Biomedical subjects

K Yamazaki

Publications and source records attributed to K Yamazaki.

At least 19 recordsLinked to original sources

PubMed2006

Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A.

Elongin A is a transcription elongation factor that increases the overall rate of mRNA chain elongation by RNA polymerase II. To gain more insight into the physiological functions of Elongin A, we generated Elongin A-deficient mice. Elongin A homozygous mutant (Elongin A(-/-)) embryos demonstrated a severely retarded development and died at between days 10.5 and 12.5 of gestation, most likely due to extensive apoptosis. Moreover, mouse embryonic fibroblasts (MEFs) derived from Elongin A(-/-) embryos exhibited not only increased apoptosis but also senescence-like growth defects accompanied by the activation of p38 MAPK and p53. Knockdown of Elongin A in MEFs by RNA interference also dramatically induced the senescent phenotype. A study using inhibitors of p38 MAPK and p53 and the generation of Elongin A-deficient mice with p53-null background suggests that both the p38 MAPK and p53 pathways are responsible for the induction of senescence-like phenotypes, whereas additional signaling pathways appear to be involved in the mediation of apoptosis in Elongin A(-/-) cells. Taken together, our results suggest that Elongin A is required for the transcription of genes essential for early embryonic development and downregulation of its activity is tightly associated with cellular senescence.

Animals↗

PubMed2006

A case of an inflammatory myofibroblastic tumor in the lung which expressed TPM3-ALK gene fusion.

We herein describe a 4-year-old boy who after being treated for pneumonia showed an abnormal shadow at the hilus of the right lung on chest X-rays with continued inflammatory findings in his laboratory data. CT and MR investigations suggested the existence of a neoplasm at that site. An open biopsy was thus performed for a definite diagnosis. The histological findings and the expression of TPM3-ALK fusion gene confirmed a diagnosis of an inflammatory myofibroblastic tumor. A right upper and middle lobectomy including the tumor was thus performed for a complete resection. In addition to the histological diagnosis, the detection of the tumor specific fusion gene provided objective evidence in making a diagnosis.

Anaplastic Lymphoma Kinase↗

PubMed2006

A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations.

Retrospective analysis has shown that activating mutations in exons 18-21 of the epidermal growth factor receptor (EGFR) gene are a predictor of response to gefitinib. We conducted a phase II trial to evaluate the efficacy and safety of gefitinib as first-line therapy for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Patients with stage IIIB or IV chemotherapy-naïve NSCLC with EGFR mutation were treated with 250 mg gefitinib daily. For mutational analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations (deletions in or near E746-A750, n=16; L858R, n=4). Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75% (95% CI, 48-93%). After a median follow-up of 12.7 months (range, 3.1-16.8 months), 10 patients demonstrated disease progression, with median progression-free survival of 8.9 months (95% CI, 6.7-11.1 months). The median overall survival time has not yet been reached. Most of the toxicities were mild. This study showed that gefitinib is very active and well tolerated as first-line therapy for advanced NSCLC with EGFR mutations.

Administration, Oral↗

PubMed2006

Prediction of blood glucose level of type 1 diabetics using response surface methodology and data mining.

In order to improve the accuracy of predicting blood glucose levels, it is necessary to obtain details about the lifestyle and to optimize the input variables dependent on diabetics. In this study, using four subjects who are type 1 diabetics, the fasting blood glucose level (FBG), metabolic rate, food intake, and physical condition are recorded for more than 5 months as a preliminary study. Then, using data mining, an estimation model of FBG is obtained, and subsequently, the trend in fluctuations in the next morning's glucose level is predicted. The subject's physical condition is self-assessed on a scale from positive (1) to negative (5), and the values are set as the physical condition variable. By adding the physical condition variable to the input variables for the data mining, the accuracy of the FBG prediction is improved. In order to determine more appropriate input variables from the biological information reflecting on the subject's glucose metabolism, response surface methodology (RSM) is employed. As a result, using the variables exhibiting positive correlations with the FBG in the RSM, the accuracy of the FBG prediction improved. Conditions could be found such that the accuracy of the predicting trends in fluctuations in blood glucose level reached around 80%. The prediction method of the trend in fluctuations in the next morning's glucose levels might be useful to improve the quality of life of type 1 diabetics through insulin treatment, and to prevent hypoglycemia.

