TAS-301, an inhibitor of smooth muscle cell migration and proliferation, inhibits intimal thickening after balloon injury to rat carotid arteries

The purpose of this study was to determine the efficacy and the possible mechanism of action of a recently synthesized drug, TAS-301 [3-bis (4-methoxyphenyl)methylene-2-indolinone], on intimal formation in comparison with those of tranilast, the clinical efficacy of which was reported earlier. Rat carotid arteries were injured using a balloon catheter. Neointimal thickening, measured 14 days after injury, was reduced by the oral administration of TAS-301 in a dose-dependent fashion (3-100 mg/kg), and the effect of TAS-301 at a dose of 100 mg/kg was significantly greater than that of tranilast (300 mg/kg). Fewer cells were found on the intima of balloon-injured arteries of TAS-301-treated rats than on arteries of tranilast-treated rats. In an in vitro assay, TAS-301 inhibited the migration of smooth muscle cells (SMCs) stimulated by platelet-derived growth factor-BB, insulin-like growth factor-1 or heparin-binding epidermal growth factor-like growth factor. In addition, TAS-301 and tranilast reduced the proliferation of medial and intimal SMCs at 4 and 8 days, respectively, after the injury. In vitro, TAS-301 inhibited basic fibroblast growth factor-induced proliferation of SMCs dose dependently. These findings indicate that TAS-301 shows a higher inhibitory potency on intimal formation than tranilast due to inhibition of both migration of medial SMCs and proliferation of medial and intimal SMCs. Our results suggest that further evaluation of TAS-301 as an inhibitor of postangioplasty intimal thickening is warranted.     

Interleukin 6 and its relationship to clinical parameters in patients with malignant pleural mesothelioma

We explored the potential therapeutic benefit of introducing GM-CSF, IFN-gamma or a combination of both factors into CT26 tumor cells. CT26 cells secreting either GM-CSF or IFN-gamma exhibited delayed tumorigenicity; however, cells expressing both GM-CSF and IFN-gamma did not form tumors. Even when wild type CT26 cells were introduced into a distant site of mice that had been inoculated with CT26/GM-CSF/IFN-gamma cells, no tumors were generated. Furthermore, when we injected GM-CSF + IFN-gamma cells into animals bearing established tumors, the tumors were either rejected or their development was delayed, suggesting that synergistic effects were induced against these tumors via a systemic immune response. Histopathological examination of the tumors injected with cells expressing GM-CSF and IFN-gamma combined showed necrosis and few signs of malignancy. The growth of tumors from mice treated with CT26/GM-CSF/IFN-gamma cells exhibited a delay in tumor formation and no effects were seen in athymic nude mice, which are deficient in T lymphocytes, or in splenectomized nude mice, which are deficient in natural killer (NK) cells, respectively. Our data indicate a dual role for T and NK cells in mediating the anti-tumor activity of this therapy. Our results suggest that transduction of tumor cells with both GM-CSF + IFN-gamma results in a powerful synergistic effect of the 2 cytokines that is of greater therapeutic benefit than transduction with either cytokine alone.     

Aberrant crypt foci of the colon as precursors of adenoma and cancer

BACKGROUND: Aberrant crypt foci of the colon are possible precursors of adenoma and cancer, but these lesions have been studied mainly in surgical specimens from patients who already had colon cancer. METHODS: Using magnifying endoscopy, we studied the prevalence, number, size, and dysplastic features of aberrant crypt foci and their distribution according to age in 171 normal subjects, 131 patients with adenoma, and 48 patients with colorectal cancer. We also prospectively examined the prevalence of aberrant crypt foci in 11 subjects (4 normal subjects, 6 with adenoma, and 1 with cancer) before and after the administration of 100 mg of sulindac three times a day for 8 to 12 months and compared the results with those in 9 untreated subjects (4 normal subjects and 5 with adenoma). All 20 subjects had aberrant crypt foci at base line. RESULTS: We identified 3155 aberrant crypt foci, 161 of which were dysplastic; the prevalence and number increased with age. There were significant (P<0.001) correlations between the number of aberrant crypt foci, the presence of dysplastic foci, the size of the foci, and the number of adenomas. After sulindac therapy, the number of foci decreased, disappearing in 7 of 11 subjects. In the untreated control group, the number of foci was unchanged in eight subjects and slightly increased in one (P<0.001 for the difference between the groups). CONCLUSIONS: Aberrant crypt foci, particularly those that are large and have dysplastic features, may be precursors of adenoma and cancer.     

