Biomedical subjects

K Takagi

Publications and source records attributed to K Takagi.

1,149 records · Page 64Linked to original sources

PubMedDate not supplied

A bovine low molecular weight bone morphogenetic protein (BMP) fraction.

A low MW bone morphogenetic protein fraction (BMP) is quantitatively extracted from bovine bone matrix by an inorganic-organic CaCl2-urea solvent mixture and fractionated by ion exchange and gel chromatography. The BMP fraction induces differentiation of perivascular mesenchymal type cells into cartilage and bone inside the mouse's thigh, outside of double walled diffusion chamber, in muscle pouches in the rabbit anterior abdominal wall, and in 0.8 cm trephine defects in the rat's skull. Bovine BMP may consist of electrophoretic components ranging from 12 K to 30 K in MW. The main components correspond to a MW of 23 K, 18 K and 12 K when they are compared with the mobilities of standard proteins. Because it was invariably present in all of the fractions with osteoinductive activity, circumstantial evidence leads to a 17 to 18 K component for a BMP. The possibility of a diameter monomer system for BMP activity also warrants consideration. The polypeptide portion constitutes only about 80% to 85% of the dry weight of the mixture of the three electrophoretic components, and suggests that the BMP fraction contains glycoproteins. Characteristically, glycoproteins migrate anomalously on SDS gels and create doubt about whether the major bands represent true MW. Nevertheless, the data clearly point to the low MW protein fractions for the direction of future work on BMP.

Animals↗

PubMedDate not supplied

Recombinant human growth hormone and protein metabolism of burned rats and esophagectomized patients.

The effects of recombinant human growth hormone (rhGH) on protein metabolism were investigated. In the experimental study, 31 male Sprague-Dawley rats were divided into two groups. One group received 200 mU/day of rhGH for 3 consecutive days, before and after being burned (GH group). The other group received no rhGH as a control. Cumulative nitrogen balance after being burned was significantly higher in the GH group, and the rates of whole-body protein turnover, synthesis, and breakdown were significantly higher in the GH group. An increase of synthesis greater than that of breakdown resulted in an improved nitrogen balance in the GH group. Protein content of the liver and the gastrocnemius muscle were also significantly greater in the GH group. In the clinical study, 13 patients receiving esophagectomy for esophageal cancer were studied. Six of them received 24 U/day of rhGH for 5 consecutive postoperative days (GH group). Cumulative nitrogen balance on postoperative days was significantly higher in the GH group than in the control group. On the 3rd postoperative day, the rate of whole-body protein synthesis was significantly greater in the GH group; those of turnover and breakdown also increased in the GH group. The arteriovenous difference of amino acid composition revealed that uptake of branched-chain amino acids into the leg muscles was significantly elevated and that release of phenylalanine and tyrosine from the muscles was significantly reduced in the GH group. Hepatic function was not affected by the administration of rhGH, and rhGH inhibited the rise of blood urea nitrogen and total bilirubin after esophagectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗

PubMedDate not supplied

Effects of nafamostat mesilate on platelets and coagulofibrinolysis during cardiopulmonary bypass surgery.

The effect of nafamostat mesilate (FUT-175) on platelet membrane glycoproteins and the coagulofibrinolytic system were analyzed. Twenty-five patients undergoing aorto-coronary bypass surgery were randomly distributed into an FUT treated group and a control group. In the control group, anticoagulation was achieved with sodium heparin (3 mg/kg) immediately before cardiopulmonary bypass (CPB). In the FUT treated group, in addition to the usual treatment with heparin, FUT-175 was infused continuously at a rate of 2 mg/kg/hr. In the control group, alpha 2 plasmin inhibitor/plasmin complex (PIC) and fibrinogen/fibrin degradation products (FDP) D-dimer increased significantly during CPB, reaching 6.1 +/- 5.1 micrograms/ml and 576 +/- 200 ng/ml, respectively, at 60 min of CPB. PIC and FDP D-dimer remained significantly lower in the FUT treated group than in the control group. GPIb on platelets decreased significantly in both groups, but remained higher in the FUT treated group (81 +/- 5% vs. 56 +/- 21% at 60 min of CPB, P < 0.01). There were no significant changes in GPIIb/IIIa on platelets throughout the procedure in either group. Blood loss after CPB was significantly lower in the FUT treated group than in the control group (778 +/- 277 ml vs. 1,342 +/- 426 ml, P < 0.01). The authors conclude that FUT-175 improves hemostasis after CPB, not only by inhibiting fibrinolysis, but also by preserving platelet GPIb during CPB.