Adult↗

PubMed2006

beta-Glucosidase inhibitory activities of phenylpropanoid glycosides, vanicoside A and B from Polygonum sachalinense rhizome.

The phenylpropanoid glycosides, vanicoside A and B, isolated from rhizomes of giant knotweed (Polygonum sachalinense) showed beta-glucosidase inhibitory activity, with IC(50) values of 59.8 and 48.3 mug/ml (59.9 and 50.5 muM), respectively. In contrast, p-coumaric acid and ferulic acid, corresponding to phenylpropanoyl moieties of vanicosides, exhibited very little inhibition.

Cinnamates↗

PubMed2006

Analysis of bifurcation phenomena in the electron internal transport barrier in the large helical device.

The electron internal transport barrier (eITB) formation in the Large Helical Device (LHD) is studied with the transport code TOTAL and a GyroBohm-like model. The reduction of anomalous transport by the E x B shear has been introduced by means of the factor [1 + (tauomega(ExB))(gamma)](-1). Simulation results show a clear critical transition between plasma regimes with rather flat electron temperature profiles (non-) to a steeped one (with eITB) when average density is low enough. With the aim of studying the eITB formation as a phase transition phenomenon, the electron average density is taken as the control parameter and the E x B shearing rate as the order parameter. Results show how the eITB formation in LHD is compatible with a continuum phase transition with critical exponent beta = 0.40.

Journal Article↗

PubMed2006

Hypoxia-induced hyaluronan synthesis by articular chondrocytes: the role of nitric oxide.

OBJECTIVE: Articular cartilage is an avascular tissue in which chondrocytes are exposed to hypoxic conditions. We previously demonstrated that reactive oxygen species (ROS) induced apoptosis of chondrocytes. We also demonstrated that nitric oxide (NO) was induced when chondrocytes were exposed to hypoxia and that NO inhibited the ROS-induced apoptosis. Hyaluronan (HA) is a high molecular weight glycosaminoglycan whose antioxidative effects have been reported. The purpose of the present study was to determine whether HA synthesis was induced in chondrocytes exposed to hypoxia, and, if so, whether the hypoxia-induced HA synthesis is regulated by NO. METHODS: Bovine articular chondrocytes were used in this study. Levels of HA were determined by the sandwich enzyme-binding assay. Expression of HA synthase (HAS) was determined with reverse transcription-polymerase chain reaction. The production of NO was examined using the Griess reaction. We also determined inducible nitric oxide synthase (iNOS) enzyme synthesis using the histochemistry and Western blot analysis. RESULTS: Chondrocytes cultured under hypoxic conditions exhibited enhanced HA synthesis. When the NO inhibitors, L-NMMA and L-NAME, were added, the hypoxia-enhanced HA levels in the culture medium were significantly inhibited. CONCLUSIONS: Endogenous NO synthesis plays an important role in hypoxia-enhanced HA synthesis.

Animals↗

PubMed2006

Balance of inflammatory response in stable gingivitis and progressive periodontitis lesions.

The balance between inflammatory mediators and their counter-regulatory molecules may be crucial for determining the outcome of immune pathology of periodontal diseases. Based on clinical and immunological findings, the immune response in stable gingivitis lesion is supposed to be in balance, whereas the response is skewed towards the predominance of proinflammatory reactivity in progressive periodontitis lesion. However, this hypothesis has not been verified. Therefore, the aim of this study was to compare the gene expression profile of inflammatory mediators including proinflammatory cytokines and other inflammatory molecules, and anti-inflammatory cytokines by using quantitative real-time polymerase chain reaction in gingivitis and periodontitis lesions showing distinct clinical entities. For inflammatory mediators, interleukin (IL)-1beta, interferon (IFN)-gamma and receptor activator of nuclear factor (NF)-kappaB ligand tended to be higher in periodontitis, whereas tumour necrosis factor (TNF)-alpha and IL-12 p40 showed no difference. Heat-shock protein 60 (HSP60) expression was up-regulated significantly in periodontitis. For anti-inflammatory cytokines, transforming growth factor (TGF)-beta1 expression tended to be higher in periodontitis compared with gingivitis, whereas no difference was observed for IL-10 and IL-4. These findings support further our previous finding that autoimmune response to HSP60 may exert in periodontitis lesion, and suggest that perhaps subtle differences in the balance of cytokines may result in different disease expression.

