Ras interaction with RalGDS effector targets.
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3T3 Cells↗
Biomedical subjects
S Koyama
Publications and source records attributed to S Koyama.
Phase I trial of weekly docetaxel combined with cisplatin in patients with non-small cell lung cancer.
The phase I study was conducted to evaluate the maximum tolerated dose (MTD) and toxicity of weekly administered docetaxel combined with cisplatin in patients with non-small-cell lung cancer (NSCLC). In a dose escalation study, 22 patients, under 75 years old, with unresectable and metastatic untreated NSCLC with performance status (0-1) were enrolled. Patients were treated with cisplatin (day 1) and weekly docetaxel (days 1, 8, 15). Dose escalation levels in mg/m(2) were for cisplatin and docetaxel; 70 and 15 (level 1), 80 and 15 (level 2), 80 and 20 (level 3), 80 and 25 (level 4), 80 and 30 (level 5), respectively. Chemotherapy was repeated for at least two cycles every 28 days. All patients were assessable for toxicities. Although grade 3 neutropenia occurred in one case in level 4, there were no significant modifications of chemotherapy schedule until level 4. Grade 3 neutropenia occurred in all cases receiving level 5. One patient developed an infection, and two had incomplete recovery of neutropenia by the 28th day after the first cycle of chemotherapy. Nonhematological toxicities, including nephrotoxicity, nausea/vomiting, alopecia and hypersensitivity reaction, were tolerable. However, one case developed severe hyponatremia. Among 21 patients evaluable for response, eight cases achieved partial response, thus the overall response was 39%. Weekly administration of docetaxel at 25 mg/m(2) (days 1, 8, 15) combined with cisplatin 80 mg/m(2) (day 1) is recommended for phase II studies. The responses observed in the present study suggest an identical high degree of activity against NSCLC with less hematotoxicity compared with a standard schedule of cisplatin and docetaxel.
Adult↗
Leukemia blast-induced T-cell anergy demonstrated by leukemia-derived dendritic cells in acute myelogenous leukemia.
OBJECTIVE: To elucidate the mechanism of immunologic escape of leukemia cells and establish an effective anti-leukemia immunotherapy, we attempted to generate dendritic cells from leukemia cells in patients with acute myelogenous leukemia (AML). Using these leukemia-derived dendritic cells, we investigated leukemia cell-associated T-cell anergy. MATERIALS AND METHODS: Leukemia cells of 30 patients with AML were cultured with granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-alpha. Cultured leukemia cells were evaluated for antigen-presenting ability by mixed leukocyte culture (MLC). Normal lymphocytes, which were cocultured with leukemia blasts in the first MLC, were cultured with leukemia-derived dendritic cells in the second MLC. RESULTS: In cultures of leukemia cells from 21 of 30 patients examined, cells with stellate morphology and cell fractions with CD1a(+) and/or CD83(+) were present. Autologous MLC using lymphocytes obtained in remission phase as responders as well as allogeneic MLC demonstrated antigen-presenting ability in leukemia-derived dendritic cells. Leukemia cells of FAB-M0, M1, M2, M3, or M6 morphology/phenotype gave rise to dendritic cells as well as leukemia cells of M5. The leukemic origin of dendritic cells was suggested by in situ hybridization. By coculture with CD80(-) leukemia blasts, the response of normal lymphocytes to leukemia-derived dendritic cells cultured from the same individual as that of leukemia blasts was markedly reduced, compared with the lymphocytes cultured with leukemia blasts from a different individual as leukemia blasts. CONCLUSIONS: Escape of leukemia cells from anti-leukemia immunity may be associated with T-cell anergy caused by leukemia blasts. The results of the present study suggest that leukemia-derived dendritic cells can be applied efficiently in anti-leukemia immunotherapy.
Adolescent↗
Automatic discriminative sensitivity inside temporal window of sensory memory as a function of time.
