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// Wen-yu Di 1 , Guang-jian Lu 2 , Bao-cai Lu 3 , Li-na Wang 4 , Jing-hang Zhang 1 , Jian Yu 1 , Wei Su 1 , Xiao-hong Kang 5, * and Ping Lu 5, * 1 Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, China 2 Department of Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, China 3 Department of ENT, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, China 4 Quality Controlling Office, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, China 5 Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, China * These authors contributed equally to this work Correspondence to: Xiao-hong Kang, email: kxhhgd@163.com Ping Lu, email: lpkxhdoctor@126.com Keywords: bufalin; ABT-737; Mcl-1; GSK-3β; Ku70 Received: August 21, 2017 Accepted: December 04, 2017 Published: January 02, 2018 ABSTRACT Mcl-1, an anti-apoptotic Bcl-2 family member, is often overexpressed in non-small cell lung cancer (NSCLC) and renders resistance to ABT-737 therapy. Bufalin, a natural cardiac glycoside extracted from Venenum Bufonis , has been reported to induce apoptosis in various tumor cells. In the present study, we discovered that bufalin functioned as a suppressor of Mcl-1. Bufalin significantly enhanced ABT-737-mediated apoptosis in A549 and H1975 cells by suppressing Mcl-1. Overexpression of Mcl-1 diminished apoptosis induced by combination of bufalin and ABT-737. Furthermore, bufalin strongly promoted Mcl-1 protein degradation via activation of GSK-3β and suppression of Ku70. However, expression of exogenous Ku70 and GSK-3β inhibitor resulted in increased levels of Mcl-1 and abrogated attenuated the apoptosis induced by bufalin. Finally, bufalin also sensitized NSCLC cells to ABT-737 treatment by suppressing Mcl-1 in vivo . Taken together, our studies suggest bufalin can potentiate ABT-737 lethality in human non-small cell lung cancer cells through Ku70- and GSK-3β-mediated Mcl-1 degradation.

An experiment on the removal of heavy metal copper ions from industrial wastewater by magnetic flocculation was studied and the influences of PFS dosage static sedimentation time，temperature，pH value and magnetic powder dosage on treatment effect were discussed at the same time .The result of the test showed that when the dosage of PFS and magnetic powder were 100 and 400 mg/l respectively the pH value was 8.0，the static sedimentation time was 20min, the said process had a good effect on copper containing wastewater treatment. The removal rate of copper ions was over 97％，and the mass concentration of copper ions in the effluent water was below 0.5mg/l. Therefore after be treated by magnetic flocculation the quality of copper-containing wastewater could meet the requirement of GB 8978-1996 Integrated Wastewater Discharge Standard .

Carbon nanoparticles were prepared by simple method. TEM image shows that the particle size is several nanometers. Furthermore, the specific surface area of the material is reached for 425.8 m2/g. It is much larger than that of carbonVulcan-XC72, which they is widely used as catalyst supports for DMFC electrodes. Carbon nanoparticles is a kind of promising material used for catalyst support in DMFC.

To observe the effects of hepatocyte growth factor (HGF) derived from tumor microenvironment and/or afatinib on the growth of human lung adenocarcinoma H1975 cells and explore the potential mechanisms by which HGF induces primary resistance to afatinib.The effects of HGF, TGF-α and afatinib on the growth of H1975 cells were evaluated by MTT assay. The HGF concentrations of normal human fetal lung fibroblasts MRC-5 cells and human lung adenocarcinoma H1975 cells co-cultured or separately cultured were determined by ELISA assay. Western blot was used to detect the expressions of EGFR and Met signal pathway-related proteins and epithelial-mesenchymal transition (EMT) markers in H1975 cells treated with HGF and/or afatinib.The MTT assay showed that H1975 cells were hyposensitive to afatinib in the presence of HGF. The ELISA assay showed that HGF production by H1975 cells was less than 0.1 ng/2.0×10(6) cells, but HGF production by MRC-5 cells was (151.37 ± 2.07)ng/2.0×10(6) cells incubated for 48 h. When H1975 cells and MRC-5 cells were co-cultured for 72 h, the concentration of HGF in the culture supernatant was (61.13 ± 16.21)ng/ml. In the presence of HGF, the expression of p-Met, p-Akt and p-ERK proteins in the H1975 cells was markedly up-regulated. afatinib inhibited p-EGFR, but did not affect the expression of p-Met, p-Akt and p-ERK proteins. In the presence of afatinib, HGF up-regulated the expression of vimentin and down-regulated the expression of E-cadherin.HGF secreted by stromal cells in the tumor micro-environment may confer resistance to afatinib in H1975 cells by activation of the Met/PI3K/Akt and Met/MAPK/ERK signaling pathways, and is involved in the epithelial-mesenchymal transition process.

