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Biomedical subjects

T Kinoshita

Publications and source records attributed to T Kinoshita.

At least 109 records · Page 6Linked to original sources
PubMed2001

Downregulation of Bim, a proapoptotic relative of Bcl-2, is a pivotal step in cytokine-initiated survival signaling in murine hematopoietic progenitors.

Two distinct signaling pathways regulate the survival of interleukin-3 (IL-3)-dependent hematopoietic progenitors. One originates from the membrane-proximal portion of the cytoplasmic domain of the IL-3 receptor (betac chain), which is shared by IL-3 and granulocyte-macrophage colony-stimulating factor and is involved in the regulation of Bcl-x(L) through activation of STAT5. The other pathway emanates from the distal region of the betac chain and overlaps with downstream signals from constitutively active Ras proteins. Although the latter pathway is indispensable for cell survival, its downstream targets remain largely undefined. Here we show that the expression of Bim, a member of the BH3-only subfamily of cell death activators, is downregulated by IL-3 signaling through either of two major Ras pathways: Raf/mitogen-activated protein kinase and the phosphatidylinositol 3-kinase/mammalian target of rapamycin. Akt/phosphokinase B does not appear to play a significant role in this regulatory cascade. Bim downregulation has important implications for cell survival, since enforced expression of this death activator at levels equivalent to those induced by cytokine withdrawal led to apoptosis even in the presence of IL-3. We conclude that Bim is a pivotal molecule in cytokine regulation of hematopoietic cell survival.

Animals↗
PubMed2001

Overexpression of sialyl Lewis x antigen is associated with formation of extratumoral venous invasion and predicts postoperative development of massive hepatic metastasis in cases with pancreatic ductal adenocarcinoma.

The clinicopathological factors and expression of sialyl Lewis antigens which are the cell adhesion molecules to endothelial cells were compared in relation to the extent of the postoperative hepatic metastasis in 23 consecutive patients with pancreatic ductal adenocarcinoma whose clinical courses were carefully monitored and documented. The overall survival of cases with massive hepatic metastasis (MHM) was significantly poorer than that of those with local or no hepatic metastasis (p = 0.0453). Postoperative MHM was significantly correlated with the presence of duodenal invasion (p = 0.0418), the presence of portal vein invasion (p = 0.0435), the presence of extratumoral venous invasion (p = 0.0052) and high expression of sialyl Lewis x antigen (p = 0.0022). Multivariate analysis confined significant correlation between the high expression of sialyl Lewis x antigen and the development of MHM (p = 0.0402). Kaplan-Meier analysis revealed that the overall survival of patients with a high expression of sialyl Lewis x antigen was significantly poorer than that of patients with a low expression of the antigen (p = 0.0216). These results indicate that the overexpression of sialyl Lewis x antigen plays an important role in the development of MHM, and also predicts a poorer overall survival of these patients. Further studies with more cases are warranted to confirm these results.

Adult↗
PubMed2001

Prostacyclin inhibits the production of MMP-9 induced by phorbol ester through protein kinase A activation, but does not affect the production of MMP-2 in Human cultured mesangial cells.

BACKGROUND/AIMS: The imbalance between degradation and synthesis of the glomerular extracellular matrix (ECM) causes glomerular sclerosis in various types of glomerulonephritis. We investigated the effect of prostacyclin, which is an inflammatory mediator, on the production of matrix metalloproteinase (MMP)-9 and MMP-2 in human cultured mesangial cells. The synthesis of Jun proteins and Ets-1 proteins, which are related with MMP-9 gene, was also studied. METHODS: The production of MMP-9 and MMP-2 was investigated by gelatin zymography. Western blotting was undertaken to analyze the protein synthesis of Jun and Ets-1. RESULTS: Prostacyclin inhibited the production of MMP-9 induced by phorbol ester. The inhibitory effect by prostacyclin was reversed in part by the pretreatment with an inhibitor of protein kinase A, such as H-89. Forskolin also inhibited the production of MMP-9. The production of MMP-2 was constitutionally seen and was not influenced by prostacyclin and forskolin. The synthesis of Jun protein augmented by phorbol ester was suppressed by prostacyclin. Ets-1 protein was constitutionally synthesized and was not affected by phorbol ester and prostacyclin. CONCLUSION: Prostacyclin plays an important role in inflammatory glomerular disorders by regulating the metabolism of ECM. The production of MMP-9 and MMP-2 may be under the different control pathways.

Carcinogens↗
PubMed2001

Spatial structure of brain electric fields during intermittent photic stimulation.

