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Saburo Sone

Publications and source records attributed to Saburo Sone.

At least 73 records · Page 4Linked to original sources
PubMed2003

Differential effects of IL-12 on the generation of alloreactive CTL mediated by murine and human dendritic cells: a critical role for nitric oxide.

We examined the mechanisms involved in interleukin (IL)-12-mediated suppression of cellular immunity in mice using allogeneic mixed leukocyte reaction (MLR) stimulated by dendritic cells (DCs) in vitro and compared the effect of IL-12 on MLR in mice and humans. Although IL-12 stimulated human MLR, the addition of IL-12 or interferon-gamma (IFN-gamma) resulted in a dose-dependent suppression of MLR in mice. The treatment with N(G)-monomethyl-L-arginine (L-NMMA) completely abrogated IL-12- and IFN-gamma-mediated suppression of MLR in mice. Furthermore, IL-12 enhanced the alloreactive cytolytic T lymphocyte (CTL) induction in human MLR, whereas the addition of L-NMMA was required to generate alloreactive CTLs in the presence of IL-12 in mice. Nitric oxide (NO) was detected only in mouse MLR. Murine DCs could produce NO, but neither human CD34(+) cell- nor monocyte-derived DCs produced a detectable amount of NO. These results suggest that NO produced by DCs might play an important role in IL-12-mediated immune suppression in mice but not in humans.

Animals↗
PubMed2003

Increased binding and chemotactic capacities of PDGF-BB on fibroblasts in radiation pneumonitis.

Although pulmonary fibrosis is a frequent and serious consequence of radiotherapy for thoracic malignant diseases such as lung cancer, the pathogenesis of this radiation-induced lung disorder remains unclear. To clarify the mechanisms underlying radiation pneumonitis and pulmonary fibrosis, we investigated the expression of platelet-derived growth factor receptor (PDGFR) on fibroblasts obtained from irradiated rat lungs and on control fibroblasts. Whole lungs of male Wistar rats were irradiated with a single dose of 15 Gy, and lung fibroblasts were isolated at 4 weeks after the irradiation. The chemotactic response of irradiated lung fibroblasts to PDGF-BB was significantly higher than that of control lung fibroblasts, whereas there was no significant difference between irradiated lung fibroblasts and control lung fibroblasts in the response to PDGF-AA. Receptor binding assay showed more specific binding sites for PDGF-BB on irradiated lung fibroblasts than on control lung fibroblasts, and the displacement of (125)I-labeled PDGF binding to fibroblasts by unlabeled PDGF showed that (125)I-labeled PDGF-BB was displaced by PDGF-BB but not by PDGF-AA. These results suggest that the increased binding sites for PDGF-BB on irradiated lung fibroblasts correspond mainly to PDGFRB. Scatchard analysis of the saturation data demonstrated an approximately twofold increase both in the number of PDGF-BB binding sites and in the binding affinity in irradiated lung fibroblasts compared to that in control lung fibroblasts. Those results suggest that the increased chemotactic response of irradiated lung fibroblasts to PDGF-BB is related to the overexpression of PDGFRB, which may have an important role in the pathogenesis of radiation-induced pneumonitis and pulmonary fibrosis.

Animals↗
PubMed2003

Phosphorylation, but not overexpression, of epidermal growth factor receptor is associated with poor prognosis of non-small cell lung cancer patients.

