Valence-band density of states of near-noble-metal (Ni,Pd,Pt) monosilicides by using soft-x-ray-emission spectroscopy.
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Journal Article↗
Biomedical subjects
M Kusaka
Publications and source records attributed to M Kusaka.
[Promotive effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on recovery from neutropenia induced by fractionated irradiation in mice].
The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on the recovery from neutropenia induced by fractionated whole-body irradiation was investigated in mice. Male 7-week old C3H/HeN mice received a total of ten exposures of 0.25 Gy/day from day 1 to 5 and from day 8 to 12. Peripheral neutropenia with a nadir on day 17 was caused by the fractionated irradiation. Daily subcutaneous injections of rhG-CSF at 0.25 and 2.5 micrograms/body/day from day 1 to 21 promoted the recovery of neutrophils in a dose-dependent manner. The kinetics of morphologically identifiable bone marrow cells were studied to clarify the mechanism behind the promotive effect of this factor. A slight decrease in mitotic immature granulocytes, such as myeloblasts, promyelocytes and myelocytes on day 5, and a drastic decrease in metamyelocytes and marrow neutrophils on days 5, 9, and 17 were seen in the femur of irradiated mice. Treatment using rhG-CSF caused an increase in immature granulocytes of all differential stages in the femur. Microscopic findings of the femurs and spleens also revealed an increase in immature granulocytes in these organs in mice injected with rhG-CSF. These results indicate that rhG-CSF accelerates granulopoiesis in the femur and spleen, thereby promoting recovery from neutropenia induced by fractionated irradiation.
Animals↗
AGM-1470, a potent angiogenesis inhibitor, prevents the entry of normal but not transformed endothelial cells into the G1 phase of the cell cycle.
AGM-1470 is a potent angiogenesis inhibitor that is very effective in inhibiting endothelial cell proliferation in both in vitro and in vivo models and that prevents tumor growth in vivo. Although this molecule appears to be a most promising anticancer drug, its mechanism of action has not yet been elucidated. In this study, we examined the effects of AGM-1470 on the cell cycle of normal and transformed endothelial cells. We showed that AGM-1470, at picomolar concentrations, specifically inhibits the proliferation of both bovine aortic endothelial cells and human umbilical vein endothelial cells. AGM-1470 was ineffective in significantly inhibiting the proliferation of Ea.hy926 cells, a hybrid cell line obtained by the fusion of human umbilical vein endothelial cells with a human carcinoma cell line, or cEnd.1 cells, a polyoma middle T oncogene-transformed endothelioma cell line derived from mouse embryo. Using a double labeling technique with anti-Ki67 antibodies and propidium iodide, we demonstrated, with flow cytometry analysis, that AGM-1470 specifically prevents the entry of endothelial cells into the G1 phase of the cell cycle. We also showed that AGM-1470 was ineffective in inhibiting endothelial cell migration toward laminin or capillary-like tube formation inside a type I collagen matrix induced by phorbol esters. Our data strongly suggest that AGM-1470 is a molecule that specifically inhibits a cell cycle control pathway active in normal cells but which could be bypassed or altered in transformed cells.
Animals↗
Homeobox genes: potential candidates for the transcriptional control of the transformed and invasive phenotype.
