A proper quantitative understanding of the dynamic interaction between gas-phase semivolatile organic compounds (SVOCs) and airborne particles is important for human exposure assessment and risk evaluation. Questions regarding how to properly address gas/particle interactions have introduced uncertainty when predicting SVOC concentrations and assessing exposures to these compounds. In this study, we have developed a dimensionless description for the dynamic interaction between SVOCs and organic particles. A better criterion to judge whether the internal resistance (diffusion in and out of aerosols) is negligible compared with the external one (from bulk air to aerosol surfaces) is presented. The analysis is applicable regardless of the phase state of particles (either liquid or amorphous semisolid/solid). It is found that for both porous and nonporous particles, the internal resistance can be reasonably neglected for particles with diameters between 0.01 and 10 µm if the particulate organic matter is in the liquid phase. A lumped description therefore can be applied to determine, with greater accuracy than in previous studies, the timescale required to attain gas/particle equilibrium for such particles. The instantaneous equilibrium assumption is found to be reasonable for relatively volatile species such as pyrene, but not for the less volatile species such as di-(2-ethylhexyl)-phthalate (DEHP). For DEHP and 2.5 µm diameter particles, the instantaneous gas/particle equilibrium assumption can cause a two orders of magnitude error in the estimation of the gas-phase concentration and a factor of two error in the estimation of the particle-phase concentration.
Background:Mesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with those of asbestos-associated disease. We previously demonstrated co-activation of multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET, and AXL in mesothelioma cell lines, suggesting that these kinases could serve as novel therapeutic targets. Although clinical trials have not shown activity for EGFR inhibitors in mesothelioma, concurrent inhibition of various activated RTKs has pro-apoptotic and anti-proliferative effects in mesothelioma cell lines. Thus, we hypothesised that a coordinated network of multi-RTK activation contributes to mesothelioma tumorigenesis.Methods:Activation of PI3K/AKT/mTOR, Raf/MAPK, and co-activation of RTKs were evaluated in mesotheliomas. Effects of RTK and downstream inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, apoptosis, activation of signalling intermediates, expression of cell-cycle checkpoints, and cell-cycle alterations.Results:We demonstrate activation of the PI3K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, but not in non-neoplastic mesothelial cells. The AKT activation, but not MAPK activation, was dependent on coordinated activation of RTKs EGFR, MET, and AXL. In addition, PI3K/AKT/mTOR pathway inhibition recapitulated the anti-proliferative effects of concurrent inhibition of EGFR, MET, and AXL. Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates. Inhibition of PI3K/AKT was also associated with MDM2-p53 cell-cycle regulation.Conclusions:These findings show that PI3K/AKT/mTOR is a crucial survival pathway downstream of multiple activated RTKs in mesothelioma, underscoring that PI3K/mTOR is a compelling target for therapeutic intervention.
Exposure to airborne semivolatile organic compounds (SVOCs) in indoor and outdoor environments of humans may lead to adverse health risks. Thus, we established a model to evaluate exposure to airborne SVOCs. In this model, SVOCs phase-specific concentrations were estimated by a kinetic partition model accounting for particle dynamics. The exposure pathways to airborne SVOCs included inhalation exposure to gas-and particle-phases, dermal exposure by direct gas-to-skin pathway and dermal exposure by direct particle deposition. Exposures of defined "reference people" to two typical classifications of SVOCs, one generated from both indoor and outdoor sources, represented by polycyclic aromatic hydrocarbons (PAHs), and the other generated mainly from only indoor sources, represented by di 2-ethylhexyl phthalate (DEHP), were analyzed as an example application of the model. For PAHs with higher volatility, inhalation exposure to gas-phase, ranging from 6.03 to 16.4 ng/kg/d, accounted for the most of the exposure to the airborne phases. For PAHs with lower volatility, inhalation exposure to particle-phase, ranging from 1.48 to 1.53 ng/kg/d, was the most important exposure pathway. As for DEHP, dermal exposure via direct gas-to-skin pathway was 460 ng/kg/d, which was the most striking exposure pathway when the barrier effect of clothing was neglected.
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