Small lung cancer demonstrated with Tc-99m tetrofosmin imaging.
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Adenocarcinoma↗
Biomedical subjects
Y Kido
Publications and source records attributed to Y Kido.
Direct determination of impact-parameter-dependent stopping powers for million-electron-volt He ions penetrating Er-doped GaAs.
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Journal Article↗
[Pseudoxanthoma elasticum with pulmonary calcification].
A woman born in 1920 had had multifocal, yellowish nodules on her skin since childhood and had been given a diagnosis of pseudoxanthoma elasticum. When she was 59-year-old, a diffuse granular shadow was seen on a chest radiograph. When she was 74-year-old, she presented with dyspnea on exertion. A thoracoscopic lung biopsy was done. Histologic examination of the lung tissue revealed small calcified nodules scattered in the alveolar septa. Pseudoxanthoma elasticum is a systemic, hereditary disorder that usually affects elastic fibers of the skin, eye, and cardiovascular system. It's incidence is quite low: 1 out of 160,000-1,000,000 population. Very few cases of pseudoxanthoma elasticum with pulmonary involvement have been reported, and we know of no previous case in Japan in which pulmonary microcalcification was confirmed histologically.
Aged↗
EGF-induced activation of 70-kDa S6 kinase in CHO cells expressing human EGF receptors.
We investigated epidermal growth factor (EGF)-induced activation of 85-kDa/110-kDa phosphatidylinositol (PI)-3-kinase and 70-kDa S6 kinase in Chinese hamster ovary cells expressing the human EGF receptor. EGF-induced activation of p70 S6 kinase was comparable to that induced by insulin, whereas that of PI-3-kinase in anti-phosphotyrosine immunoprecipitates was very small compared with insulin. Wortmannin, a p85/p110 PI-3-kinase inhibitor, inhibited EGF-induced activation of p70 S6 kinase in a dose-dependent manner. Given that several proteins homologous to catalytic subunit of p85/p110 PI-3-kinase have been identified and that wortmannin inhibits distinct form of PI-3-kinase, the present results suggest that wortmannin-sensitive kinases that resemble catalytic subunit of p85/p110 PI-3-kinase may participate in the signaling pathway from EGF receptors to p70 S6 kinase.
Androstadienes↗
Concurrent chemotherapy (5-fluorouracil and cisplatin) and radiation therapy for inoperable squamous cell carcinoma of the esophagus potentially followed by surgery.
Twenty-four previously untreated patients with primary inoperable squamous cell carcinoma of the esophagus showing no evidence of hematogenous metastasis were treated with concurrent chemotherapy and radiation therapy (CRT) followed by surgical resection if possible. The chemotherapy regimen consisted of 5-fluorouracil 750 mg/m2 on days 1-4 and 21-24, and cisplatin 70 mg/m2 on days 1 and 21. Radiation therapy was administered over days 1-26 (200 cGy/day five times per week with an initial planned dose of 40 Gy). Five patients (8%) showed complete response (CR), 14 patients (58%) had partial response (PR), and 19 had good local control (CR 2, PR 17). Eleven cases (48%) underwent esophageal resection with no operative mortality. Curative resection was accomplished in eight cases (35%). Toxicities observed in CRT were leukopenia (grades 3 and 4) 38%, nausea and vomiting (grades 2 and 3) 67%, esophagitis 42%, and fever 42%. The median survival time (MST) for 11 neoadjuvant cases was 349 days (P < 0.05) compared to 212 days for palliative treatment (six cases) and 126 days for no treatment (six cases) after CRT. The MST of eight patients who received curative resection had not been reached after a 17-month median follow-up time. Concurrent chemotherapy with 5-fluorouracil plus cisplatin and radiation proved to be a safe regimen yielding a satisfactory response and minimal toxicity in this particular group of patients. Extensive surgery was thus determined to be feasible after CRT and to contribute to prolonging survival.
Aged↗
Evolution of the active sequences of the HpaI short interspersed elements.
