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Knowledge based approach is effective for renovating design and manufacturing processes. The objective of this paper is to investigate roles and usages of expert engineering knowledge in high-quality manufacturing, and to study a practical knowledge capturing method for realizing engineering support tools. An engineer oriented interface for a capturing method is proposed, and a flexible representation framework is studied for various types of expert knowledge. An integrated knowledge-based system has been developed for mold design support. The results have been evaluated by design and manufacturing of molds for cellular phones, and have shown substantial reduction of lead time for mold production.

(1999). Effects of welding parameters on laser weldability of Inconel 718. Study of laser weldability of Ni-base, heat-resistant superalloys (1st Report) Welding International: Vol. 13, No. 12, pp. 945-951.

(1999). Comparison of hot cracking susceptibilities of various Ni-base, heat-resistant superalloys by U-type hot cracking test. Study of laser weldability of Ni-base, heat-resistant superalloys (2nd Report) Welding International: Vol. 13, No. 12, pp. 952-959.

In human platelets, a rapid rise in cytoplasmic Ca2+ and slower rise in cytoplasmic pH follow stimulation by thrombin. With the Ca2+ probe Fura-2 and the pH probe SNARF-1 for digitized fluorescence microscopy, we studied simultaneously the distribution and changes with time of [pH]i and [Ca2+]i in individual human platelets. In platelets coloaded with both probes, the probes had no detectable fluorescence at each other's excitation wavelength. The monovalent cation ionophore, nigericin (2 μM), produced a homogeneous rise in pH but no change in [Ca2+]. Platelets, in contact with glass, spread and developed an irregular, apparently mutually independent rise in both [Ca2+]and pH. Stimulation of platelets by thrombin 1.0 U/ml elevated [Ca2+]i and produced slow alkalinization without initial acidification. Replacement of extracellular Na+ by choline abolished thrombin-induced alkalinization, but had no effect on thrombin-induced [Ca2+]; elevation. ADP 10 μM caused a rapid rise of [Ca2+]i and transient alkalinization. Most stimulated platelets developed a gradient in pH, that was highest in the center. ADP and thrombin caused oscillation of [Ca2+]; but not of [pH]i. We conclude that alkalinization in stimulated platelets, presumably involving Na+/H+ antiport, is not essential for the rise of [Ca2+]i that may accompany it.

The protooncogene c-myb is responsible for elevating intracellular calcium concentration ([Ca2+]i) at the G1/S interface in vascular smooth muscle cells (VSMC). However, the molecular components of this pathway are undefined, and the biological effects of increased levels of divalent cation are unknown. We have demonstrated that growth-arrested c-myb-transfected VSMC, compared with wild type VSMC, exhibit a fourfold increased number of insulin-like growth factor I (IGF-I) receptors, increased amount of secreted IGF-I activity, and a twofold increased level of [Ca2+]. The c-myb transfected cells, compared with wild type cells, also possess a twofold increased rate of calcium influx and a twofold decreased rate of calcium efflux. The elevated calcium influx rate of transfected cells is decreased to that of wild type cells with IGF-I neutralizing antibody, whereas the decreased calcium efflux rate of transfected cells is increased to that of wild type cells with antisense c-myb oligonucleotides. Proliferating wild type VSMC exhibit an increased calcium influx rate in late G1, which is dependent on production of augmented amounts of IGF-I activity but not increased levels of IGF-I receptors. The wild type VSMC also show a decreased calcium efflux rate at the same point in the cell cycle, which is dependent on expression of c-myb. The treatment of wild type cells with antisense c-myb or IGF-I receptor oligonucleotides induces a late G1 block in cell proliferation, which can be overcome by exposure to the calcium ionophore, 4-bromo-A-27318, in amounts sufficient to raise [Ca2+]i to levels observed at the G1/S interface. We conclude that IGF-I/IGF-I receptors and c-myb are involved in control of [Ca2+]i at the G1/S interface by separately regulating the rates of calcium influx and efflux and that elevated levels of divalent cation are necessary for progression of VSMC into the S phase of the cell cycle.

