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Biomedical subjects

H Shiku

Publications and source records attributed to H Shiku.

At least 127 records · Page 7Linked to original sources
PubMed1998

[Clinical study of itraconazole for systemic fungal infections complicated with hematological malignancies--multicenter cooperative study. West-Japan Systemic Fungal Infection Study Group].

Itraconazole, an oral antifungal agent, was evaluated for the clinical efficacy and safety in patients documented or suspected of systemic fungal infection (SFI) complicated with hematological malignancies. The data was also evaluated according to serological tests and fungal culture. Out of a total of 79 patients, the clinical efficacy of itraconazole was evaluated in 52 patients, comprising 4 patients with proven SFI, 33 with clinical SFI, and 15 with suspected SFI. The overall efficacy was 67.3% (35/52), in which 25.0% in the established SFI group (1/4), 78.8% in the clinical SFI group (26.33), and 53.3% in the suspected SFI (8/15). When assessed according to the severity of SFI, the effectiveness rates were 75.0% in the mild group (15/20), 76.2% in the moderate group (16/21), and 36.4% in the severe group (4/11), resulting in significantly higher rates in the mild and the moderate groups than in the severe group (p = 0.0479). Out of the 10 patients who were switched from the previous antifungals, 7 patients were judged as showing marked or good responses. All of these patients were switched from intravenous fluconazole therapy. With respect to the safety of itraconazole, among 79 patients eligible for safety evaluation, adverse events such as hepatic dysfunction, increase in GOT and/or GPT, nausea and vomiting, and chest pain were observed in 6 patients (7.6%), and itraconazole may have been associated with them. As a conclusion, itraconazole proved to be effective and safe on SFI developed in patients with various hematological malignancies.

Administration, Oral↗
PubMed1998

Successful treatment of aplastic anemia with G-CSF and high dose erythropoietin.

We report the successful treatment of pancytopenia with G-CSF and high dose erythropoietin (Epo) in an elderly patient diagnosed with aplastic anemia (AA). Furthermore this effect is dose dependent for Epo in vivo. Detection of apoptosis by gel electrophoresis shows that high dose Epo protects bone marrow mononuclear cells from spontaneous apoptosis in vitro. These findings may explain some of the mechanisms of aplastic anemia.

Aged↗
PubMed1998

Possible involvement of calcineurin in retinoic acid-induced inhibition of leukemic HL-60 cell proliferation.

Differentiation of leukemic HL-60 cells by all transretinoic acid (ATRA) resulted in a reduced rate of growth. Cyclosporin A and FK506, at concentrations that inhibited calcineurin activity, abrogated the ATRA-induced inhibition of HL-60 cell growth but these immunosuppressants had no effect on the ATRA-induced granulocytic differentiation. Treatment with 1 microM ATRA led to a progressive increase in calcineurin phosphatase activity of HL-60 cells; the increase in this activity appeared to parallel the functional change of HL-60 cells during granulocytic differentiation. Increase in calcineurin activity was concordant with the increased expressions of calcineurin A and calcineurin B subunit proteins. The FKBP12 expression increased during ATRA-induced differentiation and expression of cyclophilin A remained unchanged. We propose that the increased expression of calcineurin is involved in the ATRA-induced inhibition of HL-60 cell proliferation, as in the case with 1,25alpha-dihydroxy-vitamin D3.

Calcineurin↗
PubMed1998

A heparin-coated circuit maintains platelet aggregability in response to shear stress in an in vitro model of cardiopulmonary bypass.

Alterations in platelet aggregability may play a role in the pathogenesis of qualitative platelet defects associated with cardiopulmonary bypass (CPB). We circulated fresh heparinized whole blood through tubing sets coated with heparin (C group, n = 10) and through non-coated sets (N group, n = 10) as a simulated CPB circuit. Shear stress (108 dyne/cm2)-induced platelet aggregation (hSIPA), plasma von Willebrand factor (vWF) activity and platelet glycoprotein (GP) Ib expression were measured, before, during, and after this in vitro set up of circulation. In the two groups, the extent of hSIPA significantly decreased during circulation and was partially restored after circulation. Decreases in the extent of hSIPA were significantly less with use of heparin-coated circuits. There was an equivalent reduction in plasma vWF activity, in the two groups. Expression of platelet surface GP Ib decreased significantly during circulation and recovered after circulation. Reduction of surface GP Ib expression during circulation was significantly less in the C group than that in the N group. Decrease in surface GP Ib expression correlated (r = 0.88 in either group) with the magnitude of hSIPA, in the two groups. The progressive removal of surface GP Ib was mainly attributed to redistribution of GP Ib from the membrane skeleton into the cytoskeleton. Our observations suggest that use of heparin-coated circuits partly blocks the reduction of hSIPA, as a result of a lesser degree of redistribution of GP Ib.

