Biomedical subjects

Masato Nakamura

Publications and source records attributed to Masato Nakamura.

At least 73 records · Page 4Linked to original sources

PubMed2004

Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450.

1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridine-4-carboxamide benzenesulfonate (R278995/CRA0450) is a newly synthesized corticotropin-releasing factor subtype 1 (CRF(1)) receptor antagonist. In the present study, in vitro and in vivo pharmacological profiles of R278995/CRA0450 were investigated. R278995/CRA0450 showed high affinity for recombinant and native CRF(1) receptors without having affinity for the CRF(2) receptor. R278995/CRA0450 attenuated CRF-induced cyclic AMP formation in AtT-20 cells and CRF-induced forepaw treading in gerbils, indicating that R278995/CRA0450 is an antagonist of the CRF(1) receptor. In addition to CRF(1) receptor antagonism, R278995/CRA0450 showed high affinity for the sigma(1) receptor, and attenuated (+)-SKF10,047-induced head-weaving behavior, suggesting sigma(1) receptor antagonism. R278995/CRA0450 showed dose-dependent in vivo occupancy when assessed by ex vivo receptor binding, indicating good brain penetration. R278995/CRA0450 did not alter spontaneous anxiety when tested in the rat elevated plus maze (up to 3 mg/kg, p.o.) or lick suppression test (up to 10 mg/kg, i.p.). However, potent anxiolytic-like properties were observed in rats subjected to swim stress prior to testing on the elevated plus-maze, indicating activity primarily in tests taxing stress-induced anxiety. R278995/CRA0450 was inactive in mouse tail suspension, rat forced swim and rat differential-reinforcement-of-low-rate 72-s (DRL72), while it showed dose-dependent antidepressant-like effects in the rat learned helplessness paradigm and the olfactory bulbectomy model, demonstrating activity in a subset of animal models of depression associated with subchronic stress exposure. No or only mild effects were seen in tests of locomotor activity, motor coordination and sedation. These results indicate that R278995/CRA0450 is an orally active CRF(1) and sigma(1) receptor antagonist with potent anxiolytic-like and antidepressant-like activities.

Animals↗

PubMed2004

Establishment of a new model of human multiple myeloma using NOD/SCID/gammac(null) (NOG) mice.

We developed a new experimental animal model of human multiple myeloma using immunodeficient NOD/SCID/gammac(null) (NOG) mice. A human myeloma cell line, U266, was intravenously inoculated into 20 NOG mice, all of which developed hind leg paralysis and distress around 6 weeks after transplantation. Pathological studies showed that only the bone marrow was infiltrated with U266 cells, and no cells were present in other organs. Osteolytic lesions in cortical bones and loss of trabecular bones were prominent in U266-transplanted NOG mice. In contrast, U266 cells were not detected in CB17scid or NOD/SCID mice 6 weeks after intravenous inoculation. Human IgE, produced by U266 cells, was detected in the serum of U266-transplanted NOG mice by ELISA. The results indicated that this hu-myeloma NOG model might be useful for studying the pathogenesis of myeloma and related osteolytic lesions, and are suggestive of its applicability to the future development of new drugs.

Animals↗

PubMed2004

KB-R9032, newly developed Na(+)/H(+) exchange inhibitor, attenuates reperfusion-induced arrhythmias in isolated perfused rat heart.

