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T Okumura

Publications and source records attributed to T Okumura.

At least 19 recordsLinked to original sources
PubMed2007

Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells.

To identify predictive molecular markers for gemcitabine resistance, we investigated changes in the expression of four genes associated with gemcitabine transport and metabolism during the development of acquired gemcitabine resistance of pancreatic cancer cell lines. The expression levels of human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), RRM1, and RRM2 mRNA were analysed by real-time light cycler-PCR in various subclones during the development of acquired resistance to gemcitabine. Real-time light cycler-PCR demonstrated that the expression levels of either RRM1 or RRM2 progressively increased during the development of gemcitabine resistance. Expression of dCK was slightly increased in cells resistant to lower concentrations of gemcitabine, but was decreased below the undetectable level in higher concentration-resistant subclones. Expression of hENT1 was increased in the development of gemcitabine resistance. As acquired resistance to gemcitabine seems to correlate with the balance of these four factors, we calculated the ratio of hENT1 x dCK/RRM1 x RRM2 gene expression in gemcitabine-resistant subclones. The ratio of gene expression decreased progressively with development of acquired resistance in gemcitabine-resistant subclones. Furthermore, the expression ratio significantly correlated with gemcitabine sensitivity in eight pancreatic cancer cell lines, whereas no single gene expression level correlated with the sensitivity. These results suggest that the sensitivity of pancreatic cancer cells to gemcitabine is determined by the ratio of four factors involved in gemcitabine transport and metabolism. The ratio of the four gene expression levels correlates with acquired gemcitabine-resistance in pancreatic cancer cells, and may be useful as a predictive marker for the efficacy of gemcitabine therapy in pancreatic cancer patients.

Antimetabolites, Antineoplastic↗
PubMed2006

Significance of nerve growth factor overexpression and its autocrine loop in oesophageal squamous cell carcinoma.

Nerve growth factor (NGF) is overexpressed not only in nervous system, but also in several types of cancers. However, the role of NGF in oesophageal squamous cell carcinoma (OESCC) remains unclear. Here, we show the first evidence of NGF-TrkA autocrine loop and clinical significance of NGF overexpression in OESCC. Immunohistochemical study of 109 OESCC specimens revealed that NGF overexpression, found in 63 out of 109 patients (57.8%), was associated with lymph node metastasis, distant metastasis, higher TNM stage, poorer tumour differentiation, and poorer survival. NGF overexpression was also associated with strong expression of TrkA and negative expression of low-affinity neurotrophin receptor (p75NTR). Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) of 19 surgical specimens showed upregulation of NGF mRNA in 17 out of 19 (89%) patients. All five OESCC cell lines tested in vitro secreted detectable NGF in enzyme-linked immunosorbent assay, and expressed TrkA and p75NTR on RT-PCR and Western blot. The motility of HSA/c, one of the OESCC cell lines overexpressing NGF, was significantly decreased by either neutralising anti-NGF antibody, an inhibitor of TrkA, or NGF-small interfering RNA in transwell migration assay. Our findings suggest that NGF is of potential interest not only as a prognostic factor, but also as a novel therapeutic target in OESCC.

Adult↗
PubMed2006

The contemporary materials cycle for radioactive 137Cs in the United States.

The materials cycle for (137)Cs, a low-level radioactive material of interest from a security perspective (as a possible source for "dirty bombs") as well as for its extensive industrial and medical uses, has been characterized for the United States for the year 2000. The focus is on products utilizing the isotope rather than on isotope production and subsequent disposal as a result of nuclear power generation. The results indicate that, during 2000, of the 1.5 PBq of (137)Cs that entered use, 94% was contained in sources in imported devices; the amounts in domestic source material recycling (4%) or as imported source materials (2%) were trivial by comparison. Losses from use were about 0.5 PBq; of this amount 86% was by radioactive decay, 11% was active source material that was recovered and recycled, and 3% was source material sent to low-level disposal sites. The current stock of (137)Cs in use is about 20 PBq; this stock is currently growing by more than 1 PBq per year (the difference between inputs to and losses from use). As a result, the security challenge related to monitoring stock in use is increasing by around 5% per year.

Cesium Radioisotopes↗
PubMed2005

The Tokyo subway sarin attack--lessons learned.

