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Biomedical subjects

H Okabe

Publications and source records attributed to H Okabe.

At least 55 records · Page 3Linked to original sources
PubMed2000

Anti-AIDS agents 38. Anti-HIV activity of 3-O-acyl ursolic acid derivatives.

Based on our previous finding that 3-O-acyl-betulinic and -oleanolic acids, especially the 3-O-(3',3'-dimethyl)-succinyl derivatives (2 and 4), demonstrated potent anti-HIV activity [EC(50) < 0.00035 and 0.00086 microM; therapeutic index (TI) > 20 000 and 22 326, respectively], several 3-O-acyl-ursolic acids were prepared and evaluated for anti-HIV activity. Ursolic acid (6) was equipotent (EC(50) 4.4 microM) with oleanolic acid (EC(50) 3.7 microM), although it was slightly toxic (IC(50) 14.3 microM, TI 3.3). 3-O-Diglycoryl-ursolic acid (10) demonstrated relatively potent anti-HIV activity with an EC(50) of 0. 31 microM and a TI of 155.5. In contrast, 3-O-(3', 3'-dimethylsuccinyl)-ursolic acid (8), which is analogous to the extremely potent anti-HIV betulinic acid and oleanolic acid derivatives 2 and 4, displayed only weak anti-HIV activity (EC(50) 2.1 microM, TI 23.6).

Anti-HIV Agents↗
PubMed2000

Assessment of disease activity and extent by magnetic resonance imaging in ulcerative colitis.

BACKGROUND: We determined whether magnetic resonance imaging (MRI) could determine the activity and site of involvement in ulcerative colitis. METHODS: Colonoscopy, double-contrast barium enema and gadodiamide-enhanced MRI were performed prospectively in six patients with ulcerative colitis, including three females aged 10-22 years, both in the active and the remission stages. RESULTS: Characteristic findings of MRI in the active stage of ulcerative colitis were loss of haustral markings and thickening and contrast enhancement of the colonic wall. In five of six patients, the site of disease distribution determined by MRI was in accordance with that determined by colonoscopy. CONCLUSIONS: Gadodiamide-enhanced MRI is a safe and useful method of determining disease activity and extent in patients with ulcerative colitis.

Adolescent↗
PubMed2000

Comprehensive allelotype study of hepatocellular carcinoma: potential differences in pathways to hepatocellular carcinoma between hepatitis B virus-positive and -negative tumors.

To examine the role of the loss of heterozygosity (LOH) in hepatitis-related carcinogenesis, we performed a genome-wide scan of LOH in 44 tumors of hepatocellular carcinoma (HCC) using 216 microsatellite markers throughout all human chromosomes. A high frequency of LOH (>30% of informative cases) was observed at 33 loci on chromosome arms 4q, 6q, 8p, 8q, 9p, 9q, 13q, 16p, 16q, 17p, and 19p. LOH on 19p has not yet been reported, and that appears to be a new candidate in the search for tumor suppressor genes. High rates of LOH are correlated with hepatitis B virus (HBV) positivity, poorly differentiated tumors, vascular invasion, and intrahepatic metastasis (P <.0001). LOH on 13q and 16q occurred more frequently in HBV(+) patients (P <.0001), and LOH on 6q occurred more frequently in virus-negative patients (P <.001). The frequency of LOH on 4q and 13q was significantly lower in well-differentiated tumors than in moderately and poorly differentiated tumors (P <.01). In contrast, LOH on 6q was frequently detected in well-differentiated tumors compared with other histological subclasses (P <.001). Our results suggest that LOH on 6q may play an important role in the early stage of hepatocarcinogenesis in virus-negative patients, but different mechanisms might underlie the initial step to carcinogenesis in HBV(+) patients. LOH on 13q and 16q may play an essential role in the progression of HBV(+) tumors. Further studies of fine deletion mapping on chromosomes 13q and 16q are required to define the genomic segments on which putative tumor suppressor genes responsible for HBV(+) tumors exist.