Adult↗

PubMed2006

Increased infiltration of CD1d and natural killer T cells in periodontal disease tissues.

BACKGROUND: Natural killer T (NKT) cells are a unique T lymphocyte subset that has been implicated in the regulation of immune responses associated with a broad range of diseases including autoimmunity, infectious diseases, and cancer. In contrast to conventional T cells, NKT cells are reactive to major histocompatibility complex (MHC) class I-like molecule CD1d. Considering the periodontitis having both aspects of infection and autoimmunity in nature, CD1d and reactive NKT cells are of particular importance. OBJECTIVE: The aim of the present study was to examine whether the expression of CD1 isoforms and Valpha24(+) invariant NKT cells is associated with different disease entities, namely gingivitis and periodontitis. MATERIAL AND METHODS: Immunohistochemical analysis was performed on cryostat sections of gingival tissues from 19 patients with periodontitis and eight patients with gingivitis using antibodies to CD1a, b, c, d, Valpha24(+) invariant NKT cells, CD83, CD3 and CD19. RESULTS: Although all four subsets of CD1 molecules were expressed in periodontal lesions, CD1d was most abundant. CD1d expression was more frequent in periodontitis than gingivitis and increased together with increase of invariant NKT cell infiltration. Double immunohistochemical staining showed co-expression of CD1d and CD19 on identical cells and proximate infiltration of CD1d(+) and invariant NKT cells. CONCLUSION: These findings suggest that CD1d-expressing B cells could activate NKT cells by CD1d-restricted manner and this NKT cell activation may play roles in pathogenesis of periodontal diseases.

Adult↗

PubMed2006

Fluctuations in carotid arterial distensibility during the menstrual cycle do not influence cardiovagal baroreflex sensitivity.

AIM: Fluctuations in autonomic nervous functions throughout the menstrual cycle and the underlying mechanism concerning them are not well known. This study was designed to test the hypothesis that fluctuations in cardiovagal baroreflex sensitivity (BRS) throughout the menstrual cycles of young women are due to fluctuations in carotid arterial distensibility. METHODS: In eight eumenorrhoeic healthy young women (18-24 years), we determined the variations in the carotid arterial distensibility coefficient (DC; via simultaneous ultrasonography and applanation tonometry), cardiovagal BRS (phase IV of the Valsalva manoeuvre and the sequence method; up- or down-sequence spontaneous BRS), and serum oestradiol and progesterone concentrations at five points in the menstrual cycle (menstrual = M, follicular = F, ovulatory = O, early luteal = EL, and late luteal = LL). RESULTS: Serum oestradiol and progesterone levels were consistent with the predicted cycle phases. Carotid arterial DC fluctuated cyclically, increasing significantly from the M (52.4 +/- 4.9 x 10(-3) kPa(-1), mean +/- SE) and F (52.7 +/- 4.4) phases to the O (57.6 +/- 4.4) phase and declining sharply in the EL (46.0 +/- 4.0) and LL (45.1 +/- 3.0) phases (F = 6.37, P < 0.05). Contrary to our prediction, however, cardiovagal BRS by the Valsalva manoeuvre (P = 0.73) or sequence method (up-sequence spontaneous BRS; P = 0.84: down-sequence spontaneous BRS; P = 0.67) did not change significantly during the menstrual cycle. CONCLUSION: The results suggest that, although carotid arterial distensibility fluctuates with the changes in ovarian hormone levels that occur during the menstrual cycle, the fluctuations in carotid arterial distensibility do not influence cardiovagal BRS.

Adolescent↗

PubMed2005

Heel bone ultrasound predicts non-spine fracture in Japanese men and women.