Requirement of atypical protein kinase clambda for insulin stimulation of glucose uptake but not for Akt activation in 3T3-L1 adipocytes

Phosphoinositide (PI) 3-kinase contributes to a wide variety of biological actions, including insulin stimulation of glucose transport in adipocytes. Both Akt (protein kinase B), a serine-threonine kinase with a pleckstrin homology domain, and atypical isoforms of protein kinase C (PKCzeta and PKClambda) have been implicated as downstream effectors of PI 3-kinase. Endogenous or transfected PKClambda in 3T3-L1 adipocytes or CHO cells has now been shown to be activated by insulin in a manner sensitive to inhibitors of PI 3-kinase (wortmannin and a dominant negative mutant of PI 3-kinase). Overexpression of kinase-deficient mutants of PKClambda (lambdaKD or lambdaDeltaNKD), achieved with the use of adenovirus-mediated gene transfer, resulted in inhibition of insulin activation of PKClambda, indicating that these mutants exert dominant negative effects. Insulin-stimulated glucose uptake and translocation of the glucose transporter GLUT4 to the plasma membrane, but not growth hormone- or hyperosmolarity-induced glucose uptake, were inhibited by lambdaKD or lambdaDeltaNKD in a dose-dependent manner. The maximal inhibition of insulin-induced glucose uptake achieved by the dominant negative mutants of PKClambda was approximately 50 to 60%. These mutants did not inhibit insulin-induced activation of Akt. A PKClambda mutant that lacks the pseudosubstrate domain (lambdaDeltaPD) exhibited markedly increased kinase activity relative to that of the wild-type enzyme, and expression of lambdaDeltaPD in quiescent 3T3-L1 adipocytes resulted in the stimulation of glucose uptake and translocation of GLUT4 but not in the activation of Akt. Furthermore, overexpression of an Akt mutant in which the phosphorylation sites targeted by growth factors are replaced by alanine resulted in inhibition of insulin-induced activation of Akt but not of PKClambda. These results suggest that insulin-elicited signals that pass through PI 3-kinase subsequently diverge into at least two independent pathways, an Akt pathway and a PKClambda pathway, and that the latter pathway contributes, at least in part, to insulin stimulation of glucose uptake in 3T3-L1 adipocytes.     

Social comparison in everyday life.

94 college students recorded details of their social comparisons over 2 wks using a new instrument, the Rochester Social Comparison Record. Major results were (1) comparison direction varied with relationship with the target; (2) precomparison negative mood led more often to upward comparison than to downward comparison, supporting a selective affect–cognition priming model in which dysphoria primes negative thoughts about the self (G. H. Bower, 1991; J. P. Forgas et al, 1990) rather than a motivational self-enhancement model (T. A. Wills, 1981, 1991); (3) upward comparison decreased subjective well-being, whereas downward comparison increased it; and (4) high self-esteem individuals engaged in more self-enhancing comparison. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Commonalities and differences in the working memory components underlying letter and category fluency tasks: A dual-task investigation.

