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Background: Systemic inflammation is believed to contribute to small cell lung cancer (SCLC) progression, but the underlying relationship remains unclear. Lipocalin‐2, a potential biomarker of inflammation, has been implicated in various cancers but its prognostic value in SCLC is underexplored. Methods: We retrospectively analyzed 191 patients with SCLC (72 with limited‐stage [LD] and 119 with extensive‐stage) treated using platinum‐based chemotherapy. Lipocalin‐2 expression was evaluated using immunohistochemistry. Optimal cutoff values for lipocalin‐2 and neutrophil‐to‐lymphocyte ratio (NLR) were determined using time‐dependent receiver operating characteristic curve analysis. The pectoralis muscle index was used to assess sarcopenia. Results: In LD‐SCLC, high lipocalin‐2 expression was associated with worse progression‐free survival (PFS; median: 7.0 vs. 15.9 months, p = 0.015) and overall survival (OS; median: 12.9 vs. 30.3 months, p = 0.035) compared with low lipocalin‐2 expression. Patients were stratified into three prognostic groups by combining lipocalin‐2 with NLR: low lipocalin‐2/low NLR, high lipocalin‐2/low NLR or low lipocalin‐2/high NLR, and high lipocalin‐2/high NLR (median PFS: 17.3 vs. 11.0 vs. 6.3 months, p = 0.004; median OS: 30.5 vs. 17.3 vs. 8.6 months, p = 0.002). Similar trends were observed when combining lipocalin‐2 with the pectoralis muscle index. High lipocalin‐2 expression was also associated with lower complete response rates (18.9% vs. 34.3%, p = 0.035). No significant prognostic implications were found for lipocalin‐2 in extensive‐stage SCLC. Conclusions: High lipocalin‐2 expression is potentially associated with poorer survival in LD‐SCLC. Combining lipocalin‐2 with other inflammation‐related markers could improve prognostic stratification. [ABSTRACT FROM AUTHOR]

A series of the chalcone derivatives of the five‐membered monoheterocyclic compounds, (E)‐1‐aryl‐3‐heteroarylpropen‐1‐ones, were prepared by aldol condensation of the corresponding aldehydes of thiophene, pyrrole, and furan with m‐ and p‐substituted acetophenones. Similar condensation of the acetyl compounds of the heterocycles with m‐ and p‐substituted benzaldehydes gave another series of the chalcone derivatives, (E)‐1‐heteroaryl‐3‐arylpropen‐1‐ones. The 13C chemical shift values (δC) of the chalcone derivatives were determined in order to find if they correlated with the Hammett σ values. A good correlation, especially for the β‐C for both series, was found for the 13C chemical shift values (δC) of the chalcone derivatives with the Hammett σ values. The chemical shift values of the β‐C of the heterocyclic compounds were plotted against those of the benzene derivatives. The resulting slopes were found to be close to the values of the aromaticity indices. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE 5-HT4 receptor agonists have been shown to be effective at treating various gastrointestinal tract disorders. However, a lack of selectivity against off-targets has been a limiting factor for their clinical use. EXPERIMENTAL APPROACH The binding affinity and selectivity of YH12852 for human 5-HT4(a) receptor in CHO-K1 cells were evaluated using radioligand binding assays, and agonistic activity was assessed using a β-lactamase reporter system. Contractile activity and propulsive motility were measured in the guinea pig isolated distal colon. Its prokinetic effect on the gastrointestinal tract was evaluated in guinea pigs, dogs and monkeys. Its tissue distribution was evaluated in rats. KEY RESULTS YH12852 exhibited high affinity and potency for human recombinant 5-HT4(a) receptor with high selectivity over other 5-HT and non-5-HT receptors, ion channels, enzymes and transporters. YH12852 induced contractions and increased propulsive motility in guinea pig isolated colon. These effects were abolished by the 5-HT4 receptor antagonist GR113808. YH12852 increased defecation more effectively than prucalopride in guinea pigs and dogs and improved gastric emptying more effectively than mosapride in guinea pigs, dogs and monkeys. YH12852 was highly distributed to the gastrointestinal tract as the target organ. CONCLUSION AND IMPLICATIONS The high in vitro potency and selectivity of YH12852 for 5-HT4 receptor translated into potent in vivo efficacy with good tolerability. YH12852 significantly improved both upper and lower bowel motility in the animal models tested and has the potential to address considerable unmet needs in patients with functional constipation, gastroparesis or both. [ABSTRACT FROM AUTHOR]