Alleles↗
PubMed2000

Clinicopathologic evaluation of hepatocellular carcinoma with bile duct thrombi.

BACKGROUND: The aim of this study was to evaluate the clinicopathologic characteristics of patients with hepatocellular carcinoma (HCC) and bile duct thrombi (BDT). PATIENTS: Seventeen patients with HCC and BDT among 671 patients with HCC who underwent hepatic resection were enrolled in this study. RESULTS: There were no significant differences in the survival rates between patients with and those without BDT, although the rate of stage IV or portal vein invasion was significantly higher in patients with HCC and BDT than in those with HCC but without BDT. In 9 of 17 patients with BDT, preoperative jaundice was observed. Five of the 17 patients underwent a bile duct resection combined with hepatic resection, and 12 patients underwent hepatic resection with removal of the BDT without bile duct resection. None of the patients had histopathologic evidence of direct tumor invasion into the bile duct wall or of any tumor recurrence related to the BDT. There were no significant differences in the survival rates between patients who underwent bile duct resection and those who did not. CONCLUSION: Hepatic resection and the removal of BDT without bile duct resection were sufficient surgical interventions to treat patients with HCC and BDT.

Adult↗
PubMed2000

Occult breast cancer presenting axillary nodal metastasis: a case report.

We report a case of a 42-year-old female with occult breast cancer presenting axillary nodal metastasis. She complained of a swelling of the right axillary lymph node, but no breast mass was palpable. Biopsy of the lymph node was performed and histological examination showed a metastatic ductal carcinoma with papillotubular formation. Estrogen receptor of the lymph node was positive. No pathological findings were obtained by mammography and ultrasonography and systemic examinations revealed no extramammary primary lesion. All these data suggested an occult carcinoma of the breast and modified radical mastectomy was performed. Pathological findings of the removed specimen failed to find the primary breast cancer lesion. The patient has been treated with hormonal therapy and she is well without evidence of disease 5 years after surgery.

Adult↗
PubMed2000

Activated protein C reduces the ischemia/reperfusion-induced spinal cord injury in rats by inhibiting neutrophil activation.

OBJECTIVE: To examine whether activated protein C (APC) reduces spinal cord injury in rats by inhibiting neutrophil activation after the transient ischemia. SUMMARY BACKGROUND DATA: Ischemic spinal cord injury is an important pathologic mechanism leading to the paraplegia observed after surgery to repair aortic aneurysms. Activated neutrophils play a pivotal role in the development of ischemia/reperfusion-induced tissue injury. Recently, the authors have reported that APC, a physiologic anticoagulant, prevents lipopolysaccharide-induced pulmonary vascular injury by inhibiting neutrophil activation. These observations strongly suggest that APC reduces ischemia/reperfusion-induced spinal cord injury by inhibiting neutrophil activation. METHODS: In rats, spinal cord ischemia was induced by using a balloon catheter placed into the aorta. After the transient ischemia, survival and motor function were evaluated, and histologic examination of the spinal cord was performed by using both hematoxylin-and-eosin staining and 2,3,5, -triphenyltetrazolium chloride (TTC) staining 24 hours after the ischemia. Tissue levels of myeloperoxidase and cytokines, including tumor necrosis factor-alpha (TNF-alpha) and rat interleukin-8, were measured in six experimental groups: sham-operated, control, APC (100 microg/kg, intravenous), dansyl glutamyl-glycyl-arginyl chloromethyl ketone-treated activated factor X (DEGR-F.Xa), a selective inhibitor of thrombin generation (1 mg/kg, intravenous), nitrogen mustard-induced leukocytopenia, and diisopropyl fluorophosphate-treated APC (DIP-APC), active site-blocked APC (100 microg/kg, intravenous). APC, DEGR-F.Xa, and DIP-APC were administered intravenously 30 minutes before aortic occlusion. Control and leukocytopenic rats received saline instead of other drugs. RESULTS: Pretreatment with APC significantly reduced motor disturbances compared with those in control animals. In contrast, neither DEGR-F.Xa nor DIP-APC had any effect. Microinfarctions, evidenced by the absence of TTC staining and histologic change, were markedly reduced in animals given APC. The increases in the tissue levels of TNF-alpha, rat interleukin-8, and myeloperoxidase in the ischemic part of the spinal cord were significantly reduced in animals that received APC. These levels were not reduced in rats given DEGR-F.Xa or DIP-APC. Leukocytopenia produced effects similar to those of APC. CONCLUSIONS: APC reduced the ischemia/reperfusion-induced spinal cord injury by inhibiting neutrophil activation. The therapeutic mechanisms of APC might depend on its inhibitory effect on the production of TNF-alpha, which is a potent activator of neutrophils. Although the anticoagulant effects of APC might not be related to its ability to inhibit TNF-alpha production, its serine protease activity appears to be essential in the therapeutic mechanism. APC appears to have potential as a therapeutic agent for prevention of spinal cord injury in patients undergoing aortic aneurysm repair.