PURPOSE: This study was conducted to elucidate the effects of KB-R9032, a newly developed Na(+)-H(+) exchange inhibitor, on reperfusion-induced ventricular arrhythmia in the isolated perfused rat heart. METHODS: Male Wistar rat hearts ( n = 48; 12 for each group) were perfused with modified Krebs-Ringer's solution equilibrated with 5% carbon dioxide in oxygen by means of the Langendorff technique. An occluder was placed around the left anterior descending coronary artery (LAD). Heart rate, coronary flow, and ECG were monitored. Drug-free perfusate was used for 10 min before switching to a perfusate containing various concentrations of KB-R9032. The added concentrations of KB-R9032 varied in the range of 0 (control) to 1 x 10(-5) mol x l(-1). Each heart was subjected to regional ischemia (occlusion of LAD for 11 min) and to 3 min of reperfusion (release of the ligation). RESULTS: In the control group, reperfusion-induced ventricular fibrillation (VF) occurred in 91.7%, and the duration was 158.2 +/- 14.4 s (mean +/- SEM); however, 1 x 10(-7), 1 x 10(-6), and 1 x 10(-5) mol x l(-1) KB-R9032 reduced the incidence of VF to 75.0%, 42.9%, and 6.7%, respectively ( P < 0.05 at 1 x 10(-5) mol x l(-1) of KB-R9032) and reduced the duration of VF to 64.8 +/- 22.1, 16.8 +/- 10.1, and 1.2 +/- 1.2 s, respectively ( P < 0.05 at 1 x 10(-6) and 1 x 10(-5) mol x l(-1) of KB-R9032). CONCLUSION: It was shown in this study that the Na(+)/H(+) exchange inhibitor KB-R9032 suppresses reperfusion arrhythmias in the ischemia-reperfusion model of isolated rat heart.

Animals↗

PubMed2004

Chronic stent recoil plays an important role in restenosis of the right coronary ostium.

OBJECTIVE: The efficacy of coronary stenting of aorto-ostial atherosclerotic lesions is still unclear. We investigated the frequency and mechanism of stent restenosis at this particular lesion. METHODS: Fifty-five consecutive patients with 64 native aorto-ostial lesions in the right coronary artery (RCA, n = 38) and the left main trunk (LM, n = 26) were treated by conventional stenting. Determinants of angiographic restenosis were established. The mechanism of stent restenosis was evaluated using post-stenting and follow-up intravascular ultrasound (IVUS) findings. RESULTS: Restenosis was more frequent in the RCA than in the LM (50% compared with 19%, P < 0.03) and determinants included diabetes mellitus (63% compared with 21%, P < 0.03), calcium deposition (58% compared with 5%, P < 0.003), smaller stent cross-sectional area (SA) (as demonstrated by post-stenting IVUS studies, 8.1 +/- 1.4 mm compared with 10.2 +/- 2.2 mm, P < 0.01), larger plaque burden (64 +/- 6% compared with 57 +/- 8%, P < 0.03) and less circular expansion at the aorto-coronary junction. Serial IVUS examination was performed in 11 patients with restenosis of the right coronary ostium. The mean reduction in the SA was 21% at the aorto-coronary junction (6.4 +/- 1.9 mm, P < 0.003), whereas the SA at the distal edge was unchanged. Thirty-three per cent of late luminal loss was due to chronic stent recoil. CONCLUSION: These findings suggest that stenosis of the right coronary ostium is a high-risk lesion for stent restenosis. In addition to excessive intimal growth, chronic stent recoil might be an important etiologic factor at this particular location.

Aged↗

PubMed2004

Cutting balloon angioplasty is superior to balloon angioplasty or stent implantation for small coronary artery disease.

The aim of this study is to demonstrate initial results and long-term outcomes of patients after receiving cutting balloon angioplasty (CBA), balloon angioplasty (BA), or stenting for small vessel diseases. We studied a total of 327 lesions of small coronary disease treated either by CBA (n=87), BA (n=130), or stenting (n=110) in two affiliated institutes. A small coronary artery was defined as a reference vessel <2.5 mm using quantitative coronary angiography (QCA). Angiographic restenosis was encountered in 31% of the CBA, 46.5% of the BA, and 43.9% of the stent (p=0.048). Major adverse cardiac events (death, myocardial infarction, and target lesion revascularization) at follow-up were significantly lower in the CBA compared to other groups (CBA, 20.3%; BA, 37.3%; stent, 33.3%; p=0.036). The CBA procedure provided superior angiographic and clinical outcomes to the stenting or BA. The CBA may be a cost-effective and reasonable approach for the treatment of lesions in small coronary diseases.

Aged↗

PubMed2004

Hemostatic and fibrinolytic activation is less following cutting balloon angioplasty of the coronary arteries.