Neural representation of preceding sound-patterns stored in the human brain, as reflected by mismatch negativity (MMN) related to the automatic discriminative process, is restricted to a duration of 160-170 ms due to the short form of auditory sensory memory termed the temporal window of integration (TWI). To examine the temporal uniformity of deviation-sensitivity inside TWI of sensory memory, magnetic MMN (MMNm) responses were measured with a dual 37-channel magnetometer for complex sounds of 170 ms duration containing an omitted (silent) segment. Frequent standard stimuli (probability of 80%) consisted of five tone segments. Deviant stimuli were different from standard stimuli in that one of four segments was occasionally (probability of 5%) omitted and replaced by a silent segment. The stimulus duration of 170 ms was intended to correspond to the postulated duration of TWI. When the silent segment occurred later in deviant stimulus, the MMNm peak amplitude was attenuated and MMNm peak latency, measured from the onset of each silent segment, was delayed. Thus, automatic deviation-detection sensitivity declines nonlinearly toward the end of TWI in auditory sensory memory. In the second experiment, two types of deviant stimuli, which differed from each other only in the period after the occurrence of the silent segment, elicited MMNm with the same peak latency but with a different peak amplitude. Thus, mismatch process is triggered at the moment of change but still lasts after the detection of deviation. In other words, both standard and deviant stimuli are treated as a unitary event within a TWI.
Acoustic Stimulation↗
A case of toxic shock-like syndrome presenting with serious hypoproteinaemia because of a protein-losing gastroenteropathy.
A 37-year-old man was admitted to our hospital because of toxic shock-like syndrome (TSLS) induced by Streptococcus pyogenes. After the pathogenic bacteria had been eradicated, serious diarrhoea appeared and a protein-losing gastroenteropathy developed. An immunohistochemical study of the biopsy specimens of both small and large intestines revealed the infiltration of T-lymphocytes, predominantly CD8+ cells, into the lamina propria of affected mucosa, villus atrophy and crypt hyperplasia. Considering these histological findings, some immunological mechanism which lead the activation of cytotoxic T-lymphocytes may play an important role in the pathogenesis of this rare intestinal manifestation of TSLS.
Adult↗
Primary synovial sarcoma of the kidney: Report of a case confirmed by molecular detection of the SYT-SSX2 fusion transcripts.
We describe an unusual case of primary synovial sarcoma of the kidney. A 47-year-old woman had a tumor massively replacing the right kidney. There were no primary extrarenal neoplastic lesions. Microscopically, the tumor was composed of a cellular proliferation of relatively uniform spindle-shaped cells having atypical spindle or oval nuclei arranged in fascicles with tumor necrosis, without epithelial areas. Immunohistochemically, a small number of the tumor cells were positive for epithelial markers such as cytokeratin and epithelial membrane antigen. The SYT-SSX2 fusion transcripts were detected by a reverse transcription-polymerase chain reaction (RT-PCR) using RNA extracted from formalin-fixed, paraffin-embedded tissue. ETV6-NTRK3 fusion gene transcripts that result from t(12; 15)(p13;q25), which is characteristic of cellular congenital mesoblastic nephroma, were not demonstrated. To our knowledge, this is the ninth case of primary renal synovial sarcoma. This case report indicates that synovial sarcoma should be taken into account for the differential diagnosis of renal spindle cell tumors and the molecular assay detecting the SYT-SSX fusion transcripts is useful for the final diagnosis of synovial sarcoma arising in an unusual location.
Base Sequence↗
Temporal bone histopathology after treatment by a large amount of cisplatin: a case study.
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Adolescent↗
Histamine stimulates alveolar macrophages to release neutrophil and monocyte chemotactic activity.
Histamine and serotonin are important inflammatory mediators in the pathophysiology of asthma, and asthmatic patients have higher plasma histamine and serotonin levels than non-asthmatic control subjects. Alveolar macrophages (AMs) synthesize and secrete a large number of substances that play a key role in acute and chronic inflammation including asthma. We postulated that AMs might release chemotactic activity for neutrophils and monocytes in response to histamine or serotonin. To test this hypothesis, bovine AMs were cultured, and the supernatant fluids were evaluated for neutrophil chemotactic activity (NCA) and monocyte chemotactic activity (MCA) by a blind well chamber technique. AMs released chemotactic activity in response to histamine and serotonin in a dose- and time-dependent manner (P <.05). Partial characterization and molecular sieve column chromatography revealed that low-molecular-weight lipid-soluble activity was predominant. Lipoxygenase inhibitors significantly blocked the release of chemotactic activity. Leukotriene B(4) receptor antagonists blocked the chemotactic activity. Immunoreactive leukotriene B(4) significantly increased in supernatant fluids in response to histamine and serotonin. The receptor responsible for the release of chemotactic activity in response to histamine was the H2 receptor. These data demonstrate that AMs release NCA and MCA in response to histamine or serotonin (or both) and may modulate the inflammatory cell recruitment into the lung.