EEG changes in 27 young healthy male right-handed volunteers on intermittent photic stimulation (IPS) were estimated using global field power (GFP), EEG microstate modeling and analysis (EMMA), and low-resolution electromagnetic brain tomography (LORETA). The GFP significantly increased at flashing frequency and high harmonics. Three model maps were extracted with the EMMA procedure, from which high alternation rates of each microstate were observed. Moreover, two of the three model maps contributed very highly, occurring most frequently. LORETA imaging of the three model maps obtained from the EMMA procedure showed that both visual dominant cortical areas were activated, especially in the left hemisphere. These results suggest that IPS does not cause peculiar spatial configurations of the brain electric field, but does cause acceleration and deviation of the microstate alternation. Also, a functional laterality between hemispheres might be enhanced by symmetric IPS.

Adult↗
PubMed2001

EEG source localization and global dimensional complexity in high- and low- hypnotizable subjects: a pilot study.

Individuals differ in hypnotizability. Information on hypnotizability-related EEG characteristics is controversial and incomplete, particularly on intracerebral source localization and EEG dimensionality. 19-channel, eyes-closed resting EEGs from right-handed, healthy, 8 high- and 4 low-hynotizable subjects (age: 26.7 +/- 7.3 years) were analyzed. Hypnotizability was rated after the subjects' ability to attain a deep hypnotic stage (amnesia). FFT Dipole Approximation analysis in seven EEG frequency bands showed significant differences (p < 0.04) of source gravity center locations for theta (6.5-8 Hz, more posterior and more left for highs), beta-1 and beta-2 frequencies (12.5-18 and 18.5-21 Hz; both more posterior and more right for highs). Low Resolution Electromagnetic Tomography (LORETA) specified the cortical anteriorization of beta-1 and beta-2 in low hypnotizables. Power spectral analysis of Global Field Power time series (curves) showed no overall power differences in any band. Full-band Global Dimensional Complexity was higher in high-hypnotizable subjects (p < 0.02). Thus, before hypnosis, high and low hypnotizables were in different brain electric states, with more posterior brain activity gravity centers (excitatory right, routine or relaxation left) and higher dimensional complexity (higher arousal) in high than low hypnotizables.

Adult↗
PubMed2001

Dynamic DNA methylation change in the CpG island region of p15 during human myeloid development.

We examined the kenetics of p15 methylation and expression during myeloid development. We treated human cord blood CD34+ cells with either GM-CSF alone or in combination with stem cell factor and followed methylation at this locus using bisulfite genomic sequencing. CD34+ cells were found to be either fully methylated or completely unmethylated at 27 CpG dinucleotide sites in exon 1 and at 18 CpG sites in the promoter region of the p15 gene. A time-course study showed that the percentage of the allelic methylation of p15 CpG island increased to approximately 50% to 60% until 7 days after cytokine stimulation, then decreased to less than 10% after 21 days. The methylation was also observed in bone marrow CD34+ cells exposed to GM-CSF. p15 expression varied inversely with methylation. Expression was negligible or at low levels until 14 days, after which it increased substantially. The frequency of myeloid colony-forming cells in the progeny decreased and myeloid-specific markers increased in the later stages. Based on our observations on cells grown with GM-CSF and 5-aza-2'-deoxycytidine, DNA methylation of the p15 promoter region CpG island appears to be associated with proliferation rather than differentiation of normal human myeloid progenitors.

Alleles↗
PubMed2001

The first example for cycloenantiomeric hexahomooxacali.

Cycloenantiomeric hexahomooxacalix[3]arenes with different substituents on the three upper rims were synthesized for the first time by fixing their conformation into a cone. A cycloenantiomeric hexahomooxacalix[3]arene 6 was resolved into both enantiomeric forms and chiroptically characterized. Preliminary 1H-NMR studies indicated that the optically resolved cycloenantiomer 6 could discriminate the enantiomers of hydrochloride of phenylalanine ethyl ester.

Chromatography, High Pressure Liquid↗
PubMed2001

[The occurrence of Churg-Strauss syndrome in two patients with remitted asthma].

We report two patients with Churg-Strauss syndrome (CSS) which occurred on the remission stage of bronchial asthma. Case 1 of a 64-year-old woman suffered from asthma in June, 1997, and got relief with treatment. In February, 1998, dysesthesia, pain and severe muscle weakness occurred in the extremities and erythematous rashes appeared on the extremities and back. She was transferred to our hospital on March 3. Peripheral blood eosinophilia was observed and a diagnosis of CSS was made. Eosinophilic tissue infiltration and vasculitis was found in the skin biopsy specimen. She was treated with prednisolone (60 mg/day) with moderate improvement. But the dysesthesia in the extremities, bilateral foot drop and the weakness of the left hand grasping power continued. Case 2 of a 62-year-old woman suffered from asthma in 1995, which improved by treatment. In March 1998, dysesthesia and pain in the lower extremities occurred and progressed. Erythematous rashes appeared on the feet and she was admitted to our hospital in May. Peripheral blood eosinophilia and eosinophilic tissue infiltration in the skin biopsy specimen were observed and a diagnosis of CSS was made. The treatment with prednisolone (60 mg/day) improved the pain but the dysesthesia continued. It is important to know the occurrence of CSS on the remission stage of bronchial asthma.