Animals↗
PubMed2000

Liposarcoma associated with multiple intramuscular lipomas. A case report.

A 71-year-old slender, previously healthy man was admitted to the authors' institution because of a huge painless mass in his left scapular area. Physical examination revealed a second soft tissue mass in his right scapular region and a third soft tissue mass in the anterior side of his right shoulder. Surgical treatment including marginal resection of the second and third small masses followed by wide local resection of the huge tumor was performed. Histologic examination showed that the first mass was a well differentiated lipomalike liposarcoma, whereas the second and third lesions were identified as intramuscular lipomas. A review of the literature showed two cases of retroperitoneal liposarcoma associated with multiple subcutaneous lipomas and two cases of liposarcoma involving an extremity associated with multiple subcutaneous lipomas. There is no previous report in which intramuscular liposarcoma was associated with multiple intramuscular lipomas.

Aged↗
PubMed2000

Dihydropyrimidine dehydrogenase and messenger RNA levels in gastric cancer: possible predictor for sensitivity to 5-fluorouracil.

We investigated the correlation between tumor sensitivity to 5-fluorouracil (5-FU) and enzymatic activities of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in human gastric cancer specimens. Forty-one patients with advanced gastric cancer gave informed consent and were enrolled in the study. Biopsy specimens of gastric cancer were obtained preoperatively through gastrofiberscopy and used to determine TS and DPD messenger RNA (mRNA) levels. TS and DPD enzyme activity and mRNA levels were also measured in resected tumor tissue samples obtained after surgical resection. TS and DPD activity were measured using the TS-binding assay and a radioenzymatic assay, respectively, while mRNA levels were measured by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), with co-amplification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. 5-FU sensitivity of resected tumor specimens was measured by the tetrazolium-based colorimetric assay (MTT assay). Both TS and DPD mRNA levels correlated well between biopsied and resected tumor specimens. A statistically significant correlation was also observed between mRNA levels in biopsied specimens and enzymatic activities in resected specimens. DPD levels significantly correlated with 5-FU sensitivity, such that high DPD activity and high DPD mRNA levels resulted in low sensitivity to 5-FU. In contrast, no correlation was observed between TS activity or TS mRNA levels and 5-FU sensitivity. We conclude that tumor DPD mRNA level, as assessed from biopsy specimens obtained by gastrofiberscopy, may be a useful indicator in predicting tumor sensitivity to 5-FU in patients with gastric cancer.

Antimetabolites, Antineoplastic↗
PubMed2000

Pulsatile flow enhances endothelium-derived nitric oxide release in the peripheral vasculature.

