 15 sections from 10 patients. These results suggest that JC virus is frequently present in the brains of aged patients.
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A cytosolic protein factor(s) is involved in the import of precursor proteins into mitochondria. PBF (presequence binding factor) is a protein factor which binds to the precursor form (pOTC) of rat ornithine carbamoyltransferase (OTC) but not to the mature OTC, and is required for the mitochondrial import of pOTC. The precursors for aspartate aminotransferase and malate dehydrogenase as well as pOTC synthesized in a reticulocyte lysate were efficiently imported into the mitochondria. However, the precursors synthesized in the lysate depleted for PBF by treatment with pOTC-Sepharose were not imported. Readdition of the purified PBF to the depleted lysate fully restored the import. pOTC synthesized in the untreated lysate sedimented as a complex with a broad peak of around 9 S, whereas pOTC synthesized in the PBF-depleted lysate sedimented at an expected position of monomer (2.5 S). When the purified PBF was readded to the depleted lysate, pOTC sedimented as a complex of about 7 S. In contrast to most mitochondrial proteins, rat 3-oxoacyl-CoA thiolase is synthesized with no cleavable presequence and an NH2-terminal portion of the mature protein functions as a mitochondrial import signal. The thiolase synthesized in the PBF-depleted lysate could be efficiently imported into the mitochondria, and readdition of PBF had little effect on the import. The thiolase synthesized in the untreated, the PBF-depleted, or the PBF-readded lysate sedimented at an expected position of monomer (2.5 S). These observations provide support for the existence of PBF-dependent and -independent pathways of mitochondrial protein import.
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Localization of calpains in human bone marrow cells was studied immunohistochemically employing monoclonal antibodies against the high-Ca(2+)-requiring form (m-calpain) and the low-Ca(2+)-requiring form (mu-calpain). Most cells were stained with anti-m-calpain more strongly than with anti-mu-calpain, and staining with anti-mu-calpain was prominent only in megakaryocytes. To confirm the result, megakaryoblastic cell line (T-33) cells were subjected to immunoblot analysis. However no immunoreactivity to mu-calpain was seen in T-33 cells. Bone marrow from a patient with idiopathic thrombocytopenic purpura showed immature megakaryocytes (stage II) strongly stained by anti-m-calpain antibody while mature cells (stage III) were strongly stained by anti-mu-calpain antibody. These results suggest that mu-calpain plays a crucial role in mature megakaryocytes, possibly in platelet production.
It is still unknown how extracellular hyperosmolarity suppresses exocytosis. To evaluate the possibility that extracellular hyperosmolarity affects one of the most important second messenger system, Ca2+ signal, we evaluated the effect of hyperosmolarity on the thyrotropin releasing hormone (TRH)-induced changes in both intracellular Ca2+ concentration ([Ca2+]i) and prolactin (PRL) secretion in GH4C1 cells. TRH caused two phases of [Ca2+]i: an initial high-amplitude phase (first phase), which was not inhibited by Ca2+ free medium, and a sustained low-amplitude phase (second phase), which was abolished by Ca2+ free medium. Medium hyperosmolarity (isotonic = 300mOsm, hypertonic = 338, 375, 450, and 600mOsm) suppressed both TRH-induced phases of [Ca2+]i in a dose dependent manner, however, the suppressive effect was clearly stronger in the second phase of [Ca2+]i than in the first phase of [Ca2+]i. Low doses of medium hyperosmolarity (338 and 375mOsm) suppressed PRL secretion, which was dependent on Ca2+ influx. However, high doses of medium hyperosmolarity (450 and 600mOsm) also blocked PRL secretion, which was dependent on Ca2+ mobilized from cytosolic Ca2+ pools. These data indicate that in GH4C1 cells medium hyperosmolarity may inhibit PRL secretion by both blocking Ca2+ influx and a mechanism unrelated to Ca2+.
The safety and possible efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) were evaluated in 40 consecutive patients who received transplants from unrelated donors. rhGM-CSF was administered by 2-hour daily intravenous infusion from day 0 to day 20 or day 27 after the marrow infusion. These patients were compared with 78 historical patients who received transplants from unrelated donors who did not receive rhGM-CSF. The rhGM-CSF-treated patients were older (P = .037) and were treated less frequently in laminar air flow rooms (P = .005) than were control patients. However, the rhGM-CSF-treated group had a higher proportion of "good risk" patients with chronic myelogenous leukemia in chronic phase (P = .006) than did the comparison group (P = .017), rendering comparisons of transplant-related complications not meaningful. rhGM-CSF was well tolerated and did not adversely increase the incidence of graft rejection or increase the incidence and severity of acute graft-versus-host disease. The median day the absolute neutrophil count reached 500/mm3 in patients who received rhGM-CSF was day 21, which was not different from that of historical patients. Nevertheless, the numbers of febrile days and septicemic episodes within the first 28 days in patients who received rhGM-CSF were less than in historical patients. The probability of nonrelapse mortality at 1 year in patients who received rhGM-CSF was 22%. In view of the retrospective nature of the control group, we cannot conclusively determine whether rhGM-CSF administration was beneficial. A prospective, randomized controlled study of rhGM-CSF is required to confirm these suggestive data.
We studied the effect of thyroid status on thyrotropin-releasing hormone receptor (TRH-R) mRNA levels both in vivo and in vitro (GH3 cells) using a cloned rat TRH-R cDNA by RT-PCR. Experimental hypothyroid rats were produced by total thyroidectomy and were then killed 7 days after the operation. TRH receptor binding in the anterior pituitary and serum TSH level were elevated approximately 2-fold and 8-fold, respectively, in 7 day thyroidectomized rats. TRH-R mRNA levels in hypothyroid rats were also increased significantly compared with those of normal rats. In GH3 cells, however, no significant change of TRH-R mRNA level was observed between cultures treated with triiodothyronine (T3, 10(-9) and 10(-7) M) and the untreated group. The present data indicate that 1) the in vivo effects of thyroid status on TRH-R mRNA levels differ from the in vitro one, and that 2) the down regulation of TRH-R binding by thyroid hormone in GH3 cells may be mediated by translational or post-translational mechanisms.