Recent studies have shown that percutaneous coronary intervention (PCI) activates systemic hemostatic activity, reflecting platelet activation and thrombin formation in the coronary arteries. The present study compared systemic levels of hemostatic markers induced by plain old balloon angioplasty (POBA), coronary stenting (STENT), and cutting balloon (CB) angioplasty. Sixty-one patients with stable angina pectoris, who underwent elective PCI or diagnostic coronary angiography (CAG) alone, were investigated. Patients who underwent PCI were divided into the POBA group (n = 11), the STENT group (n = 27), and the CB group (n = 11). Patients who underwent CAG alone were assigned to the CAG group (n = 12). Blood samples were collected before, 24 hours after, and 3 days after PCI or CAG. Plasma concentrations of prothrombin fragment 1+2 (F1+2), fibrinopeptide A (FPA), thrombin-antithrombin III complex (TAT), and plasminogen activator inhibitor-1 (PAI-1) were measured. In the CB group, the F1+2 (1.23 +/- 0.4 nmol/L) level 3 days after PCI was significantly smaller than that of the POBA group (2.37 +/- 0.5 nmol/L) (P < 0.05). The FPA (1.81 +/- 0.9 ng/mL), TAT (3.36 +/- 1.2 ng/mL) and PAI-1 (23.0 +/- 4.1 ng/mL) levels in the CB group 3 days after PCI were significantly smaller than those of the POBA group (P < 0.05, respectively) and STENT group (P < 0.05, respectively), but similar to the CAG group. Systemic hemostasis is activated to a greater extent after POBA and stenting than it is after CB angioplasty of the coronary arteries. This may contribute to the favorable long-term outcome of CB angioplasty.

Aged↗

PubMed2004

Ribozyme mediated down-regulation of thrombospondin receptor CD36 inhibits the growth of the human osteosarcoma cell line.

Thrombospondin-1 (TSP1) is known to possess tumor suppressor functions. In contradiction, TSP1 enhances the stromal vascularization and growth of certain cancers. A cell adhesion receptor, CD36, has been shown to interact with a ligand TSP1. We studied how CD36 affects the growth of the osteosarcoma cell line (HOS) expressing TSP1. We used the anti-CD36 ribozyme to specifically suppress CD36 gene expression in the HOS. The expression of the CD36 mRNA was significantly suppressed in the ribozyme-introduced cell line (HOS/Rz). The transformant HOS/Rz markedly decreased its growth. The growth of the osteosarcoma cell line HOS may be regulated by autocrine or paracrine loop TSP1 and CD36.

Antigens, CD↗

PubMed2004

Ribozyme against mutant K-ras mRNA suppresses tumor growth of pancreatic cancer.

Point mutations in the K-ras gene are observed at a high incidence in human pancreatic carcinomas. These alterations can be used as potential targets for specific ribozyme-mediated reversal of the malignant phenotype. We designed an anti-K-ras ribozyme against codon 12 of the mutant K-ras gene transcripts (GGT right curved arrow GTT), and generated a recombinant adenovirus to express the ribozyme (rAd/anti-K-ras Rz). We inoculated Capan-1 human pancreatic carcinoma cells in athymic mice, and made Capan-1 tumor xenografts. When the Capan-1 tumors in athymic mice became approximately 100 mm(3), rAd/anti-K-ras Rz was directly injected into the tumor xenografts. Fifteen (68%) of 22 tumors injected with rAd/anti-K-ras Rz showed tumor growth suppression or tumor regression; 6 of 15 tumors were completely regressive, and 1 tumor was recurrent after the tumor regression. By using the recombinant adenovirus in a mice model system, it was possible to accomplish efficient reversion of the malignant phenotype in human pancreatic tumors with K-ras gene mutation.

Adenoviridae↗

PubMed2004

Clinicopathological significance of sialyl Lex expression in human gallbladder carcinoma.

Sialyl Lex antigen, a member of a family of high molecular weight glycoproteins, is a ligand for E-selectin and may play an important role in tumor metastasis. However, expression patterns of sialyl Lex have not yet been established in human gallbladder carcinomas. In this study, we analyzed the clinicopathological significance of sialyl Lex expression and patients' prognosis in cases of human gallbladder adenocarcinoma. Sialyl Lex immunoreactivity was detected not only in cancer cells (cytoplasmic type; 51.9%, 28/54) but also in cancer stroma (stromal type; 38.9%, 21/54). Stromal sialyl Lex expression was detected in 50.0% (20/40) and 7.1% (1/14) of T2-4 and T1 cancers, respectively (p<0.05). Stromal sialyl Lex-positive gallbladder cancers frequently showed lymphatic invasion, venous invasion and lymph node metastasis (54.3, 50.0 and 60.0%, respectively) (p<0.05), and the expression was associated with a poor outcome. Sialyl Lex expression plays important roles in the vascular invasion and metastasis of human gallbladder adenocarcinoma.