The effects of pulsatility in blood flow on endothelium-derived nitric oxide (EDNO) release in the peripheral vasculature were investigated. The basal and flow-stimulated EDNO release were compared between pulsatile and nonpulsatile systemic flows before and after the administration of NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA). Peripheral vascular resistance (PVR) was significantly lower in pulsatile flow than in nonpulsatile flow, but this difference disappeared after L-NMMA. The percent increase in PVR by L-NMMA was significantly larger in pulsatile flow. In reactive hyperemia in the hindlimb, the peak flow did not differ; however, both the repayment flow and the duration were significantly larger in pulsatile flow. Percent changes of these parameters by L-NMMA were significantly larger in pulsatile flow. These data indicated that pulsatility significantly enhances the basal and flow-stimulated EDNO release in the peripheral vasculature under in vivo conditions. We also studied the involvement of the Ca(2+)-dependent and Ca(2+)-independent pathways in flow-induced vasodilation using calmodulin inhibitor calmidazolium and tyrosine kinase inhibitor erbstatin A. PVR was significantly elevated by erbstatin A but not by calmidazolium, suggesting that flow-induced vasodilation was largely caused by tyrosine kinase inhibitor-sensitive activation of NO synthase.

Angiotensin II↗
PubMed2000

Recombinant tissue factor pathway inhibitor reduces lipopolysaccharide-induced pulmonary vascular injury by inhibiting leukocyte activation.

Tissue factor pathway inhibitor (TFPI) is an important physiologic inhibitor of the extrinsic pathway of the coagulation system. We investigated whether recombinant TFPI (rTFPI) could reduce pulmonary vascular injury by inhibiting leukocyte activation in rats given lipopolysaccharide (LPS). Pre- or posttreatment of animals with rTFPI significantly inhibited LPS-induced pulmonary vascular injury, as well as coagulation abnormalities. rTFPI significantly inhibited increases in lung tissue levels of tumor necrosis factor (TNF)-alpha, cytokine-induced neutrophil chemoattractant, and myeloperoxidase. Expression of TNF-alpha messenger RNA in the lung after LPS administration was significantly reduced by rTFPI administration. However, neither DX-9065a, a selective inhibitor of Factor Xa, nor recombinant Factor VIIa treated with dansyl-glutamylglycylarginyl-chloromethyl ketone, a selective inhibitor of Factor VIIa, had any effects on LPS-induced pulmonary vascular injury despite their potent anticoagulant effects. rTFPI significantly inhibited TNF-alpha production by LPS-stimulated monocytes in vitro. rTFPI also significantly inhibited several formyl-Met-Leu-Phe-induced neutrophil functions, as well as increases in the expression of CD11b and CD18 on the neutrophil cell surface in vitro. Additionally, rTFPI inhibited increases in levels of intracellular calcium, a second messenger of neutrophil activation, in formyl-Met-Leu-Phe-stimulated neutrophils in vitro. These results strongly suggested that rTFPI reduces pulmonary vascular injury by inhibiting leukocyte activation, as well as coagulation abnormalities in rats given LPS.

Animals↗
PubMed2000

Pharmacokinetics and bioavailability of tacrolimus in rats with experimental renal dysfunction.

The effects of renal failure on the pharmacokinetics and bioavailability of tacrolimus were investigated in rats. Experimental renal dysfunction was induced by intraperitoneal injection of cisplatin (5 mg kg(-1)) into rats. The blood concentration of tacrolimus was measured after intravenous and intra-intestinal administration of the drug. The blood concentration of tacrolimus after intravenous administration (1 mg kg(-1)) was slightly increased (up to 1.3 fold) by induction of renal dysfunction. In contrast, the peak tacrolimus concentration after intra-intestinal administration (1 mg kg(-1) or 3 mg kg(-1)) in rats with renal failure was about 2-fold higher than that in normal controls. The bioavailability was increased by about 35% in rats with impaired renal function as compared with normal controls. These results suggested that the bioavailability of tacrolimus, which is mainly metabolized in the liver and intestine after oral administration, is also influenced by renal function.

Alanine Transaminase↗
PubMed2000

Synthesis and anti-HIV activity of 3-alkylamido-3-deoxy-betulinic acid derivatives.

