Interval prediction of molecular properties in parametrized quantum chemistry.

The accurate evaluation of molecular properties lies at the core of predictive physical models. Most reliable quantum-chemical calculations are limited to smaller molecular systems while purely empirical approaches are limited in accuracy and reliability. A promising approach is to employ a quantum-mechanical formalism with simplifications and to compensate for the latter with parametrization. We propose a strategy of directly predicting the uncertainty interval for a property of interest, based on training-data uncertainties, which sidesteps the need for an optimum set of parameters.

Pathways to soot oxidation: reaction of OH with phenanthrene radicals.

Energetics and kinetics of the oxidation of possible soot surface sites by hydroxyl radicals were investigated theoretically. Energetics were calculated by employing density functional theory. Three candidate reactions were selected as suitable prototypes of soot oxidation by OH. The first two, OH + benzene and OH + benzene-phenol complex, did not produce pathways that lead to substantial CO expulsion. The third reaction, OH attack on the phenanthrene radical, had multiple pathways leading to CO elimination. The kinetics of the latter reaction system were determined by solving the master equations with the MultiWell suite of codes. The barrierless reaction rates of this system were computed using the VariFlex program. The computations were carried out over the ranges 1500-2500 K and 0.01-10 atm. At higher temperatures, above 2000 K, the oxidation of phenanthrene radicals by OH followed a chemically activated path. At temperatures lower than 2000 K, chemical activation was not sufficient to drive the reaction to products; reaction progress was impeded by intermediate adducts rapidly de-energizing before reaching products. In such cases, the reaction system was modeled by treating the accumulating adducts as distinct chemical species and computing their kinetics via thermal decomposition. The overall rate coefficient of phenanthrene radical oxidation by OH forming CO was found to be insensitive to pressure and temperature and is approximately 1 × 10(14) cm(3) mol(-1) s(-1). The oxidation of phenanthrene radicals by OH is shown to be controlled by two main processes: H atom migration/elimination and oxyradical decomposition. H atom migration and elimination made possible relatively rapid rearrangement of the aromatic edge to form oxyradicals with favorable decomposition rates. The reaction then continues down the fastest oxyradical pathways, eliminating CO.

The combination of tamoxifen and the rexinoid LG100268 prevents ER-positive and ER-negative mammary tumors in p53-null mammary gland mice.

In pursuit of effective therapeutic agents for the estrogen receptor (ER)-negative breast cancer, we previously showed that bexarotene reduced mammary tumor development by 75% in ErbB2 mice. To further improve the effectiveness of breast cancer prevention, we have now investigated the effects of a combinatorial therapy consisting of two cancer preventive drugs. On the basis of the hypothesis, rexinoid LG100268 plus tamoxifen would more effectively prevent the development of both ER-positive and ER-negative breast cancer. We treated p53-null mammary gland mice with tamoxifen and LG100268, individually and in combination. By 60 weeks of age, vehicle-treated mice developed tumors in 52% of transplanted mammary glands, whereas mice treated with tamoxifen and LG100268 developed tumors in only 13% of transplanted mammary glands. To further define the mechanistic effects of this combinatorial treatment, we investigated the effects of tamoxifen and LG100268 on mammary tissue biomarkers. In mammary tissue harvested before tumor development, the proliferation markers Ki67 and cyclin D1 were significantly reduced in mice treated with the combination therapy. In addition, the rexinoid target genes ABCA1 and ABCG1 were induced in both the rexinoid and combination treatment groups, whereas expression remained constant in tamoxifen group. These results show that tamoxifen-LG100268 combinatorial treatment is more effective in preventing mammary tumors than either agent alone. In addition, these studies have identified relevant tissue biomarkers that can be used to show the effect of these agents on mammary tissue. These results support the development of clinical trials of antiestrogen and rexinoid combinatorial therapy for the prevention of patients with high-risk breast cancer.