AZD7545 Based on the above presumption activation of Sox and
Based on the above presumption, activation of Sox11 and FAK might be beneficial for alleviating the VILI. Previous studies have showed the relevance of Sox11 or FAK up-regulation with improvement of tissue injury. For example, over-expression of Sox11 protected and improved the tissue function or structure and optimized the functional output of stimulated neurons in the spinal injury . Down-regulation of Sox18 was essentially involved in the disruption of endothelial cell barrier integrity associated with LPS-induced lung injury . On the other hand, the improvement of FAK on lung injury has also been reported. FAK improved the acute lung injury induced by LPS by regulating pulmonary endothelium barrier function . FAK upregulation induced by dexmedetomidine attenuated pulmonary microvascular hyper-permeability following kidney injury . Therefore, according to the relevance of Sox11 and FAK to the tissue injury and repair, we directly observed the effect of exogenous supplement of Sox11 on the pathogenesis of VILI by transfection of Sox11 plasmid in the present study. We found that the transfection of Sox11 plasmid significantly up-regulated the expression of Sox11 and FAK and then alleviated VILI induced by HMV, which represented with improvement of pulmonary edema and inflammatory response, pathological abnormalities, and apoptosis of alveolar epithelial cells. These findings provided convincing evidence to indicate the involvement of down-regulation of Sox11 and FAK in the pathogenesis of VILI induced by HMV, and suggested a potential target by facilitating the activity of Sox11 and FAK in the prevention and treatment of VILI.
To prove the role of FAK as a downstream signal of Sox11 in the alleviating effect of Sox11 plasmid transfection on the VILI, we further investigated the effect of FAK antagonism on the protective effect of Sox11 transfection on VILI induced by HMV. It was shown that co-administration of FAK antagonist blocked the improvement of Sox11 transfection on VILI, which represented with the aggravation of lung injury compared with single Sox11 transfection in HMV mice. Previous reports have showed the relevance of FAK inhibition with tissue injury or cell death. For example, inhibition of FAK can trigger apoptosis of type 2 alveolar epithelial AZD7545 , while activation of FAK played anti-apoptosis effect by blocking caspase-8 . In contrast, FAK phosphorylation level was decreased when type 2 alveolar epithelial cells were mechanically dissociated from matrix in vitro . These reports support our findings and further strengthened the evidence to illustrate the important role of dysregulation of Sox11 and FAK in the VILI. Taken together, it could be concluded that down-regulation of Sox11 and FAK after HMV play an important role in the pathogenesis of VILI, and that facilitating the activity of Sox11 and FAK might be an effective target and a potential option in the prevention and treatment of VILI in clinic.
Although we found dysregulation of Sox11 and FAK during VILI, the mechanism of the deysegulation is still unknown. It has been reported that mechanical stretch could induce inflammation response and then trigger changes in epigenetic and gene expression and modification such as DNA methylation, or histone [26,27]. These changes during VILI might contribute to the dysregulation of Sox11 and FAK activity . In addition, the present study showed that FAK antagonist not only inhibited the function of FAK, but also the expression of FAK gene and protein. Although the similar phenomenon was found in Xus' studies  as well, the mechanism needs to be further explored.
Conflicts of interest
Introduction Pancreatic cancer (PC) has a mortality rate which closely parallels the corresponding incidence rate  making it the most lethal malignancy among digestive tract tumors. The American Cancer Society estimates that PC will be the fourth leading cause of cancer death in the USA by the end of 2018 with approximately 55440 newly diagnosed cases and nearly 45000 related deaths in 2018 . Similar data from the National Central Cancer Registry of China suggested the incidence and related mortality rates of PC rapidly increased between 2000 and 2011 , meaning PC is a global health issue which is causing a significant medical burden around the world. Radical resection followed by adjuvant therapy remains the standard treatment for PC. However, due to its early recurrence/metastasis and resistance to chemotherapy, the 5-year survival is only up to 25% even after receiving potential curative resection . Moreover, even the newly developed immunotherapies, including anti-programmed death 1 or programmed death 1 ligand 1 (PD-1/PDL-1) treatment, showed a poor effect on PC . Therefore, detailed investigation of the molecular mechanisms of tumor cell metastasis and chemo-resistance to gemcitabine in PC is necessary and may provide insight for new treatment targets and evidence to improve PC prognosis.