Asthma↗
PubMed2001

Natural killer activity and its changes among participants in a smoking cessation intervention program--a prospective pilot study of 6 months' duration.

We examined the effect of smoking cessation on natural killer (NK) activity of peripheral blood lymphocytes in terms of a prospective study of 27 Japanese subjects who participated in a smoking cessation intervention program. This program was delivered by means of group-counseling offering 7 sessions of about 2 hours over 6 months to help smokers to discontinue the habit. Thirteen subjects ceased smoking (quitters), while 14 continued to smoke (cigarette smokers). NK activity before the intervention was correlated positively with age (correlation coefficient=0.46, P<0.05). NK activity remained almost constant among quitters, comparing the activity before and after the intervention, while it decreased among cigarette smokers although it was not statistically significant. In the subgroup analysis, NK activity increased among those aged less than 65 years, or urine cotinine levels over 800 ng/ml before the intervention, especially among quitters, but there were no statistical significances. Multiple regression analysis showed changes in NK activity were correlated significantly only with age (standard regression coefficient=-0.44, P<0.05). These findings suggest that smoking cessation intervention programs might have been more effective for younger than elder subjects in consideration of NK activity.

Aged↗
PubMed2001

Results of degenerative spondylolisthesis treated with posterior decompression alone via a new surgical approach.

OBJECT: The purpose of this study was to assess radiologically demonstrated results and clinical outcomes in patients with degenerative spondylolisthesis who underwent posterior decompressive surgery via a new (unilateral) approach. This approach allows surgeons to perform central and bilateral decompression while only stripping the muscles unilaterally, thus preserving the posterior osteoligamentous complexes. METHODS: The authors evaluated 51 consecutive patients in whom surgery was performed between 1987 and 1996. The mean follow-up period was 4.7 years. There was no statistically significant difference between the pre- and postoperative measurements in percentage of vertebral slippage. Postoperative dynamic angulation statistically decreased compared with its preoperative value (p < 0.05). Improvement of an average of 67% was shown on the Japanese Orthopaedic Association scale, and in 78% of these patients, good to excellent results were demonstrated. Secondary fusion was required in only three patients (5.9%). CONCLUSIONS: This new surgical technique offers a potential alternative for the treatment of degenerative spondylolisthesis in a minimally invasive manner, avoiding the risk of causing or aggravating postoperative spinal instability.

Adult↗
PubMed2001

Ammocidin, a new apoptosis inducer in Ras-dependent cells from Saccharothrix sp. I. Production, isolation and biological activity.

A new apoptosis inducer, ammocidin, was isolated from the culture broth of Saccharothrix sp. AJ9571. Ammocidin induced apoptotic cell death in Ras-dependent Ba/F3-V12 cells with an IC50 of 66 ng/ml. No cell death was observed in IL-3-dependent Ba/F3-V12 cells at less than 100 microg/ml of ammocidin. Ammocidin significantly reduced the phosphorylation level of MAPK and S6K that mediate the anti-apoptotic function of Ras.

Actinomycetales↗
PubMed2001

[A case report of total repair in a 71-year-old patient with tetralogy of Fallot].

A 71-year-old male is presented as ever the oldest patient of tetralogy of Fallot who underwent successful radical surgery. Heart murmur was pointed out at the age of 10 years. The patient consulted us because of dyspnea and cough, and was noted to have cyanosis and clubbing fingers. Polycythemia was also detected by hemoglobin of 20.8 g/dl and hematocrit of 58.4%, and a low PaO2 of 48.5 mmHg at room temperature was pointed out. Preoperative echocardiography and cardiac catheterization indicated a ventricular septal defect, overriding of the aorta, and right ventricular outflow tract stenosis with a pressure gradient of 115 mmHg between the right ventricle and the main pulmonary artery. Under cardiopulmonary bypass, the ventricular septal defect was closed with a dacron patch and the right ventricular outflow tract was enlarged by a patch of collagen-coated vascular graft with a commissurotomy of the pulmonary valve. Postoperatively, cyanosis disappeared and the pressure gradient was decreased to 26 mmHg.

Aged↗
PubMed2001

Xerl, a novel CNS-specific secretory protein, establishes the boundary between neural plate and neural crest.