Adult↗

PubMedDate not supplied

Platelet dysfunction during cardiopulmonary bypass surgery. With special reference to platelet membrane glycoproteins.

Changes in platelet membrane glycoproteins (GPIb, GPIIb/IIIa, and GMP-140) were evaluated using flow cytometry after binding with monoclonal antibodies in 22 adult patients undergoing cardiopulmonary bypass (CPB) surgery. The amount of GPIb on platelets decreased significantly during CPB, reaching a minimum level of 64 +/- 26% of the pre CPB value at 120 min of CPB. There was no significant change in the amount of GPIIb/IIIa on platelets. In accordance with these changes, ristocetin induced agglutination decreased to 56.7 +/- 16.2% of the pre CPB value during CPB. However, there were no significant changes in ADP and collagen induced aggregation throughout the procedure. The number of the activated platelets expressing GMP-140 on their surfaces increased significantly during CPB. There was an upper limit to the amount of GMP-140 expression on each platelet in the circulating blood, suggesting that excessively activated platelets are removed from the circulation. The authors conclude that CPB reduces the amount of GPIb on platelets, which results in platelet dysfunction. In addition, removal of excessively activated platelets from the circulation may lead to thrombocytopenia after CPB.

Adult↗

PubMedDate not supplied

Instrumentation surgery for funnel chest.

Thirty four patients with funnel chest were operated on using the Zimmer plate and/or U shaped rod. There were no recurrences of the chest deformity and 78.6% were satisfied with the result. The low % VC significantly improved after the operation. Five cases had one of the following complications, massive bleeding from the internal thoracic artery, partial skin necrosis, rotational dislodgement of the rod, temporal subcutaneous infection or partial rupture of the pectoral muscle incision. The blood loss ensuing in one operation during the last 8 years has been less than 300 ml and the postoperative bed rest was less than 7 days. All the patients could get back to the preoperative daily activities within three weeks without wearing brace or chest protector. Therefore, our method is considered to be less invasive and very useful for correction of the funnel chest deformity.

Adolescent↗

PubMedDate not supplied

Bidirectional feedback regulation on 17 kD tumor necrosis factor (TNF) production by 26 kD membrane-bound TNF precursor.

Based on the hypothesis that 26 kD membrane-bound rumor necrosis factor precursor (proTNF) may act as a principle regulator to maintain homeostasis in an adult, we tried to examine whether proTNF shows bidirectional regulation in specific cellular response. We focused on production of 17 kD mature TNF by acute monocytic leukemia cells THP-1 after stimulation by lipopolysaccharide. ProTNF of primed THP-1 cells had been shown to act as a positive regulator for production of mature TNF by homologous cells (primed THP-1) after LPS stimulation, whereas when THP-1 cells were co-cultivated with NIH3T3 which expressed pro-TNF, production of mature TNF by THP-1 by LPS was significantly suppressed. These results suggested that pro-TNF was really involved in bidirectional feedback regulation for TNF production by THP-1 cells themselves through cell to cell contact.

3T3 Cells↗

PubMedDate not supplied

Beneficial effect on nebracetam on energy metabolism after microsphere-induced embolism in rat brain.

The present study was undertaken to examine the possible therapeutic effects on nebracetam on the energy metabolism of rat brain regions in microsphere-induced, sustained ischemia. Microsphere embolism was induced by injection of 900 microspheres (48 microns in diameter) into the right internal carotid artery of rats, and changes in the energy metabolism of the cerebral cortex, striatum and hippocampus of the right hemisphere were determined without and with nebracetam treatment. Microsphere embolism induced increases in lactate and glucose contents and decreases of ATP and creatine phosphate contents in these regions, suggesting that sustained impairment of cerebral energy metabolism occurred. These changes were gradually reversed with time after the operation. Treatment of microsphere-injected rats with 30 mg/kg of nebracetam, p.o., twice a day, was started one day after the onset of cerebral ischemia. The effects of treatment with nebracetam on cerebral energy metabolites were determined on the 3rd and 7th day after operation. Treatment of microsphere-injected rats with nebracetam significantly improved these variables on the 3rd day after the onset of ischemia, but the improvement was small on the 7th day, except for reversal of the hippocampal ATP content. These results suggest that nebracetam is a possible therapeutic agent for the restoration of cerebral energy metabolism against microsphere-induced, sustained cerebral ischemia.