The transformation of a cell and the acquisition of the invasive and metastatic phenotype result from the activation of a group of complex cellular processes rather than from the effect of a single gene product. It is likely that the coordination of the multiple genes involved in malignancy is under the control of a few genes that act as master genes or orchestrator genes. The latter probably code for transcription factors that control the genetic program for tumor invasion and metastasis. Homeobox genes are a family of transcription factors that contain a 183 bp highly conserved nucleotide sequence coding for a 61 amino acid domain that binds specifically to DNA. First discovered in Drosophila as genes controlling segmentation and segment identity, homeobox genes have since been identified in many other species including nematodes, frog, mouse and human. There is strong support for the suggestion that homeobox genes play a key role in development and differentiation. In humans, there are 38 homeobox genes organized in four clusters that are localized on chromosomes 2, 7, 12 and 17. The specific functions of each of these genes are generally unknown. Alterations in expression of several homeobox genes have been reported in a variety of malignant lesions, suggesting that they could play a role in the development of cancer. Using reverse transcriptase reaction coupled with polymerase chain reaction and degenerate oligonucleotides corresponding to the 5' and 3' ends of the highly conserved homeodomain, we amplified 130 bp cDNA fragments from the human breast cancer cell line MCF7 that were subsequently cloned into pBluescript vector. Sequencing of the clones, resulted in the identification of the homeodomains of four different human homeobox genes: HOXB6, HOXA1, HOXA10 and HOXC6. Further studies should determine the specific role of these four homeobox genes in the development and progression of human breast cancer and potentially determine if they might be good targets for gene therapy.
Amino Acid Sequence↗
Depressed responsiveness to angiotensin II in ventricular myocytes of hypertrophic cardiomyopathic Syrian hamster.
Electromechanical responsiveness to angiotensin II (Ang II) receptor stimulation in ventricular myocardium and myocytes of hypertrophic cardiomyopathic Syrian hamsters (BIO 14.6) was examined and compared with that in preparations of normal hamsters (F1B) using conventional microelectrode and patch clamp techniques. Action potential duration (APD) and developed tension (DT) corrected for the cross-sectional area of the papillary muscles of 14-20 week-old BIO 14.6 hamsters were significantly smaller than those in preparations of age-matched normal hamsters. An Ang II (1 microM)-induced increase in DT in BIO 14.6 papillary muscles (24.7 +/- 11.0%) was significantly smaller than that in F1B papillary muscles (53.8 +/- 8.5%), which was associated with a smaller increase in APD in BIO 14.6 papillary muscles. In ventricular myocytes of both BIO 14.6 and F1B hamsters. Ang II increased the calcium current (ICa) following a transient decrease in ICa. However, the magnitude of the Ang II-induced increase in ICa in BIO 14.6 myocytes (35.5 +/- 7.5%) was significantly smaller than that in F1B myocytes (86.0 +/- 19.7%), suggesting a causal relationship between ICa and mechanical response to Ang II in these hamsters. The depressed responsiveness to Ang II receptor stimulation in hypertrophic cardiomyopathic hamster is in a marked contrast with the enhanced responsiveness to alpha 1-adrenergic stimulation, which was demonstrated by previous studies, and may be one of adaptational changes to the activated renin-angiotensin system in the cardiomyopathy.
Action Potentials↗
Pharmacological effects of recombinant human granulocyte colony-stimulating factor modified by polyethylene glycol on anticancer drug-induced neutropenia in mice.
1. To clarify the pharmacological effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) conjugated to polyethylene glycol (PEG), its effects on the number of circulating neutrophils in mice made neutropenic by cyclophosphamide (CPA) or 5-fluorouracil (5-FU) were compared with rhG-CSF lacking PEG. 2. In normal mice, PEG-conjugated rhG-CSF (PEG-rhG-CSF, 10 micrograms protein/kg) induced an increase in neutrophils which lasted for 72 h after injection whereas the effect of rhG-CSF (10 micrograms protein/kg) disappeared by 24 h after injection. 3. In CPA or 5-FU-induced neutropenic mice, PEG-rhG-CSF inhibited neutropenia or accelerated recovery from neutropenia and its potency was higher than that of rhG-CSF. 4. These results indicate that PEG-rhG-CSF has a longer duration of action than rhG-CSF and is more effective in the recovery from neutropenia.
Animals↗
Cytostatic inhibition of endothelial cell growth by the angiogenesis inhibitor TNP-470 (AGM-1470).