Acetates↗
Inflammatory cytokines modulate eotaxin release by human lung fibroblast cell line.
Eotaxin, a potent eosinophil-specific chemotactic factor, is increased in the lower respiratory tract of asthma patients. Recently, lung fibroblasts have been reported to produce eotaxin and their activation can be modulated by inflammatory cytokines. To test the hypothesis that inflammatory cytokines modulate the eotaxin release from lung fibroblasts, we investigated the potential of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), or interferon-gamma (IFN-gamma) to induce the release of eotaxin and eotaxin mRNA by the human fetal lung fibroblast cell line, HFL-1, was evaluated. HFL-1 released eotaxin constitutively without stimulation, but IL-1beta or TNF-alpha stimulated eotaxin release in a dose- and time-dependent manner. IL-1beta or TNF-alpha treatment of HFL-1 also resulted in the augmented expression of eotaxin mRNA. Although IFN-gamma alone had negligible effect on eotaxin release and mRNA expression, IFN-gamma induced a significant, concentration-dependent attenuation of eotaxin release and eotaxin mRNA expression from HFL-1 stimulated with IL-1beta or TNF-alpha. These findings are consistent with the concept that lung fibroblast-derived eotaxin may in part be responsible for the eosinophil infiltration observed in the airways of asthmatic patients and that network of cytokines may modulate the eosinophil recruitment to the airways by stimulation of fibroblasts to release eotaxin.
Cell Line↗
Segmental cardiac function computed from ECG-gated SPECT images through solution of equations of continuity for fluids.
Segmental contractions were quantified from images of electrocardiographic-gated single-photon emission computed tomography. Counts were integrated in 64 angles about the centre on short-axis images and projected onto a cylindrical screen. Changes in the projected count were shown to obey the equation of continuity for two-dimensional fluids (the Poisson equation). Displacements of each pixel point were calculated from the velocity field to quantify the amount of dislocation. Changes in the configuration of the pixel points were projected back on the cardiac wall, and finally segmental contractions were evaluated as a percentage reduction of the area. Computer simulations were performed for numerical models of circumferential and long-axial contractions, uneven eccentric contractions and rotations. These models were blurred with a three-dimensional Gaussian function. The results obtained using this method (quantification of segmental function by solving the Poisson equation (QSFP)) were compared with the wall-thickening method (WTM) and the maximum-count method. Both QSFP and WTM yielded good agreement with predicted values for circumferential and long-axial contractions. Only QSFP gave satisfactory results for uneven eccentric contractions, and rotation models. QSFP should provide a useful tool for in vivo quantification of contraction tangential to the cardiac wall by eliminating errors due to displacements.
Aged↗
Further reduction of radiation dose in helical CT for lung cancer screening using small tube current and a newly designed filter.
A new aluminum filter, 5.8 mm thick at the center, was designed. The effective energy, exposure dose, absorbed dose, and noise were measured by using low-dose technique, very low-dose technique with a conventional filter, and very low-dose technique with a new filter on a chest phantom. Accuracy of very low-dose computed tomography (CT) with a new filter was compared against standard helical CT in 40 patients and against chest radiography in 35 patients. Effective energies were 42.6 keV and 51.6 keV at a conventional filter and the new filter, respectively. Compared against 20mA with a conventional filter, exposure dose was reduced by 17%, and absorbed dose was equivalent, at 30 mA with the new filter. Noise was improved by 9%. Compared with standard helical CT, the sensitivity, specificity, and accuracy of very-low-dose helical CT were 100%, 88%, and 95%, respectively. Very-low-dose helical CT was found to be significantly superior to chest radiography in the detection of lung cancers. Using a smaller tube current and an appropriate filter allows a further reduction in radiation dose in helical CT for lung cancer screening.
Adult↗
Epidemiological survey of Orientia tsutsugamushi distribution in field rodents in Saitama Prefecture, Japan, and discovery of a new type.