Adenocarcinoma↗

PubMed2004

Helicobacter pylori induces chronic active gastritis in p53-knockout mice.

Gastritis and peptic ulcers result from Helicobacter pylori (H. pylori) infection. To analyze the influence of Helicobacter on inflammatory responses and cell proliferation, we used an animal model of H. pylori-induced gastritis in p53-knockout mice. H. pylori were introduced by gastric intubation into p53-knockout C57BL/6 mice. The animals were then followed-up for 1 year and compared with uninfected controls of the same genotype. Serum levels of anti-H. pylori antibody and histopathological changes were analyzed according to the updated Sydney System. Immunohistochemistry for proliferating cell nuclear antigen (PCNA) and TUNEL staining were also performed. The infected mice showed significantly increased levels of anti-H. pylori antibody in serum. Histologically, p53-knockout mice exhibited increased scores of chronic and active inflammation compared with uninfected controls. The PCNA and TUNEL indices were 25.5% and 10/mm, respectively, in the inflammatory foci of infected mice, and were increased compared with the controls. In the p53-knockout mice, H. pylori infection caused severe inflammatory reactions. The p53 gene may play an important role in inflammatory responses including cell proliferation and apoptosis.

Animals↗

PubMed2004

Insulin resistance in nondiabetic patients is associated with expansive remodeling in coronary arterial lesions.

OBJECTIVE: Insulin resistance has been implicated as an important initiating factor in coronary atherosclerosis. However, associations between insulin resistance and specific morphologic features of atherosclerotic coronary arteries remain unclear. We ultrasonographically evaluated the morphologic features of atherosclerotic coronary arteries in nondiabetic patients with insulin resistance. METHODS: Before intervention, 90 patients with 105 culprit lesions underwent intravascular ultrasound examination through which vessel area, lumen area and plaque area were evaluated. Expansive remodeling (lesion vessel area more than 5% greater than at the proximal reference segment) and constrictive remodeling (lesion vessel area more than 5% less than at the distal reference segment) were also evaluated. Insulin resistance was determined by homeostasis model assessment and defined as values above the 75th percentile (that is, 1.71). RESULTS: Insulin-resistant patients numbered 23, while nonresistant patients numbered 67. Culprit lesions in the insulin-resistant group showed larger vessel area (18.16 +/- 6.94 compared with 13.64 +/- 4.28 mm, P = 0.0001) and plaque area (16.64 +/- 6.78 compared with 12.05 +/- 4.12 mm, P = 0.0001) and more frequently showed expansive remodeling (56% compared with 14%, P < 0.0001) and calcific plaque (33% compared with 12%, P = 0.01). Multivariable logistic regression analysis identified only insulin resistance (odds ratio, 4.9, P = 0.008) as an independent predictor of expansive remodeling. CONCLUSIONS: Insulin resistance independently predicted expansive remodeling, underscoring the importance of insulin resistance in coronary atheroscrelosis.

Adult↗

PubMed2004

The subunits of glutamate cysteine ligase enhance cisplatin resistance in human non-small cell lung cancer xenografts in vivo.