Recently, we reported the anti-angiogenic action along with anti-tumour activity of TNP-470 (AGM-1470). In this study, the effect of TNP-470 on the growth of human umbilical vein endothelial (HUVE) cells was examined. TNP-470 inhibited the growth of HUVE cells in a biphasic manner. The inhibition was cytostatic in the first phase (complete inhibition at 300 pg ml-1 to 3 micrograms ml-1 with an IC50 of 15 pg ml-1) and cytotoxic in the second phase (> or = 30 micrograms ml-1). The cytostatic inhibition of HUVE cell growth by TNP-470 was durable after washing out TNP-470 in culture. Incorporation of thymidine but not uridine and leucine by HUVE cells was inhibited in the first phase, while that of all three compounds was inhibited in the second phase. Human and rat endothelial cells among various types of cells were the most sensitive to the cytostatic inhibition, while differences in the cytotoxic inhibition were minimal. These results suggest that TNP-470 exerts its specific anti-angiogenic action by inhibiting cytostatically growth of endothelial cells in a relatively specific manner.
Antibiotics, Antineoplastic↗
Dapsone N-acetylation, metoprolol alpha-hydroxylation, and S-mephenytoin 4-hydroxylation polymorphisms in an Indonesian population: a cocktail and extended phenotyping assessment trial.
We examined dapsone N-acetylation and metoprolol alpha-hydroxylation and S-mephenytoin 4-hydroxylation phenotypings using the respective test probes (dapsone and racemic metoprolol and mephenytoin) administered separately and in a cocktail manner to an Indonesian subject group (n = 30). After ascertaining that the separate and cocktail phenotyping tests of the probe drugs correlated with each other (all rs values > 0.84; p < 0.001), the cocktail phenotyping assessment was extended to the other 74 Indonesians. In a total of 104 Indonesians phenotyped with the cocktail test, a visual antimode was apparent only in the dapsone N-acetylation and S-mephenytoin 4-hydroxylation polymorphisms: the frequencies of slow acetylators and poor hydroxylators were 43.3% (95% confidence interval, 33.7% to 52.8%) and 15.4% (95% confidence interval, 8.5% to 22.3%), respectively. The distribution histogram and probit plots of the metabolic ratio of metoprolol gave no clear evidence for bimodality, and therefore no poor alpha-hydroxylator of metoprolol was considered to exist in the present sample size. The findings indicate that the Indonesian subjects have a greater incidence of slow acetylator phenotype compared with Japanese and Chinese, as well as a frequency of poor metabolizer phenotype of S-mephenytoin similar to that of Korean and Chinese subjects. They resemble an African population (Nigerians) in metoprolol alpha-hydroxylation polymorphism, with no apparent antimode derived from white populations.
Acetylation↗
Oxytocin induces an inward current in pregnant rat myometrial cells.
The effects of oxytocin (OT) on holding current were studied in uterine smooth muscle cells freshly isolated from the longitudinal layer of 18-20 day pregnant rats, using the nystatin method of whole-cell voltage clamp. As we previously reported, the voltage-dependent Ca2+ current (L type) was partially inhibited by OT (about 30% inhibition at 1 microM). When the cells were held at the holding potential (HP) of -60 mV and the holding current was monitored, OT induced an inward current. The amplitude of this OT-induced current was 72 +/- 26 pA (n = 27). When the cell was held at more positive potentials (HP 0 or +40 mV), the OT-induced current reversed direction, becoming outward. This current usually was long lasting (74% of cells responding to OT); a transient current was observed in 26% of the cells. In the absence of either Na+ or Ca2+ in the bath solution, OT induced an inward current (at HP -60 mV). However, the OT-induced current was absent when both of these ions were omitted from the bath. These results suggest that OT induces an inward current through receptor-activated nonselective cation channels. The resulting increase of intracellular Ca2+ may contribute to the inhibition of voltage-dependent Ca2+ current produced by OT. This OT-induced current may also play an important role for membrane depolarization and accompanying contraction produced by OT in pregnant rat myometrium.