Adenosine Triphosphate↗

PubMedDate not supplied

Antitumor mechanism of intradermal administration of lipopolysaccharide.

We earlier demonstrated that 50% of the lethal dose of lipopolysaccharide (LPS) from Pantoea agglomerans given by the intradermal (i.d.) route is about 300 times greater than that given by the intravenous (i.v.) route, and that 400 micrograms/kg of LPS administered i.d. significantly suppressed metastasis whereas administered i.v., it did not. To learn the specific mechanism involved in this i.d. administration, the fate of LPS at the skin following administration and the concurrent production of endogenous tumor necrosis factor (TNF) in serum was examined. Histological observation following the i.d. administration of LPS (40 micrograms/kg) revealed neutrophiles in the skin 6 hours later. After 24 or 48 hours inflammatory cells were assembled at the site of injection. Endogenous TNF activity was found in the skin 24 hours after the injection and was significantly detectable even after 48 hours. Endogenous TNF was induced around tumor lesions of Meth A fibrosarcoma, MH134 hepatoma and Lewis lung carcinoma by treatment of LPS administered i.d. Taken together, these findings suggest that the antitumor activity of i.d. administered LPS results from the continuous supply of a small amount of this substance producing free TNF and activating inflammatory cells such as macrophages having membrane bound proTNF on their surface from the injected site to the tumor lesion for more than 48 hours.

Animals↗

PubMedDate not supplied

Anti-tumor effect of lipopolysaccharide by intradermal administration as a novel drug delivery system.

We examined the antitumor effect of lipopolysaccharide extracted from Pantoea agglomerans, a Gram-negative bacterium, using intradermal administration on murine syngeneic tumors, Meth A fibrosarcoma, MH134 hepatoma and Lewis lung (LL) carcinoma. The latter two tumors are known to be relatively low in immunogenicity, highly metastatic and to have low sensitivity to biological response modifiers. Although the intradermal administration of LPSp had a significantly suppressive effect on the growth of all tumors, including seventy-five percent of complete regression of mice bearing Meth A tumor, no complete regression was observed in MH134 or LL tumors. In combination with cyclophosphamide given once prior to the administration of LPS, however, the antitumor effects by intradermal administration of LPS were significantly augmented and there was complete regression in all types of tumors. Pretreatment by anti-tumor necrosis factor antibody reduced the effect exerted by LPS, suggesting that induced tumor necrosis factor might have a crucial role. Toxicity of intradermal administration of LPS was 230-380 times less than that by the intravenous route. Thus clinical application of LPS administered intradermally in combination with chemotherapeutics such as cyclophosphamide appears promising in terms of its antitumor effect as well as toxicity.

Animals↗

PubMedDate not supplied

In vivo tumouricidal effect of T lymphocytes activated by liposomes containing adriamycin on chemically-induced rat malignant fibrous histiocytoma.

The augmentative effect of liposomes containing adriamycin (LADM) in the host-tumour immune mechanism was assessed using 9,10-dimethyl-1,2-benzanthracene induced rat malignant fibrous histiocytoma (MFH). The antitumour effect of LADM was analyzed using a double grafted tumour system in which F344 rats first received simultaneous s.c. inoculations of MFH cells in both right and left flanks and were then injected with 0.2 mg of LADM into the right tumour on Day 10, 12, and 14. The growth of a remote, non-treated tumour was strongly inhibited, and the infiltration of CD8+ or CD4+ cells at the tumour periphery was histologically revealed. This inhibition was not observed in F344 nu/nu athymic rats. Winn neutralizing assay with T cell-rich splenic lymphocytes from each drug-treated MFH-bearing rat showed that complete regression of the tumour at a low effector/target ratio occurred only in the LADM-treated group. Furthermore, the tumouricidal effects were demonstrated in coexistence with CD8+ cells and CD4+ cells by assay with FACS sorting splenic lymphocytes. These results strongly suggest that intratumoural administration of LADM caused the systemic augmentation of the MFH-bearing host immune mechanism, and that the augmented response after LADM treatment was induced by the cytotoxic CD8+ lymphocytes dependent on the CD4+ lymphocytes.