Glutamate cysteine ligase (GCL) is a key enzyme in glutathione (GSH) synthesis, and is thought to play a significant role in the intracellular detoxification of anticancer drugs, especially of cisplatin (CDDP). GCL is composed of a modifier or light chain subunit (GCLM) and a catalytic or heavy chain subunit (GCLC). It was unclear whether the subunits are essential to CDDP-resistance. We examined the gene expression of GCLM and GCLC in 39 xenografts of human non-small cell lung cancer [NSCLC; 10 adenocarcinoma (Ad), 17 squamous cell carcinoma (Sq) and 12 large cell carcinoma (La)] by real-time polymerase chain reaction (PCR) with human-specific primers. Drug sensitivity to CDDP was evaluated in the 9 xenografts (4 Ad, 2 Sq and 3 La) using an in vivo drug sensitivity test. There was a significant association between the expression of GCLM and GCLC mRNA in each xenograft (Fisher's test, p<0.045). Squamous cell carcinoma xenografts significantly showed higher expression of GCLM gene than adenocarcinoma xenografts (p=0.023, t-test), while there was no significant difference in GCLC gene expression levels between each histopathological xenograft. Three of nine xenografts were sensitive to CDDP (Mann-Whitney U test, p<0.01, one-sided), while the other 6 xenografts were resistant. There was a significant relationship between drug sensitivity to CDDP and the co-overexpression of GCL subunits (chi2 test for independence, Yates' correction, p=0.014). These results suggested that the co-overexpression of GCL subunits correlated with CDDP-resistance in human NSCLC xenograft in vivo.

Animals↗

PubMed2004

An anti-K-ras ribozyme suppresses oncogene expression and cell growth of human pancreatic cancer.

Hammerhead ribozymes are effective modulators of gene expression due to their simple structure, site-specific cleavage activity and catalytic potential. The K-ras oncogene is thought to play an important role in the growth of pancreatic cancer, because an activated (mutated) ras gene is found in approximately 90% of human pancreatic cancers. In this study, we designed a hammerhead ribozyme directed against K-ras mRNA at codon 25 [K-ras Rz (25)], and investigated its efficacy in a cultured human pancreatic carcinoma cell line, MIA PaCa-2. K-ras Rz (25) significantly reduced the cellular K-ras mRNA level when introduced into the MIA PaCa-2 cells. The ribozyme suppressed cell growth. K-ras Rz (25) appears capable of reversing the malignant phenotype in human pancreatic carcinoma cells.

Cell Line, Tumor↗

PubMed2004

[The effects of Na+ -H+ exchange inhibitor, KB-R9032, administered at the time of reperfusion in perfused rat heart].

BACKGROUND: We have reported that pretreatment with KB-R9032, a newly developed Na+ -H+ exchange inhibitor is protective against reperfusion-induced ventricular arrhythmia in the isolated perfused rat heart. This study was conducted to elucidate whether the drug is equally effective when it is given at the time of reperfusion. METHODS: Male Wistar rat hearts (n=32, 16 for each group) were perfused by means of Langendorff technique. Each heart was subjected to regional ischemia (occlusion of the left anterior descending coronary artery for 11 minutes) and to three minutes of reperfusion (release of the occlusion). KB-R9032 4 mg (one shot group) or a vehicle without drug (control) were given 30 seconds before the reperfusion to 30 seconds after the reperfusion. RESULTS: In the control group reperfusion-induced ventricular fibrillation (VF) occurred in 91.7% and the duration was 165 +/- 14.4 seconds, but, in one shot group, the incidence of VF decreased to 6.3% and the duration of VF was reduced to 0.4 +/- 0.4 seconds, respectively (P<0.05 vs control group). CONCLUSIONS: It has been shown in this study that the Na+/H+ exchange inhibitor KB-R9032 given at the time of reperfusion suppresses reperfusion arrhythmias in the ischemia-reperfusion model of isolated rat heart.

Animals↗

PubMed2004

[Influence on 5-fluorouracil metabolism by combination of interferon-alpha and 5-fluorouracil against human hepatocellular carcinoma xenografts].

To investigate the effect of biochemical modulation on antitumor activity shown by the combination of 5-Fluorouracil (5-FU) and interferon-alpha (IFN-alpha), experimental therapy was performed on human hepatocellular carcinoma cell (HuH7, PLC/PLF/5) xenografts inoculated into nude mice, using 5-FU and IFN-alpha, either alone or in combination. These agents showed antitumor activity in different degrees. Although IFN-alpha, given as 100,000 units/mouse/3 times/week subcutaneously x 6, and 5-FU, given as 0.5 mg/mouse/3 times/week intraperitoneally, showed addititive antitumor effect against HuH7 and PLC/PLF/5, the activities of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), uridine phosphorylase (UP) and uridine kinase (UK) were not significantly influenced in the tumors treated with the 5-FU/IFN-alpha combination, compared with those treated with 5-FU or IFN-alpha alone. This suggested that antitumor activity of 5-FU and IFN-alpha in combination was not significantly involved in 5-FU metabolism in two human hepatocellular carcinoma cell lines examined.

