No abstract

CS-1008 has a selective toxicity toward tumor cells expressing DR5 and the potential for antitumor efficacy in human malignancies.

Abstract. Folic acid and cAMP are chemoattractants in Dictyostelium discoideum, which bind to different surface receptors. The signal is transduced from the receptors via different G proteins into a common pathway which includes guanylyl cyclase and acto-myosin. To investigate this common pathway, ten mutants which do not react chemotactically to both cAMP and folio acid were isolated with a simple new chemotactic assay. Genetic analysis shows that one of these mutants (KI-10) was dominant; the other nine mutants were recessive, and comprise nine complementation groups.In wild-type cells, the chemoattractants activate adenylyl cyclase, phospholipase C, and guanylyl cyclase in a transient manner. In mutant cells the formation of cAMP and IP3 were generally normal, whereas the cGMP response was altered in most of the ten mutants. Particularly, mutant KI-8 has strongly reduced basal guanylyl cyclase activity; the enzyme is present in mutant KI-10, but can not be activated by cAMP or folic acid. The cGMP response of five other mutants is altered in either magnitude, dose dependency, or kinetics. These observations suggest that the second messenger cGMP plays a key role in chemotaxis in Dictyostelium.

We have previously identified a protein factor, PEBP2 (polyomavirus enhancer-binding protein), in the nuclear extract from mouse NIH 3T3 cells which binds to the sequence motif, PEA2, located within the polyomavirus enhancer A element. Upon cellular transformation with activated oncogene c-Ha-ras, this factor frequently undergoes drastic molecular modifications into an altered form having a considerably reduced molecular size. In this study, the altered form, PEBP3, was purified to near homogeneity. The purified PEBP3 comprised two sets of families of polypeptides, f-1 to a-4 and j-1 to I-2, which were 30 to 35 kilodaltons and 20 to 25 kilodaltons in size, respectively. Both kinds of polypeptides possessed DNA-binding activities with exactly the same sequence specificity. Individual a or polypeptides complexed with DNA showed faster gel mobilities than did PEBP3. However, the original gel retardation pattern was restored when ax and polypeptides were mixed together in any arbitrary pair. These observations along with the results of UV-and chemical-cross-linking studies led us to conclude that PEBP3 is a heterodimer of ft and fi subunits, potentially having a divalent DNA-binding activity. Furthermore, PEBP3 was found to bind a second, hitherto-unnoticed site of the polyomavirus enhancer that is located within the B element and coincides with the sequence previously known as the simian virus 40 enhancer core homology. From comparison of this and the original binding sites, the consensus sequence for PEBP3 was defined to be PuACCPuCA. These findings provided new insights into the biological significance of PEBP3 and PEBP2.

Objective-To examine the circadian variation in the signal averaged electrocardiogram (saECG) and heart rate variability and investigate their relations in healthy subjects. Methods-24 hour ECGs were obtained with a three channel recorder using bipolar X, Y, and Z leads in 20 healthy subjects. The following variables were determined hourly: heart rate, filtered QRS (f-QRS) duration, low and high frequency components of heart rate variability (LF and HF), and the LF/HF ratio. Results-Heart rate, f-QRS duration, HF, and the LF/HF ratio showed significant circadian rhythms, as determined by the single cosinor method. Heart rate and the LF/HF ratio increased during daytime, and f-QRS duration and HF increased at night. f-QRS duration was negatively correlated with heart rate (r = 0.95, p < 0.001) and the LF/HF ratio (r = 0.94, p < 0.001) and positively with HF (r = 0.93, p < 0.001). Conclusions-f-QRS duration has a significant circadian rhythm in healthy subjects and is closely related to the circadian rhythm of autonomic tone. (Heart 1998;79:493-496) Keywords: signal averaged ECG; f-QRS duration; circadian rhythm; heart rate variability Signal averaged electrocardiography (saECG) is a non-invasive method of detecting the substrate for malignant ventricular arrhythmias and is widely used to identify individuals at high risk for such arrhythmias and for sudden cardiac death. [1][2][3][4][5] Although the saECG has been assumed to measure fixed parameters, several studies have shown that these are altered by changes in factors such as heart rate and autonomic tone.6-8 Analysis of heart rate variability has been used to evaluate cardiac autonomic tone. 9-11Heart rate, heart rate variability, cardiac autonomic tone, and ventricular arrhythmias are known to have a circadian rhythm, [12][13][14][15][16] but information on the possibility of a circadian rhythm of the saECG and on the contribution of circadian fluctuations in autonomic function to the saECG is limited. We investigated whether the saECG has a circadian rhythm in healthy subjects and examined the relation between circadian fluctuations of the saECG and heart rate variability. Methods STUDY POPULATIONWe analysed 24 hour ECG recordings obtained in 44 healthy volunteers (28 men and 16 women, mean age (SD): 28.2 (3.3) years) in whom no abnormalities were detected by the medical history, physical examination, biochemical profile, 12 lead ECG, echocardiogram, or chest x ray. No subjects were on drug treatment. ANALYSIS OF 24 HOUR ECG RECORDINGSThe 24 hour ECG recordings were made with a three channel recorder (model 459, Del Mar Avionics, Irvine, California, USA) using bipolar leads X, Y, and Z. saECG analysisSignal averaging was performed on the data obtained from the first 500 seconds of every hour over the 24 hour period and filtered with a bidirectional filter at 40 to 250 Hz. The filtered leads were combined to form a vector as: √X 2 +Y 2 +Z 2 . The QRS onset and oVset were determined by a computer algorithm. The computer determined QRS oVset point w...