T lymphocytes bearing gamma/delta-type T-cell receptor in thymic tumor tissues.
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Humans↗
Biomedical subjects
T Yano
Publications and source records attributed to T Yano.
High potency of a new bombesin antagonist (RC-3095) in inhibiting serum gastrin levels; comparison of different routes of administration.
This study was performed to evaluate the efficacy and duration of action of a new bombesin antagonist D-Tpi6,Leu13 psi (CH2NH)Leu14-bombesin (6-14) (RC-3095), given by different routes of administration, in suppressing gastrin releasing-peptide (GRP(14-27))-stimulated gastrin release in rats. First, we showed that GRP(14-27) itself was highly active when administered by different routes. GRP(14-27), given to rats at a dose of 25 micrograms/100 g b.w. significantly increased serum gastrin levels 3 and 6 min after intravenous and for more than 30 min after subcutaneous administration or pulmonary inhalation. RC-3095 was then injected subcutaneously, intravenously and also delivered by pulmonary inhalation at a dose of 10 micrograms/100 g b.w. in each case to seven male rats 2, 30, 60 or 120 min prior to i.v. administration of 5 micrograms GRP(14-27). RC-3095 administered 2 min prior to GRP(14-27) decreased the gastrin response to GRP(14-27), measured as area under the curve, by 81% in the intravenously injected group and 64% in the pulmonary inhalation group in the first 6 min. When GRP(14-27), was given 30 min after administration of RC-3095, the gastrin response was decreased by 52% in the subcutaneous group, 49% in the pulmonary inhalation group and 11% in the intravenous group during the first 6 min. RC-3095 delivered subcutaneously or by pulmonary inhalation 1 h before GRP(14-27) was also able to significantly inhibit gastrin release. Analysis of the data revealed that the bioavailability of RC-3095 given by the pulmonary inhalation route was about 69% of the s.c. route.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Inhalation↗
Stimulation by bombesin and inhibition by bombesin/gastrin-releasing peptide antagonist RC-3095 of growth of human breast cancer cell lines.
Recently, it was reported that bombesin/gastrin-releasing peptide (GRP) have mitogenic effects on some human breast cancer cell lines. In this study, we investigated the effects of bombesin/GRP and its receptor antagonist (RC-3095) on the proliferation of three breast cancer cell lines, MDA-MB-231, MCF-7 MIII, and MCF-7. Stimulation by bombesin and inhibition by RC-3095 of cell growth were found in MDA-MB-231 and MCF-7 MIII cells cultured in phenol red-free medium with 5% heat-inactivated and dextran-coated charcoal-treated fetal bovine serum (DCC-FBS). A stimulatory effect by bombesin was not observed in the presence of untreated FBS. [3H]Thymidine incorporation into DNA in these cells was suppressed by RC-3095. MCF-7 cells failed to respond to bombesin and RC-3095 in the presence of either FBS or DCC-FBS. GRP-like immunoreactivity was found in the cell extracts and FBS, but it was undetectable in DCC-FBS. It appears that the stimulatory effect of bombesin on cell proliferation of MCF-7 MIII and MDA-MB-231 cell lines could be obtained because of reduction in the levels of some serum factors in DCC-FBS. These results suggest that bombesin/GRP can act as growth factors through bombesin/GRP receptors in some human breast cancers.
Bombesin↗
MYC rearrangements in histologically progressed follicular lymphomas.
Histologic transformation of low-grade follicular lymphoma to an aggressive-grade lymphoma occurs in 60% to 80% of patients during their clinical course. The events that drive the transformation process are poorly understood. Deregulation of the MYC gene has been implicated in a small number of cases. This observation led us to examine the molecular organization of the MYC oncogene in 38 cases of histologically transformed lymphomas that arose from follicular lymphomas, and in 18 of the initial pretransformation follicular lymphomas. In addition, we examined 58 "control" low-grade follicular lymphomas that had not yet shown evidence of histologic progression. Immunoglobulin heavy chain and light chain gene rearrangements were detected in all biopsies and rearrangements of the BCL-2 locus were seen in 36 of 38 of the transformed lymphomas (consistent with their origin from follicular lymphomas), in 18 of 18 of the pretransformation follicular lymphomas, and in 51 of 58 of the control follicular lymphomas. All 18 pretransformation follicular lymphoma specimens displayed at least one immunoglobulin gene and BCL-2 rearrangement in common with the corresponding histologically progressed lymphoma, indicating a clonal relationship between the original follicular lymphoma and the histologically transformed lymphoma. MYC rearrangements were detected in 3 of 38 (8%) transformed lymphomas and in 1 of 58 (2%) control follicular lymphomas. The latter MYC rearranged follicular lymphoma was clinically aggressive and transformed to a high-grade lymphoma that led to the death of the patient within 20 months. None of the 18 pretransformation follicular lymphomas showed MYC rearrangement, including two from patients who later demonstrated MYC rearrangement in the progressed aggressive lymphoma. PvuII mutational analysis failed to identify additional MYC gene abnormalities in the progressed lymphomas. Because the Epstein-Barr virus (EBV) is associated with a fraction of high-grade lymphomas and is known to upregulate BCL-2, we looked for a potential role for this agent in our progressed lymphomas. We did not detect viral sequences in any case indicating that EBV does not play a major role in progression. The presence of MYC rearrangements in a small fraction of progressed aggressive lymphomas, and not in the corresponding antecedent follicular lymphomas, suggests that acquisition of a MYC rearrangement is in some cases associated with the transformation event.