The sarin gas attack in the Tokyo subway system is reviewed from a clinical toxicology perspective. Based on the lessons learned from this attack, the following areas should be addressed on a global scale. First, an adequate supply of protective equipment is required, including level B protective equipment with a pressure demand breathing apparatus. In addition, a system should be established that enables a possible cause to be determined based on symptoms, physical findings, general laboratory tests, and a simple qualitative analysis for poisonous substances. If an antidote is needed, the system should enable it to be administered to the victims as quickly as possible. Preparation for a large-scale chemical attack by terrorists requires the prior establishment of a detailed decontamination plan that utilizes not only mass decontamination facilities but also public facilities in the area. A system should be established for summarizing, evaluating, and disseminating information on poisonous substances. Finally, a large-scale scientific investigation of the Tokyo sarin attack should be conducted to examine its long-term and subclinical effects and the effects of exposure to asymptomatic low levels of sarin.

Antidotes↗
PubMed2004

Detection of circulating oesophageal squamous cancer cells in peripheral blood and its impact on prognosis.

BACKGROUND: Many studies have attempted to detect cancer cells using the reverse transcription-polymerase chain reaction (RT-PCR) for specific mRNAs. None has examined the correlation between the presence of circulating oesophageal cancer cells in peripheral blood and long-term outcome. METHODS: Blood samples were obtained on admission, and before, during and after operation from 70 patients with squamous oesophageal cancer who had complete clinicopathological records and who underwent curative oesophagectomy between June 1997 and June 2000. RT-PCR for mRNA encoding squamous cell carcinoma antigen (SCCA mRNA) was used to detect oesophageal cancer cells in peripheral blood. RESULTS: Twenty-three patients (33 per cent) were positive for SCCA mRNA on admission and 17 of these patients developed recurrent disease. SCCA mRNA on admission correlated with the depth of tumour invasion (P < 0.001) and with venous invasion (P < 0.001). Eleven of 24 patients with a positive intraoperative result were positive for SCCA mRNA only during operation, of whom seven also developed recurrence. CONCLUSION: RT-PCR for SCCA mRNA can detect oesophageal cancer cells in peripheral blood. The presence of such cells in blood samples obtained on admission or during operation is a useful predictor of outcome in patients with oesophageal squamous cell carcinoma.

Aged↗
PubMed2004

Evidence for a role of basal ganglia in the regulation of rapid eye movement sleep by electrical and chemical stimulation for the pedunculopontine tegmental nucleus and the substantia nigra pars reticulata in decerebrate cats.

The present study was to determine how afferents from the substantia nigra pars reticulata (SNr) of the basal ganglia to the pedunculopontine tegmental nucleus (PPN) in the brainstem could contribute to the control of behavioral states. We used anesthetized and acutely decerebrated cats (n=22). Repetitive electrical stimulation (10-100 Hz, 20-50 microA, for 4-20 s) to the ventrolateral part of the PPN produced rapid eye movement (REM) associated with a suppression of postural muscle tone (REM with atonia). Although repetitive electrical stimuli (10-200 Hz, 10-60 microA, for 5-20 s) delivered to the dorsolateral part of the SNr did not evoke eye movements or muscular tonus in baseline conditions, it altered the PPN-induced REM with atonia. The following three types of effects were induced: (1) attenuation of the REM with atonia; (2) attenuation of muscular atonia without changes in REM (REM without atonia); and (3) attenuation of only REM. The optimal stimulus sites for these effects were intermingled within the lateral part of the SNr. The PPN-induced REM with atonia was abolished by an injection into the PPN of muscimol (1-15 mM, 0.1-0.25 microl), a GABAA receptor agonist, but not altered by an injection of baclofen (1-10 mM, 0.1-0.25 microl), a GABAB receptor agonist. Moreover, an injection of bicuculline (1-15 mM, 0.1-0.25 microl), a GABAA receptor antagonist, into the PPN, resulted in REM with atonia. On the other hand, an injection of muscimol into the dorsolateral part of the SNr (1-15 mM, 0.1-0.25 microl) induced REM with atonia, which was in turn eliminated by a further injection of muscimol into the PPN (5-10 mM, 0.2-0.25 microl). These results suggest that a GABAergic projection from the SNr to the PPN could be involved in the control of REM with atonia, signs which indicate REM sleep. An excessive GABAergic output from the basal ganglia to the PPN in parkinsonian patients may induce sleep disturbances, including a reduction of REM sleep periods and REM sleep behavioral disorders (REM without atonia).

Animals↗
PubMed2004

Induction of inducible nitric oxide synthase in hepatocytes isolated from rats with ischemia-reperfusion injury.