Renal pelvic cancer with a large vein tumor thrombus is very rare. We report a case of transitional cell carcinoma of the right renal pelvis with tumor thrombus in the inferior vena cava. Based on the radiological findings, the patient was diagnosed having renal cell carcinoma with tumor thrombus in the vena cava preoperatively. Radical nephrectomy with thrombectomy was performed. A literature review of 17 reported cases revealed that 13 cases (76.5%) were diagnosed as renal cancer preoperatively. Prognosis of transitional cell carcinoma with vena cava tumor thrombus is relatively poor compared to that of renal cell carcinoma with a large vein tumor thrombus.

The authors consider the problem of finding the most area-efficient floorplan for macro cell (or general cell) layout, which satisfies all the constraints imposed not only on the area and the aspect ratio of each block but also on the length of the abutment between blocks. The floorplanning is implemented on the assumption that the relative position of each block has been specified in terms of a rectangular dual. The main task is composed of two algorithms; one is to find an area-efficient drawing of a rectangular dual D under these constraints, and the other is to estimate a lower bound to the area required to draw D. Using these algorithms together with the one to enumerate all rectangular duals, a floorplanning scheme is described. >

An efficient heuristic approach to state encoding of sequential circuits is described. With the approach, the total area of silicon used by the PLA-based two-level implementation for combinational circuits can be minimized. Apart from the conventional methods, in which state encoding is determined one after another in a predetermined order of states, this approach is distinctive in that top priority is given to how to seek cubes which constitute a cover to be allocated to each group of states (where a group of states denotes a set of states which have the same next state and the same output for an input) on the basis of a magnitude estimation of cubes so that the total number of cubes to be used can be minimized. Implementation results are also shown to reveal how this approach is of practical use. >

Although adherence and aggregation of platelets on an active surface such as exposed subendothelial matrix or foreign surfaces is integral to the occlusion of blood vessels, its mode of action is not fully understood.The role of cytoplasmic ionized Ca(2+) concentration ([Ca(2+)](i)) in platelet activation induced by contact with a glass surface under shear-stress was studied by employing confocal laser scanning microscopy (CLSM) in conjunction with a parallel plate flow chamber. Changes in [Ca(2+)](i) and morphology of aggregating platelets on glass surface was simultaneously examined.Under static condition, contact with glass caused platelet adhesion to the surface, which was associated with [Ca(2+)](i) rise and morphological change; however, platelets did not develop a large aggregation on the surface. Under lower shear-stress, the number of the single platelets adsorbed on the surface was less than that under static condition. Although shear-stress increased the number of single platelets involved and enhanced morphological change in aggregating platelets in a shear-stress related manner, the peak [Ca(2+)](i) value in individual platelets were not increased.These observations may suggest the crucial roles of shear-stress in platelet aggregate formation at the site of arterial stenosis. Shear-stress might enhances platelet aggregate growth not through the enhancement of [Ca(2+)](i) rise.

An early Phase II study with TUT-7 (menogaril), a new anthracycline antitumor antibiotic, was conducted in patients with various malignant tumors at 81 departments of 65 institutions nationwide. One course of TUT-7 treatment consisted of seven (7) or fourteen (14) consecutive days of administration at 75 or 100 mg/body/day with two-week drug withdrawal; at least two courses of treatment were given in principle. Among the 165 patients registered, 145 patients were eligible and 128 patients were evaluable for antitumor efficacy. In 11 patients with malignant lymphoma, one (1) had CR and five (5) had PR (54.5%); in three (3) patients with prostate cancer, one (1) had PR (33.3%); and in 12 patients with uterine cervical cancer, two (2) had PR (16.7%). Adverse drug reactions frequently observed were digestive organ disorders (anorexia and nausea/vomiting) and malaise. The abnormality in laboratory tests observed frequently was myelosuppression (leukopenia and neutropenia).

Renal pelvic cancer with a large vein tumor thrombus is very rare. We report a case of transitional cell carcinoma of the right renal pelvis with tumor thrombus in the inferior vena cava. Based on the radiological findings, the patient was diagnosed having renal cell carcinoma with tumor thrombus in the vena cava preoperatively. Radical nephrectomy with thrombectomy was performed. A literature review of 17 reported cases revealed that 13 cases (76.5%) were diagnosed as renal cancer preoperatively. Prognosis of transitional cell carcinoma with vena cava tumor thrombus is relatively poor compared to that of renal cell carcinoma with a large vein tumor thrombus.