Ninety-nine members of the salmonid HpaI and AvaIII families of short interspersed repetitive elements (SINEs) were aligned and a general consensus sequence was deduced. The presence of 26 correlated changes in nucleotides (diagnostic nucleotides) from those in the consensus sequence allowed us to divide the members of the HpaI family into 12 subfamilies and those of the AvaIII family into two subfamilies. On the basis of the average sequence divergences and the phylogenetic distributions of the subfamilies, the relative antiquity of the subfamilies and the process of sequential changes in the respective source sequences were inferred. Despite the higher mutation rates of CG dinucleotides in individual dispersed members, no hypermutability of CG positions was observed in changes in the source sequences. This result suggests that sequences of SINEs located in a nonmethylated or hypomethylated genomic region could have been selected as source sequences for retroposition and/or that some CG sites are the parts of recognition sequences of retropositional machineries.
Animals↗
Modulation of muscle protein metabolism in disseminated intravascular coagulation.
Muscle protein degradation and intracellular protease activities were investigated in disseminated intravascular coagulation (DIC), which is frequently associated with severe catabolic states such as sepsis and multiple organ failure. DIC was introduced in rats by repeated intravenous thrombin injections. Saline was injected in control rats. In the 28 rats (14 with DIC and 14 controls), the bilateral soleus (SOL) muscles were incubated in an oxygenated medium without cycloheximide (CH) to determine the release of tyrosine (Tyr) into the incubated medium. From 24 rats (12 with DIC and 12 controls), the SOL and extensor digitorum longus (EDL) muscles were harvested to measure the activities of proteasome and of cathepsins L and B. The contralateral muscles were incubated in a medium with 0.5 mM CH to determine the release of Tyr and 3-methylhistidine (3-MH). The release of Tyr without CH (net proteolysis) from SOL muscles with DIC was greater than in controls (218 +/- 83.3 vs. 145 +/- 47.7 pmol/mg/h. However, the release of Tyr and 3-MH with CH (total proteolysis) and the activities of proteasome and cathepsins in DIC were nearly the same as those in controls. In both DIC and control rats, the total release of Tyr and proteasome activity were greater in SOL than in EDL muscles. These results suggest that reutilization of Tyr, reflecting protein synthesis, is suppressed in DIC and that the red slow muscle is more active in nonfibrillar proteolysis than the white fast muscle.
Animals↗
Alteration of the respiratory burst and phagocytosis of macrophages under protein malnutrition.
To understand the role of macrophages in impaired host defense under protein malnutrition (PM), we examined the activities of the respiratory burst and phagocytosis of resident peritoneal macrophages from weaning female mice fed 5% casein or 5% soy protein isolate (SPI) diet for 14 days. Resident macrophages from the low-protein diet groups released larger amounts of superoxide anion (O2-) after stimulation by phorbol 12-myristate 13-acetate (PMA) or opsonized zymosan than those from the 20% casein and 20% SPI diet groups. Activation of macrophages from protein-deficient mice in vitro with lipopolysaccharide (LPS) or macrophage colony-stimulating factor (M-CSF) under LPS-free conditions did not further enhance O2- production. In spite of the increased O2- production with opsonized zymosan, macrophages from protein-deficient mice did not show any acceleration of phagocytosis of Candida albicans in the presence of normal serum. Our results confirm that the phagocytic function of macrophages is susceptible to PM, and suggest that functional alterations of macrophages may be involved in the failure of development of a specific immune response under PM. Furthermore, the enhanced production of oxygen intermediates by macrophages may augment tissue damage under PM.
Animals↗
Amino acids and glucose differentially increased extracellular 5-hydroxyindoleacetic acid in the rat brain.
To reveal the role of serotonergic neurons in the regulation of feeding, the levels of 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, in the striatum and the hypothalamus were continuously monitored by an in vivo microdialysis technique. Intake of 20% casein diet did not induce significant changes in the 5-HIAA level in these regions. When rats were fed on 5% casein diet (83.5% carbohydrate diet) for 2 h, the level of 5-HIAA in the striatum gradually increased and reached a maximum (226 +/- 44% of basal level, M +/- SEM, n = 7) at 4 h after stopping the diet. In the medial hypothalamus, its level also increased to 183 +/- 19% (n = 10) at 2 h after starting the diet. On the other hand, a 60% casein diet increased the level of 5-HIAA in the lateral hypothalamus to 138 +/- 19% (n = 10) at 2 h after starting the diet. The intravenous infusion of each of these nutrients, glucose, amino acid mixture or lipid, produced more rapid elevation of the 5-HIAA level than oral intake of the diets. When rats were infused with glucose, its level in the striatum continued to be elevated. In the medial hypothalamus, glucose infusion increased 5-HIAA to the maximum (189 +/- 38%, n = 7) at 4 h after starting infusion. In contrast, serotonergic neurons in the lateral hypothalamus seemed to respond only to infusion of the amino acid mixture, and the level of 5-HIAA reached 163 +/- 14% (n = 5) of the basal level at 1 h after starting the infusion. These results suggest that rapid elevation of glucose or amino acids may independently stimulate serotonin metabolism in these brain areas, participating in the feedback regulation of nutrient intake.