BACKGROUND: Recent evidence indicates that nitric oxide (NO) has a crucial role in hepatic ischemia-reperfusion (I/R) injury. However, little is known about how I/R influences the gene expression of inducible nitric oxide synthase (iNOS) in hepatocytes. Under inflammatory conditions, we compared the induction of iNOS in hepatocytes isolated from normal and I/R-treated rats. METHODS: Hepatocytes were isolated using the collagenase perfusion method from rats treated with I/R (30-minute ischemia of middle and left lobes, followed by 3-hour reperfusion) or sham operation (control): Primary cultures of rat hepatocytes were incubated with an inflammatory cytokine, interleukin-1beta (IL-1beta), to compare the iNOS induction/NO production between the 2 groups. RESULTS: Both control and I/R groups had no production of nitrite (a stable metabolite of NO) in the absence of IL-1beta. In the control group, IL-1beta stimulated dose- and time-dependent production of NO. The I/R group showed more than 2-fold increased levels of NO production. Western and Northern blot analyses revealed that the I/R group also showed increased levels of iNOS protein and its messenger RNA. CONCLUSION: These results suggest that I/R directly affects the inducibility of the iNOS gene in hepatocytes by IL-1beta. Increased NO may be associated with protective or toxic effects in hepatic I/R injury.

Animals↗
PubMed2004

Pirfenidone protects endotoxin-induced liver injury after hepatic ischemia in rats.

BACKGROUND: Pirfenidone (PFD), an experimental antifibrotic agent, was investigated for its effects on endotoxin-induced liver injury after hepatic ischemia-reperfusion. METHODS: Male Sprague-Dawley rats were subjected to 30 minutes of partial hepatic ischemia, followed by reperfusion for 24 hours. Lipopolysaccharide (LPS) was injected at 30 minutes of reperfusion. PFD (300 mg/kg) or its vehicle (0.5% carboxymethylcellulose) was given orally following LPS administration. RESULTS: PFD prevented the increase in activities of serum alanine transaminase, aspartate transaminase, and lactate dehydrogenase after reperfusion. PFD inhibited the increase of cytokine-induced neutrophil chemoattractant in serum and liver tissue. The number of neutrophils infiltrating the liver was significantly lower in the PFD-treated group than the control group. CONCLUSION: These results indicate that PFD prevents endotoxin-induced liver injury after hepatic ischemia-reperfusion, in part through the decrease of neutrophil infiltration to the liver.

Alanine Transaminase↗
PubMed2004

Effects of pirfenidone on endotoxin-induced liver injury after partial hepatectomy in rats.

BACKGROUND: In living donor liver transplantation, restrictions on graft size are a serious obstacle to expand indications for adult recipients. The sequence of gram-negative infection, septicemia, and multiple-organ failure is a common cause of early mortality after liver transplantation. An effective therapy has not been established for endotoxemia following extended hepatectomy in donors or small-for-size grafts in recipients. Pirfenidone (PFD), a new experimental antifibrotic agent, was used to ameliorate on endotoxin-induced liver injury following partial hepatectomy. METHODS: Male Sprague-Dawley rats were intravenously administered lipopolysaccharide (LPS) 48 hours after 70% hepatectomy. Prior to LPS administration, PFD (300 mg/kg) or its vehicle (0.5% carboxymethylcellulose) was given orally twice. RESULTS: The survival rate of the PFD-treated group was markedly improved compared with that of the controls. PFD prevented the increases in the activities of serum enzymes (aspartate transaminase [AST], alanine transaminase [ALT], and lactate dehydrogenase [LDH]) and total bilirubin. The serum and liver tissue levels of inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, interferon-gamma, and interleukin-6, were significantly lower among the PFD than the control group. Furthermore, the degree of necrosis in the remnant liver was significantly decreased in the PFD-treated rats compared with controls. CONCLUSION: These results indicate that PFD alleviates endotoxin-induced liver injury after partial hepatectomy through the inhibition of production of inflammatory cytokines in the residual liver. PFD may be useful to prevent endotoxin-induced liver injury after hepatectomy.

Animals↗
PubMed2004

Effect of hepatocyte growth factor on induction of cytokine-induced neutrophil chemoattractant in rat hepatocytes.