Animals↗

PubMed2004

[Successful treatment for advanced cholangiocellular carcinoma with intrahepatic metastasis and/or portal vein tumor thrombi by intraarterial chemotherapy combined with 5-fluorouracil, adriamycin and cisplatin (FAP)--two cases report].

The patients of unresectable cholangiocellular carcinoma (CCC) have extremely poor prognosis. Case 1 was a 72-year-old male who had CCC in the left lobe of liver with intrahepatic metastasis. From June 2003, he received hepatic arterial infusion chemotherapy (FAP: 5-fluorouracil 250 mg/day continuous infusion, day 1-5, adriamycin 10 mg/day, day 1, and CDDP 10 mg/day, day 1). After 5 courses, abdominal CT revealed that the main tumor had regressed. Case 2 was a 66-year-old male who had CCC with portal vein tumor thrombus of anterior branch (Vp2). He received FAP arterial infusion chemotherapy that was a same regimen as with the case 1 patient. After 5 courses were administered, Abdominal CT revealed that the size of the main tumor at S8 had not changed, and that portal vein tumor thrombus had disappeared. In both cases, there was no complication related to the chemotherapy. They are alive for more than 1 year after chemotherapy had started. FAP hepatic arterial infusion chemotherapy might be promising as an effective therapy for non-resectable CCC without extra hepatic metastasis.

Aged↗

PubMed2004

[A case of long-term survivor with multiple pulmonary metastases of HCC after hepatic resection].

A 52-year-old male was admitted to our hospital with huge hepatoma of the right lobe. He underwent a right lobectomy of the liver in July 1999. After five months from the surgery, multiple recurrences in the liver and lung were revealed with Computed tomography (CT). TAE was performed for intrahepatic recurrence and a combination therapy, consisting of UFT and interferon-alpha, was started for pulmonary metastasis. Then 5-FU/CDDP/interferon-alpha therapy was given in 2001 and TS-1/interferon-beta therapy was given thereafter in 2002. Consequently, the patient survived for 31 months with no disturbance in quality of life. No intrahepatic recurrence was also detected during the survival period. It was suggested that a good prognosis may be expected, even in the HCC case with distant metastasis after hepatic resection, if the primary cite was curatively treated.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Use of 11p15 mucins as prognostic factors in small adenocarcinoma of the lung.

PURPOSE: Patients with small adenocarcinoma of the lung (SACL) generally have a good prognosis. However, some SACL cases show lymph node metastasis, with poor prognosis. The expression pattern of 11p15 mucins (clustered on the p15 arm of the chromosome 11) is known to change during carcinogenesis in lung cancer. EXPERIMENTAL DESIGN: We evaluated the expression of the 11p15 mucins (MUC2, MUC5AC, and MUC6) in 79 surgical specimens of SACL cases by immunohistochemical analysis. Lymph node metastasis was estimated by pathological staging. RESULTS: Six (7.6%) and 11 (13.9%) of the 79 SACL cases showed MUC2 and MUC6 expression, respectively. Three SACL cases showed both MUC2 and MUC6 expression, and a significant correlation was found between MUC2 and MUC6 expression (Fisher's test, P = 0.033). Six (7.6%) SACL cases showed MUC5AC expression. Five of the 6 cases with MUC2 expression and 6 of the 11 cases with MUC6 expression were had lymph node metastasis. SACL cases with MUC2 or MUC6 expression showed a significantly higher incidence of nodal metastasis than those without expression (P < 0.001 and P = 0.006, chi(2) test, respectively). There was no significant correlation between MUC5AC expression and nodal involvement in SACL, whereas three of the six cases with MUC5AC expression showed lymph node metastasis. The SACL cases with MUC2 expression had a significantly poorer prognosis than those without MUC2 expression (P = 0.011, log-rank test). CONCLUSIONS: These results suggest that 11p15 mucins MUC2 and MUC6 are related to lymph node metastasis in SACL.

Adenocarcinoma↗