Amino Acids↗
A new antiherpetic agent produced by Streptomyces sp. strain no. 758.
A new antiherpetic agent, AH-758, was isolated from the culture broth of Streptomyces sp. strain No. 758. The structure was determined by NMR special analyses to be a new antibiotic belonging to bafilomycin group containing (5-oxo-2-pyrrolin-2-yl) methyl fumarate in its C-21.
Anti-Bacterial Agents↗
Grb2/Ash binds directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of activated human epidermal growth factor receptors in intact cells.
The activation of receptor tyrosine kinases generates tyrosine-phosphorylated recognition motifs for the binding of signaling proteins containing Src homology 2 domains. We determined the binding sites of Grb2/Ash, an Src homology 2 domain-containing adaptor protein, within epidermal growth factor (EGF) receptors, using Chinese hamster ovary cells overexpressing human EGF receptor mutants in which one of the autophosphorylation sites was retained. In intact cells, the amount of Grb2/Ash coimmunoprecipitated with mutant receptors retaining tyrosines 992, 1068, 1086, 1148, or 1173 was approximately 10, 85, 55, 50, or 20% of wild-type levels, respectively. The association of Grb2/Ash with in vitro autophosphorylated EGF receptor mutants was detectable in those retaining either tyrosines 1068 or 1086 but not in other mutants including those retaining tyrosine 1148. In peptide inhibition assay, phosphorylated peptides representing tyrosines 1068 and 1086 inhibited the binding of Grb2/Ash to in vitro autophosphorylated wild-type EGF receptors, whereas the other peptides representing tyrosines 992, 1148, and 1173 failed to inhibit the binding. Given that tyrosine 1148 of the activated EGF receptor is a major binding site of Shc (Okabayashi, Y., Kido, Y., Okutani, T., Sugimoto, Y., Sakaguchi, K., and Kasuga, M. (1994) J. Biol. Chem. 269, 18674-18678), these results indicate that tyrosines 1068 and 1086 of activated human EGF receptors are direct high affinity binding sites of Grb2/Ash and that tyrosine 1148 is an indirect binding site through Shc in intact cells.
Adaptor Proteins, Signal Transducing↗
Amplification of distinct subfamilies of short interspersed elements during evolution of the Salmonidae.
There are at least three different kinds of short interspersed repetitive elements in salmonid genomes. Of these, members of the HpaI family are found to be most widely distributed in salmonid species. The HpaI family is present with high copy numbers in all members of the subfamily Salmoninae, such as salmon, trout and charr. In order to determine whether the amplification of the Hpa sequence occurred rapidly within a short evolutionary period or gradually, over the long term, a search was made for Hpa sequences in primitive salmonids; namely, grayling and whitefish. A grayling species has fivefold fewer copies of these sequences than the Salmoninae species, whereas several whitefish species have 200-fold to 20-fold fewer copies than the Salmoniae species. Characterization of the Hpa sequences in these species allowed us to recognize two distinct Hpa subfamilies on the basis of diagnostic substitutions as well as a new short interspersed element with an Hpa-related sequence. The distribution of these sequences revealed that distinct members of the HpaI or Hpa-related family were amplified during establishment of each subfamily lineage in a manner very similar to the amplification of the human Alu family. We provide evidence for the validity of a model that involves "multiple source genes" to explain diagnostic substitutions of the Hpa subfamilies and the timing of their appearance during evolution.
Animals↗
Correlation of total and interstrand DNA adducts in tumor and kidney with antitumor efficacies and differential nephrotoxicities of cis-ammine/cyclohexylamine-dichloroplatinum(II) and cisplatin.