Chromosome Aberrations↗
[Complications of arterial infusion of CDDP in the treatment of malignant neoplasms].
Arterial infusion of cis-diamminedichloroplatinum (CDDP) is an effective therapy for malignant neoplasms. Severe complications after this therapy in 298 patients with malignant tumors were reviewed in our institute from March 1982 to August 1989. Arteries infused with CDDP and the number of infusions were as follows: bronchial artery (a.) 277, hepatic a. 153, internal iliac a. 51, femoral or popliteal a. 15, lumbar a. 6, pulmonary a. 5, esophageal a. 3 and intercostal a. 3. Eight cases of severe complications were encountered: 3 of esophageal ulcer, 3 of spinal paralysis, and one each of mediastinitis and toe necrosis. The arteries responsible for complications were the bronchial a. in 3 cases of esophageal ulcer and 2 of spinal paralysis, intercostal a. in one of spinal paralysis, esophageal a. in one of mediastinitis and popliteal a. in toe necrosis. Complication rates were 2.7% (8/298 cases) and 1.5% (8/518 infusions). Angiotensin II was infused in 6 of 8 of the cases with complications. The complication rate was 2.9% (6/209 infusions) in the group with CDDP and angiotensin II and 0.6% (2/309 infusions) in the group with CDDP only. Arterial infusion of CDDP, especially combined with angiotensin II, should be done in consideration of the arteries responsible for such complications.
Adenocarcinoma↗
Role of Asp222 in the catalytic mechanism of Escherichia coli aspartate aminotransferase: the amino acid residue which enhances the function of the enzyme-bound coenzyme pyridoxal 5'-phosphate.
Asp222 is an invariant residue in all known sequences of aspartate aminotransferases from a variety of sources and is located within a distance of strong ionic interaction with N(1) of the coenzyme, pyridoxal 5'-phosphate (PLP), or pyridoxamine 5'-phosphate (PMP). This residue of Escherichia coli aspartate aminotransferase was replaced by Ala, Asn, or Glu by site-directed mutagenesis. The PLP form of the mutant enzyme D222E showed pH-dependent spectral changes with a pKa value of 6.44 for the protonation of the internal aldimine bond, slightly lower than that (6.7) for the wild-type enzyme. In contrast, the internal aldimine bond in the D222A or D222N enzyme did not titrate over the pH range 5.3-9.5, and a 430-nm band attributed to the protonated aldimine persisted even at high pH. The binding affinity of the D222A and D222N enzymes for PMP decreased by 3 orders of magnitude as compared to that of the wild-type enzyme. Pre-steady-state half-transamination reactions of all the mutant enzymes with substrates exhibited anomalous progress curves comprising multiphasic exponential processes, which were accounted for by postulating several kinetically different enzyme species for both the PLP and PMP forms of each mutant enzyme. While the replacement of Asp222 by Glu yielded fairly active enzyme species, the replacement by Ala and Asn resulted in 8600- and 20,000-fold decreases, respectively, in the catalytic efficiency (kmax/Kd value for the most active species of each mutant enzyme) in the reactions of the PLP form with aspartate. In contrast, the catalytic efficiency of the PMP form of the D222A or D222N enzyme with 2-oxoglutarate was still retained at a level as high as 2-10% of that of the wild-type enzyme. The presteady-state reactions of these two mutant enzymes with [2-2H]aspartate revealed a deuterium isotope effect (kH/kD = 6.0) greater than that [kH/kD = 2.2; Kuramitsu, S., Hiromi, K., Hayashi, H., Morino, Y., & Kagamiyama, H. (1990) Biochemistry 29, 5469-5476] for the wild-type enzyme. These findings indicate that the presence of a negatively charged residue at position 222 is particularly critical for the withdrawal of the alpha-proton of the amino acid substrate and accelerates this rate-determining step by about 5 kcal.mol-1. Thus it is concluded that Asp222 serves as a protein ligand tethering the coenzyme in a productive mode within the active site and stabilizes the protonated N(1) of the coenzyme to strengthen the electron-withdrawing capacity of the coenzyme.