Epidermal growth factor receptor (EGFR) is commonly overexpressed in non-small cell lung cancer (NSCLC) and its tyrosine kinase phosphorylation is thought to be an ideal target in the treatment of patients with NSCLC. In the present study, we examined surgically obtained specimens from a series of 36 NSCLC patients for expression of EGFR, phosphorylated EGFR (p-EGFR), and HER2 by immunohistochemistry, and also examined the correlation with clinical characteristics. The positive rate of EGFR, p-EGFR, and HER2 was 97.2%, 44.4%, and 88.6%, respectively, and the overexpression rate was 80.6%, 0.0%, and 27.8%, respectively. EGFR overexpression and phosphorylation were seen at almost the same rate in each histological type of squamous and nonsquamous cell carcinoma (squamous vs. nonsquamous; 78.6% vs. 81.8% for EGFR, 35.7% vs. 50.0% for p-EGFR), while HER2 overexpression was seen less frequently in squamous cell carcinoma than in nonsquamous cell carcinoma (0.0% vs. 45.5%, P = 0.003). Univariate analysis revealed that EGFR overexpression was related to good performance status (P = 0.038) but not related to EGFR phosphorylation. EGFR phosphorylation was correlated to short time to progression (TTP) (P = 0.002) and poor prognosis (P = 0.002), although EGFR overexpression, HER2 overexpression, or EGFR-HER2 coexpression were not correlated to TTP or survival. Bivariate analysis showed EGFR phosphorylation was related to short TTP and poor prognosis both in early and advanced stages. Multivariate analyses confirmed that clinical stage, performance status, and p-EGFR expression were independently associated with increasing risk of short TTP and poor prognosis. These results suggest that phosphorylation, but not overexpression, of EGFR may be an important predictor for clinical outcome of NSCLCs.

Adult↗
PubMed2003

Inhaled steroid therapy and hospitalization for bronchial asthma: trend in Tokushima University Hospital.

With the recognition that airway inflammation is present even in patients with mild bronchial asthma, therapy with inhaled corticosteroids is now indicated in various stages of patients. In the present article, we retrospectively examined the prescriptions for inhaled corticosteroids and other drugs for the treatment of outpatients with bronchial asthma at Tokushima University Hospital. We also analyzed asthma control in these patients, in terms of the incidence of emergency consultations and hospitalizations due to asthma exacerbations. To analyze the recent trend, the patients observed from 1998 to 2000 (recent years) were included, and for control purpose, those in 1990 and 1991 (earlier years) were also included. The percentage of patients treated with inhaled corticosteroids remarkably increased in recent years (mean; 81.3%) compared to earlier years (mean; 23.5%). In contrast, the usage of oral corticosteroids, oral xanthine derivatives, beta-adrenergic receptor agonists and anti-allergic agents tended to decrease in the 10 years period. After the introduction in 1995, considerable patients up to 25% have been treated with anti-leukotrienes. Emergency consultations decreased in recent years (mean; 0.18/patient/year) compared to earlier years (mean; 0.79/patient/year). Emergency hospitalizations also decreased in recent years (mean; 0.043/patient/year) compared to earlier years (mean; 0.23/patient/ year). In the present study, spread of inhaled corticosteroid therapy and decline in incidence of emergency consultation and hospitalization were simultaneously observed at Tokushima University Hospital, and the former has, at least in part, a contribution to the latter.

Administration, Inhalation↗
PubMed2003

Effect of human airway trypsin-like protease on intracellular free Ca2+ concentration in human bronchial epithelial cells.

It has been shown that human airway trypsin-like protease (HAT) is localized in human bronchial epithelial cells (HBEC), and trypsin activates protease-activated receptor-2 (PAR-2). Activation of PAR-2 activates G-protein followed by an increase of intracellular free Ca2+, [Ca2+]in. This study was undertaken to clarify whether HAT can activate PAR-2 in HBEC or not. RT-PCR showed that HAT mRNA is expressed in HBEC, and PAR-2 mRNA is the most strongly expressed of the known PARs in HBEC. Both PAR-2 agonist peptide (PAR-2 AP) and HAT increased [Ca2+]in in HBEC in a biphasic fashion; a prompt, sharp increase (peak I) and a sustained low plateau (peak II). PAR-2 AP over 100-200 microM and HAT over 200-300 mU/ml (0.08-0.12 microM) induced both peak I and II, and PAR-2 AP below 100 microM and HAT below 200 mU/ml induced only peak II. Both PAR-2 AP-induced and HAT-induced peak I were induced by Ca2+ mobilization from intracellular stores, because they appeared even in Ca2+-free medium. Both PAR-2 AP-induced and HAT-induced peak II were induced by an influx of extracellular Ca2+, because they were abolished in Ca2+-free medium. The Ca2+ response to HAT was desensitized by exposure of HBEC to PAR-2 AP. These results indicate that HBEC have a functional PAR-2, and HAT regulates cellular functions of HBEC via activation of PAR-2.