A number of prospective studies in the USA and Europe have demonstrated that quantitative ultrasound (QUS) measurements predict fracture risk. To our knowledge, there has been no such study in a Japanese population, and very few studies have measured the prognostic value of QUS measurements among men, even in the USA and Europe. We performed a three-center prospective study to investigate the relationship between baseline heel QUS measurements and non-spine fracture risk. There were 4,028 subjects (1,004 men and 3,024 women), 67.5+/-8.9 years [mean +/- standard deviation (SD)] of age), who underwent heel QUS (Achilles device) at three centers between 1993 and 2000. In 2002, the subjects were mailed a standardized questionnaire that asked about their history of fracture. The mean follow-up period was approximately 5 years. The Achilles measured speed of sound (SOS) and broadband ultrasound attenuation (BUA). We used Cox regression analysis to determine the hazard ratio (HR), using weighted coefficients. SOS, BUA, and stiffness index (SI) predicted self-reported hip, wrist, and total non-spine fractures. After we had adjusted for age, gender, and weight, the HRs of total non-spine fracture were 1.54 [95% confidence interval (CI) 1.39-1.69], 1.53 (1.37-1.70), and 1.80 (1.62-1.98) for 1 SD decrease in SOS, BUA, and SI, respectively. In men, SOS and SI also predicted total non-spine fractures with HRs similar to those in women. The HR of prediction for hip fracture by SOS and SI was better in the short term than in the long term, and the prediction for hip, wrist, and non-spine fracture remained significant between 5 to 10 years of follow-up. Measurements obtained from heel QUS predicted non-spine fracture in Japanese men and women, and the HRs of Japanese of both genders was similar to the risk ratio (RR) of Caucasian men and women. QUS parameters can predict hip, wrist, and non-spine fracture up to 10 years.

Adult↗

PubMed2005

Elevation of both cyclooxygenase-2 and prostaglandin E2 receptor EP3 expressions in rat placenta after uterine artery ischemia-reperfusion.

Intrauterine growth restriction (IUGR) has a multifactorial pathogenesis and is an important cause of perinatal mortality. The relationship between fetal weight and placental blood flow in an animal model of IUGR has been investigated, showing that fetal growth is regulated by placental blood flow. The aim of the present study was to determine whether ischemia-reperfusion (I/R) injury stimulates the prostaglandin E2 (PGE2) system or the vascular endothelial growth factor (VEGF) system in the placenta of a rat IUGR model. COX-2 is reported to be involved in ischemic damage in many organs. There are 4 types of PGE2 receptor (EP1, EP2, EP3 and EP4). It is well known that EP1 and EP3 is associated with vasoconstriction. In the present study, vessels were occluded in the right uterine horn on day 17 of pregnancy in rats, and the clamps were removed after 30 min of ischemia. At 24h, 48 h, and 5 days after I/R injury, the live fetuses and placentas were obtained by cesarean section. This study revealed that I/R injury caused IUGR 5 days after the treatment. COX-2 expression and EP3 receptor expression were significantly elevated at 24h after I/R injury, but VEGF mRNA expression was not altered in the placenta from the ischemic horn compared with the non-ischemic horn. These results suggested that induction of the COX-2-EP3 system in the placenta may be one of the causes of IUGR induced by uterine ischemia, because the EP3 receptor and PGE2 are well known to mediate vasoconstriction in many organs.

Animals↗

PubMed2005

Effect of aging on carotid artery stiffness and baroreflex sensitivity during head-out water immersion in man.

