Effects of 3-octen-2-one on human olfactory receptor responses to vanilla flavor.

Most of the odors that humans perceive daily are complex odors. It is believed that the modulation, enhancement, and suppression of overall complex odors are caused by interactions between odor molecules. In this study, to understand the interaction between odor molecules at the level of human olfactory receptor responses, the effects of 3-octen-2-one, which has been shown to modulate vanilla flavors, were analyzed using a human olfactory receptor sensor that uses all human olfactory receptors (388 types) as sensing molecules. As a result, the response intensity of 1 common receptor (OR1D2) was synergistically enhanced in vanilla flavor with 3-octen-2-one compared with vanilla flavor, and the response of 1 receptor (OR5K1) to vanilla flavor was completely suppressed. These results strongly suggested that the response of human olfactory receptors to complex odors is enhanced or suppressed by relatively few other odor molecules.

[Effect of Olfactory Stimulation with Vanilla Odor on Degree of Gastric Myoelectrical Activity].

OBJECTIVES: Olfactory stimulation elicits various physiological responses. However, few reports exist on the changes in gastric motility during olfactory stimulation in humans. In this regard, we carried out electrogastrography (EGG) to non-invasively measure the gastric myoelectrical activity, which regulates gastric motility. Moreover, subjective sensory evaluation was performed to determine which characteristics of vanilla odor at two different concentrations affect the myoelectrical activity. METHODS: The participants consisted of eight healthy young males. EGG and electrocardiography (ECG) recordings were obtained approximately 20 min prior to and during olfactory stimulation. Autonomic nervous system activity was evaluated in terms of heart rate variability (HRV) and mean heart rate (HR) from ECG signals. EGG signals were analyzed by spectral analysis. In addition, the translation error was estimated by the Wayland algorithm. Sensory evaluation was performed using the Visual Analog Scale (VAS). RESULTS: There were no significant differences in HRV and HR values and results of spectral analyses of EGG signals in all sample presentations. The translation error of EGG signals and the rating of perceived odor intensity significantly increased in a concentration-dependent manner. There was a strong positive correlation between translation error and odor intensity. CONCLUSIONS: The correlation found between translation error and odor intensity suggests that the higher the vanilla odor intensity was perceived, the greater the randomness of EGG signals was. Our results suggest that the application of the Wayland algorithm to EGG signals can be used as an objective indicator in odor evaluation.

[Long-term survival case of advanced gastric cancer with paraaortic lymph node metastasis and peritoneal metastasis from S-1/CDDP combination therapy after reductive operation].

A 72-year-old female patient with type 5 gastric cancer in the upper gastric region underwent surgery. Due to paraaortic lymph node metastasis (#16a1, #16a2) and peritoneal metastasis, total gastrectomy and D0 lymph node dissection were performed. Surgical and pathological findings were poorly differentiated adenocarcinoma, INFbeta, pT3(SE), PM (-), DM (-), ly0, v2, sN3 (#7, #9, #16a1-a2), M0, stage IV. The patient was administered S-1 for 2 weeks at 80 mg/day, received 24-hour continuous intravenous infusion of 80 mg/day on day 8, and then discontinued chemotherapy for 2 weeks, which was regarded as one course. After one course, CT scan showed that the paraaortic lymph node metastasis had almost entirely disappeared. However, due to grade 3 neutropenia, and grade 2 nausea and anorexia in the first course, the treatment was changed to oral administration of UFT (400 mg/day) , which was discontinued one month later due to anorexia. The patient has been in good health without a recurrence for 4 years after surgery. This case suggests that reduction surgery combined with a S-1 regimen is an effective treatment for long-term survival.

Correlation of translocation of tight junction protein Zonula occludens-1 and activation of epidermal growth factor receptor in the regulation of invasion of pancreatic cancer cells.

Mitogen-activated protein kinase signal transduction pathway was isolated as a potential factor related to cancer cell dissociation in dissociated (PC-1.0 and AsPC-1) and non-dissociated (PC-1 and Capan-2) pancreatic cancer cells in our previous works. On the other hand, changes of structure and function of tight junction (TJ) are reported to be correlated with carcinogenesis and tumor development. In this study, the translocation of TJ protein Zonula occludens-1 (ZO-1) and the activation of epidermal growth factor receptor (EGFR) were examined to demonstrate the involvement and correlation of TJ protein translocation and EGFR activation in the cell dissociation and subsequent invasion of pancreatic cancer. Immunocytochemistry, fluorescence intensity analysis and in vitro invasion assay were performed in dissociated and non-dissociated pancreatic cancer cells. The obvious translocation of cell-cell junction localized ZO-1 protein to the cytoplasm and nucleus, simultaneous activation of EGFR, as well as the dissociation of cell colonies of non-dissociated pancreatic cancer cells were induced by dissociation factor treatment. However, EGFR inhibitor, AG1478, treatment significantly induced the redistribution of ZO-1 protein to the sites of cell-cell junction and the cell aggregation, as well as simultaneous suppression of EGFR activation in both the dissociated and the non-dissociated pancreatic cancer cells. In addition, AG1478 treatment markedly enhanced the in vitro invasion of non-dissociated pancreatic cancer cells. Translocation of TJ protein ZO-1 is closely involved in the induction of invasion through EGFR activation in pancreatic cancer cells.