Adult↗
PubMed2003

[Globalization of clinical trials].

Based on reviews of the Japanese clinical trial situation in lung cancer, gastric cancer, prostate cancer and breast cancer, it was clear that much progress has been made in short time. There are considerable differences between Japan and the West and also differences between clinical areas in Japan. For regulatory purposes bridging studies have become increasingly important. Use of identical protocols are required for effective bridging. Participations in global phase III trials is the best way of achieving registration in Japan. For successful global trials in Japan it is important to include Japanese investigators in the preparation of the protocol and to recognise the challenges facing such a project. Clinical practice in diagnosis and treatment have many differences, thus it is recommended to have clear and detailed information in the protocol. Hard end points like survival are important since they are not biased by cultural differences. There are clear difficulties with HE or QOL outcomes. The emergence of focus on evidence based medicine is also happening in Japan and will help to harmonize documentation across the world. For large adjuvant or prevention cancer global trials are essential. To facilitate global studies further development of infrastructure is necessary in Japan. Use of electronic data capture web based communication etc. will help overcome communication difficulties. Other improvements that will make Japanese participation in global trials easier and better include establishment of clinical trial centre at each hospital, introduction of trial coordinators or study nurses and an improved collaboration with company staff. A critical issue that also need addressing is agreement of centre target recruitment. We need to introduce a new flexible system in Japan if participation in global trial is to be optimised. If we can address these issues Japanese investigators and collaborative groups should be able to initiate and lead global trials in the future.

Antineoplastic Agents↗
PubMed2003

Genome-wide analysis of organ-preferential metastasis of human small cell lung cancer in mice.

Although a number of molecules have been implicated in the process of cancer metastasis, the organ-selective nature of cancer cells is still poorly understood. To investigate this issue, we established a metastasis model in mice with multiple organ dissemination by i.v. injection of human small cell lung cancer (SBC-5) cells. We analyzed gene-expression profiles of 25 metastatic lesions from four organs (lung, liver, kidney, and bone) using a cDNA microarray representing 23,040 genes and extracted 435 genes that seemed to reflect the organ specificity of the metastatic cells and the cross-talk between cancer cells and microenvironment. Furthermore, we discovered 105 genes that might be involved in the incipient stage of secondary-tumor formation by comparing the gene-expression profiles of metastatic lesions classified according to size (<1 or >2 mm) as either "micrometastases" or "macrometastases." This genome-wide analysis should contribute to a greater understanding of molecular aspects of the metastatic process in different microenvironments, and provide indicators for new strategies to predict and prevent metastasis.

Animals↗
PubMed2003

[A case of septic pulmonary embolism accompanied with tricuspid valve endocarditis and pyogenic spondylitis].

A 54-year-old man was admitted with complaints of high fever and lumbago. A chest radiograph on admission showed bilateral multiple patchy infiltrations. Chest CT showed multiple nodules of various sizes, some with necrotic centers and feeding vessels in the peripheral areas. Some nodules had wedge-shaped consolidations aboutting the pleura. Echocardiography showed vegetation about 12 x 7 mm in size attached to the tricuspid valve. MR imaging of the lumbar vertebrae showed increased signal intensity in the vertebral bodies in L1-4 in T2-weighted images and a further increase of signal intensity by gadolinium enhancement in T1-weighted images. These findings led to a diagnosis of septic pulmonary embolism accompanied with tricuspid valve endocarditis and pyogenic spondylitis irrespective of a negative blood culture. The fever was reduced and the inflammatory findings and chest radiographs were improved by antibiotic therapy, and then tricuspid valvuloplasty was performed. The characteristic CT features of septic pulmonary embolism, mentioned above, can contribute to an accurate and early diagnosis and proper treatment.

Endocarditis, Bacterial↗
PubMed2002

Organ heterogeneity of host-derived matrix metalloproteinase expression and its involvement in multiple-organ metastasis by lung cancer cell lines.