Calpain is distributed ubiquitously in virtually every tissue (Croall, D. E., and DeMartino, G. N. (1991) Physiol. Rev. 71, 813-846), but its physiological role remains to be determined. The identification of its natural endogenous substrates would be of great interest. Since pp60src, a major tyrosine kinase in platelets, is known to be easily cleaved during purification from cells (Feder, D., and Bishop, J. M. (1990) J. Biol. Chem. 265, 8205-8211), we examined the possibility that it is an endogenous substrate of calpain. In the whole cell lysate from resting platelets, which was analyzed by Western blotting with monoclonal antibody 327, we found pp60src almost exclusively in a 60-kDa form, with a trace of 52-kDa form. Addition of A23187 (a calcium ionophore) or dibucaine, which are known to be activators of platelet calpain (Croall and DeMartino, 1991; Fox, J. E., Reynolds, C., Morrow, J. S., and Phillips, D. R. (1987) Blood 76, 2510-2519; Fox, J. E., Austin, C. D., Boyles, J. K., and Steffen, P. K. (1990b) J. Cell Biol. 111, 483-493), caused dose- and time-dependent cleavage of actin-binding protein and p235 protein (talin). At the same time, loss of the 60-kDa species of pp60src and generation of the 52-kDa (occasionally seen as doublets) and 47-kDa species were detected by the Western blotting. In platelets aggregated by 1 unit/ml thrombin, apparently identical cleavage products were found. The cleavage of pp60src was inhibited by calpeptin (20 microM), an inhibitor of calpain (Tsujinaka, T., Kajiwara, Y., Kambayashi, J., Sakon, M., Higuchi, N., Tanaka, T., and Mori, T. (1988) Biochem. Biophys. Res. Commun. 153, 1201-1208; Tsujinaka, T., Ariyoshi, H., Uemura, Y., Sakon, M., Kambayashi, J., and Mori, T. (1990) Life Sci. 46, 1059-1066; Fox, J. E., Clifford, C. C., and Austin, C. D. (1990) Blood 76, 2510-2519; Fox, J. E., Austin, C. D., Boyles, J. K., and Steffen, P. K. (1990) J. Cell. Biol. 111, 483-493; Fox, J. E., Austin, C. D., Clifford, C. C., and Steffen, P. K. (1991) J. Biol. Chem. 266, 13289-13295). Addition of EGTA (3 mM) to the extracellular media completely inhibited the cleavage of actin-binding protein, talin, and pp60src in response to A23187 (1 microM). Intact pp60src was distributed in both cytosolic and particulate (membrane) fractions. Cleaved species were found exclusively in the cytosolic fraction. pp60src-associated enolase kinase activity was reduced. Thus, pp60src is an endogenous substrate for calpain, the cleavage of which may have regulatory effects on the kinase.

Intracellular localization of calpain (calcium dependent cysteine proteinase) was studied in resting or activated human platelets. When stimulated with 2 U/ml thrombin, approximately 40% of total cellular calpain activity and 25% of antigen translocated mainly to the intracellular membrane fractions with autolytic activation. Translocation of calpain was completely abolished by the addition of EDTA to the sonication medium. However an endogenous calpain inhibitor (calpastatin) activity was not detected in the membrane fractions both in resting and in thrombin stimulated platelets. Translocation of calpain was also observed in the platelets stimulated with ionomycin, collagen or phorbor myristate acetate (PMA). These data suggest that cytosolic calpain reversibly translocates to the intracellular membranes during platelet activation without an interference by calpastatin.

The binding of calpain-I (Ca2+ activated neutral protease with high Ca2+ sensitivity) to the membranes of human platelets and the subsequent autolytic activation of calpain-I were analyzed by an immunoblot technique. In A23187 stimulated platelets, cytosolic calpain-I translocated to the membranes with autolysis in a Ca2+ dependent manner and simultaneously underwent autolysis. Although calpeptin, a cell permeable calpain inhibitor, inhibited autolysis of calpain-I, it was unable to prevent the translocation of calpain-I. In a cell re-constituted system, the membrane binding of calpain-I was also Ca2+ dependent and was significantly inhibited by a substrate of calpain. It was suggested that the binding of calpain-I to the membranes required the substrate binding site of this enzyme.

