Survival prediction for patients with lung adenocarcinoma: A prognostic risk model based on gene mutations.

BACKGROUND: Lung adenocarcinoma is the most common type of lung cancer, and it is one of the most aggressive and rapidly fatal tumor types. OBJECTIVE: To identify a signature mutation genes for prognostic prediction of lung adenocarcinoma. METHODS: Four hundred and sixty-two lung adenocarcinoma cases were screened out and downloaded from TCGA database. Mutation data of 18 targeted genes were detected by MuTect. LASSO-COX model was used to screen gene loci, and then a prognosis model was established. Afterwards, 40 clinical patients of lung adenocarcinoma were collected to verify the mutation features and the predictive function of the above prognostic model. The mutations of above 18 genes were sequenced with targeted next generation sequencing (NGS) and analyzed with GATK and MuTect. RESULTS: TP53 (282, 32.38%), NF1 (82, 9.41%) and EGFR (80, 9.18%) were the top 3 most frequent mutation genes. A total of 7 variables were screened out after lasso-COX analysis (tumor stage, age, diagnostic type, SMARCA4, GNAS, PTCH2, TSC2). SMARCA4, GNAS and TSC2 were a gene mutation signature to predict a poor prognosis. CONCLUSIONS: We established a prognostic model for lung adenocarcinoma, and further concluded that SMARCA4, GNAS and TSC2 were a gene signature which plays a prognostic role.

Two Ca(2+)-Binding Sites Cooperatively Couple Together in TMEM16A Channel.

TMEM16A is the molecular basis of calcium-activated chloride channels and shows Ca(2+)-dependent gating. It is critical to understand how the Ca(2+) sensors dynamically control the gate of TMEM16A. However, the detailed mechanism by which the calcium ions bind and open the channel is still obscure. In this study, the authors confirmed that there are two Ca(2+) sensors which cooperatively couple together in TMEM16A. Our data show that mutations at both Ca(2+)-sensitive domains, E447Y and E702Q-E705Q, weaken the Ca(2+) affinity for TMEM16A channel. The EC50 for WT, E447Y, and E702Q-E705Q are 0.53 ± 0.11, 14.5 ± 0.3, and 26.5 ± 3.6 µM, respectively. The triple mutation, including both of the Ca(2+) sensors, E447Y-E702Q-E705Q, with EC50 as 55.6 ± 5.1 µM, results in much further right-shifted dose response curve than the single sensor's mutations (E447Y, E702Q-E705Q) do, which indicates that there is a cooperation between the two Ca(2+)-sensitive domains. We also found that the divalent cations, both Ca(2+) and Sr(2+), share common mechanism of gating the TMEM16A.

Molecular simulation assisted identification of Ca(2+) binding residues in TMEM16A.

Calcium-activated chloride channels (CaCCs) play vital roles in a variety of physiological processes. Transmembrane protein 16A (TMEM16A) has been confirmed as the molecular counterpart of CaCCs which greatly pushes the molecular insights of CaCCs forward. However, the detailed mechanism of Ca(2+) binding and activating the channel is still obscure. Here, we utilized a combination of computational and electrophysiological approaches to discern the molecular mechanism by which Ca(2+) regulates the gating of TMEM16A channels. The simulation results show that the first intracellular loop serves as a Ca(2+) binding site including D439, E444 and E447. The experimental results indicate that a novel residue, E447, plays key role in Ca(2+) binding. Compared with WT TMEM16A, E447Y produces a 30-fold increase in EC50 of Ca(2+) activation and leads to a 100-fold increase in Ca(2+) concentrations that is needed to fully activate the channel. The following steered molecular dynamic (SMD) simulation data suggests that the mutations at 447 reduce the Ca(2+) dissociation energy. Our results indicated that both the electrical property and the size of the side-chain at residue 447 have significant effects on Ca(2+) dependent gating of TMEM16A.

Estimating the impact of the home appliances trade-in policy on WEEE management in China.

The ever-increasing amount of waste electric and electronic equipment (WEEE) has become a global problem. In view of the deleterious effects of WEEE on the environment and the valuable materials that can be reused in them, many countries have focused their attention on the management of WEEE and the recovery technologies of WEEE. The Chinese government has been active in creating a legislative and institutional framework to realize WEEE recycling. In June 2009, Chinese government launched home appliances and electronics trade-in implementation solution. This paper elaborates the home appliances trade-in policy and its significant impact on the WEEE management. The trade-in policy is not only conducive to expanding the consumption demand and promoting the balance of domestic and overseas demand, but also favorable to improving the energy efficiency and reducing environmental pollution. Under this policy, China has successfully established an effective WEEE recycling system, using the financial means and network design. Experiences gained from the trade-in policy have shown that management systems of WEEE need to be designed and implemented in a multi-stakeholder dialogue.