To examine the possible age-related blood pressure (BP) deregulation in response to central hypervolemia, we measured spontaneous baroreflex sensitivity (SBRS), carotid arterial compliance (CC), and R-R interval coefficient of variation (RRICV) during basal and thermoneutral resting head-out-of-water immersion (HOWI) in 7 young (YG = 24.0 +/- 0.8 years) and 6 middle-aged/older (OL = 59.3 +/- 1.3 years) healthy men. Compared with basal conditions (YG = 19.6 +/- 4.0 vs OL = 6.1 +/- 1.5 ms/mmHg, P < 0.05), SBRS remained higher in YG than OL during rest HOWI (YG = 23.6 +/- 6.6 vs OL = 9.3 +/- 2.1 ms/mmHg, P < 0.05). The RRICV was significantly different between groups (YG = 6.5 +/- 1.4 vs OL = 2.8 +/- 0.4%, P < 0.05) under HOWI. The OL group had no increase in CC, but a significant increase in systolic BP (basal = 115.3 +/- 4.4 vs water = 129.3 +/- 5.3 mmHg, P < 0.05) under HOWI. In contrast, the YG group had a significant increase in CC (basal = 0.16 +/- 0.01 vs water = 0.17 +/- 0.02 mm(2)/mmHg, P < 0.05) with no changes in systolic BP. SBRS was positively related to CC (r = 0.58, P < 0.05 for basal vs r = 0.62, P < 0.05 for water). Our data suggest that age-related vagal dysfunction and reduced CC may be associated with SBRS differences between YG and OL groups, and with BP elevation during HOWI in healthy older men.

Adult↗

PubMed2005

Update results of FEC followed by docetaxel neoadjuvant trials for primary breast cancer.

This study has been initiated to evaluate the safety, clinical and pathologic response as well as the relation of response (pCR or non-pCR) and survival (overall and relapse-free) of fluorouracil, epirubicin and cyclophosphamide (FEC) followed by docetaxel (DOC) as preoperative chemotherapy in patients with operable breast cancer. Japanese patients with primary breast cancer, Tlc-3N0M0 or T1-3NIM0, age 20-60, PS 0-1 were included in this study. Preoperative chemotherapy consisted of 4 cycles of FEC (500 mg/m(2), 100 mg/m(2), 500 mg/m(2)) every 3 weeks followed by 4 cycles of DOC (75 mg/m(2)) every 3 weeks. Since June 2002, 200 patients were enrolled in this study, and the time of this interim analysis, 80 patients were evaluable for safety and clinical efficacy. The overall clinical response rate was 71.4% (14% CR, 44% PR, 42% SD/PD), and the only G3,4 toxicities, neutropenia and febrile neutropenia were observed in 54% and 14% of patients, respectively. Eighty nine patients were evaluable for pathologic response by central review. Pathologic response was evaluated among invasive tumors on multiple cross-section specimens based on a modified version of the Japanese grading system for Japanese Breast Cancer Society. The pathologic response rate was 17%. In this ongoing trial, FEC followed by DOC was active and well tolerated.

Antineoplastic Agents, Phytogenic↗

PubMed2005

PGE1 inhibits the expression of PAI-1 mRNA induced by TNF-alpha in human mesangial cells.

We examined the effect of PGE1 on the expression of plasminogen activator inhibitor-1 (PAI-1) mRNA induced by tumor necrosis factor-alpha (TNF-alpha) in human mesangial cells, because PAI-1 is one of major factors for the progression of glomerulosclerosis. The expression of PAI-1 mRNA was increased after stimulation with TNF-alpha, and it was diminished by pre-incubation with PGE1. Next, we examined the effect of PGE1 on the phosphorylation of mitogen activated protein kinase (MAPK) family and Akt. TNF-alpha activated the phosphorylation of p44/42 MAPK, p38 MAPK, SAPK/JNK and Akt in mesangial cells. PGE1 inhibited the TNF-alpha induced phosphorylation of SAPK/JNK and Akt, but not p44/42 MAPK and p38 MAPK. The TNF-alpha induced expression of PAI-1 mRNA was not affected by PD98059, an inhibitor of MEK, SB203580, an inhibitor of p38 MAPK, nor LY294002, an inhibitor of PI3 K. However, DMAP, an inhibitor of SAPK/JNK, inhibited the expression of PAI-1 mRNA, suggesting that the TNF-alpha induced expression of PAI-1 mRNA is regulated by the SAPK/JNK dependent pathway in human mesangial cells. By the incubation with H8, an inhibitor of PKA, the inhibitory effect of PGE1 on the expression of PAI-1 mRNA was abolished, suggesting that PGE1 inhibited the PAI-1 mRNA expression via the PKA pathway. Our results suggest that the inhibition of PAI-1 synthesis by PGE1 in human mesangial cells may have therapeutic implications for glomerulosclerosis such as occurs in diabetic nephropathy.