Clinical significance of MHC class II-associated invariant chain expression in human gastric carcinoma.

MHC class II antigens serve as restricted elements for cell presenting antigens to CD4+ helper T cells. CD4+ T cells and CD8+ cytotoxic T cells, which are tumor-infiltrating lymphocytes (TILs), and play a major role in the survey and attack against tumor cells in primary lesions. Invariant chain (Ii) has several functions in MHC class II-restricted antigen presentation. In addition, Ii is found to be closely involved in the regulation of anti-tumor immunity in several tumor types. However, the significance of Ii expression in tumor cells is not fully illustrated. Immunohistochemical staining of Ii expression was performed in 58 cases of human gastric carcinoma specimens. The prognostic analysis of patients with gastric carcinoma was also performed. A total of 67.2% (39/58) gastric carcinomas were found to be Ii-positive, whereas only 20.7% (12/58) showed positive immunoreactivity with anti-MHC class II determinants. Furthermore, Ii expression showed significant correlation with the differentiation of gastric carcinoma (p<0.05). Ii expression also showed an inverse correlation with the frequency of TILs around carcinoma tissues, as well as with the prognosis of gastric carcinoma (p<0.01). Ii expression is closely correlated with anti-tumor immunity in human gastric carcinoma. Therefore, Ii may serve as an independent clinical marker for poor biological behavior and prognostic analysis in patients with gastric carcinoma.

Arg389Gly polymorphism of the human beta1-adrenergic receptor in patients with nonfatal acute myocardial infarction.

BACKGROUND: We sought to investigate the relation between the Arg389Gly polymorphism in the human beta1-adrenergic receptor (ADRB1) gene and acute myocardial infarction (AMI). It was previously reported that augmented sympathetic activity might play an important role as a trigger of AMI by enhanced hemodynamic or mechanical forces through ADRB1 activation. Recently, a common polymorphism has been identified at amino acid position 389 (Arg or Gly) of the human ADRB1, within a region important for receptor-Gs protein coupling and subsequent agonist-stimulated adenylyl cyclase activation. METHODS: To investigate the relation between the Arg389Gly polymorphism in the ADRB1 gene and AMI, we genotyped 354 patients with AMI and 354 age- and sex-matched control subjects by use of polymerase chain reaction amplification and the restriction fragment length polymorphism analysis. RESULTS: The prevalence of the Arg389 homozygote (CC) genotype was significantly more frequent in patients with AMI than in control subjects (68.1% vs 47.2%, P <.0001). In logistic regression models, the odds ratio (OR) of Arg389 homozygote (CC) versus Arg389Gly heterozygote (CG) + Gly389 homozygote (GG) genotypes between control subjects and patients with AMI was 2.86 (95% CI 1.92-4.26, P =.0001). The association of the Arg389Gly polymorphism of ADRB1 with AMI was statistically significant and independent of other risk factors. CONCLUSION: Our findings suggest that the genotype of Arg389Gly polymorphism in the human ADRB1 gene is associated with AMI.

Relationship between the expression of extracellular signal-regulated kinase 1/2 and the dissociation of pancreatic cancer cells: Involvement of ERK1/2 in the dissociation status of cancer cells.

Mitogen-activated protein kinase kinase 2 (MEK2), the upstream kinase of extracellular signal-regulated kinase 1/2 (ERK1/2) was previously isolated as cancer cell dissociation related factor. In this study, to further clarify the regulatory mechanism of cancer cell dissociation, two hamster (PC-1.0 and PC-1) and human (Capan-2 and AsPC-1) pancreatic cancer cell lines were analyzed immunocytochemically with anti-ERK1, anti-ERK2 and anti-phosphorylated ERK1/2 (p-ERK1/2) antibodies. U0126 (a MEK1/2 inhibitor) significantly suppressed ERK2 and p-ERK1/2 expressions in PC-1.0 and AsPC-1 cells (P<0.05). Cancer cell dissociation factor (DF) markedly induced ERK2 and p-ERK1/2 expressions in PC-1 and Capan-2 cells (P<0.05), and the induced ERK2 and p-ERK1/2 expressions were inhibited by subsequent U0126-treatment (P<0.05). Simultaneously, light microscopic images showed that DF clearly induced cell dissociation in PC-1 and Capan-2 cells, while U0126-treatment induced cell aggregation in these pancreatic cancer cells. ERK2 activation is closely involved in cell dissociation of pancreatic cancer cells.