BACKGROUND: Restrictions on graft size are a serious obstacle to the expansion of indications for adult recipients in living donor liver transplantation. Hepatocyte growth factor (HGF) has a crucial role in regeneration following hepatic injury. Rat cytokine-induced neutrophil chemoattractant (CINC), a member of the interleukin-8 superfamily in humans, has been implicated in chronic liver diseases or development of liver ischemia-reperfusion injury. Studies were performed to examine whether HGF influences the induction of CINC in hepatocytes. METHODS: Primary cultures of rat hepatocytes were treated with or without recombinant human (rh) HGF. The release of CINC into the culture medium and levels of CINC mRNA were measured using an enzyme-linked immunosorbent assay and Northern blot analysis. Transcription of nuclear factor (NF)-kappa B was detected by electrophoretic mobility shift assays. RESULTS: rhHGF increased the release of CINC in the medium dose- and time-dependently, showing a maximal effect at 100 ng/mL. Genistein (100 mumol/L) blocked the release of CINC stimulated by rhHGF. Levels of CINC mRNA were also increased, reaching a maximum at 8 hours after addition of rhHGF. Electrophoretic mobility shift assays revealed rhHGF activated transcription factor, NF-kappa B. CONCLUSION: These results suggest that HGF stimulates the induction of CINC gene expression through activation of NF-kappa B. CINC may be involved in the function of HGF during liver regeneration.

Animals↗
PubMed2004

Effect of pirfenidone on induction of chemokines in rat hepatocytes.

BACKGROUND: Hepatic ischemia-reperfusion results in a neutrophil-dependent liver injury. The process of neutrophil recruitment and activation in this injury is at least partially dependent on the induction of chemokines, such as cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) in rats. In the liver, parenchymal cells (hepatocytes), in addition to nonparenchymal cells such as Kupffer cells, have been reported to produce chemokines in the regulation of hepatic inflammation. Pirfenidone (PFD) is a new experimental drug used as an antifibrotic agent. Studies were performed to determine whether PFD influences the production of CINC and MIP-2 stimulated by interleukin (IL)-1beta in a primary culture model of rat hepatocytes. METHODS: Primary cultures of rat hepatocytes were treated with IL-1beta in the presence and absence of PFD. The protein and mRNA of CINC and MIP-2 were analyzed using enzyme-linked immunosorbent assays and Northern blots. RESULTS: IL-1beta increased the release of CINC and MIP-2 into culture media in a dose- and time-dependent manner. PFD inhibited both CINC and MIP-2 release in dose-dependent fashion. However, PFD had no effect on the levels of CINC mRNA induced by IL-1beta. CONCLUSION: These results suggest that PFD inhibits the production of CINC and MIP-2 by IL-1beta at a posttranscriptional step in hepatocytes.

Animals↗
PubMed2003

Estrogenic and thyroid hormone activity of a series of hydroxy-polychlorinated biphenyls.

A series of novel synthetic monohydroxy polychlorinated biphenyls (OH-PCBs) (5 trichloro-, 5 tetrachloro- and 5 pentachloro-compounds) have been characterized (1H and 13C NMR and high resolution MS) and their estrogenic and thyroid hormone activities assessed using a yeast two-hybrid assay, both with and without possible metabolic activation by rat liver S9 preparation. Moderate estrogenic activity was found for 2,3,4(')-trichlorobiphenyl-4-ol (compound 5) but this was eliminated when exposed to the S9 mix. 2,2('),3('),4,6-Pentachlorobiphenyl-3-ol (13) and 2('),3,3('),6-tetrachlorobiphenyl-4-ol (10) both showed weak estrogenicity in the absence of the S9 mix. The estrogenicity of compound (10) was enhanced 10-fold by exposure to S9 metabolic activation but that of compound (13) remained unchanged. 2('),4,5('),6-Tetrachlorobiphenyl-2-ol (6) showed strong thyroid hormonal activity (5% of that of T4) whereas 3('),4,6-trichlorobiphenyl-3-ol (4), compound (10) and 2,3('),4,5('),6-pentachlorobiphenyl-3-ol (14) showed moderate activity, and 2('),3,3('),5-tetrachlorobiphenyl-2-ol (8) and 3,3('),5,5('),6-pentachlorobiphenyl-2-ol (11) showed weak activity. The activity of (4) was eliminated by S9 metabolic activation whereas those of (6) and (14) were weakened and that of (10) remained unchanged.

Biological Assay↗
PubMed2003

Relationship of regional adiposity to serum leptin level in nonobese Japanese type 2 diabetic male patients.