Cancer metastasis is tightly regulated by the interaction of tumor cells and host organ microenvironments. Matrix metalloproteinases (MMPs), produced by both tumor cells and host stromal cells, play a central role in tumor invasion and angiogenesis. We determined whether metastatic potential of lung cancer to multiple organs is dependent solely on the expression of MMPs by tumor cells, using two metastasis models of human lung cancer cell lines expressing various levels of MMPs and a MMP inhibitor (ONO-4817). In the lung metastasis model, tumor cells (PC14, PC14PE6, H226, A549) inoculated i.v. into nude or SCID mice metastasized only in the lung. In the multiple-organ metastasis model, tumor cells (RERF-LC-AI, SBC-3/DOX, H69/VP, which express low levels of MMPs) inoculated i.v. into natural killer cell-depleted SCID mice metastasized into the liver, kidneys, and systemic lymph nodes. Film in situ zymography analysis revealed that the nontumor parenchyma of the lung had no gelatinolytic activity, whereas gelatinolytic activity of the liver and kidney was high and low, respectively. In the lung metastasis model, gelatinolytic activity of lung nodules directly correlated with the in vitro expression of MMP-2 and MMP-9 by tumor cells. Inhibition of MMP activity by ONO-4817 suppressed lung metastasis by the cell lines that expressed MMPs, but not those that did not express MMP, via the inhibition of MMP activity of lung tumors. In the multiple-organ metastasis model, liver parenchyma, but not liver nodules, showed gelatinolytic activity. The MMP inhibition reduced metastasis to the liver, but not to the kidney or lymph nodes, via inhibition of MMP activity of liver parenchyma. These findings suggest that MMP expression varies among the host organ microenvironments and that stromal MMPs may promote metastasis of lung cancer. Therefore, antimetastatic effects based on MMP inhibition may be dependent on MMPs derived not only from tumor cells but also from organ-specific microenvironments.

Adenocarcinoma↗
PubMed2002

MYO18B, a candidate tumor suppressor gene at chromosome 22q12.1, deleted, mutated, and methylated in human lung cancer.

Loss of heterozygosity on chromosome 22q has been detected in approximately 60% of advanced nonsmall cell lung carcinoma (NSCLC) as well as small cell lung carcinoma (SCLC), suggesting the presence of a tumor suppressor gene on 22q that is involved in lung cancer progression. Here, we isolated a myosin family gene, MYO18B, located at chromosome 22q12.1 and found that it is frequently deleted, mutated, and hypermethylated in lung cancers. Somatic MYO18B mutations were detected in 19% (14/75) of lung cancer cell lines and 13% (6/46) of primary lung cancers of both SCLC and NSCLC types. MYO18B expression was reduced in 88% (30/34) of NSCLC and 47% (8/17) of SCLC cell lines. Its expression was restored by treatment with 5-aza-2'-deoxycytidine in 11 of 14 cell lines with reduced MYO18B expression, and the promoter CpG island of the MYO18B gene was methylated in 17% (8/47) of lung cancer cell lines and 35% (14/40) of primary lung cancers. Furthermore, restoration of MYO18B expression in lung carcinoma cells suppressed anchorage-independent growth. These results indicate that the MYO18B gene is a strong candidate for a novel tumor suppressor gene whose inactivation is involved in lung cancer progression.

Cell Division↗
PubMed2002

Activity of a new vascular targeting agent, ZD6126, in pulmonary metastases by human lung adenocarcinoma in nude mice.