The 1H and 13C chemical shifts and the mass spectral fragmentation patterns of 1-aryl-3-phenylpropanes with m- or p-substituents (H, NO2 , Br, Cl, OCH3 , CH3 ) were studied. The electronic effects of the substituents seemed to be transmitted by the through-space as well as by a through-bond mechanism, resulting in an inverse correlation in the plot of the chemical shift values of i-C vs. the Hammett σ values. The mass spectra showed the substituted benzyl fragments as the base peaks when the substituents were electron donating, whereas the benzyl fragment was observed as the base peaks with the electron-withdrawing substituents. [ABSTRACT FROM AUTHOR]

1H and 13C NMR spectra of aryl esters of propionic acid, acrylic acid, and propiolic acid were systematically examined to find out the substituent effect on the chemical shift. The values of the chemical shift of the carbonyl carbon showed an inverse correlation with the Hammett σ values, and the magnitude of the slope was the largest with the propiolates. The α carbons of acrylates and propiolates also showed an inverse correlation with much smaller values of the slopes than those of the carbonyl carbons; but those of the propionates showed absolutely no correlation. However, the β carbons of acrylates and propiolates showed normal correlation with larger values of the slopes. The signs and the magnitudes of the slopes may be understood by the transmission of the substituent electronic effect through bonds as well as through space. The propiolyloxy group also showed a significantly large effect on the 13C chemical shift values of the benzene ring. [ABSTRACT FROM AUTHOR]

It has been proposed that Wnt signaling pathway may be a key radioprotective mechanism in irradiated cancer cells; however, the specific radioresistance mechanisms remain not to be fully clarified. Here we elucidate a novel signaling pathway of radioresistance in head and neck cancer (HNC) cell lines involving interactions among the Wnt signaling pathway, cyclooxygenase-2 (COX-2) and Ku expression. Activation of the Wnt signaling pathway by (2′Z,3′E)-6-bromoindirubin-3′-oxime (BIO) resulted in β-catenin cytoplasmic accumulation and translocation to the nucleus, upregulated Ku expression and increased radioresistance in the COX-2-expressing HNC cell line. In contrast, Wnt singaling activation by BIO had no effects on Ku expression and radiosensitivity in a HNC cell line negative for COX-2. Interactions between Wnt singaling and Ku were indirectly regulated by COX-2. Blockage of COX-2 signaling led to the suppression of β-catenin-induced Ku expression, and to consequent recovery of the radiosensitivity in HNC cells. Our results conclusively suggest that β-catenin plays a pivotal role in the regulation of Ku expression via the proposed COX-2 intracellular pathway, thus supporting a novel radioresistance mechanism of HNC. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background and Purpose: 5-HT4 receptor agonists have been shown to be effective at treating various gastrointestinal tract disorders. However, a lack of selectivity against off-targets has been a limiting factor for their clinical use.Experimental Approach: The binding affinity and selectivity of YH12852 for human 5-HT4(a) receptor in CHO-K1 cells were evaluated using radioligand binding assays, and agonistic activity was assessed using a β-lactamase reporter system. Contractile activity and propulsive motility were measured in the guinea pig isolated distal colon. Its prokinetic effect on the gastrointestinal tract was evaluated in guinea pigs, dogs and monkeys. Its tissue distribution was evaluated in rats.Key Results: YH12852 exhibited high affinity and potency for human recombinant 5-HT4(a) receptor with high selectivity over other 5-HT and non-5-HT receptors, ion channels, enzymes and transporters. YH12852 induced contractions and increased propulsive motility in guinea pig isolated colon. These effects were abolished by the 5-HT4 receptor antagonist GR113808. YH12852 increased defecation more effectively than prucalopride in guinea pigs and dogs and improved gastric emptying more effectively than mosapride in guinea pigs, dogs and monkeys. YH12852 was highly distributed to the gastrointestinal tract as the target organ.Conclusion and Implications: The high in vitro potency and selectivity of YH12852 for 5-HT4 receptor translated into potent in vivo efficacy with good tolerability. YH12852 significantly improved both upper and lower bowel motility in the animal models tested and has the potential to address considerable unmet needs in patients with functional constipation, gastroparesis or both. [ABSTRACT FROM AUTHOR]