Biomedical subjects

H Isobe

Publications and source records attributed to H Isobe.

At least 19 recordsLinked to original sources

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↗

PubMed2004

Activated protein C reduces stress-induced gastric mucosal injury in rats by inhibiting the endothelial cell injury.

BACKGROUND AND OBJECTIVE: Activated protein C (APC) is a natural anticoagulant with anti-inflammatory activity. APC inhibits neutrophil activation through inhibition of tumor necrosis factor (TNF)-alpha production. Such anti-inflammatory activity of APC has recently been shown to be critical in the treatment of patients with severe sepsis. We previously demonstrated that activated neutrophils play a crucial role in the development of stress-induced gastric mucosal injury. Thus, inhibition of neutrophil activation by APC should reduce endothelial cell damage, maintain gastric blood flow, and lessen gastric mucosal injury. In the present study, we examined this possibility by using a rat model of water-immersion restraint stress (WIRS)-induced gastric mucosal injury. METHODS AND RESULTS: Gastric mucosal injury was observed 4 h after WIRS, without increases in gastric mucosal levels of either myeloperoxidase activity or TNF-alpha, but with significant increases in plasma levels of TNF-alpha 1 h after WIRS. Intravenous administration of APC (100 micro g kg-1) significantly reduced WIRS-induced gastric mucosal injury by inhibiting decrease in gastric mucosal blood flow. Administration of APC also inhibited both the decrease in gastric tissue levels of 6-keto-prostaglandin F1alpha and the increase in gastric mucosal micorvascular permeability in animals subjected to WIRS. Furthermore, APC inhibited WIRS-induced increases in plasma levels of TNF-alpha. Neither active site-blocked factor Xa, which is a selective inhibitor of thrombin generation, nor active site-blocked APC had any effect on these events. Intraperitoneal administration of anti-rat TNF-alpha antibody produced effects similar to those of APC. CONCLUSIONS: The observations in the present study strongly suggest that APC reduces stress-induced gastric mucosal injury by inhibiting the decrease in gastric mucosal blood flow through attenuation of the activated neutrophil-induced endothelial cell injury via inhibition of TNF-alpha production. In addition, we show that serine protease activity of APC, rather than its anticoagulant activity, is critical for the protective mechanism(s) by which TNF-alpha production could be inhibited.

Animals↗

PubMed2001

Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting excessive production of nitric oxide.

BACKGROUND: Excessive production of nitric oxide (NO) by the inducible isoform of NO synthase (iNOS) is critically involved in endotoxin (ET)-induced hypotension. Tumor necrosis factor-alpha (TNF-alpha) plays an important role in induction of iNOS. Because activated protein C (APC), a physiological anticoagulant, inhibits TNF-alpha production, it might prevent hypotension by inhibiting excessive production of NO. In this study, we examined this possibility using a rat model of septic shock. METHODS AND RESULTS: Intravenous administration of APC prevented both ET-induced hypotension and the increases in plasma levels of NO(2)(-)/NO(3)(-). The hypotension was also inhibited when APC was administered 30 minutes after ET administration. APC inhibited the increases in lung levels of iNOS activity by inhibiting expression of iNOS mRNA in animals given ET. APC significantly inhibited the increases in lung tissue levels of TNF-alpha and expression of TNF-alpha mRNA in animals given ET. Neither DEGR-F.Xa, a selective inhibitor of thrombin generation, nor DIP-APC, an active site-blocked APC, showed any effect on these ET-induced changes. Both inhibition of TNF-alpha production by leukocytopenia and treatment with anti-rat TNF-alpha antibody produced effects similar to those induced by APC. Aminoguanidine, a selective inhibitor of iNOS, inhibited both the hypotension and the increases in plasma levels of NO(2)(-)/NO(3)(-) in this animal model. CONCLUSIONS: These observations strongly suggest that APC inhibits iNOS induction by decreasing TNF-alpha production, leading to the prevention of ET-induced hypotension. Furthermore, such effects of APC were not dependent on its anticoagulant effects but rather on its serine protease activity.

Amino Acid Chloromethyl Ketones↗

PubMed2001

Spherical bilayer vesicles of fullerene-based surfactants in water: a laser light scattering study.

The low solubility of fullerenes in aqueous solution limits their applications in biology. By appropriate substitution, the fullerenes can be transformed into stabilized anions that are water soluble and can form large aggregated structures. A laser light scattering study of the association behavior of the potassium salt of pentaphenyl fullerene (Ph5C60K) in water revealed that the hydrocarbon anions Ph5C60- associate into bilayers, forming stable spherical vesicles with an average hydrodynamic radius and a radius of gyration of about 17 nanometers at a very low critical aggregation concentration of less than 10(-7) moles per liter. The average aggregation number of associated particles in these large spherical vesicles is about 1.2 x 10(4).