Animals↗
Protein kinase C stimulates Ca2+ current in pregnant rat myometrial cells.
The factors that regulate the voltage-dependent Ca2+ channels in pregnant uterine smooth muscle cells have not been elucidated, including any roles for protein kinase C (PKC). Therefore, the role of PKC in the regulation of the slow (L type) Ca2+ channels was examined in myometrial cells isolated from late pregnant (18-19 day) rat uterus, using the nystatin-perforated whole-cell voltage clamp. A PKC activator, phorbol 12,13-dibutyrate (PDB), increased the L-type Ca2+ current (ICa(L)). Bath application of PDB (0.03 and 0.3 microM) increased the peak amplitude of ICa(L) by 21 +/- 14% (n = 6) and 37 +/- 8% (n = 9, p < 0.01), respectively. PDB did not change the holding current or shift the current-voltage relationship for ICa(L). The PKC inhibitors, H-7 (20 microM) or staurosporine (10 nM), reversed the effect of PDB. These results indicate that PKC may play a role in regulating Ca2+ channel function in pregnant rat myometrial cells and, therefore, may be involved in control of uterine contraction.
Animals↗
Fast sodium currents induced by serum in human uterine leiomyosarcoma cells.
We previously demonstrated that fast Na+ channels are expressed in uterine smooth muscle cells during pregnancy [Y. Ohya, and N. Sperelakis. Am. J. Physiol. 257 (Cell Physiol. 26): C408-C412, 1989; Y. Inoue, and N. Sperelakis. Am. J. Physiol. 260 (Cell Physiol. 29): C658-C663, 1991]. In the present study, we investigated the possible expression of fast Na+ channels and resultant fast Na+ current [INa(f)] using whole cell voltage clamp in cultured uterine leiomyosarcoma cells (SK-UT-1B), which are derived from human myometrium. The expression of INa(f) was dependent on the concentration of fetal bovine serum (FBS) in the culture medium. The mean current densities of peak INa(f) in cells incubated with 0, 1, 5, and 10% FBS were (in pA/pF) 1.3 +/- 0.5, 1.6 +/- 0.9, 9.8 +/- 2.4, and 9.8 +/- 1.7, respectively. Two types of INa(f) were identified based on different time courses of current decay. Both types of current were equally tetrodotoxin sensitive (half-maximal inhibitory concentration approximately 50 nM) and had similar electrical properties. These characteristics are consistent with those in the pregnant myometrial cells, yet the current density in the sarcoma cells is much higher. These findings suggest that one or more factors in serum induce INa(f) in the uterine sarcoma cells, and this cell line could be a good model for the study of the fast Na+ channels in uterine smooth muscle.
Animals↗
Effect of recombinant human granulocyte colony-stimulating factor on efficacy of radiation therapy in tumor-bearing rats.
The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on radiation-induced neutropenia and on growth of transplanted tumors treated by irradiation was investigated using tumor-bearing rats as a model for radiation therapy. In a preliminary study using normal rats, neutropenia induced by upper hemi-body irradiation at 3 Gy/day 5 times a week for 3 weeks was prevented by consecutive subcutaneous injections of rhG-CSF at 100 micrograms/kg/day. Rats bearing Walker-256, a mammary tumor, were scheduled to receive upper hemibody irradiation at 3 Gy/day for 15 times in 3 weeks if white blood cell (WBC) counts were maintained above 3,000/microliters. In control tumor-bearing rats not receiving rhG-CSF, irradiation was often withheld because of the decrease in WBC counts below 3,000/microliters. In contrast, a decrease in WBC counts below 3,000/microliters was rarely found in tumor-bearing rats injected daily with rhG-CSF. The average number of radiation treatments in control rats and rats treated with rhG-CSF was about 8 and 14, respectively, out of the scheduled 15 treatments in 3 weeks. Treatment with rhG-CSF made it possible to complete the radiation therapy regimen and thus inhibit the growth of the transplanted tumor more effectively. These results suggest that rhG-CSF may be useful to ensure radiation therapy on schedule in cancer patients.