To observe the effect of bufalin combined Gefitinib on lung cancer H1975 cells, and to explore its potential mechanisms for anti-tumor.The cytostatic effects of bufalin (1 -100 nmol/L), gefitinib (0.1-20 micromol/L), and bufalin plus gefitinib on H1975 cells were evaluated by MTT assay. Their effects on apoptosis of H1975 cells were determined by flow cytometry (FCM). Their effects on expressions of epidermal growth factor receptor (EGFR) and Met signal pathway related proteins in H1975 cells were detected by Western blot.Results of MTT assay showed that gefitinib over 5 micromol/L could inhibit H1975 cells. But combined therapy of bufalin and gefitinib could potently inhibit the growth of H1975 cells. Results of FCM showed the apoptotic rate was 61.64% +/- 5.61% in the bufalin plus gefitinib group, obviously higher than that of the bufalin group (18.34% +/- 3.42%) and the gefitinib group (7.32% +/- 1.08%), showing statistical difference (P0.01). Results of Western blot showed the protein expressions of p-EGFR, p-Met, p-Akt, and p-mTOR in H1975 cells could be markedly down-regulated by bufalin plus gefitinib.Combination of bufalin and gefitinib potently inhibited the growth of H1975 cells, and induced cell apoptosis. The potential mechanism for anti-tumor might be involved in blocking EGFR-PI3k/Akt pathway.

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, have shown promising therapeutic efficacy in nonsmall cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor- (EGFR-) activating mutation. However, the inevitable recurrence resulting from acquired resistance has limited the clinical improvement in therapy outcomes. Many studies demonstrate that hepatocyte growth factor- (HGF-) Met axis plays an important role in tumor progression and drug sensitivity. HGF may induce resistance to EGFR-TKIs in EGFR mutant lung cancer cells by Met/PI3K/Akt signaling. The purpose of this study was to determine whether bufalin, a major bioactive component of Venenum Bufonis, could reverse HGF-induced resistance to reversible and irreversible EGFR-TKIs in mutant lung cancer cells PC-9, HCC827, and H1975. Our studies showed that bufalin could reverse resistance to reversible and irreversible EGFR-TKIs induced by exogenous HGF in EGFR mutant lung cancer cells by inhibiting the Met/PI3K/Akt pathway and inducing death signaling. These results suggested that bufalin might have a potential to overcome HGF-induced resistance to molecular-targeted drugs for lung cancer.

This work is concern with stochastic farmer's problem where the fuzzy probability distribution is taken into consideration. We present a two-stage stochastic programming with fuzzy probability distribution (SPFPD) for farmer's problem, and solve this model by making use of the improved L-shaped algorithm. The developed approach in this paper has two major transformation steps with fuzzy transformation and stochastic transformation. In the fuzzy transformation step, we use the alpha cut technique to defuzzify, and in the stochastic transformation step, we adopt minimax rule to establish the deterministic equivalent program associated to the stochastic programming. The numerical examples show the efficiency of the method developed in this paper.

Oxygen chemisorption and electron spin resonance spectroscopy (ESR) have been used to characterize sulfided CoMo/..gamma..-Al/sub 2/O/sub 3/ catalysts with different atomic Co/(Co + Mo) ratios (..cap alpha..). Chemisorption of O/sub 2/ on sulfided Mo/..gamma..-Al/sub 2/O/sub 3/ and CoMo/..gamma..-Al/sub 2/O/sub 3/ samples was proportional to the Mo content, but was only slightly affected by addition of Co. Neither chemisorption of O/sub 2/ nor oxo-Mo/sup +5/ ESR signal intensity correlated with thiophene or benzothiophene hydrodesulfurization (HDS) activity of sulfided CoMo/..gamma..-Al/sub 2/O/sub 3/. 21 refs., 5 figs., 1 tab.