This study used a dual-task interference paradigm to test the hypothesis that different subcomponents of working memory differentially contribute to performance on letter fluency and category fluency tasks. College students (N = 96) performed each type of verbal fluency task in isolation and concurrently with I of 3 secondary tasks. The secondary tasks were chosen for their putative involvement in different working memory subcomponents. Two subsystems of working memory, the phonological loop and the visuospatial sketchpad, were identified as important contributors to fluency performance, especially to performance on letter fluency and category fluency tasks, respectively. Moreover, the results also suggest that the executive function, mental set shifting, may be deployed to perform both letter fluency and category fluency tasks. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Low-density lipoprotein receptor mutation that deletes exons 2 and 3 by Alu-Alu recombination

A deletion mutant in the low density lipoprotein receptor gene of a Japanese patient with heterozygous familial hypercholesterolemia was analyzed. Genomic Southern blotting showed abnormal size restriction fragments with BamHI (7.8 kb), EcoRI (3.8 kb), BglII (17 kb), KpnI (> 23 kb), EcoRV (13 kb), and XbaI (14 kb). The abnormal EcoRI fragment, 3.8 kb, was cloned into lambda phage vector, and the deleted region of 10 kb including exons 2 and 3 was identified. The nucleotide sequence around the deletion joint was determined. The sequence of the eight nucleotides in the deletion-joint region of the mutant gene was identical to the corresponding sequences of both introns 1 and 3 of the normal gene. The deletion seemed to occur by an unequal recombination between the Alu-like sequences in the same direction in introns 1 and 3.     

Application and monitoring of SF6 gas‐insulated NGR (neutral grounding resistor) using ceramic resistors

About 15 years have passed since ceramic‐resistor NGRs (Neutral Grounding Resistors) were developed as new materials for power equipment. This paper describes the cumulative numbers of applications of ceramic‐resistor‐type SF₆ gas‐insulated NGRs and the typical construction of the 22‐, 66‐, and 110‐kV NGRs, and also describes monitoring methods for measuring the residual leakage current of the 110‐kV NGR that depend on the neutral unbalance voltage of power transformers, and the use of thermal detection devices for the ceramic resistors of the 66‐kV NGRs. © 2001 Scripta Technica, Electr Eng Jpn, 137(4): 32–37, 2001     

Re‐ignition surge and high‐frequency arc extinction phenomena at 550‐kV shunt reactor current interruption

At substations connected with transmission lines and cables, shunt reactors are sometimes installed to compensate the capacitive current of these lines and cables. It is known that re‐ignitions occur and high‐frequency currents flow during interruption of the shunt reactor currents by switches. When the high‐frequency currents are interrupted immediately after the re‐ignitions (which is called high‐frequency arc extinction), the result is often repetitive re‐ignitions or voltage escalations that produce dangerous overvoltages. The authors investigated the occurrence of high‐frequency arc extinctions in a 550‐kV one‐break SF₆ gas circuit breaker during interruption of a 550‐kV shunt reactor current. Computations for a real 550‐kV substation gave a minimum frequency of 290 kHz for the high‐frequency current. However, 550‐kV reactor current interruption tests showed that high‐frequency arc extinctions did not occur even when this frequency was lowered to 26 kHz. Since high‐frequency arc extinction is generally likely to occur at lower frequencies, it was concluded that high‐frequency arc extinction will not occur in a 550‐kV one‐break SF₆ gas circuit breaker during interruption of shunt reactor current in real substations. © 2001 Scripta Technica, Electr Eng Jpn, 136(2): 18–25, 2001     

Stability condition of a class of nonlinear feedback systems:reduction to a convex problem

This paper gives a new criterion for input-output stability of a class of nonlinear feedback systems, roughly speaking, it is most useful in such a practical situation where the nonlinearity in the system is “almost time-invariant and memoryless” but with “slight time-variations and dynamics”. It involves two free parameters and contains the circle criterion and the Popov criterion as special cases. In fact, it extends these two famous criteria in such a way that the conservatism of the circle criterion can be reduced when the time-variations and dynamics of the nonlinearity are “relatively small”. It is also shown that the existence of the free parameters that fulfil the stability condition can be checked exactly by reducing it to a convex problem in the frequency domain