Aspartate Aminotransferases↗
[Combined treatment of invasive bladder cancer by intra-arterial infusion chemotherapy of cisplatin with or without other anticancer agents and concurrent radiotherapy--initial response and side effects].
Fourteen patients with invasive bladder cancer were treated by bilateral internal iliac artery infusion of cisplatin, with or without other anticancer agents, and concurrent radiotherapy. Angiotensin II was simultaneously infused in 10 cases. Of the 14 patients, complete response and partial response were achieved in 9 (64%) and 3, respectively. Hematuria was controlled in all 8 patients, and pain was relieved in 3 of 4 patients. Side effects were observed in 8 patients: appetite loss in 8, nausea and/or vomiting in 7, and leukocytopenia in 6 patients, in 3 of whom radiotherapy had to be intermittent because of severe leukocytopenia (less than 2000/mm3). However, restoration of leukocytopenia occurred one week later. Thus, intra-arterial anticancer agents including cisplatin together with concurrent radiation may be one of the most effective therapies for invasive bladder cancer.
Aged↗
The effect of glycerol and 4-nitroquinoline 1-oxide on active oxygen formation in sub-cellular fractions of lung tissue.
Glycerol enhances pulmonary tumorigenesis in mice treated with 4-nitroquinoline 1-oxide (4NQO). The present study shows that active oxygen formation by glycerol may be responsible for this enhanced tumorigenesis. Male ddY mice were treated with 4NQO and given a 5% glycerol solution instead of drinking water for up to 4 weeks after 4NQO injection. There was no difference in NADH-dependent active oxygen formation of the mitochondria between the 4NQO- and 4NQO-plus-glycerol-treated groups but the ratios of NADH- and NADPH-dependent active oxygen formation of the microsomes and nuclei of the 4NQO-plus-glycerol-treated group to the 4NQO-treated group increased with increasing time after 4NQO injection. Significant differences in the maximum NADH- and NADPH-dependent active oxygen formation were observed 2 or 4 weeks after 4NQO injection.
4-Nitroquinoline-1-oxide↗
Molecular cloning of the gene encoding Thiobacillus ferrooxidans Fe(II) oxidase. High homology of the gene product with HiPIP.
The amino-terminal sequence of Thiobacillus ferrooxidans Fe(II) oxidase (linked to cytochrome c552) was determined, and the iro gene that encodes this enzyme was cloned using degenerate oligonucleotides as a probe. The DNA sequence of a region (856 base pairs) which encompasses the iro gene revealed that the enzyme was encoded by a 273-base pair open reading frame and consists of 90 amino acids, including a possible 37-residue signal sequence. The iro gene seems to be transcribed independently of any other gene because the transcriptional products are 0.45 and 0.6 kilobases in size. Current protein databases revealed that the iro gene product is a new member of the high redox potential iron sulfur proteins, which generally function in electron transport but do not show enzymatic activity.
Amino Acid Sequence↗
Cytocidal effects of bromocriptine, somatostatin analog, and heat on growth hormone-secreting pituitary adenoma in vitro.
The effects of bromocriptine (BC), a somatostatin analog (SMS), and heat on the secretion of growth hormone (GH) and prolactin (PRL), and on the morphologic features of human GH-secreting pituitary adenoma were studied in vitro. The treatment with BC, SMS, or heat (41.5 degrees C and 42.5 degrees C) markedly suppressed the secretion of GH and PRL from the adenoma cells and reduced the number of cells immunoreactive with GH or PRL. The combined treatment with BC and heat induced a marked reduction in the number of GH and PRL cells consistent with the effect on the secretion of GH and PRL. These results suggest that BC, SMS, and heat treatments produced the cytotoxic effects on pituitary adenoma cells, and that the simultaneous treatment of BC and heat enhanced this effect.
Adenoma↗
Molecular cloning of cDNAs for human fibroblast nucleotide pyrophosphatase.