A novel gene, Xerl, has been found as a CNS-specific gene encoding a secretory protein. In order to clarify a function of Xerl, we first examined Xerl-expressing areas during early development. Comparison with XlSox-2-positive neural plate and ADAM13-positive neural crest showed that Xerl expression was limited within the neural plate area. Microinjection of Xerl mRNA into 2- or 4-cell stage embryos indicated that Xerl overexpression caused the regional expansion of XlSox-2- and NCAM-positive neural plate, which was concomitant with the outer shift of ADAM13-positive region. The Xerl injection resulted in incomplete neural closure because of the local overproduction of the neuroepithelium. In contrast, loss of function analysis of Xerl indicated that Xerl inhibition caused the ectopic differentiation of neural crest cells. In the conjugation experiment using chordin-injected animal caps, Xerl promoted chordin-induced XlSox-2 expression, whereas Xerl inhibition caused ADAM13expression even in the injection with a high dose of chordin. Animal cap assays also showed that Xerl expression was induced by chordin. In the functional analysis using truncated forms of Xerl, Xerl deltaL (lacking LNS domain) worked as a dominant negative form that induced the overproduction of neural crest cells. These results suggest that Xerl is involved in the boundary formation of the neural plate through exclusion of neural crest cell differentiation.

Animals↗
PubMed2000

Memory of chirality in diastereoselective alpha-alkylation of isoleucine and allo-isoleucine derivatives.

[reaction: see text] alpha-Methylation of 3 gave 5 as a major product whereas 4 gave 6 predominantly, although both 3 and 4 have an (S)-chiral center at C(3). This indicates that chirality at C(2) in 3 and 4 was memorized in the corresponding intermediate enolates and the induced chirality made a major contribution in the stereochemical course of the reaction, while chirality at the adjacent chiral center C(3) had little effect.

Alkylation↗
PubMed2000

Total Synthesis of (+)-Eurylene and (+)-14-Deacetyleurylene We thank K. Ujihara (Sumitomo Chemical Co.) for generously supplying an authentic sample and a copy of the (1)H NMR spectrum of synthetic eurylene. We are grateful to Prof. H. Iio and Dr. Y. Usuki (Osaka City University) for the HPLC purification. T.I. thanks the Japan Society for the Promotion of Science for providing a JSPS Research Fellowship for Young Scientists. This research was supported by the Naito Foundation, the Fujisawa Pharmaceutical Award in Synthetic Organic Chemistry, Japan, the SUNBOR GRANT from the Suntory Institute for Bioorganic Research, and a Grant-in Aid for Encouragement of JSPS Research Fellows from the Japan Society for the Promotion of Science.

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Journal Article↗
PubMed2000

Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy.

We hypothesized that the tolerance for nutrient deprivation as well as angiogenesis might be an important factor for tumor progression under hypovascular conditions. When normal human fibroblasts were subjected to extreme nutrient starvation by culturing in a medium without serum, glucose, and amino acids, cells died within 24 h. When substituted with liver cancer cell lines HepG2, Hep3B, HLE, and HuH-7, cell death occurred within 36 h. In contrast, four of six pancreas cancer cell lines, PANC-1, AsPC-1, BxPC-1, and KP-3, survived for remarkably longer periods; >50% of the cells survived, even after starvation for 48 h. Among three gastric cancer cell lines, MKN28, MKN45, and MKN74, only the most poorly differentiated MKN45 cells survived >36 h. More than 50% of the cells in colon cancer cell lines SW480, WiDr, and DLD-1 survived after 36 h, and the most undifferentiated SW480 cell line survived longest. We examined the possible involvement of PKB/Akt expression in the survival of various cell lines under nutrient starvation conditions. High expression of PKB/Akt was found to be associated with tolerance for nutrient starvation. When Akt antisense RNA expression vectors were introduced into PANC-1 cells, the tolerance was partially but significantly diminished by vectors for Akt1 and Akt2 but not Akt3. Because elimination of the tolerance might serve as a new strategy for cancer therapy, several compounds were tested for this purpose, and troglitazone, an insulin sensitizer, as well as LY294002, a phosphatidylinositol 3-kinase inhibitor, were found to kill PANC-1 cells only under nutrient starvation conditions.

Antineoplastic Agents↗
PubMed2000

Cell density-dependent regulation of hepatic development by a gp130-independent pathway.

We previously demonstrated that oncostatin M (OSM) promotes hepatic development in concert with glucocorticoid. The livers from mice deficient for gp130, a signaling subunit of the OSM receptor, displayed reduced expression of hepatic differentiation marker and defective glycogenic function. However, these phenotypes were not completely abolished in gp130(-/-) mice, suggesting that there is an alternative pathway regulating hepatic development in vivo. To test this possibility, we cultured gp130(-/-) fetal hepatic cells and investigated a signal that induces hepatic differentiation. When hepatocytes were forced to interact with each other by inoculating cells at high densities, hepatic differentiation was induced even in the absence of gp130. Moreover, cells stimulated with OSM and/or cultured at a high density possess many other metabolic functions. These observations suggest that fetal hepatic cells acquire multiple characteristics of differentiated hepatocytes in response to the signals generated by cell-cell contacts as well as by OSM.

Ammonia↗