Journal Article↗

PubMed2001

Recombinant tissue factor pathway inhibitor prevents lipopolysaccharide-induced systemic hypotension in rats by inhibiting excessive production of nitric oxide.

Excessive production of nitric oxide (NO) by the inducible form of NO synthase (iNOS) plays a key role in the development of endotoxin shock. Tumor necrosis factor-alpha (TNF-alpha) induces iNOS, thereby contributing to the development of shock. We recently reported that recombinant tissue factor pathway inhibitor (r-TFPI), an important inhibitor of the extrinsic pathway of the coagulation system, inhibits TNF-alpha production by monocytes. In this study, we investigated whether r-TFPI could ameliorate hypotension by inhibiting excessive production of NO in rats given lipopolysaccharide (LPS). Pretreatment of animals with r-TFPI prevented LPS-induced hypotension. Recombinant TFPI significantly inhibited the increases in both the plasma levels of NO2-/NO3- and lung iNOS activity 3 h after LPS administration. Expression of iNOS mRNA in the lung was also inhibited by intravenous administration of r-TFPI. However, neither DX-9065a, a selective inhibitor of factor Xa, nor an inactive derivative of factor VIIa (DEGR-F.Vlla) that selectively inhibits factor VIIa activity, had any effect on LPS-induced hypotension despite their potent anticoagulant effects. Moreover, neither the plasma levels of NO2-/NO3- nor lung iNOS activity were affected by administration of DX-9065a and DEGR-F.VIIa. These results suggested that r-TFPI ameliorates LPS-induced hypotension by reducing excessive production of NO in rats given LPS and this effect was not attributable to its anticoagulant effects, but to the inhibition of TNF-alpha production.

Animals↗

PubMed2000

One-step multiple addition of amine to

A secondary amine undergoes a one-step multiple addition to [60]fullerene under photochemical aerobic conditions to produce tetra(amino)fullerene epoxide 1 in moderate to excellent yield.

Journal Article↗

PubMed2000

Intracellular distribution of macrophage migration inhibitory factor predicts the prognosis of patients with adenocarcinoma of the lung.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is known to be a proinflammatory cytokine and glucocorticoid-induced immunomodulator as well as a regulator of tumor growth. Although positive and negative effects of MIF on tumor cell growth have been reported, to the authors' knowledge the precise role of MIF in tumorigenesis remains unclear. In the current study the authors assessed expression of MIF protein and mRNA in lung adenocarcinomas with regard to patient prognosis. METHODS: Immunohistochemical analysis was performed on tissue specimens surgically obtained from 74 patients with primary lung adenocarcinoma (American Joint Committee on Cancer pathologic Stages I, II, and IIIa). In addition, expression of MIF mRNA in the cancerous tissue was investigated using in situ hybridization. Patient prognosis was evaluated with regard to MIF expression levels and its distribution was analyzed with the Kaplan-Meier method. RESULTS: MIF mRNA and MIF protein were observed in the bronchial epithelium, alveolar epithelium, vascular smooth muscle, and alveolar macrophages in the normal lung tissue. In tumor tissue from lung adenocarcinoma specimens, both MIF mRNA and protein were observed at much higher levels than in the normal alveolar epithelium. MIF protein was observed diffusely in the cytoplasm of tumor cells in all tumor specimens examined. MIF protein also was observed in the nuclei of tumor cells from 59 patients (79.7%), whereas it was not observed in the nuclei of tumor cells from 15 patients (20.3%). The patients without nuclear MIF expression had a worse prognosis compared with those patients with MIF expression in the nuclei (P = 0.04). CONCLUSIONS: The results of the current study suggest that intracellular MIF distribution predicts patient prognosis in individuals with adenocarcinoma of the lung.

Adenocarcinoma↗

PubMed2000

Primary carcinoid tumor in a horseshoe kidney.

A case of primary carcinoid tumor arising within a horseshoe kidney in a 51-year-old woman is reported. The tumor was found incidentally by computed tomography (CT) during a check-up for a suspected gall bladder polyp. Histologic, immunohistochemical and electron microscopic analyses of this tumor revealed features typical of carcinoid tumor. Primary carcinoid tumor of the kidney is extremely rare and only 32 cases were previously reported, including five cases in horseshoe kidneys. None of these five cases in horseshoe kidneys demonstrated any evidence of local or distant metastases and all were alive at the time of reporting without evidence of disease after up to 3 years of follow up. The present case, even with accompanying lymph nodal metastasis, also has had no evidence of local recurrence or distant metastasis for 3 years post operation. Primary carcinoid tumor arising within horseshoe kidneys appear to be more benign than those within non-horseshoe kidneys.