Okadaic acid and calyculin A, specific and cell permeable inhibitors of protein phosphatase 1 and 2A, inhibited aggregation, secretion and delta [Ca++]i in thrombin stimulated platelets. The inhibitory effect of calyculin A (IC50: 3.6-4.8nM) was about two hundred times more potent than that of okadaic acid (IC50: 0.8-1.3 microM), which is consistent with the difference of the reported Ki values for protein phosphatase 1. These phosphatase inhibitors and PGI2 synergistically enhanced the phosphorylation of 50kDa protein (P50), which is solely related to the inhibition of platelet reaction. These results indicate that serine/threonine protein phosphatase 1 might play a role in platelet activation.

We conducted a phase I study of CI-898 (trimetrexate), a new diaminoquinazoline antifolate in 22 patients with solid cancer in a multicenter collaborative study. The dosage schedule was single-dose intravenous administration (single treatment), followed by one or two courses of 5-day intravenous administration (5-day treatment) at 3-week intervals. Starting at 2 mg/m2 (1 n), the dose was increased up to 15 mg/m2 (7.5 n) for single treatment and 12 mg/m2 (6 n) for 5-day treatment. Evaluable cases numbered 18 for single treatment and 17 for 5-day treatment. In single treatment, the highest dose of 15 mg/m2 caused no serious side effect and did not reach the maximum tolerated dose (MTD). In 5-day treatment, leukocytopenia and thrombocytopenia were found dose dependently, the dose-limiting factor was bone marrow depression, and MTD was 10 mg/m2/day. The leukocyte and platelet counts reached the nadir in 1-3 weeks after initiation of 5-day treatment. The recovery from the nadir required about one week. Subjective side effects included mucitis (mouth, anus), malaise and gastro-intestinal symptoms (nausea, anorexia, diarrhea). None of alopecia, cardiotoxicity and nephrotoxicity were found. In the present phase I study, a tendency of tumor reduction was found in one case each of breast cancer (adenoma) and lung cancer (squamous cell carcinoma). The plasma concentration of the unchanged compound after single treatment showed a biphasic elimination pattern (t1/2 alpha 0.8-1.4 hr, t1/2 beta 9.4-13.0hr). The urinary excretion of the unchanged compound was 14.7-23.5% of the administered dose. In 5-day treatment, no accumulation was found. From the results of the present study, the recommended dosage of CI-898 in the early phase II study was considered to be 8 mg/m2/day intravenously for 5 days (every 3-4 weeks).

Calpeptin (a cell permeable synthetic peptide calpain inhibitor) inhibited the generation of thromboxane B2 (TxB2) by the direct inhibition on Tx synthetase in platelets at the concentrations more than 30 microM. Calpeptin, its analogues and E-64d (EST) were further examined with regard to cell permiability and inhibitory spectra. Among all compounds, only calpeptin inhibited the degradation of substrate proteins of calpain with negligible effect on TxB2 generation in intact platelets at the concentrations less than 30 microM. These concentrations of calpeptin did not inhibit the platelet aggregation, the elevation of [Ca2+], nor the formation of inositol 1,4,5-trisphosphate (IP3) in thrombin or collagen activated platelets. These results indicate that calpain dose not participate in the process of platelet activation induced by thrombin or collagen.

An early phase II study of a new camptothecin analog and an inhibitor of topoisomerase I, CPT-11, was conducted in 62 patients with refractory leukemia and lymphoma by four different treatment schedules in a multiinstitutional cooperative study. CPT-11 therapy resulted in four complete remissions (CRs) and three partial remissions (PRs) in 29 assessable non-Hodgkin's lymphoma (NHL) patients, one PR in three Hodgkin's disease (HD), one CR and one PR in 11 acute lymphoblastic leukemia (ALL), and one PR in 15 acute myelogenous leukemia (AML) patients. Single infusion of 200 mg/m2 every 3 to 4 weeks produced no response in both leukemia and lymphoma patients. Sixty-minute infusions of 40 mg/m2/d for 5 days every 3 to 4 weeks or for 3 days weekly produced four CRs (17%) and four PRs (17%) in 24 patients with malignant lymphoma. Sixty-minute infusions of 20 mg/m2 twice a day for 7 days every 3 to 4 weeks resulted in one CR and two PRs in 12 patients with acute leukemia. No response was seen in an acute leukemia patient by another treatment schedule. CPT-11 was effective in two (15%) of 13 primarily refractory leukemia and lymphoma cases, in two of four relapsed cases, and in seven (17%) of 41 relapsed and refractory cases. Major side effects were leukopenia (91%) and gastrointestinal (GI) (76%). CPT-11 was shown to be effective against refractory leukemia and lymphoma, and thus deserves further clinical study; the novel antitumor activity mode of this drug predicts no cross-resistance to presently available antitumor drugs.