Mixed amine platinum complexes have been identified as a new class of antitumor agents with activity in some cisplatin-resistant tumor models. cis-Ammine/cyclohexylamine-dichloroplatinum(II) is one such analog that we have evaluated in vivo and found it to have antitumor activity that was comparable to that of cisplatin in a solid murine fibrosarcoma tumor model. In contrast to the nephrotoxicity observed with cisplatin, the analog was free from inducing this side-effect. Pharmacokinetics of the two compounds administered i.v. at equitoxic dose levels to tumor-bearing mice indicated similar decay kinetics of total platinum in plasma, kidney and the tumor. Furthermore, DNA-platinum adducts of the two agents were similar in the tumor. Total adduct levels in the kidney, on the other hand, were significantly greater (P < 0.5) by up to 4-fold for cisplatin compared with the mixed amine analog. Likewise, the levels of interstrand cross-links of the two platinum complexes were comparable in the tumor, but significantly greater (P < 0.05) in the kidney for cisplatin. The data indicate that the greater renal levels of total and interstrand DNA-platinum adducts formed by cisplatin correlate with renal damage associated with this agent, and suggest that adduct levels, and not total tissue platinum levels, provide a more useful correlation with pharmacodynamic observations.
Animals↗
Tyrosines 1148 and 1173 of activated human epidermal growth factor receptors are binding sites of Shc in intact cells.
Autophosphorylation of receptor tyrosine kinases provides binding sites for signaling proteins containing Src homology 2 (SH2) domains. We determined the binding sites of Shc, SH2-containing adaptor protein, within epidermal growth factor (EGF) receptors, using Chinese hamster ovary cells overexpressing EGF receptor mutants in which autophosphorylation sites, either alone or in combination, were replaced by phenylalanine. Binding of Shc to EGF receptor mutants lacking single tyrosine residues at 1148 or 1173 decreased by approximately 60 or approximately 15%, respectively, whereas other single point mutants bound the wild-type level of Shc. Binding of Shc markedly decreased in mutants lacking both tyrosine residues at 1148 and 1173. In peptide inhibition assay, phosphorylated nonameric peptide representing tyrosine 1148, DNPDpYQQDF, but not pentameric peptide, pYQQDF, inhibited the binding of glutathione S-transferase-Shc SH2 domain fusion protein to in vitro autophosphorylated EGF receptors, suggesting that N-terminal sequences adjacent to phosphotyrosine are necessary for the association of Shc. Based on results of peptide inhibition assays in which phosphorylated peptides representing tyrosines 992, 1148, and 1173 inhibited Shc binding to the receptor, we constructed another EGF receptor mutant in which one of these tyrosine residues was retained. The amount of Shc bound to mutant receptors retaining tyrosines 1148, 1173, or 992 was approximately 80, approximately 40, or approximately 10% of wild-type level, respectively. These results indicate that tyrosine 1148 of activated human EGF receptors is a major binding site of Shc and tyrosine 1173 is a secondary binding site in intact cells.
Amino Acid Sequence↗
Impact-parameter dependent stopping powers for axially channeled and semichanneled MeV He ions in GaAs:Er.
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Journal Article↗
Glutathione-mediated modulation of tetraplatin activity against sensitive and resistant tumor cells.
Tetraplatin (Ormaplatin) has good antitumor activity against some cisplatin-resistant cells and is currently being studied in clinical trials. We have studied the effect of extracellular reduced glutathione (GSH) on the cytotoxicity and biochemical pharmacology of tetraplatin in L1210 leukemia cells. Parent L1210/0 cells were exposed to tetraplatin for 2 hr with or without GSH in Hanks' balanced salt solution (HBSS), and cytotoxicity was assessed by a soft agar clonogenic assay. GSH (10 or 100 microM) increased tetraplatin (10 microM)-induced cell kill by about 2 logs; concentrations of the thiol 10-fold below or above these levels increased cell kill to a lesser degree. GSH-mediated increases in the cytotoxicity of tetraplatin were also observed against cisplatin-resistant L1210/DDP and tetraplatin-resistant L1210/DACH cells. An equimolar concentration of 1,2-diaminocyclohexane-platinum(II) dichloride [DACH-Pt(II)Cl2] alone was as cytotoxic as the combination of tetraplatin and GSH. Intracellular accumulations of tetraplatin in both L1210/0 and L1210/DDP cells were increased by GSH, whereas in L1210/DACH cells platinum uptake decreased in the presence of the thiol. Reactions between tetraplatin and salmon sperm DNA in the presence or absence of GSH (1 or 100 microM), performed at 37 degrees in HBSS, revealed that levels of total and interstrand DNA-platinum adducts were minimal in the absence of GSH, whereas in the presence of GSH DNA adducts of tetraplatin were substantial and similar to those seen with DACH-Pt(II)Cl2. Tetraplatin (10 microM) incubated at 37 degrees in HBSS with GSH (10 microM-1 mM) was reduced chemically to the DACH-Pt(II) species within 5 min; a 200-microM tetraplatin solution required a GSH concentration of at least 100 microM for substantial reduction to occur. This chemical reduction of tetraplatin appears to be a prerequisite for its biological activity. Thus, extracellular GSH can modulate the biological activity of tetraplatin, and the combination may prove useful in specific clinical applications, such as intracavitary platinum therapy.
