Augmented antitumor efficacy of combination chemotherapy of nedaplatin with 5-fluorouracil in in vivo murine and human tumor model

Augmented antitumor activity was demonstrated in combination chemotherapy of Nedaplatin (NDP) or Cisplatin (CDDP) with 5-fluorouracil (5-FU) against murine lung carcinoma and human squamous carcinoma from head and neck. Either NDP or CDDP (1/4 to 1 maximum tolerated dose; MTD) was injected once and 5-FU (1/16 MTD) was injected daily for five days via tail vein to tumor-implanted mice. The sequential administration of either NDP or CDDP prior to 5-FU (NF or CF therapy) showed severe body weight loss followed by the toxic death of tumor-bearing mice at the MTD of NDP or CDDP. In contrast, the reverse sequence of the treatment, that is, 5-FU prior to NDP or CDDP (FN or FC therapy), resulted in the synergistically enhanced inhibition of tumor growth and the prolonged survival in comparison with NDP, CDDP or 5-FU monotherapy. The antitumor activities of the combinations of CDDP with 5-FU was less than those of the combination of NDP with 5-FU. Especially, at the MTD of NDP in FN therapy, long-term tumor-free survival was frequently observed. Thus, FN therapy was thought to be the most efficient regimen in combination of NDP with 5-FU as a clinical therapy.     

Activation of the protein kinase p38 in the spindle assembly checkpoint and mitotic arrest

The mitogen-activated protein kinase (MAPK) superfamily comprises classical MAPK (also called ERK), c-Jun amino-terminal or stress-activated protein kinase (JNK or SAPK), and p38. Although MAPK is essential for meiotic processes in Xenopus oocytes and the spindle assembly checkpoint in Xenopus egg extracts, the role of members of the MAPK superfamily in M phase or the spindle assembly checkpoint during somatic cell cycles has not been elucidated. The kinase p38, but not MAPK or JNK, was activated in mammalian cultured cells when the cells were arrested in M phase by disruption of the spindle with nocodazole. Addition of activated recombinant p38 to Xenopus cell-free extracts caused arrest of the extracts in M phase, and injection of activated p38 into cleaving embryos induced mitotic arrest. Treatment of NIH 3T3 cells with a specific inhibitor of p38 suppressed activation of the checkpoint by nocodazole. Thus, p38 functions as a component of the spindle assembly checkpoint in somatic cell cycles.     

A decentralized control system for stabilizing multimachine power systems

A decentralized control system is studied for stabilizing multimachine power systems. A longitudinal power system with three areas, each having one machine, is considered in this study. A decentralized control design method is proposed, which is based on the optimal regulator theory. First a centralized control system is designed without any consideration on whether state variables are all available or not. Second a pseudo-decentralized control system is designed by omitting control gains corresponding to state variables which give hardly any effects on the power system stability. It is found that only one variable of phase angle of each machine is absolutely necessary for the pseudo-decentralized control system. This leads to an idea based on power system engineering, that is to say, new variables of tieline power flow are introduced in the decentralized control system design to substitute for the phase angle of each machine. Thus a decentralized control system for power system stability can be designed using the new variables of tieline power flow. It is demonstrated from simulation studies that the decentralized control system improves even longitudinal power system stability as well as the centralized control system.     

The branching nonhomogeneous Poisson process and its application to a replacement model

In studying and analysing the failure patterns of complex system, plausible stochastic models are needed to represent the sequence of events. A simple and frequently used model is derived by the assumption that the times-between-failures of a system are exponentially distributed and independent. Experience has shown, however, that successive times-between-failures are not exponentially distributed and not independent.These deviations are due to imperfect search of failed components. We constitute a plausible stochastic process which describes the sequence of events, and obtain the interval reliability and the expected number of failures.As an application of these results, we deal with the replacement model where a system undergoes minimal repair before time T and is replaced at time T. We discuss an optimum policy minimizing the total expected cost per unit time.     

A study on predicting factors of the effect of intra-arterial infusion chemotherapy in patients with bladder cancers: the usefulness of in-vitro chemisensitivity test measuring intracellular ATP contents (ATP assay)

We studied a relationship between in vitro sensitivity of the tumors to anti-cancerous drugs and histopathological effectiveness of an intra-arterial infusion chemotherapy in 15 patients with bladder cancers. The in vitro sensitivity test was performed by measuring intra-cellular ATP contents (ATP assay). The intra-arterial chemotherapy were performed by injecting methotrexate (MTX), adriamycin (ADM) and eisplatin (CDDP) from the internal iliac artery. When the intra-cellular ATP contents of the tumor cells treated with an anti-cancerous drug decreased to less than 50% of the untreated tumor cells, the tumor was evaluated as sensitive to the drug. The effectiveness of the chemotherapy were histopathologically evaluated by a pathologist according to the response criteria for bladder cancer treatment. When the histopathological responses of higher than grade 2 were observed in the tumor, the chemotherapy was evaluated as effective. In 8 of 9 tumors sensitive to ADM, chemotherapy were effective histopathologically and in all 6 tumors resistant to ADM, histopathological response of the chemotherapies were poor. The overall coincidence ratio between sensitivity to ADM and the histopathological effectiveness of the chemotherapy was 93%, showing statistically significant correlation. In 7 of 12 tumors sensitive to CDDP, the chemotherapies were effective and in 2 of 3 tumors resistant to CDDP, the chemotherapies were ineffective. Although the overall coincidence ratio between the sensitivities to CDDP and chemotherapeutic effectiveness was 60%, there was no significant correlation between them. In 7 of 8 tumors sensitive to both of ADM and CDDP, the chemotherapies were effective and in 6 of 7 tumors resistant to at least one of them, the chemotherapies were ineffective. (ABSTRACT TRUNCATED AT 250 WORDS)     