Carcinoid Tumor↗

PubMed2000

[A case of non-small-cell lung cancer with intramedullary spinal cord metastasis diagnosed pre-mortem].

The patient was a 54-year-old man who in May 1999 received a diagnosis of squamous cell carcinoma, T4 N2 M1, stage IV. Systemic chemotherapy and stereotactic radiosurgery were performed only to result in further progression of the disease. In August 1999, he experienced gait disturbance due to lumbar pain. Rehabilitation improved the gait disturbance and he was discharged. In October, since the pain reappeared and there was numbness in the right leg, he was readmitted. Brain MRI revealed multiple brain metastasis and whole brain irradiation was performed. But his symptoms deteriorated, and palsy of the right leg ensued. Later, bladder dysfunction also developed. Since spinal cord MRI revealed intramedullary metastasis at Th 12 and L1 levels, we performed radiotherapy for the lumbar medullary lesion, together with systemic chemotherapy. After chemoradiotherapy the tumor size decreased and the pain improved. Cases of lung cancer with intramedullary metastasis are rare, especially those diagnosed before death.

Brain Neoplasms↗

PubMed1999

Nonstatistical binding of a protein to clustered carbohydrates.

Carbohydrate-derivatized self-assembled monolayers (SAMs) are used as a model system to address issues involving cell-surface carbohydrate-protein interactions. Here we examine the influence of carbohydrate surface density on protein-binding avidity. We show that the binding selectivity of Bauhinia purpurea lectin switches from one carbohydrate ligand to another as the surface density of the carbohydrate ligands increases from values of chi(sugar) approximately 0.1-1.0. Polyvalent binding is possible at all surface densities investigated; hence, the switch in selectivity is not due simply to the achievement of a critical density that permits polyvalent contacts. Instead, secondary interactions at high surface densities promote a switch in carbohydrate-binding selectivity. These findings may have implications for how changes in the composition and the density of cell-surface carbohydrates influence biological recognition processes and regulatory pathways.

Carbohydrate Metabolism↗

PubMed1999

Porous Silica Particles Prepared from Silicon Tetrachloride Using Ultrasonic Spray Method.

Silica particles having the median diameter of 1 to 3 µm were prepared from silicon tetrachloride vapor by a reaction with water droplets using the ultrasonic spray method. The particle sizes of silicas were controlled by changing the composition of silicon tetrachloride and water. These silica particles had microporous structures from nitrogen and water adsorption measurements. The microporous and mesoporous particles were prepared from the reaction of water droplets including sodium and potassium carbonates with silicon tetrachloride vapor. Copyright 1999 Academic Press.

Journal Article↗

PubMed1999

Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin.

We investigated whether antithrombin (AT) can reduce ischemia/reperfusion (I/R)-induced injury of rat liver by promoting prostacyclin release from endothelial cells. Although intravenous administration of AT (250 U/kg) markedly reduced hepatic injury, neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Hepatic levels of 6-keto-PGF1, a stable prostacyclin (PGI2) metabolite, were increased significantly after I/R of the rat liver. AT significantly increased the hepatic level of 6-keto-PGF1, whereas neither DEGR-Xa nor Trp49-modified AT increased it. Hepatic tissue blood flow was markedly reduced after I/R. Although AT significantly increased the hepatic tissue blood flow after I/R, neither DEGR-Xa nor Trp49-modified AT increased the blood flow. Hepatic levels of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO) were significantly increased after hepatic I/R. The levels of these two indicators were reduced by AT but were unaffected by either DEGR-Xa or Trp49-modified AT. Pretreatment of animals with indomethacin (IM) completely inhibited the protective effects of AT on the I/R-induced hepatic damage and the leukocyte activation as well as the AT-induced increase in hepatic 6-keto-PGF1 levels after I/R. Iloprost, a stable analog of PGI2, exhibited effects similar to those of AT and also significantly inhibited the exacerbation of liver injury, the decrease in hepatic tissue blood flow, and the increases in hepatic CINC and MPO levels seen in rats subjected to I/R but pretreated with IM. These findings suggest that AT may prevent I/R-induced hepatic injury by increasing the hepatic levels of PGI2 through the interaction of AT with cell-surface glycosaminoglycans, thus increasing hepatic tissue blood flow and inhibiting leukocyte activation in animals subjected to I/R.