Animals↗
[Comprehensive study on the membrane currents of porcine granulosa cells in culture].
The membrane currents of primary cultured porcine granulosa cells have been studied using the whole-cell configuration of the patch-clamp technique. And effects of K+ channel blockers upon progesterone production of the cells have been also studied. The author has identified and characterized two types of K+ currents, transient outward current (Ito) and a delayed rectifier K+ current (Ik), and Ca2+ current (Ica). Ito and Ik were voltage -and calcium-dependent. Both of the currents were blocked by 4-aminopyridine (4-AP), a K+ channel blocker, but only Ik was sensitive to tetraethylammonium (TEA), another K+ channel blocker. Ica was inactivated within 50 ms of the test pulse. Nifedipine and verapamil, L-type Ca2+ channel blockers, did not suppress Ica even at a concentration of 10 microM. Tetramethrin (1 microM), a T-type Ca2+ channel blocker, decreased Ica. These findings suggested that the current was T-type Ca2+ current. LH and dibutyryl cAMP, potent stimulants of steroid production, attenuated Ito by 13.9 +/- 1.8% (n = 7) and 21.0 +/- 1.5% (n = 4), respectively. However, they did not affect Ik and Ica. These results indicated that LH did not modulate Ca2+ current directly, but it suppressed Ito through cAMP. 4-AP (0.2-5 mM) suppressed basal and LH-induced progesterone production of porcine granulosa cells dose-dependently, but TEA (2-10 mM) did not influence progesterone production. These data suggest that Ito may play a role in steroid secretion or other functions in granulosa cells.
Animals↗
Membrane currents of porcine granulosa cells in primary culture: characterization and effects of luteinizing hormone.
In ovarian granulosa cells, LH depolarizes the membrane potential and induces steroid production. The membrane currents of porcine granulosa cells in primary culture were studied by means of the whole cell configuration of the patch-clamp technique to investigate whether the ionic channels are involved in the effects of LH. We identified and characterized two types of K+ currents--a transient outward current (Ito) and a delayed rectifier K+ current (IK)--and one Ca2+ current (ICa). Ito and IK were voltage- and calcium-dependent. Both currents were blocked by 4-aminopyridine, a K+ channel blocker, but only IK was sensitive to tetraethylammonium, another K+ channel blocker. ICa was inactivated within 50 ms of the test pulse. Nifedipine and verapamil, L-type CA2+ channel blockers, did not suppress ICa even at a concentration of 10 microM. Tetramethrin (1 microM), a T-type Ca2+ channel blocker, decreased ICa by 38.4 +/- 5.6% (n = 3). These findings suggest that the current may be a T-type Ca2+ current. LH and dibutyryl cAMP, potent stimulants of steroid production, attenuated Ito only by 13.9 +/- 1.8% (n = 7) and 21.0 +/- 1.5% (n = 4), respectively. However, they did not affect IK and ICa. These results indicated that LH does not modulate CA2+ current directly, but it slightly decreased Ito through cAMP elevation. The LH-induced inhibition of Ito may be involved in the depolarizing effect of LH and may play some role in steroid secretion or other functions in granulosa cells.
4-Aminopyridine↗
Ultrasound imaging for stereotactic evacuation of hypertension-associated intracerebral hematomas with aqua-stream and aspiration.