3-Alkylamido-3-deoxy-betulinic acids were synthesized and evaluated for anti-HIV activity as part of the structure-activity relationship study of the potent anti-HIV agent 3-O-(3',3'-dimethyl)-succinyl-betulinic acid (DSB) (2). 3Alpha-diglycorylamide-3-deoxy-betulinic acid demonstrated relatively potent anti-HIV activity (EC50 0.24 microm, TI 728). However, replacing the ester group at C-3 in 2 and its analogues with an amido group yielded inactive or much less potent compounds against HIV replication, indicating that the ester group at C-3 in 2-4 is essential for potent anti-HIV activity.

Anti-HIV Agents↗
PubMed2000

The characteristics and applications of recombinant cholesterol dehydrogenase.

Mass production of an r-CDH derived from Nocardia species was made possible by gene technology. (Horinouchi et al., Applied and Environmental Microbiology, 57, 1386-1393 (1991)). However, the characteristics of the r-CDH have not been studied in detail and have not been improved enough for industrial use. We accordingly characterized both the native-CDH and the r-CDH prepared from Streptomyces lividans. Both CDHs were monomers with molecular masses of 37 kDa. The Km of r-CDH was 2.50 x 10(-3) M for cholesterol and 2.33 x 10(-4) M for NAD. The activators of CDHs were TritonX-100 and cholate. TritonX-405, Ag+, and Zn2+ inhibited both enzymes. The residual activity of native CDH after heat treatment was 32% (37 degrees C, 60 min), while the r-CDH showed a residual activity of 87% (37 degrees C, 60 min). The r-CDH is an enzyme with high substrate specificity for cholesterol as well as native CDH and higher thermal stability than native CDH. We have developed a novel serum cholesterol assay using the r-CDH, which permits the direct measurement of cholesterol by measuring NADH reaction products. We conclude that this r-CDH enzyme is useful and can be used to measure cholesterol in a clinical chemistry setting.

Cholesterol↗
PubMed2000

Epitope analysis and utility of monoclonal antibodies to native and recombinant human thymidylate synthase.

The expression of thymidylate synthase (TS) in human cancer tissues has been suggested to be a prognostic factor for patients receiving 5-fluorouracil-based chemotherapy. We generated monoclonal antibodies to both recombinant and native TS and analyzed the epitopes on the TS molecule. Two monoclonal antibodies were obtained from recombinant human TS proteins (RTSMA1 and RTSMA2) and two monoclonal antibodies raised to native TS in human cancers (NTSMA1 and NTSMA2) were obtained, and were found to have a high affinity and specificity for TS proteins. To identify the human TS epitope that these monoclonal antibodies recognized, we constructed plasmids to produce full-length and two partially deleted TS proteins fused to glutathion-S-transferase (GST). Western blot analysis showed that RTSMA1 and 2 only reacted with full-length TS and NTSMA1 and 2 reacted with all three recombinant TS proteins, suggesting that the epitopes of the former were located at C-terminal sites (D186-V313), and those of the latter were at N-terminal sites (M1-M61). The RTSMA 1 and 2 epitopes were more accurately mapped using 8 oligopeptides to the region of I267 to L282 which was situated at the surface of the TS protein. Highly sensitive detection of human TS was also possible by sandwich ELISA using a combination of different types of antibody rather than a single type. In conclusion, different type monoclonal antibodies to human TS protein may contribute to the detection of TS in cancer patients.

Amino Acid Sequence↗
PubMed2000

Experimental postoperative adjuvant chemotherapy by UFT using primary tumor amputation model.