6-Ketoprostaglandin F1 alpha↗

PubMed1999

Antithrombin prevents stress-induced gastric mucosal injury by increasing the gastric prostacyclin level in rats.

The interaction of antithrombin (AT) with cell surface glycosaminoglycans has been shown to promote the endothelial release of prostacyclin (PGI2). Because PGI2 plays an important role in gastric cytoprotection, we examined whether AT prevents water-immersion restraint stress (WIR)-induced gastric mucosal injury in rats by promoting the endothelial release of PGI2. Intravenous administration of AT (250 U/kg) prevented WIR-induced gastric mucosal injury in rats. Gastric levels of 6-keto-prostaglandin F1alpha, a stable metabolite of PGI2, were significantly increased 0.5 and 1 hour after WIR in animals administered AT compared with control animals. The effects induced by AT in animals subjected to WIR were not observed in animals that were administered DEGR-Xa, a selective inhibitor of thrombin generation, or Trp49-modified AT, which lacks affinity for heparin. In animals subjected to WIR gastric mucosal blood flow was significantly reduced with a simultaneous increase in gastric mucosal microvascular permeability. Activated neutrophils have been implicated in the WIR-induced reduction of gastric mucosal blood flow by increasing microvascular permeability. Although AT prevented the reduction of gastric mucosal blood flow and the increase in gastric mucosal microvascular permeability in animals subjected to WIR, neither DEGR-Xa nor Trp49-modified AT had any effect. Pretreatment of animals with indomethacin completely inhibited the protective effects of AT against WIR-induced gastric mucosal injury and the AT-induced increase in post-WIR gastric 6-keto-prostaglandin F1alpha levels. These results strongly suggest that AT prevents stress-induced gastric mucosal injury by increasing the gastric levels of PGI2 through the interaction of AT with cell-surface glycosaminoglycans, thus increasing gastric mucosal blood flow both by vasodilation and by inhibiting neutrophil activation.

6-Ketoprostaglandin F1 alpha↗

PubMed1999

Gastric prostacyclin (PGI2) prevents stress-induced gastric mucosal injury in rats primarily by inhibiting leukocyte activation.

We investigated whether, in rats, gastric prostacyclin (PGI2) prevented gastric mucosal injury that was induced by water-immersion restraint stress by inhibiting leukocyte activation. Gastric levels of 6-keto-PGF1alpha, a stable metabolite of PGI2, increased transiently 30 min after stress, followed by a decrease to below the baseline 6-8 h after stress. Gastric mucosal blood flow decreased to approximately 40% of the baseline level 8 h after stress. Myeloperoxidase activity was significantly increased 8 h after stress. Treatment with indomethacin before stress inhibited the increase in 6-keto-PGF1alpha levels and markedly reduced mucosal blood flow. It also markedly increased leukocyte accumulation and mucosal lesion formation. Iloprost, a stable PGI2 analog, inhibited the indomethacin-induced decrease in mucosal blood flow, mucosal lesion exacerbation, and increase in leukocyte accumulation. Nitrogen mustard-induced leukocytopenia inhibited the indomethacin-associated lesion exacerbation and the increase in leukocyte accumulation, but not the decreases in mucosal blood flow. These observations indicate that gastric PGI2 decreases gastric mucosal lesion formation primarily by inhibiting leukocyte accumulation.

6-Ketoprostaglandin F1 alpha↗

PubMed1999

Plaunotol prevents indomethacin-induced gastric mucosal injury in rats by inhibiting neutrophil activation.

BACKGROUND: Activated neutrophils play a critical role in indomethacin-induced gastric mucosal injury. AIM: To investigate the effect of plaunotol, an anti-ulcer agent, on neutrophil activation in vitro and its effect on gastric mucosal injury and gastric accumulation of neutrophils in rats given indomethacin. METHODS: Human monocytes and neutrophils were isolated from the peripheral blood of healthy volunteers. We examined the effect of plaunotol on neutrophil elastase release, production of O2-, intracellular calcium concentration and expression of adhesion molecules CD11b and CD18 in activated neutrophils in vitro. The effect of plaunotol on TNF-alpha production by monocytes stimulated with endotoxin also was investigated in vitro. The effect of plaunotol (100 mg/kg, p.o.) on gastric mucosal injury and neutrophil accumulation was investigated in male Wistar rats given indomethacin (30 mg/kg, p.o.). RESULTS: Plaunotol inhibited the fMLP-induced release of neutrophil elastase from activated neutrophils, as well as the opsonized zymosan-induced production of O2- by neutrophils. Plaunotol significantly inhibited increased levels of intracellular calcium, a second messenger of neutrophil activation, in vitro. The fMLP-induced increases in CD11b and CD18 expression were also inhibited by plaunotol in vitro. Plaunotol inhibited monocytic production of TNF-alpha, a potent activator of neutrophils. Both gastric mucosal injury and gastric neutrophil infiltration in rats given indomethacin were significantly inhibited by the oral administration of plaunotol. CONCLUSIONS: Plaunotol inhibits indomethacin-induced gastric mucosal injury, at least in part by inhibiting neutrophil activation.