BACKGROUND: The aim of the present study was to investigate the relationships between serum leptin levels and regional adipose fat area, BMI, and the measures of variables including serum insulin in nonobese Japanese type 2 diabetic patients. METHODS: A total of 121 nonobese Japanese type 2 diabetic patients [aged 35 to 83 years, body mass index (BMI) (15.4 to 26.8 kg/m(2))] were studied. They all were male patients. In conjunction with serum leptin level, BMI, glycosylated hemoglobin (HbA(1c)), and fasting concentrations of plasma glucose and serum insulin and lipids (triglycerides, total and HDL cholesterol) were measured. RESULTS: Univariate regression analysis showed that serum leptin levels were positively correlated to subcutaneous (r=0.566, P<0.0001) and visceral (r=0.481, P<0.001) fat area in our diabetic patients. Furthermore, serum leptin levels were positively correlated to serum insulin (r=0.517, P<0.0001), BMI (r=0.428, P<0.0001), serum triglycerides (r=0.279, P<0.005), and age (r=0.225, P<0.05). There was, however, no relationship between serum leptin levels and measures of other variables including total and HDL cholesterol. Multiple regression analyses showed that serum leptin levels were predicted by subcutaneous fat area (F=5.92, P<0.0001) and serum insulin level (F=5.60, P<0.0001), which explained 29.0% of the variability of serum leptin concentrations in our nonobese Japanese type 2 diabetic male patients. Visceral fat area, BMI, serum triglycerides, and age, however, were not independently associated with serum leptin levels in our patients. CONCLUSIONS: These results indicate that serum leptin levels are reflective of subcutaneous fat area in nonobese Japanese type 2 diabetic male patients.

Adipose Tissue↗
PubMed2002

Effect of short-term low-intensity exercise on insulin sensitivity, insulin secretion, and glucose and lipid metabolism in non-obese Japanese type 2 diabetic patients.

The aim of the present study was to investigate the effects of short-term physical exercise that did not change body mass on insulin sensitivity, insulin secretion, and glucose and lipid metabolism in 39 non-obese Japanese type 2 diabetic patients. Insulin sensitivity and insulin secretion were estimated with homeostasis model assessment insulin resistance (HOMA-IR) and HOMA-B-cell function proposed by Matthews et al., respectively. All patients were hospitalized and were engaged in low-intensity exercise that consisted of walking and dumbbell exercise for successive 7 days. There were no changes in hospital diet and the dose of any medications used throughout the study. Fasting glucose, insulin, and lipids were measured before and after exercise. After exercise, serum triglyceride levels significantly decreased, but no significant changes were observed in total and HDL cholesterol concentrations. Fasting glucose, insulin, and HOMA-IR levels significantly decreased after exercise, but HOMA-B-cell function did not change during the study. There was no significant difference between BMI levels before and after exercise. From these results, it can be concluded that short-term (7 days) low-intensity physical exercise combined with hospital diet reduces serum triglycerides, insulin resistance, and fasting glucose levels without affecting BMI in non-obese Japanese type 2 diabetic patients.

Adult↗
PubMed2002

Effect of low or high dietary calcium on the morphology of the rat femur.

The present study compared the effect of a calcium deficit or surfeit on femurs. Young female rats were fed with the normal (1.18%), low (0.05%), or high (2.00%) calcium diet for 3, 7, 15 or 30 days. Two groups received the low calcium diet for the first 15 days and then were followed by the normal (L-N) or high calcium diets (L-H) for the sequential 15 days. The morphology of the femur was studied together with serum calcium, parathyroid hormone (PTH), calcitonin and bone mineral density (BMD). We did not find any significant changes in the serum PTH level and bone morphology in the high calcium group. In the low calcium group, the serum PTH level increased, BMD of the whole body, the femoral weight and the femoral trabecular bone decreased as compared with the normal calcium group. There was a greater proportion of resorbing surface, less resting surface and larger vascular canal openings in the femoral endosteal surfaces in the low calcium group. In the L-N or L-H group, the femoral trabecular bone increased and the femoral resorbing surface decreased as compared with those of the low calcium group. These findings suggest that high calcium intakes do not affect the bone mass, and low calcium intakes have a deleterious effect on bone status, which may be related to vascular alternations of the bone. Reversing the low income calcium intake by a higher calcium diet can partially improve the bone alternations induced by low calcium intake.

Animals↗