Activation of nuclear factor-kB (NF-kB) signaling was observed in pancreatic adenocarcinoma cell lines and tumours. However, information on the expression of RelA/p65, the major transcription activating NF-kB subunit, in these carcinomas and possible correlations thereof with NF-kB activation and patient survival is not available. To provide this missing translational link, we analysed expression of RelA/p65 in 82 pancreatic adenocarcinomas by immunohistochemistry. Moreover, we measured activation of the NF-kB pathway in 11 tumours by quantitative PCR for NF-kB target genes. We observed strong cytoplasmic or nuclear expression of RelA/p65 in 42 and 37 carcinomas, respectively. High cytoplasmic and nuclear expression of RelA/p65 had negative prognostic impact with 2-year survival rates for patients without cytoplasmic or nuclear RelA/p65 positivity of 41 and 40% and rates for patients with strong cytoplasmic or nuclear RelA/p65 expression of 22 and 20%, respectively. High RelA/p65 expression was correlated to increased expression of NF-kB target genes. The observation that high expression of RelA/p65 is correlated to an activation of the NF-kB pathway and indicates poor patient survival identifies a patient subgroup that might particularly benefit from NF-kB-inhibiting agents in the treatment of pancreatic cancer. Based on our findings, this subgroup could be identified by applying simple immunohistochemical techniques.
Ten human subjects inhaled zlzPb carried on natural aerosols. Deposition in thc lung varied from 14 to 45% of the amount inhaled. Clearance from the lung to the systemic tissues occurred with an estimated half-time of 6.5 hr. The average 24-hr urinary excretion of $lzPb was 2.8 f 0.15% of the body contcnt. The total loss by fecal excretion adjusted to zero time averaged 3% body content. The lead absorbed from the lungs into the blood is in part fixed by the circulating red cells and in part distributed to other tissues. The red cell 21zPb burden grows to a steady state level which averages 50% of the total body burden. The results are interpreted to indicate that the clearance of radon daughters from the lung parenchyma by absorption into the blood has little dosimetric significance, whereas, in the case of thoron daughters, the average lung dose is reduced to less than half.
In contrast to wild rats the percentage of animals showing predatory behaviour is very low among laboratory rats. Stimulation of this specific drive by systemic drug application has been mentioned only for pCPA and delta9-tetrahydrocannabinole. As detailed investigations concerning this stimulating property of pCPA are not published, the effect was studied in selected non-biting rats (without starvation and isolation) regarding dose- and time-dependence after single and repeated drug administration; further, D- and L-isomers of pCPA were included in the investigation. After single oral application of 200 to 3200 mg/kg DL-pCPA a dose-dependent stimulation of predatory behaviour was found. Smaller doses (200 or 400 mg/kg p.o.) given repeatedly on 3 consecutive days showed effects comparable with those after single administration of much higher doses (1600 or 3200 mg/kg p.o.). With repeated oral application of 50, 100 or 200 mg/kg on 10 consecutive days no difference was found between D- and L-pCPA concerning efficacy and time course of drug effect. Both after single and repeated administration in all series of tests the effect reached its maximum not before several days and faded almost completely in the drug-free after-period. D-methamphetamine HCl, investigated comparatively as a CNS stimulant, provoked no predatory behaviour in a wide dose-range (0.125 to 8.0 mg/kg p.o.) with repeated administration on 10 consecutive days. Within the control groups (total number of rats = 100) no animal showed predatory attach during an observation-period of at least 3 weeks.
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