We evaluated the postoperative adjuvant chemotherapy by UFT using the primary tumor amputation-pulmonary metastasis model. When Lewis lung carcinoma (LLC) primary tumors on the hind foot pad grew palpable, they were amputated on two different days. In experiment (A) (earlier amputation model), micrometastases were detected on the day of amputation only by the histopathological examination. In the experiment (B) (later amputation model), nodules could be determined even by necropsy. Long-term (60-day) consecutive administration of UFT (22 mg/kg/day), which produced no body weight loss, markedly prolonged the survival period in experiment (A) (ILS: over 118%), 1 of the 15 mice being cured. UFT had a relatively weak but significant effect (67% of ILS) in schedule (B). Using the same model, we examined the inhibitory effect of UFT (2-week administration) on the number of metastatic nodules. A significant decrease of metastatic nodules was observed by UFT with both amputation schedules, but its effect was superior with schedule (A). In the same model using Colon 26 PMF-15, UFT markedly prolonged the survival period of mice (150% of ILS) and significantly decreased the metastatic nodules (86% inhibition). The dose of UFT used was relatively low, and did not significantly inhibit the growth of large tumors. However, the sensitivity to the micrometastases was high. These findings suggest that the postoperative adjuvant chemotherapy by the long-term consecutive administration of UFT would be effective for clinical cancer especially in curatively resected cases.

Amputation, Surgical↗
PubMed2000

Clinical implications of immunoreactivity of thymidylate synthase and dihydropyrimidine dehydrogenase in gastric cancer treated with oral fluoropyrimidine (S-1). Study Group of S-1 for Gastric Cancer.

Many reports have demonstrated that thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are biomarkers for the response and prognosis of patients treated with 5-fluorouracil (5-FU)-based chemotherapy. A newly developed orally administered drug, fluoropyrimidine (S-1), has been developed with clinical efficacy when combined with an inhibitor of DPD. In this study, the relationship between immunoreactivity to TS and DPD in biopsy specimens and the effects of chemotherapy was investigated in 41 patients treated with S-1 therapy for advanced gastric cancer. Response rates were 54% (13/24) in TS(+) and 53% (9/17) in TS(-) patients (p=0.938), and those of DPD(+) and (-) patients were 61% (11/18) and 48% (11/23) (p=0.397), respectively. The median survival time of all the subjects was 253 days. There was no significant difference in median survival time between TS(+) patients (284 days) and (-) patients (189 days: p=0.670). The 18 DPD(+) patients had median survival times slightly longer (338 days) than the 23 patients with DPD(-) (207 days: p=0.206). This study indicates that S-1 may be effective in the treatment of gastric cancer patients, regardless of intratumoral TS and DPD immunoreactivity status. Further studies are needed to confirm these results with larger numbers of patients.

Adult↗
PubMed2000

[Expression of recombinant human dihydropyrimidine dehydrogenase and its application to the preparation of anti-DPD antibodies for immunochemical detection].

Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the catabolism of 5-fluorouracil (5-FU), and its expression in a tumor is thought to reduce the efficacy of 5-FU against the tumor. To detect a DPD molecule by immunoblotting and/or immunohistochemical methods, we attempted to prepare highly specific antibodies against recombinant human DPD (rhDPD) expressed in the baculovirus-expression system using hDPD cDNA. The expressed rhDPD protein was found to retain its entire molecular form and to show a high 5-FU-degrading activity equivalent to that of human liver DPD. Using this recombinant protein, both monoclonal and polyclonal antibodies to ehDPD were generated and their specificities, relationship to enzyme activity and the possibility of immunohistochemical measurement of tumoral DPD expression were investigated. The results revealed that anti-rhDPD monoclonal antibodies recognized only human DPD, while anti-rhDPD polyclonal antibodies reacted with both human and rodent DPD. The DPD content in 26 tumor cells, estimated by immunoblotting, was closely related to the 5-FU-degrading activities in those cells (r = 0.874). Moreover, immunohistochemical evaluation of tumor cellular DPD expression using our anti-rhDPD antibodies revealed that tumor cells expressing high levels of DPD showed strongly positive staining, but not those expressing low level or no DPD. These results suggest that immunochemical detection of tumoral DPD expression using our anti-rhDPD antibodies may be a means to predict the clinical response to 5-FU-based chemotherapy.

Animals↗