Nucleotide pyrophosphatase (NPPase) activity is markedly elevated in cultured skin fibroblasts from patients of Lowe's syndrome. cDNA clones encoding the NPPase were isolated using synthetic oligonucleotide probes designed on the basis of partial amino acid sequence of the enzyme purified from human placenta. The complete sequences of these clones yielded a merged sequence of 3508 bases. The polypeptide chain of the enzyme was deduced to comprise 873 amino acids with a calculated molecular weight of 99,703 and had the characteristics of a class II transmembrane protein. Ten potential N-glycosylation sites were detected in the protein. RNA blot analysis showed that human fibroblasts contain two minor mRNAs of 7.0 and 8.2 kb, respectively, in addition to a major 3.6-kb species that coincides with the merged cDNA in size. A computer search of a nucleotide sequence data-base revealed that plasma cell membrane glycoprotein PC-1, whose function was unknown at the time, is identical with the NPPase. Comparison of the amino acid sequence of the NPPase with the active site sequence of bovine 5'-nucleotide phosphodiesterase allowed the assignment of a putative active site domain to the central region of the COOH-terminal extracellular domain of the NPPase. The gene for human NPPase was localized to chromosome 6 at q22-q23 by in situ hybridization with a fragment of the NPPase cDNA.
Amino Acid Sequence↗
[Case of pulmonary valve stenosis due to tuberculous pericardio-pleural calcification].
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Calcinosis↗
Superoxide anion-generating activity of polymorphonuclear leukocytes and monocytes in patients with lung cancer.
Superoxide anion (O2-) production by polymorphonuclear leukocytes (PMN) and monocytes (MN) was measured in the peripheral blood of 70 patients with lung cancer. The O2- production by these cells was decreased in many, but not all, patients. The incidence of patients with lower O2- production increased as the stage advanced. The correlation between O2- production by these cells and peripheral blood smears was evaluated in patients with cancer. Patients with 80% granulocytes and 40% monocytes or more in their peripheral blood had a significantly lower O2- production by PMN and MN compared with those with less than 80% granulocytes and 40% monocytes, respectively. These results indicate that an abnormally increased number of granulocytes and monocytes in the peripheral blood of patients with cancer may depress immunoregulatory function. In addition, decreased O2- production by these cells should be considered when assessing the defense mechanisms and susceptibility to infection of these patients.
Adult↗
Histogenetic correlations between subcategories of small noncleaved cell lymphomas.
To assess the biologic relevance of the morphologic distinctions between subtypes of small noncleaved cell lymphomas (SNCL), ie, the sporadic Burkitt's type (sBT) and the non-Burkitt's type (nBT), we have examined the molecular organization of several lymphomagenic oncogenes (c-myc, bcl-1, bcl-2) and the potential pathogenetic contribution of the Epstein-Barr virus (EBV). Twenty-nine cases of SNCL, not associated with immunodeficiency syndromes, were reviewed and classified as sBT (18 cases) or nBT (11 cases) without knowledge of the clinical or molecular data. Southern blot analysis of 18 sBTs found 17 to contain c-myc rearrangements. Fifteen of these comigrated with an Ig heavy-chain gene segment, indicating t(8;14) translocation. Chromosome 8 breakpoints were clustered in the first exon and the first intron of the c-myc gene. Chromosome 14 breakpoints mapped to the JH locus in three tumors, the S mu locus in nine tumors, and the S alpha locus in the remaining three tumors. Cases involving the S alpha locus appeared to have a more rapid clinical course. All sBTs possessed germline bcl-2 and bcl-1 gene fragments. In contrast, Southern blot analysis of 11 nBTs found none with c-myc rearrangements. Rather, three of 10 evaluable nBTs had bcl-2 rearrangements. The remaining seven showed no evidence of involvement by any of the lymphoma-associated oncogene/breakpoint regions studied. EBV genome was detected in two sBTs and in one nBT, and thus was not a distinguishing feature. These results indicate that the subtle histologic differences that distinguish subcategories of SNCL are significant biologically and reflect distinct molecular mechanisms of lymphomagenesis. Furthermore, the data suggest that the nBTs comprise a heterogeneous group with respect to their molecular genetic composition and confirm the remarkable molecular genetic homogeneity of the sBT group.
Adolescent↗
Tumor-reactive T-cells accumulate in lung cancer tissues but fail to respond due to tumor cell-derived factor.