High-frequency characteristics of low-temperaturepseudo-heterojunction bipolar transistors

The high-frequency characteristics of a pseudojunction bipolar transistor (pseudo-HBT), which operates like an HBT despite a metallurgical homojunction utilizing a bandgap narrowing effect, are analyzed both theoretically and experimentally. Several design features used to achieve a high cutoff frequency at low temperatures are discussed. They include (1) a low-impurity-concentration graft base, (2) an abrupt base profile to obtain a large effective-bandgap difference between the base and the emitter, and (3) an inversely graded base profile, in which the impurity concentration increases from the emitter side to the collector side, to effectively reduce the base transit time. The pseudo-HBT with a low-concentration graft base shows a higher cutoff frequency below 100 K than at room temperature. These features are also appropriate for conventional bipolar transistors operating at low temperatures     

Requirement of p38 mitogen-activated protein kinase for neuronal differentiation in PC12 cells

Nerve growth factor (NGF) induces sustained activation of classical MAP kinase (MAPK, also known as ERK) and neuronal differentiation in PC12 cells, whereas epidermal growth factor (EGF) induces transient activation of ERK/MAPK and stimulates proliferation of the cells. Although previous studies showed that sustained activation of ERK/MAPK is important for neuronal differentiation of the cells, a recent report revealed that inhibition of the sustained phase of ERK/MAPK activation alone does not block neurite outgrowth caused by NGF. These results suggest requirement for an additional signaling pathway(s) triggered by NGF in neuronal differentiation. Here we show that NGF induces sustained activation of p38, a subfamily member of the MAPK superfamily, and that inhibition of the p38 pathway blocks neurite outgrowth in PC12 cells. Surprisingly, expression of constitutively active MAPK/ERK kinase (MAPKK, also known as MEK) results in p38 activation as well as ERK/MAPK activation, and a p38 inhibitor blocks neurite outgrowth caused by the constitutively active MAPKK/MEK. Moreover, constitutive activation of p38 is able to induce neurite outgrowth when combined with EGF treatment. These results reveal an essential role of p38 in neuronal differentiation in PC12 cells.     

Angiotensin-converting enzyme gene polymorphism in essential hypertensive patients in Japanese population

Association between angiotensin-converting enzyme (ACE) gene polymorphism and essential hypertension in a Japanese population with the same socioeconomic background was investigated. Insertion-deletion (I/D) polymorphism of the ACE gene located on intron 16 was detected by polymerase chain reaction. Association between ACE gene polymorphism and family history of essential hypertension as well as the development of vascular damage in eye fundi were also investigated. Variation at ACE loci did not contribute to essential hypertension and the vascular damages in eye fundi. These results suggest that the ACE gene was not directly responsible for essential hypertension in this particular Japanese population with the same socioeconomic background.     

Dielectric spectroscopy of metal nanoparticle doped liquid crystal displays exhibiting frequency modulation response

Twisted nematic liquid crystal displays (TN-LCDs), doped with the nanoparticles of metal, such as Pd, Ag, or Ag-Pd, which are protected with ligand molecules, such as nematic liquid crystal, exhibit a frequency modulation (FM) electro-optical (EO) response with short response time of milliseconds (ms) or sub-ms order together with the ordinary rms voltage response. These devices are called FM/AM-TN-LCDs; they are distinct from the ordinary LCDs featured by the amplitude modulation (AM) response. The phenomena of the FM/AM LCDs may be attributed to the dielectric dispersion of a heterogeneous dielectric medium known as the Maxwell-Wagner effect. It is experimentally shown that the frequency range spreads from several tens hertz to several tens kilohertz and the spectrum is more or less centered about the dielectric relaxation frequency. We formulated a theory based on an equivalent circuit model to evaluate the dielectric relaxation frequency and the dielectric strengths; and we succeeded in explaining the dependence of the dielectric relaxation frequency on the concentration of nanoparticles and the their dielectric and electrical properties, whereas conventional theories based on electromagnetic theory are unable to explain this concentration dependence. This paper reports on the experimental results of the EO effects and the dielectric spectroscopy including the dielectric relaxation times and the dielectric strengths of nematic liquid crystal, 5CB (4-pentyl-4'-cyanobiphenyl), doped with the metal nanoparticles of I'd alone and Ag-Pd composite; and discusses how the observed dielectric relaxation frequency or dielectric relaxation time depend on the concentration of the doped nanoparticles and also their electrical and dielectric properties.