Animals↗

PubMed1999

Video-assisted transsternal radical esophagectomy: three-field lymphadenectomy without thoracotomy for esophageal cancer.

To reduce the invasiveness of radical esophagectomy, we developed a new approach: video-assisted transsternal radical esophagectomy (VATRE). This article presents the operative techniques and our initial results. In our new procedure, cervical U-shaped and longitudinal sternoabdominal incisions are made, and a complete midline sternotomy is carried out. Lymph node clearance from the neck to the upper mediastinum and from the lower mediastinum to the upper abdomen is performed under direct vision. In the middle mediastinum, a video-assisted technique is used to dissect the lymph nodes. After esophageal resection and three-field lymphadenectomy, reconstruction is performed. One-lung ventilation is unnecessary. We have performed this procedure in two cases. These patients had no major complications and recovered more rapidly than patients undergoing conventional transthoracic esophagectomy. Our initial experience shows that VATRE is a technically feasible and less invasive procedure for cancer surgery, and it enables us to easily perform three-field lymphadenectomy.

Aged↗

PubMed1999

Regulation of the genes for arginase isoforms and related enzymes in mouse macrophages by lipopolysaccharide.

Arginase exists in two isoforms, the hepatic (arginase I) and extrahepatic types (arginase II). Arginase I is markedly induced in rat peritoneal macrophages and rat tissues in vivo by bacterial lipopolysaccharide (LPS). In contrast, both arginase I and arginase II are induced in LPS-activated mouse peritoneal macrophages. In the present study, expression of arginase isoforms and related enzymes was studied in mouse tissues in vivo and in peritoneal macrophages with RNA blot and immunoblot analyses and enzyme assay. When mice were injected intraperitoneally with LPS, inducible nitric oxide synthase (iNOS) and arginase II were induced early in the lung and spleen. mRNAs for argininosuccinate synthase (AS) and ornithine decarboxylase (ODC) were also induced early. In comparison, arginase I was induced later in the lung. Early induction of iNOS, arginase II, AS, ODC, and cationic amino acid transporter 2 and late induction of arginase I were observed in LPS-activated peritoneal macrophages. These results indicate that the genes for the two arginase isoforms are regulated differentially. Possible roles of the arginase isoforms in the regulation of nitric oxide production and in polyamine synthesis are discussed.

Animals↗

PubMed1999

Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small-cell lung cancer.

PURPOSE: The target area under the plasma-concentration-versus-time curve (AUC)-based dosing of carboplatin using Calvert's formula is expected to result in more acceptable toxicity and greater efficacy in elderly patients with small-cell lung cancer (SCLC) than the body surface area-based dosing strategy. This phase II study was designed to determine the toxicity and efficacy of carboplatin based on Calvert's formula plus the standard dose of intravenous etoposide for elderly patients with SCLC. PATIENTS AND METHODS: Carboplatin, dosed to a target AUC of 5 x (24-hour creatinine clearance + 25), was given intravenously on day 1 and etoposide 100 mg/m(2) was given intravenously on days 1, 2, and 3. Patients aged >/= 70 years old with a performance status of 0 to 2 were eligible. RESULTS: Thirty-six patients were enrolled onto the study. The patient characteristics were as follows: median age, 73 years; limited disease (LD), 16 patients; and extensive disease (ED), 20 patients. Grades 3 and 4 leukopenia occurred in 57% and 3% of patients, and grades 3 and 4 thrombocytopenia occurred in 40% and 11% of patients, respectively. There was one treatment-related death due to hemoptysis. Other toxicities were relatively mild. There were two complete responses and 25 partial responses, for a response rate of 75%. The median survival time was 10.8 months (LD, 11.6 months; ED, 10.1 months), and the 1-year survival rate was 47%. CONCLUSION: This carboplatin/etoposide combination chemotherapy is an active and relatively nontoxic regimen in elderly patients with SCLC, which suggests that the combination may be suitable for randomized controlled trials.

Aged↗