The purpose of this study was to elucidate a possible immune response to tumor cells mediated by tumor-infiltrating lymphocytes (TIL) in lung cancer. In flow cytometry, the majority of T-cells of TIL were CD45RA-, CD45RO+, and CDw29high, and expressed HLA-DR. The expression of interleukin 2 receptor beta chain increased in both CD4+ and CD8+ TIL compared with both types of T-cells in peripheral blood. These results indicate that the major population of TIL is activated memory T-cells. The TIL preparation, which was usually contaminated with 5 to 10% tumor cells, did not exhibit any response in autologous mixed lymphocyte-tumor culture even in the presence of interleukin 2 (IL-2) in all five cases tested. Although purified T-cells from TIL showed the positive response in only 1 of 10 cases tested without addition of IL-2, it occurred in 7 of 10 cases in the addition of a low concentration of IL-2. The IL-2-dependent response to irradiated autologous tumor cells was suppressed when nonirradiated autologous tumor cells were added to the culture. Culture supernatants of four lung cancer cell lines and freshly prepared lung cancer cells obtained from 6 cases exhibited suppressive activity against anti-CD3 antibody-induced mitogenesis of peripheral blood mononuclear cells from healthy donors. We suggest that, taken together, (a) the major population of TIL in lung cancer are activated memory T-cells, and they include tumor-reactive ones, and that (b) the function of the TIL is impaired by unavailability of IL-2 and/or by suppression due to lung cancer cell-derived factor(s).
Antigens, CD↗
Two different protein kinases act on a different time schedule as glial filament kinases during mitosis.
Glial fibrillary acidic protein (GFAP) is a component of glial filaments specific to astroglia. We now report the spatial and temporal distributions of four phosphorylated sites in the GFAP molecule during mitosis of astroglial cells, determined by antibodies which can distinguish phosphorylated epitopes from non-phosphorylated-epitopes. Immunofluorescence microscopy showed that the Ser8 residues in the entire cytoplasmic glial filament system are initially phosphorylated when the cells enter mitosis. In cytokinesis, the phosphoSer8 residues become dephosphorylated, whereas Thr7, Ser13 and Ser34 in glial filaments at the cleavage furrow become the preferred sites of phosphorylation. The cdc2 kinase purified from mitotic cells can phosphorylate GFAP at Ser8 but not at Thr7, Ser13 or Ser34, in vitro. These results suggest that cdc2 kinase acts as a glial filament kinase only at the G2-M phase transition while other glial filament kinases are probably activated at the cleavage furrow before final separation of the daughter cells.
Amino Acid Sequence↗
Blockade of the LH response induced by the agonist D-Trp-6-LHRH in rats by a highly potent LH-RH antagonist SB-75.
During treatment of prostate cancer patients with luteinizing hormone-releasing hormone agonist, a transient LH and sex steroid release, which precedes the secretion blockade, may result in a flare-up of the disease, whereas the antagonists induce an immediate suppression. The administration of the modern, superactive LHRH antagonist SB-75 before or together with the agonist D-Trp-6-LHRH should prevent the "flare-up" phenomena. In order to demonstrate that the LHRH antagonist can prevent the initial stimulation of gonadotropins in response to LHRH agonists, groups of 5-7 male rats were injected s.c. with the antagonist SB-75 in doses in 100, 500, and 1,000 micrograms/rat 1 hour prior to or 1, 2, and 3 days before administration of D-Trp-6-LHRH agonist (50 micrograms/rat). Supraphysiological doses of the agonist were used in order to obtain prolonged stimulation of LH release, which was necessary to study the duration and the extent of LH release inhibition. Blood samples were taken before and 2, 6, 24, 48, and 72 hours after D-Trp-6-LHRH stimulation for measurement of LH levels. The administration of SB-75 in doses of 500 and 1,000 micrograms/rat 3 days prior to administration of the agonist significantly lowered LH response (P less than 0.01), as compared to animals injected with D-Trp-6-LHRH alone. The D-Trp-6-LHRH-stimulated LH secretion was markedly more suppressed by all 3 doses of the antagonist in rats pretreated with SB-75 2 days prior to the stimulation with the agonist. An even greater reduction in LH response could be observed in rats injected with SB-75 1 day prior to the agonist, the magnitude of LH response being decreased by 75% with 500 micrograms/rat SB-75 and by 90% with 1 mg/rat SB-75. The LH response was virtually abolished when the antagonist, SB-75 was given in doses of 500 or 1,000 micrograms/rat 1 hour prior to the D-Trp-6-LHRH injection. Under these conditions, the agonist-induced LH and testosterone secretion was completely suppressed during the whole period of the experiment. The antagonist to agonist dose ratio of 2 to 1 produced a 90% decrease in the LH response to D-Trp-6-LHRH at 2 hours and 75% at 5 hours after agonist administration. The effects of LHRH decapeptide itself (500 micrograms/rat) on LH secretion could be totally suppressed by an injection of 50 micrograms/rat of SB-75 1 hour beforehand.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