Stereotactic aqua-stream and aspiration (SASA) has been used for the evacuation of intracerebral hematomas. The authors have introduced ultrasound imaging (US) to monitor the evacuations of the hematoma during the surgical procedure. Hematomas were reproduced in an agar hematoma model which showed that if air collected in the hematoma cavity, it produced a strong artifact, and the hematoma could not be monitored. In the clinical trial, hematomas were visualized, and the surgical procedures were monitored in real time. The needle of the SASA and the air that collected in the hematoma cavity produced only weak artifacts, and the SASA water jet showed as a hyperechoic region on US, so that the procedure could be monitored in real time. In all cases, the average amount of evacuated hematoma exceeded 92%, as calculated from the preoperative and postoperative computed tomography images. The level of consciousness improved from a preoperative level of 1-20 (Japan Coma Scale) to 0-3 postoperatively. The addition of US monitoring to computed tomography guided stereotactic evacuation of hematomas with SASA enabled hypertension-associated intracranial hematomas to be evacuated more safely and more completely than has been achieved hitherto.
Agar↗
Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics.
We studied the genetically determined hydroxylation polymorphism of S-mephenytoin in a Korean population (N = 206) and the pharmacokinetics of diazepam and demethyldiazepam after an oral 8 mg dose of diazepam administered to the nine extensive metabolizers and eight poor metabolizers recruited from the population. The log10 percentage of 4-hydroxymephenytoin excreted in the urine 8 hours after administration showed a bimodal distribution with an antimode of 0.3. The frequency of occurrence of the poor metabolizers was 12.6% in the population. In the panel study of diazepam in relation to the mephenytoin phenotype, there was a significant correlation between the oral clearance of diazepam and log10 urinary excretion of 4-hydroxymephenytoin (rs = 0.777, p less than 0.01). The plasma half-life of diazepam in the poor metabolizers was longer than that in the extensive metabolizers (mean +/- SEM, 91.0 +/- 5.6 and 59.7 +/- 5.4 hours, p less than 0.005), and the poor metabolizers had the lower clearance of diazepam than the extensive metabolizers (9.4 +/- 0.5 and 17.0 +/- 1.4 ml/min, p less than 0.001). In addition, the plasma half-life of demethyldiazepam showed a statistically significant (p less than 0.001) difference between the extensive metabolizers (95.9 +/- 11.3 hours) and poor metabolizers (213.1 +/- 10.7 hours), and correlated with the log10 urinary excretion of 4-hydroxymephenytoin (rs = -0.615, p less than 0.01). The findings indicate that the Korean subjects have a greater incidence of poor metabolizer phenotype of mephenytoin hydroxylation compared with that reported from white subjects and that the metabolism of diazepam and demethyldiazepam is related to the genetically determined mephenytoin hydroxylation polymorphism in Korean subjects.
Adult↗
Utility of a one-point (3-hour postdose) plasma metabolic ratio as a phenotyping test using metoprolol in two east Asian populations.
We examined the utility of the postdose 3-h plasma metabolic ratio (MR) as a phenotyping method for assessing genetically determined debrisoquine-type oxidation polymorphism after an oral dose of 100 mg of metoprolol tartrate administered to 402 unrelated, healthy, and native East Asian (218 Korean and 184 Japanese) subjects. All of them were phenotyped simultaneously with the reported MR employing urine samples collected during an 8-h postdose period. In the two populations, the distribution histograms and probit plots of log10plasma MRs derived from the metoprolol/alpha-hydroxymetoprolol concentration values indicated a large gap between the extensive and poor metabolizers who were phenotyped by the reported criteria of the 8-h urinary MR. There were statistically significant (p less than 0.001) correlations (rs = 0.688 and 0.810, respectively) between the postdose urinary and plasma MRs in the Korean and Japanese populations. Two poor metabolizers (one each included in the two racial groups) identified according to the 8-h urinary MR gave the greatest plasma MRs (i.e., 549.7 among the Koreans and 150.0 among the Japanese). The results suggest that the one-point, postdose 3-h plasma MR is also useful for the phenotyping purpose of oxidation pharmacogenetic polymorphism of metoprolol, a widely prescribed beta-adrenoceptor blocking drug.
Adolescent↗
Caution in the use of a 100 mg dose of racemic mephenytoin for phenotyping southeastern Oriental subjects.
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Adult↗