Mechanistic Evidence (mechanistic + evidence)

Distribution by Scientific Domains

Selected Abstracts

Use of mechanistic data in IARC evaluations

Vincent James Cogliano
Abstract Consideration of mechanistic data has the potential to improve the analysis of both epidemiologic studies and cancer bioassays. IARC has a classification system in which mechanistic data can play a pivotal role. Since 1991, IARC has allowed an agent to be classified as carcinogenic to humans (Group 1) when there is less than sufficient evidence in humans but there is sufficient evidence in experimental animals and "strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity." Mechanistic evidence can also substitute for conventional cancer bioassays when there is less than sufficient evidence in experimental animals, just as mechanistic evidence can substitute for conventional epidemiologic studies when there is less than sufficient evidence in humans. The IARC Monographs have used mechanistic data to raise or lower a classification that would be otherwise based on epidemiologic studies and cancer bioassays only. Recently, the IARC Monographs have evaluated several agents where mechanistic data were pivotal to the overall evaluation: benzo[a]pyrene, carbon black and other poorly soluble particles, ingested nitrates and nitrites, and microcystin-LR. In evaluating mechanistic data, it is important to consider alternative mechanistic hypotheses, because an agent may induce tumors through multiple mechanisms. Environ. Mol. Mutagen., 2008. 2008 Wiley-Liss, Inc. [source]

Chemosensitization in non-small cell lung cancer cells by IKK inhibitor occurs via NF-,B and mitochondrial cytochrome c cascade

Xianqing Jin
Abstract In this study, we demonstrated with mechanistic evidence that parthenolide, a sesquiterpene lactone, could antagonize paclitaxel-mediated NF-,B nuclear translocation and activation by selectively targeting I-,B kinase (IKK) activity. We also found that parthenolide could target IKK activity and then inhibit NF-,B; this promoted cytochrome c release and activation of caspases 3 and 9. Inhibition of caspase activity blocked the activation of caspase cascade, implying that the observed synergy was related to caspases 3 and 9 activation of parthenolide. In contrast, paclitaxel individually induced apoptosis via a pathway independent of the mitochondrial cytochrome c cascade. Finally, exposure to parthenolide resulted in the inhibition of several NF-,B transcript anti-apoptotic proteins such as c-IAP1 and Bcl-xl. These data strengthen the rationale for using parthenolide to decrease the apoptotic threshold via caspase-dependent processes for treatment of non-small cell lung cancer with paclitaxel chemoresistance. [source]

Effects of 0.4 T rotating magnetic field exposure on density, strength, calcium and metabolism of rat thigh bones

Xiao-yun Zhang
Abstract The current study investigated the effects of 0.4 T rotary non-uniform magnetic field (RMF) exposure on bone density in ovariectomized (OVX) rats. Results showed that many bone indexes are significantly elevated after RMF exposure compared to the control OVX group and confirmed mechanistic evidence that strong magnetic field (MF) exposure could effectively increase bone density and might be used to treat osteoporosis. Synergy of daily RMF exposure (30 min a day for 30 days using an 8 Hz rotary 0.4 T MF) with calcium supplement tended to increase the indexes of thigh bone density, energy absorption, maximum load, maximum flexibility, and elastic deformation as compared to those of untreated OVX control group. Results also revealed that the indexes of alkaline phosphatase (ALP), serum phosphate, and serum calcium were higher in rats exposed to RMF with calcium than in the untreated OVX control group. Changes in bone mineral density (BMD) and bone mineral content (BMC) were observed in rats for three months including the first month RMF exposure. Bone density in rats exposed each day for 60 min increased during 1-month exposure and continued to increase during the post-exposure period. Furthermore, bone density and calcium content in rats exposed for 90 min daily decreased initially in the exposure month; however, ratio of increase was well above the control values by the end of the post-exposure period suggesting possible window and delayed effects. The study indicated that RMF exposure to both male and OVX female rats for 120 min a day over 15 day period should effectively promote increase of bone calcium contents (BCC) and bone-specific alkaline phosphatase (BAP) in rats thigh bone as well as a corresponding decrease in deoxypyridinoline crosslinks (DPD). Bioelectromagnetics 27:1,9, 2006. 2005 Wiley-Liss, Inc. [source]

Efficient Intramolecular Hydroalkoxylation of Unactivated Alkenols Mediated by Recyclable Lanthanide Triflate Ionic Liquids: Scope and Mechanism

Alma Dzudza Dr.
Abstract Lanthanide triflate complexes of the type [Ln(OTf)3] (Ln=La, Sm, Nd, Yb, Lu) serve as effective, recyclable catalysts for the rapid intramolecular hydroalkoxylation (HO)/cyclization of primary/secondary and aliphatic/aromatic hydroxyalkenes in imidazolium-based room-temperature ionic liquids (RTILs) to yield the corresponding furan, pyran, spirobicyclic furan, spirobicyclic furan/pyran, benzofuran, and isochroman derivatives. Products are straightforwardly isolated from the catalytic solution, conversions exhibit Markovnikov regioselectivity, and turnover frequencies are as high as 47,h,1 at 120,C. The ring-size rate dependence of the primary alkenol cyclizations is 5>6, consistent with a sterically controlled transition state. The hydroalkoxylation/cyclization rates of terminal alkenols are slightly more rapid than those of internal alkenols, which suggests modest steric demands in the cyclic transition state. Cyclization rates of aryl-functionalized hydroxyalkenes are more rapid than those of the linear alkenols, whereas five- and five/six-membered spirobicyclic skeletons are also regioselectively closed. In cyclization of primary, sterically encumbered alkenols, turnover-frequency dependence on metal-ionic radius decreases by approximately 80-fold on going from La3+ (1.160,) to Lu3+ (0.977,), presumably reflecting steric impediments along the reaction coordinate. The overall rate law for alkenol hydroalkoxylation/cyclization is v,k[catalyst]1[alkenol]1. An observed ROH/ROD kinetic isotope effect of 2.48 (9) is suggestive of a catalytic pathway that involves kinetically significant intramolecular proton transfer. The present activation parameters,enthalpy (,H,)=18.2 (9),kcal,mol,1, entropy (,S,)=,17.0 (1.4),eu, and energy (Ea)=18.2 (8),kcal,mol,1,suggest a highly organized transition state. Proton scavenging and coordinative probing results suggest that the lanthanide triflates are not simply precursors of free triflic acid. Based on the kinetic and mechanistic evidence, the proposed catalytic pathway invokes hydroxyl and olefin activation by the electron-deficient Ln3+ center, and intramolecular H+ transfer, followed by alkoxide nucleophilic attack with ring closure. [source]