Involvement of the mitogen-activated protein kinase kinase 2 in the induction of cell dissociation in pancreatic cancer.

In our previous investigation, mitogen-activated protein kinase kinase 2 (MEK2) was detected as a factor which was correlated to the potential of invasion-metastasis. In this study, the immunocytochemical, immunohistochemical and mRNA expressions of MEK2 were examined in pancreatic cancer cell lines and tissue samples, respectively. Constitutive expressions of MEK2 and phosphorylated MEK (p-MEK) were observed in PC-1.0 and ASPC-1 cells, which exhibited a growth pattern of single cells, whereas the relevant expressions were quite faint in PC-1 cells and CAPAN-2 cells, which exhibited a growth pattern of island-like clonies. Simultaneous inductions of MEK2 expressions and cell dissociation were observed after the treatment with a conditioned medium (CM) of PC-1.0 cells. The expression of MEK2 and p-MEK were reduced and the cell aggregation was found in PC-1.0 and ASPC-1 cells after U0126 (a MEK inhibitor) treatment. In vivo, both the MEK2 and p-MEK overexpressed in human pancreatic cancer tissues and p-MEK was found to be more strongly expressed in the invasive front than that in the center of tumor (P<0.05). MEK2 is closely related to pancreatic cancer cell dissociation. MEK2 activation is probably involved in the first step of the cascade in the invasion-metastasis of pancreatic cancer.

Analysis of invasion-metastasis mechanism in pancreatic cancer: involvement of tight junction transmembrane protein occludin and MEK/ERK signal transduction pathway in cancer cell dissociation.

Mitogen-activated protein kinase kinase 2 (MEK2) was detected as an invasion-metastasis related factor between highly invasive (PC-1.0) and weakly invasive (PC-1) pancreatic cancer cell lines in our previous study. On the other hand, tight junction (TJ) was found to be correlated with carcino-genesis and tumor development. In this study, the expressions and correlation of TJ transmembrane protein occludin and MEK/extracellular signal-regulated kinase (ERK) signaling pathway were analyzed to clarify the regulatory mechanism of cell dissociation in pancreatic cancer cells. Two hamster (PC-1.0 and PC-1) and human (AsPC-1 and CAPAN-2) pancreatic cancer cell lines were analyzed immunocytochemically with anti-occludin, phosphorylated MEK1/2 (p-MEK1/2), phosphorylated ERK1/2 (p-ERK1/2) antibodies. MEK1/2 inhibitor U0126 significantly induced the expression of occludin at the cell-cell junction and substantially suppressed the p-MEK1/2 and p-ERK1/2 expressions in PC-1.0 and AsPC-1 cells. In contrast, dissociation factor (DF) treatment obviously disrupted the occludin expressions at the sites of cell-cell junction and markedly induced the p-MEK1/2 and p-ERK1/2 expressions in PC-1 and CAPAN-2 cells. In addition, occludin expressions at cell-cell junction were restored and p-MEK1/2 and p-ERK1/2 expressions were suppressed by subsequent U0126-treatment in DF treated PC-1 and CAPAN-2 cells. Correspondingly, light microscopic images showed that DF induced the dissociation of cell island-like colonies in PC-1 and CAPAN-2 cells, and U0126-treatment induced cell aggregation in these pancreatic cancer cells. Occludin is involved in the cell dissociation in pancreatic cancer cells. Moreover, MEK/ERK signaling pathway probably regulates the cell dissociation status of pancreatic cancer through influencing the intracellular localization and expression of occludin.

Immunohistochemical expression of SKALP/elafin in squamous cell carcinoma of human lung.

The immunohistochemical expression of skin-derived anti-leukoproteinase (SKALP)/elafin in lung squamous cell carcinoma (SqCC) and in uninvolved bronchial epithelium was studied. The results were compared with the immunohistochemical staining of proliferating cell nuclear antigen (PCNA) and the TDT-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay. SKALP/elafin was expressed in SqCC with high incidence (82.6%). By contrast, the expression was not observed in uninvolved bronchial epithelium. SKALP/elafin expression was located in the cell layers just underneath the cornified envelope of each cell nest, and DNA fragmentation was observed in the same cell layers. PCNA was expressed in the basal layer of each cornified envelope, and both expressions were clearly separated. Immunoreactive score of SKALP/elafin expression was significantly correlated with the differentiation and it tended to increase in accordance with the degree of differentiation. These results suggested that SKALP/elafin was possibly involved in the cell differentiation program, finally leading to keratinization in SqCC of human lung. SKALP/elafin may be a beneficial molecular target for detection or even the development of a new therapeutic method against cancer.