Reliability evaluation tests for multilayer ceramic chip capacitors mounted on a hybrid IC were implemented. Failure modes, failure mechanisms, and drift of characteristics were analyzed. Humidity acceleration as well as voltage and temperature accelerations were investigated to estimate the chip capacitor reliability. The chip capacitor reliability proved to be high and adequate for the service period of the communication system.

An accurate numerical analysis for predicting characteristics of MOSFET's Fabricated on an epitaxial Si layer on top of a buried SiO 2 layer formed by oxygen ion implantation is presented. Basic equations, that is, the current continuity equation for minority carriers, Poisson's equation, and the equation for the majority-carrier concentration including carrier multiplication due to impact ionization, are iteratively calculated for obtaining a self-consistent solution. Good agreement between theoretical and experimental results was obtained over a wide range of device parameters and terminal biases. Threshold dependence upon Si/buried SiO 2 interface charge as well as Si film thickness is shown. As the Si film and buried SiO 2 thicknesses are reduced, the threshold voltage shift with channel shortening becomes smaller. Finally, theoretical analysis shows that the short-channel effect in MOSFET fabricated on an epitaxial layer with an underlining buried SiO 2 layer is smaller than those in bulk Si MOSFET and MOSFET/SOS.

A study of hybrid IC's produced by solder refiow technology was carried out to achieve optimum miniaturization and substantial cost reduction. Thin-film resistor and capacitor network (R-C) chips and silicon integrated circuit (SIC) chips are mounted on a multilayered thick-film conductor substrate and connected to the substrate by solder joining. The chips are first supported by solder bumps, and then they are self-aligned by the surface tension of the solder through the reflow process. This process results in a joint that compensates for the deviation and undulation of the substrates. Mechanical supports and electrical contacts of hybrid IC's are accomplished through a single reflow process. These hybrid IC's have proven to be completely satisfactory and reliable.

In this paper an efficient method of generating separating sets of a given graph with the use of a newly defined concept-a cutset graph-is discussed. The cut-set graph of a given graph G is defined such that each edge of the graph corresponds to a pair of basic branch cut-sets of G having the relation that the ring sum of these cut-sets coincides with an incident cut-set with respect to a vertex in G . The present paper shows that the cut-set graph is a useful tool for solution of the problem of generating all of the basic vertex cut-sets and the basic mixed cut-sets of a given graph.

Zirconium nitridefilms were prepared by reactive RF sputtering in argon-nitrogen mixtures, and various electrical properties of these films were investigated. The resistivities of zirconium nitride films varied from 5 X 102to 2 X 104µohm-cm, depending on sputtering pressure. In the resistivity range from 5 X 102to 1.3 X 103µ;ohm-cm, the films , display a reasonably small temperature coefficient of resistance (zero to -200 ppm/°C). After thermal aging, the zirconium nitride film resistors exhibit high stability.

In 1943, a large dengue epidemic occurred in the Osaka district and several samples of dengue virus were isolated from patients with dengue fever by workers in this Institute. These were inoculated into human volunteers to confirm that they were dengue virus. In the present study, serum samples were collected from the volunteers who had been inoculated with dengue virus and were examined serologically. In the neutralization test, all the sera showed a higher titer against dengue type 1 virus (DEN-1) than against the other three types of dengue virus, indicating that the virus strain isolated in 1943 was DEN-1.

