Despite an initial response to EGFR tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer, most patients eventually become resistant and result in treatment failure. Recent studies have shown that epithelial to mesenchymal transition (EMT) is associated with drug resistance and cancer cell metastasis. Strong multiple gene signature data indicate that EMT acts as a determinant of insensitivity to EGFR-TKI. However, the exact mechanism for the acquisition of the EMT phenotype in EGFR-TKI resistant lung cancer cells remains unclear. In the present study, we showed that the expression of Notch-1 was highly upregulated in gefitinib-resistant PC9/AB2 lung cancer cells. Notch-1 receptor intracellular domain (N1IC), the activated form of the Notch-1 receptor, promoted the EMT phenotype in PC9 cells. Silencing of Notch-1 using siRNA reversed the EMT phenotype and restored sensitivity to gefitinib in PC9/AB2 cells. Moreover, Notch-1 reduction was also involved in inhibition of anoikis as well as colony-formation activity of PC9/AB2 cells. Taken together, these results provide strong molecular evidence that gefitinib-acquired resistance in lung cancer cells undergoing EMT occurs through activation of Notch-1 signaling. Thus, inhibition of Notch-1 can be a novel strategy for the reversal of the EMT phenotype thereby potentially increasing therapeutic drug sensitivity to lung cancer cells.

Background. Transcutaneous auricular vagus nerve stimulation (ta-VNS) could evoke parasympathetic activities via activating the brainstem autonomic nuclei, similar to the effects that are produced after vagus nerve stimulation (VNS). VNS modulates immune function through activating the cholinergic anti-inflammatory pathway. Methods. VNS, ta-VNS, or transcutaneous electrical acupoint stimulation (TEAS) on ST36 was performed to modulate the inflammatory response. The concentration of serum proinflammatory cytokines and tissue NF-kappa B p65 (NF-κB p65) were detected in endotoxaemia affected anesthetized rats. Results. Similar to the effect of VNS, ta-VNS suppressed the serum proinflammatory cytokines levels, such as tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) as well as NF-kappa B p65 expressions of lung tissues. ST36 stimulation also decreases LPS-induced high TNF-α level and NF-κB signal, but it did not restrain proinflammatory cytokine IL-1β and IL-6. Neither ta-VNS nor ST36 stimulation could suppress LPS-induced TNF-α and NF-κB after vagotomy or with α7nAChR antagonist injection. Conclusions. The present paper demonstrated that ta-VNS could be utilized to suppress LPS-induced inflammatory responses via α7nAChR-mediated cholinergic anti-inflammatory pathway.

Background: Gefitinib, a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), is used both as a single drug and concurrently with whole brain radiotherapy (WBRT) the standard treatment for brain metastases (BM), and is reported to be effective in a few small studies of patients with BM from non-small-cell lung cancer (NSCLC). However, no study has compared the two treatment modalities.

This work provided the first example of selective hydrodeoxygenation of 5-hydroxymethylfurfural (HMF) to 2,5-dimethylfuran (DMF) over heterogeneous Fe catalysts. A catalyst prepared by the pyrolysis of an Fe-phenanthroline complex on activated carbon at 800 °C was demonstrated to be the most active heterogeneous Fe catalyst. Under the optimal reaction conditions, complete conversion of HMF was achieved with 86.2 % selectivity to DMF. The reaction pathway was investigated thoroughly, and the hydrogenation of the C=O bond in HMF was demonstrated to be the rate-determining step during the hydrodeoxygenation, which could be accelerated greatly by using alcohol solvents as additional H-donors. The excellent stability of the Fe catalyst, which was probably a result of the well-preserved active species and the pore structure of the Fe catalyst in the presence of H , was demonstrated in batch and continuous flow fixed-bed reactors.

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