Blood Platelets↗
PubMed1998

Tissue factor expression and metastatic potential of colorectal cancer.

Several studies have previously demonstrated tissue factor (TF) expression in solid tumors. In our study, we evaluated by immunohistochemical staining TF expression in 79 cases of colorectal cancer and 17 cases of metastatic cancer of the liver from colorectal cancer, and investigated the relationship between the clinicopathological features and TF expression. TF was detected in the tumor of 57% of colorectal cancer patients, and its expression was significantly increased (p=0.01) in metastatic tumors (88%). TF expression was more commonly observed in metastatic tumors than in any Dukes' stage of primary cancer. In primary cancer, the detection of TF was more frequent in cases with lymph node metastasis (Dukes' C, 63%) or with hematogenous metastasis (Dukes' D, 82%) than in tumors without lymph node or hematogenous metastasis (Dukes' A and B, 46%, p=0.03). These results suggest that the expression of TF is related with the metastatic potential of colorectal cancer.

Adenocarcinoma↗
PubMed1997

Regulation of myosin phosphatase through phosphorylation of the myosin-binding subunit in platelet activation.

Human platelets were found to contain myosin phosphatase consisting of a 38-kD catalytic subunit of protein phosphatase type 1delta, a 130-kD myosin-binding subunit (MBS) and a 20-kD subunit, all of which cross-reacted with antibodies against these subunits of smooth muscle myosin phosphatase. Anti-MBS antibody coimmunoprecipitated RhoA and Rho-kinase of human platelets. Platelets MBS is a substrate for Rho-kinase and phosphorylation of MBS decreases the activity of myosin phosphatase. Treatment of intact platelets with 9, 11-epithio-11,12-methano-thromboxane A2 led to a dramatic increase in phosphorylation of MBS and a significant decrease in the activity of myosin phosphatase. These findings suggest a putative mechanism for agonist-induced regulation of myosin phosphatase activity in platelets.

Binding Sites↗
PubMed1997

Transcription effect of nm23-M2/NDP kinase on c-myc oncogene.

Transactivating factor PuF which interacts with a nuclease hypersensitive element locates upstream from the c-myc gene. PuF was recently identified as being encoded by nm23-H2/ NDP kinase gene [Postel, E. H., Berberich, S. J., Flint, S. J., and Ferrone, C. A. (1993) Science 261, 428-429]. Here we have studied the correlation of expression between c-myc and nm23 genes in vitro. By a comparative study of the expression of 2 genes in cell lines, no direct correlation of kinetics was found. A plasmid containing the human c-myc fragment (c-myc CAT) was cloned upstream from the bacterial chloramphenicol acetyltransferase (CAT) gene. When the murine melanoma cell line was cotransfected with a nm23-M2/ NDP kinase expression vector and c-myc CAT, CAT activity was elevated. In addition, cell cycle phases in the murine cell lines transfected with nm23/NDP kinase were estimated; an alteration of the cell cycle, prolonged S-phase was found in the cell lines transfected with nm23-M2/NDP kinase, whereas human nm23-H2/NDP kinase did not play a role in transactivating the c-myc gene or in S-phase prolongation in murine cell lines. From these results we conclude that the murine nm23-M2 gene transactivates the c-myc gene and controls the cell cycle, S-phase, indirectly via a cellular cofactor in the murine cell line, which does not work with the human nm23-H2 gene.

Animals↗
PubMed1997

Peptides derived from a wild-type murine proto-oncogene c-erbB-2/HER2/neu can induce CTL and tumor suppression in syngeneic hosts.