9,10-Dimethyl-1,2-benzanthracene↗

PubMedDate not supplied

Clinical experience of EET therapy for 75 advanced cancer patients.

BACKGROUND: Exogenous/endogenous TNF (EET) therapy has a strong effect which causes inflammation in the body. Together with the antitumor effect of a single administration, the complementary effect of immunotherapy based on specific immunostimulation of tumor cells is also expected. We studied the characteristics of EET therapy in cases of advanced cancer. PATIENTS AND METHODS: The patients were 75 cases with advanced cancer including 48 cases of colon cancer, 10 cases of urological cancer, and 9 cases of gynecological cancer. One course of therapy was composed of the intravenous administration of either IFN-gamma or TNF-SAM2 followed 3 hours later by OK-432. At least 2 courses were repeated during a 2 weeks period. RESULTS: As response cases, partial response (PR) was observed in 7 of the 42 cases of colon cancer (17%) which had an evaluable lesion. Objective responses of lung metastases were found in the patients with multiple organ metastases of cervical cancer, ovarian cancer and uterine rhabdomyosarcoma. The group of colorectal cancer patients with liver metastases which underwent more than 5 courses of the therapy showed a longer survival period compared to the control group. One of the side effects, transitory hypotension, was observed in 46% of the cases. CONCLUSION: In spite of restricted objective responses to date with EET therapy alone, anticancer effects observed in various kinds of tumors and activation of a cytokine network by which Th1 cells might be specifically activated suggest that a new biotherapy based on EET therapy may have potential.

Antineoplastic Agents↗

PubMedDate not supplied

Mechanisms by which chemotherapeutic agents augment the antitumor effects of tumor necrosis factor: involvement of the pattern shift of cytokines from Th2 to Th1 in tumor lesions.

BACKGROUND: The antitumor effect exerted by tumor necrosis factor (TNF) is characteristic in that it causes central necrosis of the tumor mass. Viable tumor cells surrounding the tumor mass remain, however, even after most of the mass is necrotized, and these cells gradually regrow and form tumors. To overcome this, we analyzed the combined effects of chemotherapeutic agents used with TNF. Alkylating agents such as cyclophosphamide altered the antitumor effect qualitatively, leading to complete regression which TNF alone could not achieve. The mechanism, behind the enhancement of endogenous TNF production and expression of mRNA of various cytokines by the combination of chemotherapeutic agents with TNF inducer was investigated in Meth A fibrosarcoma. METHODS: Seven days after the inoculation of Meth A fibrosarcoma into BALB/c mice, cyclophosphamide (CY, 100-150 mg/kg) was injected intraperitoneally, and 7 days later endogenous TNF was induced by the intradermal administration of lipopolysaccharide (LPS, 400 micrograms/kg) or intravenous injection of ONO-4007, a synthetic lipid A derivative (30 mg/kg). RESULTS: A combination therapy of LPS or ONO-4007 with CY showed the effect of complete regression in 50-100% of tested mice, while CY, LPSp or ONO-4007 alone did not cause complete regression. The amount of endogenous TNF induced by LPSp or ONO-4007 around a tumor lesion with CY was 4-5 fold higher than that without CY. The expression of mRNA of transforming growth factor-beta was suppressed by CY seven days after the injection, and expressions of mRNA of IL-1 beta and TNF-alpha were augmented by the administration of CY 1 to 3 hours after the administration of ONO-4007. CONCLUSION: Some chemotherapeutic agents thus appear to augment the antitumor effect of TNF around tumor lesions, leading to tumor regression through a mechanism in which the agent changes the host's immune status, especially around a tumor lesion and pattern shift of cytokines from Th2 to Th1.

Animals↗

PubMedDate not supplied

Preservation of metastatic ability of colorectal tumor cells stratified by inducibility of endogenous tumor necrosis factor after orthotopic transplantation in nude mice.