Animals↗
Tumor-derived components were responsible for suppression of ornithine decarboxylase activity in the rat wounded skin.
To elucidate the principal cause of delayed wound healing in a tumor-bearing host, the effect of Yoshida sarcoma-derived components on dermal wound healing was investigated in rats with the aid of ornithine decarboxylase (ODC) activity and in vivo bromodeoxyuridine (BrdU) labeling index. The ODC activity in the wounded skin decreased 3 and 7 days after intraperitoneal inoculation of Yoshida sarcoma cells (378.0 +/- 37.3 on Day 3, 280.0 +/- 140.0 on Day 7 vs. 809.3 +/- 109.5 pmol/mg protein/hour on Day 0). When administered 24 hours before and immediately after wounding, the crude nuclear component of the tumor cells significantly decreased the ODC activity in the wounded skin as compared with the control (185.9 +/- 159.8 vs. 534.0 +/- 59.1), but the non-nuclear component was not effective. When nuclear extracts of Yoshida sarcoma cells were intraperitoneally administered immediately after wounding, the 0.15 M or 0.35 M NaCl extract significantly suppressed ODC activity in the wounded skin (233.5 +/- 14.5 and 352.3 +/- 63.2 pmol/mg protein/hour, respectively) in comparison to the control (445.9 +/- 73.6). The BrdU labeling index of epidermal basal cells adjacent to the edge of the wound decreased up to 52% of the control by injection of the 0.15 M extract. It seems that tumor-derived nuclear components may be responsible for delayed wound healing which is commonly observed in cancer cachexia.
Animals↗
Thermal enhancement of drug uptake and DNA adducts as a possible mechanism for the effect of sequencing hyperthermia on cisplatin-induced cytotoxicity in L1210 cells.
An optimal scheduling of hyperthermia and cis-diammine-dichloroplatinum(II) (cisplatin) may increase the therapeutic gain of the combination of these two modalities. In this study, intracellular platinum accumulation, total platinum binding to DNA, and DNA interstrand crosslinks (ISC) were assayed to investigate the molecular mechanisms responsible for the effect of sequencing hyperthermia on the thermal enhancement of cisplatin-induced cytotoxicity in mouse leukemia L1210 cells. Simultaneous treatment with heat (41.5 degrees C, 60 min) and cisplatin produced maximal cell killing with a 4-fold decrease in the 50% growth-inhibitory concentration (IC50) of the platinum complex. Super-additive cell killing was also shown when cells were exposed to heat before cisplatin treatment, whereas no thermal enhancement in cisplatin-mediated cytotoxicity was observed in cells given heat after exposure to cisplatin. These results correlated with the degree of formation of ISC observed in cells following various treatments. A 2- to 3-fold increase in ISC formation was observed in cells given heat before or during cisplatin exposure, whereas heat after cisplatin treatment did not alter either the formation or the reversal of ISC as compared with cisplatin alone. The increased ISC formation was associated with an increase in intracellular platinum accumulation and total platinum binding to DNA in cells given heat before or during cisplatin exposure. These data, showing that hyperthermia potentiates cisplatin cytotoxicity by increasing drug uptake and the formation of DNA adducts without inhibiting the repair of DNA lesions, demonstrate the potential utility of sequencing hyperthermia combined with cisplatin as a clinical anticancer therapy.
Animals↗