Alprostadil↗

PubMed2005

Mode of action of piscicocin CS526 produced by Carnobacterium piscicola CS526.

AIMS: Piscicocin CS526 is a unique class IIa bacteriocin produced by Carnobacterium piscicola CS526. The mode of action against the sensitive strain Listeria monocytogenes IID581 was evaluated. METHODS AND RESULTS: Piscicocin CS526 was adsorbed on both sensitive and insensitive gram-positive and gram-negative bacterial cells. Treatment of L. monocytogenes cells with trypsin, lipase and Triton X-100 did not reduce subsequent adsorption of piscicocin CS526. The activity of piscicocin CS526 against L. monocytogenes cells was bactericidal rather than bacteriostatic, but did not cause bacteriolysis. Piscicocin CS526 induced the efflux of K+ ions from the target cells which cause dissipation of the transmembrane potential (DeltaPsi) of the cell membrane. Moreover, after exposure to piscicocin CS526, intracellular adenosine 5'-triphosphate (ATP) level of the target cells rapidly reduced without leakage of ATP from the cells, indicating that ATP depletion occurred in the cells. CONCLUSIONS: Pore formation by piscicocin CS526 caused a rapid efflux of small molecules such as K+ from the indicator cells and dissipation of proton motive force (PMF), which lead to the cell death. SIGNIFICANCE AND IMPACT OF THE STUDY: Molecular mechanism of action of piscicocin CS526 is very similar to that of other pediocin-like bacteriocins, although piscicocin CS526 possesses a unique N-terminal sequence in which Val is substituted for by Leu in the amino acid at position 7.

Adenosine Triphosphate↗

PubMed2005

Interleukin-6 (IL-6)--373 A9T11 allele is associated with reduced susceptibility to chronic periodontitis in Japanese subjects and decreased serum IL-6 level.

We investigated whether interleukin-6 (IL-6) gene polymorphisms could be associated with chronic periodontitis (CP) and serum IL-6 level. One hundred and twelve CP and 77 non-CP Japanese subjects were analyzed for IL-6 -597 (G/A), -572 (C/G), -373 (A(n)T(m)), -190 (C/T), and -174 (G/C) polymorphisms. We could only detect -572 and -373 polymorphisms and found that the frequency and carriage rate of the -373 A9T11 allele were significantly higher in non-CP subjects. Enzyme-linked immunosorbent assay confirmed that the -572 and -373 G[A9T11] haplotypes were associated with lower serum IL-6 level. These findings suggest that IL-6 -373 A9T11 allele could be associated with reduced susceptibility to CP among Japanese subjects and decreased serum IL-6 level.

Alleles↗

PubMed2005

Effects of Porphyromonas gingivalis antigens and proinflammatory cytokines on human coronary artery endothelial cells.

OBJECTIVE: Individuals with periodontitis have been cited as having a significantly increased risk of developing coronary heart disease. Although accumulating evidence suggests that periodontal infection is involved in the development and progression of atherosclerosis, the underlying mechanisms remain to be elucidated. In the present study, we examined how periodontal infection could contribute to endothelial dysfunction. METHODS: Human coronary arterial endothelial cells were stimulated with tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, both of which are reported to be elevated in the serum of periodontitis patients. Cells were also stimulated with lipopolysaccharide, outer membrane protein and heat shock protein 60 derived from Porphyromonas gingivalis, a representative periodontopathic bacterium which is known to stimulate myeloid cells. RESULTS: Although TNF-alpha and IL-1beta, at concentrations a little higher than those in sera of periodontitis patients, up-regulated the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, P. gingivalis antigens had only a slight stimulatory effect. CONCLUSION: Experiments in which the total pathogen burden is considered, rather than a single species of bacteria, would increase our understanding of the contribution of which periodontal infection to atherogenesis.

Antigens, Bacterial↗