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The number one cause of cancer death in Taiwan is lung cancer. Of the few studies describing the experience of patients living with lung cancer, most use bivariate analyses to test associations between individual symptoms. Few have systematically investigated multiple symptoms. This prospective study was undertaken to explore the phenomenon of symptom distress, to investigate the presence of symptom clusters, and to examine the relationship of symptom clusters to symptom interference with daily life in Taiwanese lung cancer patients. A sample of 108 lung cancer patients was recruited using the Taiwanese version of the M. D. Anderson Symptom Inventory. Data were analyzed by hierarchical cluster analysis, factor analysis, Pearson correlation, t-test, and regression analysis. The top five most-severe symptoms were fatigue, sleep disturbance, lack of appetite, shortness of breath, and general distress. Factor analysis generated a two-factor solution (general and gastrointestinal symptoms) for symptom severity items. Consistent with the result from factor analysis, cluster analysis also indicated the same two cluster groups (general and gastrointestinal symptoms). Both clusters were significantly correlated with symptom interference items; however, the general symptom cluster presented higher correlation coefficients than did the gastrointestinal symptom cluster. These results provide an important basis for developing novel strategies to manage multiple symptoms in lung cancer patients and thereby improve their well-being.

We have shown that, in murine J774 macrophages, binding of UTP to pyrimidinoceptors stimulates phosphoinositide (PI) breakdown and an increase in [Ca 2؉ ] i . In this study, UTP modulation of the expression of inducible nitric-oxide synthase (iNOS) was investigated. Although UTP alone had no effect, stimulation of J774 cells with a combination of UTP (10 -300 M) and LPS (0.1-3 g/ml) resulted in a potentiated increase in nitrite levels. In parallel, the amount of iNOS protein induced by LPS was also potentiated by UTP treatment. The UTP potentiating effect was attenuated by U73122, suggesting involvement of the downstream signaling pathways of phosphatidylinositide turnover. The tyrosine kinase inhibitor genistein inhibited both the LPS-induced nitrite response and the UTP potentiation. Conversely, two protein kinase C inhibitors, Ro 31-8220 and Go 6976, and a phosphatidylcholine-specific phospholipase C inhibitor, D609, inhibited LPS-stimulated nitrite induction, but did not affect the potentiating effect of UTP, which was also unaffected by pretreatment with phorbol 12-myristate 13-acetate for 8 h. Furthermore, the UTP-induced potentiation was abolished by BAPTA/AM or KN-93 (a selective inhibitor of Ca 2؉ /calmodulin-dependent protein kinase (CaMK)). Nitrite potentiation and iNOS induction were prominent when UTP was added simultaneously with LPS, with the potentiating effect being lost when UTP was added 3 h after treatment with LPS. Pyrrolidinedithiocarbamate (3-30 M), an inhibitor of NF-B, caused a concentration-dependent reduction in the nitrite response to LPS and UTP. In electrophoretic mobility shift assays, LPS produced marked activation of NF-B and AP-1, which was potentiated by UTP. LPS-induced degradation of IB-␣ as well as the phosphorylation of IB-␣ were also increased by UTP. Moreover, the UTP-potentiated activation of NF-B and AP-1 and the degradation and phosphorylation of IB-␣ were inhibited by KN-93. Taken together, these data demonstrate that nucleotides, especially UTP, can potentiate the LPS-induced activation of NF-B and AP-1 and of iNOS induction via a CaMK -dependent pathway and suggest that the UTP-dependent up-regulation of iNOS may constitute a novel element in the inflammatory process.

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In this study, we investigated the signaling pathways involved in bradykinin (BK)-induced NF-κB activation and cyclooxygenase-2 (COX-2) expression in human airway epithelial cells (A549). BK caused concentration- and time-dependent increase in COX-2 expression, which was attenuated by a selective B2 BK receptor antagonist (HOE140), a Ras inhibitor (manumycin A), a Raf-1 inhibitor (GW 5074), a MEK inhibitor (PD 098059), an NF-κB inhibitor (pyrrolidine dithiocarbate), and an IκB protease inhibitor (l-1-tosylamido-2-phenylethyl chloromethyl ketone). The B1 BK receptor antagonist (Lys-(Leu8)des-Arg9-BK) had no effect on COX-2 induction by BK. BK-induced increase in COX-2-luciferase activity was inhibited by cells transfected with the κB site deletion of COX-2 construct. BK-induced Ras activation was inhibited by manumycin A. Raf-1 phosphorylation at Ser338 by BK was inhibited by manumycin A and GW 5074. BK-induced ERK activation was inhibited by HOE140, manumycin A, GW 5074, and PD 098059. Stimulation of cells with BK activated IκB kinase αβ (IKKαβ), IκBα phosphorylation, IκBα degradation, p65 and p50 translocation from the cytosol to the nucleus, the formation of an NF-κB-specific DNA-protein complex, and κB-luciferase activity. BK-mediated increase in IKKαβ activity and formation of the NF-κB-specific DNA-protein complex were inhibited by HOE140, a Ras dominant-negative mutant (RasN17), manumycin A, GW 5074, and PD 098059. Our results demonstrated for the first time that BK, acting through B2 BK receptor, induces activation of the Ras/Raf-1/ERK pathway, which in turn initiates IKKαβ and NF-κB activation, and ultimately induces COX-2 expression in human airway epithelial cell line (A549).