This study analyzes single factors that affect the prognosis of severe acute respiratory syndrome (SARS) and establishes a prognosis model by multivariate analysis. We retrospectively analyzed the clinical features of SARS in 165 clinically confirmed severe cases. Both age and existence of other diseases before SARS were significantly correlated with prognosis (r=0.506 and r=0.457, respectively; P<.001). During the acute phase of SARS, lactate dehydrogenase level, degree of hypoxemia, respiratory rate, alpha -hydroxybutyric dehydrogenase level, creatine kinase isoenzyme-MB, platelet count, and number of involved lobes noted on chest radiographs, and so on, correlated markedly with the prognosis (r=0.257-0.788; P<.05). The multivariate prognosis regression model was associated with degree of hypoxemia and platelet count. The model was defined by the formula Py=1=es/(1+es), where S is [2.490 x degree of hypoxemia]-[0.050 x number of platelets], and it had a high sensitivity (91.67%), specificity (98.33%), and accuracy (96.42%). The model could be used to effectively judge the state of illness and the prognosis.
Paclitaxel is often used in combination with small molecule kinase inhibitors to enhance antitumor efficacy against various malignancies. Because paclitaxel is metabolized by CYP2C8 and CYP3A4, the possibility of drug-drug interactions mediated by enzyme inhibition may exist between the combining agents. In the present study, a total of 12 kinase inhibitors were evaluated for inhibitory potency in human liver microsomes by monitoring the formation of CYP2C8 and CYP3A4 metabolites simultaneously. For reversible inhibition, nilotinib was found to be the most potent inhibitor against both CYP2C8 and CYP3A4, and the inhibition potency could be explained by strong hydrogen binding based on molecular docking simulations and type II binding based on spectral analysis. Comparison of K i values revealed that the CYP2C8 pathway was more sensitive toward some kinase inhibitors (such as axitinib), while the CYP3A4 pathway was preferentially inhibited by others (such as bosutinib). Pathwaydependent inactivation (time-dependent inhibition) was also observed for a number of kinase inhibitors against CYP3A4 but not CYP2C8. Further studies showed that axitinib had a K I of 0.93 mM and k inact of 0.0137 min 21 , and the observed inactivation toward CYP3A4 was probably due to the formation of reactive intermediate (s). Using a static model, a reasonably accurate prediction of drug-drug interactions was achieved by incorporating parallel pathways and hepatic extraction ratio. The present results suggest that potent and pathway-dependent inhibition of CYP2C8 and/or CYP3A4 pathways by kinase inhibitors may alter the ratio of paclitaxel metabolites in vivo, and that such changes can be clinically relevant as differential metabolism has been linked to paclitaxel-induced neurotoxicity in cancer patients.
B7-H3 is a recently discovered member of the B7 superfamily molecules and has been found to play a negative role in T cell responses. In this study, we identified a new B7-H3 isoform that is produced by alternative splicing from the forth intron of B7-H3 and encodes the sB7-H3 protein. Protein sequence analysis showed that sB7-H3 contains an additional four amino acids, encoded by the intron sequence, at the C-terminus compared to the ectodomain of 2Ig-B7-H3. We further found that this spliced sB7-H3 plays a negative regulatory role in T cell responses and serum sB7-H3 is higher in patients with hepatocellular carcinoma (HCC) than in healthy donors. Furthermore, we found that the expression of the spliced sb7-h3 gene is higher in carcinoma and peritumor tissues than in PBMCs of both healthy controls and patients, indicating that the high level of serum sB7-H3 in patients with HCC is caused by the increased expression of this newly discovered spliced sB7-H3 isoform in carcinoma and peritumor tissues.
Sulfur hexafluoride (SF6) is considered as a potent greenhouse gas, whose effective degradation is challenging. Here we report a computational study on the nucleophilic activation of sulfur hexafluoride by N‐heterocyclic carbenes and N‐heterocyclic olefins. The result shows that the activation of SF6 is both thermodynamically and kinetically favorable at mild condition using NHOs with fluoro‐substituted azolium and sulfur pentafluoride anion being formed. The Gibbs free energy barrier during the activation of SF6 has a linear relationship with the energy of HOMO of substrates, which could be a guideline for applying those compounds that feature higher energy in HOMO to activate SF6 in high efficiency.
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