ZD6126 (ANG453) is a novel vascular targeting agent that selectively disrupts the cytoskeleton of endothelial cells in tumor. In mouse s.c. xenograft models, ZD6126 was found to induce selective occlusion of tumor blood vessels, cessation of tumor blood flow, and death of tumor cells because of the starvation of oxygen and nutrition. Here, we investigated whether ZD6126 inhibited the metastatic formation of human non-small cell lung cancer cells. PC14PE6 (adenocarcinoma) and H226 (squamous cell carcinoma) cells were injected into the tail vein of nude mice, and lung metastases were estimated. ZD6126 treatment involved either a single dose on 24 h before killing or daily doses from day 14 until the end of the experiment. Single treatment with i.p. injection of 200 mg/kg ZD6126 caused bleeding and necrotic changes in the tumor by 24 h. Histological analysis revealed that apoptotic tumor cells were markedly increased in the ZD6126-treated group. Moreover, ZD6126 induced the apoptosis of CD31-positive vascular endothelial cells in tumors but not in the normal lung parenchyma. When mice were treated daily with 100 mg/kg ZD6126 from day 14 until the end of the experiment, the lung weight was significantly less in the ZD6126-treated group than that of the control group, despite no difference in the number of metastatic nodules. These data suggest that ZD6126 could demonstrate its antitumor activity against both already established and early phase of lung cancer metastasis by causing the selective apoptosis of tumor endothelial cells and destruction of the tumor vasculature.

Adenocarcinoma↗
PubMed2002

Age-related changes in control of blood pressure and heart rate during sleep in the rat.

STUDY OBJECTIVES: The aim of this study was to determine age-related changes in the control of mean arterial pressure (MAP) and heart rate (HR) during sleep, and its relationship to the baroreflex in aging. DESIGN: MAP, HR, body temperature (TP), spontaneous activity (ACT), and sleeping/waking duration were monitored for 24 hours in groups of young (10-12 wk old) and old (23-24 mo old) rats. SETTING: The sleep laboratory at the University of Tokushima. PARTICIPANTS: Subjects were 8 young (10-12 wk old) and 7 old (23-24 mo old) Wistar rats. INTERVENTIONS: Reflex control of HR was evaluated by examining various pressure responses to an intravenous bolus injection of phenylephrine and sodium nitroprusside. MEASUREMENTS AND RESULTS: MAP and TP were recorded by a radiotelemetry system. HR was detected from the AP signal. ACT was counted by a photo-sensor system. In the case of old rats, the sensitivity of baroreflex control of HR was significantly depressed, and the spontaneous increase of MAP and HR during REM sleep and the MAP drop at the end of REM sleep were significantly enhanced. The old rats showed no large deterioration of the circadian profiles of MAP, HR, TP, and the amount of sleep. CONCLUSIONS: The baroreflex dysfunction is considered to appear in an early stage of the aging process, and to affect the control of MAP and HR during sleep.

Age Factors↗
PubMed2002

CD13/aminopeptidase N-induced lymphocyte involvement in inflamed joints of patients with rheumatoid arthritis.

OBJECTIVE: We previously showed that CD13/aminopeptidase N (EC 3.4.11.2) induces chemotactic migration of T lymphocytes by its enzymatic activity. In this study, we examined the role of CD13/aminopeptidase N in lymphocyte involvement in rheumatoid arthritis (RA). METHODS: Synovial fluids were obtained from 27 RA patients and 6 osteoarthritis (OA) patients. Synovial tissue specimens were obtained from 3 RA patients and 3 OA patients. Protease activity of aminopeptidase in synovial fluids and synovial fibroblasts was assayed fluorometrically using the specific substrate. Expression of CD13/aminopeptidase N in synovial fibroblasts was determined by flow cytometry analyses, Western blotting, and reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: The mean value of aminopeptidase activity in synovial fluid samples from RA patients was significantly higher than that in samples from OA patients. Increased enzymatic activity of aminopeptidase was detected on synovial fibroblasts from RA patients compared with those from OA patients. Flow cytometry showed that the expression of CD13/aminopeptidase N on synovial fibroblasts from RA patients was higher than the expression on synovial fibroblasts from OA patients, and Western blots and RT-PCR showed that synovial fibroblasts from RA patients contained a greater amount of CD13/aminopeptidase N. The activity of CD13/aminopeptidase N correlated significantly with lymphocyte counts in synovial fluids from RA patients. Synovial fluids from RA patients in which high aminopeptidase activity was detected contained considerable chemotactic activity for lymphocytes, and bestatin, a specific inhibitor of aminopeptidases, partially inhibited the chemotactic activity. CONCLUSION: CD13/aminopeptidase N may participate in the mechanism of lymphocyte involvement in inflamed joints of RA patients as a lymphocyte chemoattractant.

Aged↗