There are various antigenic variants of Orientia tsutsugamushi which are distinguished by immunological and molecular genetic methods targeted at the antigenic diversity of 56-kDa type-specific antigen proteins. The present study was performed to analyze 15 strains successfully isolated from rodents in Saitama Prefecture, Japan, by 56-kDa gene sequence homologies, reactivities with type-specific monoclonal antibodies and polymerase chain reaction (PCR) using type-specific primer-pairs. We demonstrated the presence of a new type of O. tsutsugamushi among the isolates. This new type, designated as the Saitama type, was located in the branch of Karp type in the phylogenetic tree based on 56-kDa gene sequences, but distant from the known Karp types, such as Karp, JP-1 and JP-2, showing less than 90% homology. Strains of this type could not be distinguished by immunological methods from Karp type strains, but a new primer-pair for PCR which specifically amplifies the DNA of this new type strain was designed. This primer-pair may serve to find this strain type in future studies.
Animals↗
Erythromycin modulates eosinophil chemotactic cytokine production by human lung fibroblasts in vitro.
Recent studies suggest that erythromycin can suppress the production of some cytokines and may be an effective treatment for asthma. Eosinophil chemotactic cytokines have been suggested to contribute to the pathogenesis of asthma by the recruitment of eosinophils. We hypothesized that erythromycin modulates eosinophil chemotactic cytokine production. To test the hypothesis, we evaluated the potential of erythromycin to modulate the release of eosinophil chemoattractants from the human lung fibroblast cell line HFL-1. HFL-1 released eotaxin, granulocyte-macrophage colony-stimulating factor, and regulated and normal T-cell expressed and presumably secreted (RANTES) in response to interleukin-1beta or tumor necrosis factor alpha. Erythromycin attenuated the release of these cytokines and eosinophil chemotactic activity by the HFL-1. The suppressive effect on eotaxin was the most marked of these cytokines. Erythromycin therapy also suppressed eotaxin mRNA significantly. These results suggest a mechanism that may account for the apparent beneficial action of macrolide antibiotics in the treatment of allergic airway disorders.
Anti-Bacterial Agents↗
Cyclophosphamide stimulates lung fibroblasts to release neutrophil and monocyte chemoattractants.
Cyclophosphamide is an alkylating antineoplastic agent used in several conditions. However, little is known about the mechanism of its pulmonary toxicity. In the present study, we determined that human lung fibroblasts release activity for neutrophils and monocytes in response to cyclophosphamide in a dose- and time-dependent manner. Checkerboard analysis revealed that both neutrophil and monocyte activities were chemotactic. The release of chemotactic activity was inhibited by lipoxygenase inhibitors and cycloheximide. Molecular-sieve column chromatography revealed that both neutrophil (NCA) and monocyte (MCA) chemotactic activities had multiple peaks. NCA was inhibited by a leukotriene B(4) receptor antagonist and anti-interleukin-8 and anti-granulocyte colony-stimulating factor antibodies. MCA was attenuated by a leukotriene B(4) receptor antagonist and anti-monocyte chemoattractant protein-1 and anti-granulocyte-macrophage colony-stimulating factor antibodies. The concentrations of interleukin-8, granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, and granulocyte-macrophage colony-stimulating factor significantly increased in response to cyclophosphamide. These data suggest that lung fibroblasts may modulate inflammatory cell recruitment into the lung by releasing NCA and MCA in response to cyclophosphamide.
Antibodies↗
Theophylline inhibits TNF-alpha-induced CD4 expression on human eosinophils and CD4+ eosinophil migration.