Clinically suspected acute myopericarditis with cardiac tamponade associated with peripheral blood eosinophilia presenting in early pregnancy: a case report.

INTRODUCTION: The clinical presentation of eosinophilic myocarditis may vary from asymptomatic to the manifestation of severe symptoms, including cardiac tamponade and arrhythmias. In pregnant patients with this condition, drugs must be used cautiously up to approximately the 4th month of pregnancy because drug use should be limited during the period of fetal organogenesis. CASE PRESENTATION: A 30-year-old Asian woman at 14 weeks of pregnancy with progressive malaise was hospitalized. The electrocardiogram revealed ST elevation and low QRS voltage. Echocardiography revealed massive pericardial effusion and myocardial swelling. A laboratory examination revealed an increase in her white blood cell count, with a predominance of neutrophils. Pericardial drainage was performed for relief of the cardiac tamponade. The pericardial effusion revealed an abundance of eosinophils. Subsequently, the peripheral blood eosinophil count began to rise, and the patient was clinically diagnosed with eosinophilic myopericarditis. The patient's condition improved rapidly following the initiation of prednisolone treatment, and she finally delivered a full-term normal infant. CONCLUSIONS: A patient with clinically suspected myopericarditis in the early stage of pregnancy who improved rapidly with pericardial drainage and prednisolone therapy, and successfully delivered a normal full-term infant; the diagnosis was made in the early stage of the disease, based on the detection of an abundance of eosinophils in the pericardial effusion preceding the subsequent development of peripheral blood eosinophilia.

Radical scavenging activity of dicaffeoyloxycyclohexanes: contribution of an intramolecular interaction of two caffeoyl residues.

Six regio- and stereoisomers of dicaffeoyloxycyclohexanes and 2,4-di-O-caffeoyl-1,6-anhydro-beta-D-glucose were synthesized as model compounds of dicaffeoylquinic acids, and their radical scavenging activity was evaluated by DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt) radical scavenging tests. Both DPPH and ABTS radical scavenging reactions of these compounds consisted of two different steps. In the first step, catechol moieties of the caffeoyl residues were rapidly converted to o-quinone structures and no significant difference in the reactivity was observed among the tested compounds. In the second step, however, the rate of the reaction increased as the intramolecular distance of the two caffeoyl residues decreased. A novel intramolecular coupling product, which could scavenge additional radicals, was isolated from the reaction mixture of trans-1,2-dicaffeoyloxycyclohexane and DPPH radical. The result suggests that the second step of the radical scavenging reaction is arising from an intramolecular interaction between the two caffeoquinone residues to regenerate catechol structures, and that the closer their distance is, the more rapidly they react. The radical scavenging activity of natural dicaffeoylquinic acids in a biological aqueous system might also depend on the positions of caffeoyl ester groups.

Suppressive effect of the Gly389 allele of the beta1-adrenergic receptor gene on the occurrence of ventricular tachycardia in dilated cardiomyopathy.

Beta-1-adrenergic receptor (beta1-AR) blockers reduce both the incidence of sudden death and the ventricular volume in heart failure. In vitro, the Gly389 variant of beta1-AR mediates less adenylyl cyclase activities than the Arg389 variant, so Arg389Gly polymorphism was investigated with regard to the genesis, progression, or arrhythmogenesis of dilated cardiomyopathy (DCM). Allele and genotype frequencies of the Arg389Gly polymorphism were determined in 163 DCM patients and 157 age- and sex-matched controls. There were no differences in genotype and allele frequencies between patients and controls. Echocardiograms, left ventriculograms and 24h-Holter electrocardiograms were evaluated in the DCM patients and none of the clinical indices, other than ventricular tachycardia (VT), differed among the 3 genotypes. The Gly389 allele was more frequent in the VT(-) group than in the VT(+) group (0.46 vs 0.24, p=0.001). In univariate analysis, the odds ratio for VT in patients carrying 1 or 2 copies of the Gly389 allele was 0.29 ([95% confidence interval, 0.13-0.64], p=0.002), when compared with the Arg389 homozygotes. The Gly389 variant supressed the occurrence of VT in DCM, suggesting that this allele confers a decreased risk of sudden death.