BACKGROUND: Inducibility of endogenous tumor necrosis factor (TNF) by colorectal tumor cells can be regarded as a novel prognostic factor in terms of distant metastasis or local recurrence following curative operation, especially at Duke's stage C. In this study, the metastatic ability of human colorectal tumor cells stratified by inducibility of endogenous TNF was analyzed by orthotopic transplantation in nude mouse. METHODS: Fifty three cases of freshly resected colorectal tumor specimens cut into about 50mg pieces were inoculated into the cecum wall of nude mice. Two to nine months after transplantation, tumor growth on this wall and metastases to the peritoneal wall as well as to the liver were assessed. RESULTS: Of forty one evaluable cases, successful transplantation was observed in twenty nine (70%), and metastases to the peritoneal wall or to the liver was found in thirteen (32%), or eight cases (20%), respectively. In the twenty nine cases with local tumor growth, incidence of the liver metastases in nude mice when tumor specimens from patients with liver metastases (4/8) were used was significantly higher than that from patients without liver metastases (4/21) (P = 0.096). Inducibility of endogenous TNF was separately analyzed in fourteen of the evaluable twenty nine cases. Seven cases belonged to the high group and seven to the low group in terms of the amount of endogenous TNF secreted by tumor cells. Incidence of metastases in mice was 1/7 in the high group and 6/7 in the low group, and there was a statistically significant difference between liver metastases in mice and inducibility of endogenous TNF by colorectal tumor cells (p = 0.0057). CONCLUSION: From these results, it is strongly suggested that inducibility of endogenous TNF by colorectal tumor cells can affect a patient's prognosis since it regulates metastatic ability to the liver.

Animals↗

PubMedDate not supplied

Endogenous TNF inducibility and prognosis of colorectal cancer.

BACKGROUND: We have demonstrated that the inducibility of endogenous TNF (en-TNF) by colorectal tumor cells is a factor in predicting a patient prognosis. The prognoses of colorectal tumor patients with the K-ras gene mutations in their tumors were poorer to those of patients with the wild type gene. Therefore, we analyzed the possible relationship between the inducibility of en-TNF by colorectal tumor cells during the follow-up of patients with K-ras mutations. MATERIALS AND PATIENTS: In 62 of 154 Dukes Stage C patients who received curative operation from June 1988 to June 1997, the prognoses in terms of the tumor-free rate and survival rate were compared with the inducibility of en-TNF by colorectal tumor cells, which were classified into three groups: grade 1: > or = 500 pg/ml, grade 2: 100-500 pg/ml, and grade 3: < 100 pg/ml. Regardless of the Dukes Stage of the patients, the K-ras gene was analyzed in 21 whose colorectal tumor cells were classified as grade 1: 8, grade 2: 4, and grade 3: 9. RESULTS: The tumor-free rate of the patients with grade 1 was significantly higher than that of the patients with grade 3, and the survival period of the patients with grades 1 and 2 was significantly longer than that of the patients with grade 3. Possible mutations disorder of K-ras were observed in 37.5% (grade 1), 50.0% (grade 2), and 88.9% (grade 3) of cases, respectively. CONCLUSION: The prognostic value of the inducibility of en-TNF by colorectal tumor cells from colorectal cancer patients who received curative operation at Dukes Stage C was confirmed. It is suggested that K-ras mutation may affect patient prognosis through modulation of the quality and/or quantity of cytokines such as TNF produced by tumor cells.

Colorectal Neoplasms↗

PubMedDate not supplied

A long-term survivor case of malignant mesothelioma treated by recombinant tumor necrosis factor-SAM2 (TNF-alpha mutein) and 5-fluorouracil (5-FU): a new therapeutic approach based on host-tumor relationship.

BACKGROUND: The prognosis of mesothelioma is very poor, and there is no established method to suppress tumor growth. Immunological approaches have recently been thought to be effective for mesothelioma and several studies using cytokines have been performed. We used a novel recombinant tumor necrosis factor-alpha (rTNF-alpha) we called rTNF-SAM2, in the treatment of a patient with this disease. PATIENT AND METHOD: A 48-year old male patient with ascites was diagnosed with malignant mesothelioma by cytological examination. TNF-SAM2 in an amount of 264 to 576 micrograms (1 to 2.2 x 10(6) U) was injected via a catheter several times. Five hundred mg of 5 fluorouracil (5-FU) was also given via catheter once a week and 5-FU derivative was given orally every day. RESULTS: No apparent tumor progression was observed for 6 years and 6 months and the patient led a normal life. During the therapy, the malignancy of tumor cells from the ascites changed from class V to class VI. CONCLUSION: TNF based therapy may be promising treatment for the suppression of malignant mesothelioma.

Antimetabolites, Antineoplastic↗