The clinical significance of serum sialyl Tn antigen as a tumor marker was evaluated using "STN Otsuka" kits. Results indicated that the antigen was frequently elevated in sera from patients with ovarian cancers (43.1%, 140/325), including serous cystadenocarcinoma (51.6%, 63/122), mucinous cystadenocarcinoma (55.6%, 30/54), endometrioid carcinoma (56.5%, 13/23), and mesonephroid carcinoma (40.0%, 6/15). The positive frequency of sialyl Tn antigen in patients with ovarian carcinoma was less than the frequency of CA 125 (75.5%, 194/257) or sialyl SSEA-1 (47.2% 83/176). However, the false positive rate of sialyl Tn antigen in patients with benign gynecological disorders (3.7%, 15/401) was much lower than the false positive rates of other antigens; such as CA 125 (48.4%, 155/320) and sialyl SSEA-1 (19.2%, 51/266). The serum level of sialyl Tn antigen reflected the clinical activity of the disease quite well in patients with ovarian cancers. The sialyl Tn antigen was concluded to be a useful serum tumor marker for ovarian cancers.

An immunoradiometric competitive inhibition assay of the serum levels of the sialyl Tn antigen using "STN Otsuka" kits is described. The assay required only duplicate 50-microliters samples, and the concentration of sialyl Tn antigen in serum was determined by reference to a standard curve ranging from 0 to 400 arbitrary units/ml. The intra-and inter-assay reproducibilities were largely satisfactory. The serum levels of the antigen in normal individuals were not affected by ABO and Lewis blood type status of the tested individuals. Normal values were 25.5 +/- 9.8 in male, and 21.3 +/- 8.0 in female, and the difference was statistically significant at p less than 0.001. The serum level of the antigen was not affected by menstrual cycle or pregnancy in female, whereas the level of other tumor markers such as CA 125 was highly variable depending upon these conditions.

Calpain is distributed ubiquitously in virtually every tissue (Croall, D. E., and DeMartino, G. N. (1991) Physiol. Rev. 71, 813-846), but its physiological role remains to be determined. The identification of its natural endogenous substrates would be of great interest. Since pp60src, a major tyrosine kinase in platelets, is known to be easily cleaved during purification from cells (Feder, D., and Bishop, J. M. (1990) J. Biol. Chem. 265, 8205-8211), we examined the possibility that it is an endogenous substrate of calpain. In the whole cell lysate from resting platelets, which was analyzed by Western blotting with monoclonal antibody 327, we found pp60src almost exclusively in a 60-kDa form, with a trace of 52-kDa form. Addition of A23187 (a calcium ionophore) or dibucaine, which are known to be activators of platelet calpain (Croall and DeMartino, 1991; Fox, J. E., Reynolds, C., Morrow, J. S., and Phillips, D. R. (1987) Blood 76, 2510-2519; Fox, J. E., Austin, C. D., Boyles, J. K., and Steffen, P. K. (1990b) J. Cell Biol. 111, 483-493), caused dose- and time-dependent cleavage of actin-binding protein and p235 protein (talin). At the same time, loss of the 60-kDa species of pp60src and generation of the 52-kDa (occasionally seen as doublets) and 47-kDa species were detected by the Western blotting. In platelets aggregated by 1 unit/ml thrombin, apparently identical cleavage products were found. The cleavage of pp60src was inhibited by calpeptin (20 microM), an inhibitor of calpain (Tsujinaka, T., Kajiwara, Y., Kambayashi, J., Sakon, M., Higuchi, N., Tanaka, T., and Mori, T. (1988) Biochem. Biophys. Res. Commun. 153, 1201-1208; Tsujinaka, T., Ariyoshi, H., Uemura, Y., Sakon, M., Kambayashi, J., and Mori, T. (1990) Life Sci. 46, 1059-1066; Fox, J. E., Clifford, C. C., and Austin, C. D. (1990) Blood 76, 2510-2519; Fox, J. E., Austin, C. D., Boyles, J. K., and Steffen, P. K. (1990) J. Cell. Biol. 111, 483-493; Fox, J. E., Austin, C. D., Clifford, C. C., and Steffen, P. K. (1991) J. Biol. Chem. 266, 13289-13295). Addition of EGTA (3 mM) to the extracellular media completely inhibited the cleavage of actin-binding protein, talin, and pp60src in response to A23187 (1 microM). Intact pp60src was distributed in both cytosolic and particulate (membrane) fractions. Cleaved species were found exclusively in the cytosolic fraction. pp60src-associated enolase kinase activity was reduced. Thus, pp60src is an endogenous substrate for calpain, the cleavage of which may have regulatory effects on the kinase.