In this analysis, we examined whether peptides derived from a wild-type murine proto-oncogene, c-erbB-2, function as tumor rejection Ags. Expression of murine c-erbB-2 examined by means of reverse transcription-PCR was observed in several normal adult tissues, such as intestine, kidney, and testis. We then transduced human and murine c-erbB-2 cDNA into two mutually noncross-reactive fibrosarcoma lines of BALB/c origin, CMS7 and CMS17. In BALB/c mice immunized with CMS17HE (CMS17 transduced with human c-erbB-2 cDNA), the growth of subsequently challenged CMS7HE (CMS7 transduced with human c-erbB-2 cDNA) was significantly suppressed. CTL against human c-erbB-2-expressing cells were generated from BALB/c spleen cells in vivo and in vitro sensitized by CMS17HE. The CTL activity was also directed against murine c-erbB-2-expressing cells, CMS7ME and CMS17ME, and was blocked by anti-CD8 or anti-Kd mAbs. A series of peptides of human or murine c-erbB-2 compatible with the Kd binding motif was synthesized. The CTL were reactive with P1.HTR (H-2d) pulsed with three of these peptides, p63-71 (human c-erbB-2 derived), p63-71(A) (murine c-erbB-2 derived), and p780-788 (common for human and murine c-erbB-2). Spleen cells immunized in vivo and in vitro with syngeneic spleen cells pulsed with these peptides became cytotoxic for CMS17HE and/or CMS17ME, but not CMS17neo (CMS17 transduced with control vector). The growth of CMS7ME was suppressed in mice immunized with the murine c-erbB-2-derived peptide, p63-71(A) or p780-788. There was no apparent pathologic change in mice that rejected CMS7ME after vaccination with these peptides.

3T3 Cells↗
PubMed1997

Involvement of T-cell subsets and natural killer (NK) cells in the growth suppression of murine fibrosarcoma cells transfected with interleukin-12 (IL-12) genes.

A 3-methylcholanthrene-induced fibrosarcoma cell line of BALB/c origin, CMS5j, was co-transfected with cDNA for the p40 and p35 subunits of interleukin-12 (IL-12). Injection of transfected cells producing 5 x 10(3) U IL-12/10(6) cells/ml/day in nude mice with an established fibrosarcoma at a contralateral site efficiently eliminated tumor growth in the early phase (injection on day 0 or 4) but not later (day 8). This effect could be abrogated by simultaneous i.v. injection of antibodies against NK1.1 or ASGM1 (asialoGM1 = ganglio-N-tetraosyl-ceramide), which indicates that natural killer (NK) cells play a major role in tumor eradication or suppression when stimulated by IL-12. In wild-type mice, application of IL-12-secreting CMS5j cells abrogated growth of tumors established 8 days before but not earlier. Based on our experiments with antibody blocking in vivo, all CD4+, CD8+ and ASGM1+ cells are involved in tumor rejection. However, in our system, CD4+ cells or CD8+ cells alone, but not ASGM1+ cells alone, also could lead to tumor rejection. IL-12-engineered fibrosarcoma cells may constitute an efficient and safe system for immunotherapy of cancer.

Animals↗
PubMed1997

Mutated mitogen-activated protein kinase: a tumor rejection antigen of mouse sarcoma.

The molecular basis of the polymorphic tumor rejection antigens of chemically induced sarcomas of inbred mice remains a mystery, despite the discovery of these antigens over 40 years ago and their critical importance to the foundation of tumor immunology. In an analysis of a panel of BALB/c 3-methylcholanthrene-induced tumors, we identified one tumor, CMS5, that elicited a strong cytotoxic T cell response with exquisite specificity for CMS5. A stable cloned line of T cells with this specificity (C18) was used to screen a CMS5 cDNA expression library. The gene encoding the C18-defined antigen was identified as a mutated form of a mouse mitogen-activated protein kinase, ERK2, and a peptide incorporating the resulting amino acid substitution (lysine to glutamine) was efficiently recognized by C18. Vaccination with this peptide elicited specific resistance to CMS5 challenge. Extensive efforts to isolate antigen-loss variants of CMS5 were unsuccessful, suggesting that the mutated mitogen-activated protein kinase is essential for maintenance of the malignant phenotype.

Amino Acid Sequence↗
PubMed1997

Plasma-activated factor VII level in patients positive for lupus anticoagulant.

We examined plasma levels of activated factor VII (F VIla) in 50 patients positive for lupus anticoagulant (LA), in 83 patients negative for LA, and in 10 healthy volunteers as controls. Plasma F VIIa was present in healthy volunteers; its level was significantly increased, compared to the level in the controls, in patients with thrombosis, collagen diseases, and disseminated intravascular coagulation (DIC), suggesting that it reflected a thrombotic state. Plasma F VIIa was correlated with thrombin-antithrombin complex (TAT) in patients negative for LA but showed no such correlation in those positive for LA. Plasma F VIIa was negatively correlated with activated partial thromboplastin time (APTT) in patients positive for LA, but not in those negative for LA, suggesting that LA could inhibit the F VIIa assay system. Plasma F VIIa level was significantly increased in patients with thrombotic diseases; however, in patients positive for LA, it is possible that increased plasma F VIIa level may not be correlated with thrombogenicity.

Collagen Diseases↗
PubMed1997

Plasma tissue factor and tissue factor pathway inhibitor levels in patients with disseminated intravascular coagulation.