BACKGROUND: Increasing evidence regarding asthma suggests that CD4+ cells are preferentially recruited to sites of bronchial inflammation. Interleukin (IL)-16 has been reported as playing an important role in the accumulation of CD4+ cells. We have shown that the CD4 molecule is expressed on normal human eosinophils by tumor necrosis factor (TNF)-alpha stimulation. METHODS: We evaluated the effects of theophylline, KF19514 [a selective phosphodiesterase (PDE) IV inhibitor] and dexamethasone on CD4 expression on eosinophils and eosinophil migration in response to IL-16, a natural soluble ligand of the CD4 molecule. RESULTS: The maximum eosinophil migration was observed when eosinophils were cultured with TNF-alpha at 10 ng/ml for 18 h and the concentration of IL-16 was 10 pg/ml. CD4+ eosinophil migration in response to IL-16 was mostly, if not fully, chemokinetic and this migration was significantly inhibited by Fab of anti-CD4 monoclonal antibody. Theophylline (10(-4)-10(-3) M), KF19514 (10(-7)-10(-6) M) and dexamethasone (10(-8)- 10(-6) M) significantly inhibited CD4 expression on eosinophils induced by TNF-alpha. Theophylline (10(-3) M) and KF19514 (10(-6) M) inhibited CD4+ eosinophil migratory responses induced by IL-16, but 10(-6) M dexamethasone did not. Theophylline and KF19514 augmented the intracellular adenosine-3',5'-cyclic monophosphate (cAMP) concentration in eosinophils, suggesting modulation by cAMP of CD4 expression and eosinophil migration. CONCLUSIONS: These data suggest that TNF-alpha-induced CD4+ eosinophils may contribute to eosinophil migratory responses induced by IL-16. Theophylline and selective PDE IV inhibitor may prevent airway inflammation by downregulating CD4 expression on eosinophils and inhibiting eosinophil migration through CD4 and IL-16 interaction.
CD4 Antigens↗
Chemotaxis of human CD4+ eosinophils.
We reviewed the biological functions of CD4+ eosinophils, which are observed in peripheral blood, sputum and bronchoalveolar lavage fluid of various diseases. We have shown that CD4 molecules on human eosinophils are induced by tumor necrosis factor-alpha (TNF-alpha) stimulation. Interleukin-16 (IL-16) has been reported to bind a natural soluble ligand for the CD4 molecule. We reported that TNF-alpha-stimulated eosinophils migrate in a time- and dose-dependent manner against IL-16. Theophylline and dexamethasone significantly inhibited CD4 expression. Theophylline inhibited CD4+ eosinophil chemotaxis, but dexamethasone did not. Theophylline may prevent airway inflammation by downregulating the expression of CD4 molecule and CD4+ eosinophil migration. However, dexamethasone may inhibit airway inflammation through the downregulation of CD4 expression.
Asthma↗
Effects of heat exposure on adrenergic modulation of insulin and glucagon secretion in sheep.
The effects of heat exposure on the adrenergic modulation of pancreatic secretion were investigated. Five ewes fed at maintenance level (ME base) were housed in thermoneutral (TN; 20 degrees C) and hot (30 degrees C) environments. Heat exposure caused an increase in respiration rate and a slightly higher rectal temperature, and decreases in basal insulin and glucose concentrations. Infusions of saline plus epinephrine caused increases in glucagon and glucose concentrations, and no significant change in insulin secretion. Phentolamine (an adrenergic alpha-antagonist) plus epinephrine augmented insulin secretion; however, this insulin secretory response was inhibited by heat exposure. Propranolol (a beta-antagonist) plus epinephrine produced a slight decrease in insulin secretion in the TN environment, whereas no effect was observed during heat exposure. While glucagon secretion through alpha-adrenergic stimulation was not affected by heat exposure, homeostatic signals controlling insulin release seemed to be affected during heat exposure. We thus hypothesised that insulin concentration is decreased in sheep fed at maintenance level in hot environments, and that this response is mediated in part by a modulation of beta-adrenergic function.
Adrenergic alpha-Antagonists↗
Rhabdomyolysis triggered by an asthmatic attack in a patient with McArdle disease.
We describe a patient with McArdle disease who developed rhabdomyolysis triggered by a bronchial asthmatic attack. A 64-year-old man had chronic pulmonary emphysema with asthma, and an asthmatic attack led to severe rhabdomyolysis that required continuous hemodiafiltration. After 2 years, a physical examination revealed atrophy of the extremities compared with previous examinations, especially of the intercostal muscles. During that time, he suffered two severe bronchial asthmatic attacks. His serum level of creatinine kinase remained between 4,000 and 7,000 IU/l when he did not suffer from asthmatic attacks and rhabdomyolysis had abated. Therefore, we suspected that his recent muscle atrophy was caused by asthmatic attacks, and discussed the possibility of his respiratory muscle weakness due to McArdle disease in relation to his severe bronchial asthmatic attacks as well as chronic obstructive pulmonary disease.
Asthma↗