We measured the plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with disseminated intravascular coagulation (DIC) to examine the relationship between TFPI and vascular endothelial cell injury. Plasma TF (273 +/- 90 pg/ml) and TFPI (252 +/- 125 ng/ml) levels were significantly increased in patients with DIC compared with non-DIC patients. Plasma TF antigen level was significantly increased in pre-DIC patients (285 +/- 85 pg/ml), while the plasma TFPI level (152 +/- 54 ng/ml) was not markedly increased in such a state. The plasma TF/TFPI ratio was high in the pre-DIC patients (2.10 +/- 0.90), and low in the DIC patients (1.40 +/- 0.87) and healthy volunteers (0.84 +/- 0.26). There was no significant difference between the DIC patients with a good outcome and those with a poor outcome in terms of plasma TF levels, although the plasma TFPI level in the DIC patients with a good outcome (289 +/- 133 ng/ml) was significantly higher than those with a poor outcome (187 +/- 75 ng/ml). During the clinical course of DIC, plasma TF antigen was increased first, and an increase of the plasma TFPI level followed the increase in plasma TF level. These findings suggest that plasma TFPI is released from vascular endothelial cells and it may reflect vascular endothelial cell injury. It is conceivable that TF and TFPI may play an important role in the onset of DIC.

Anticoagulants↗
PubMed1997

Increased tissue factor pathway inhibitor in patients with acute myocardial infarction.

We examined hemostatic abnormalities in 23 patients with acute myocardial infarction (AMI), 10 with pulmonary embolism (PE), and 10 with deep vein thrombosis (DVT). At the onset of AMI, plasma levels of tissue-type plasminogen activator (t-PA), PA inhibitor-I (PAI-I), fibrin-D-dimer, thrombin-antithrombin complex (TAT), and plasmin-plasmin inhibitor complex (PPIC) were significantly increased. Both the plasma total TFPI and free-TFPI levels in the AMI patients were significantly higher than those in the healthy volunteers, PE patients, and DVT patients. There was no significant difference in total TFPI or free-TFPI among patients with PE, those with DVT, and healthy volunteers. One hour after percutaneous transluminal coronary angioplasty (PTCA) in the AMI group, the total TFPI level was further increased, and it was significantly reduced 24 hr after PTCA, to a level similar to that in healthy volunteers. Free-TFPI showed a pattern similar to that of total TFPI. The ratio of free-TFPI/total TFPI was highest 1 hr after PTCA. Increased TFPI in AMI patients might be released from ischemic tissues.

Adult↗
PubMed1997

K-ras gene mutations in intrahepatic bile duct tumors of Syrian golden hamsters.

BACKGROUND AND OBJECTIVES: In our laboratory, we have developed a new model of carcinoma of the bile duct in Syrian golden hamsters, using N-nitrosobis(2-oxopropyl)amine (BOP). Morphologic and biologic characteristics of the carcinoma induced in this model are similar to those seen in humans. In order to examine the gene-related carcinogenesis of intrahepatic bile duct carcinoma, we investigated mutations in the K-ras gene in various early hyperplastic and neoplastic lesions of these hamsters, according to the original sites of the lesions. METHODS: Inbred female hamsters were given a subcutaneous injection of N-nitrosobis(2-oxopropyl)amine (BOP) following dissection of the extrahepatic bile duct on the distal end of the common duct and preparation of a cholecystoduodenostomy (CDDB) or simple laparotomy (SL). Neoplastic lesions arising from the intrahepatic bile duct were histologically examined, and K-ras mutations were investigated. RESULTS: Mutations of K-ras codon 12 were evident in 12% of tubular hyperplasias, 19% of tubular adenocarcinomas, 15% of papillary hyperplasias and 36% of papillary adenocarcinomas. In papillary adenocarcinoma arising from a large bile duct, K-ras mutations occurred more frequently than in tubular adenocarcinoma arising from ductule or ductular proliferation. K-ras mutations were present even in a hyperplasia; the positive rates of the mutations increased in the presence of a carcinoma. Genetic changes in carcinoma of the intrahepatic bile duct varied based on sites of the duct and the histological type. CONCLUSIONS: A part of the hyperplastic lesions of the intrahepatic bile duct presented K-ras gene mutation. This suggests that K-ras gene mutation is an early event in the carcinogenic process. In carcinoma of the intrahepatic bile duct, the lesion arising from a large bile duct of the hepatic hilum tended to exhibit a higher frequency of K-ras gene mutation than did a tubular lesion arising from ductule or ductal proliferation. This hamster model is useful to examine the carcinogenesis of human intrahepatic bile duct carcinoma.

Adenocarcinoma↗