We found that among four master epithelial-to-mesenchymal transition (EMT)-inducing genes (ZEB1, SIP1, Snail, and Slug) ZEB1expression was most significantly correlated with the mesenchymal phenotype (high Vimentin and low E-cadherin expression) in non-small cell lung cancer (NSCLC) cell lines and tumors. Furthermore, ZEB1 knockdown with RNA interference in three NSCLC cell lines with high ZEB1 expression suppressed to varying degrees mass culture growth and liquid colony formation but in all cases dramatically suppressed soft agar colony formation. In addition, ZEB1 knockdown induced apoptosis in one of the three lines, indicating that the growth inhibitory effects of ZEB1 knockdown occurs in part through the activation of the apoptosis pathway. These results suggest that inhibiting ZEB1 function may be an attractive target for NSCLC therapeutic development.
Background: FLAURA, the prospective trial of osimertinib as a first-line therapy compared with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), did not show superior survival benefit for osimertinib in either the subgroup of Asians or the subgroup with the L858R mutation. In addition, the superiority of osimertinib compared with second-generation EGFR-TKI is thus far unclear. Patients and methods: We reviewed the clinical data of all consecutive patients who were treated with osimertinib or afatinib as first-line therapy between May 2016 and October 2019 from 15 institutions in Japan. We defined the groups based on first-line EGFR-TKI as the afatinib group and the osimertinib group. Outcomes included time to discontinuation of any EGFR-TKI (TD-TKI), overall survival (OS), and time to treatment failure, with propensity score analysis carried out as an exploratory analysis in the survival and subgroup analyses. Results: A total of 554 patients were enrolled. Data on 326 patients in the osimertinib group, and 224 patients in the afatinib group were analyzed. TD-TKI adjusted by propensity score in the afatinib and osimertinib groups was 18.6 months (95% confidence interval 15.8 to 22.0) and 20.5 months (95% confidence interval 13.8 to not reached), respectively, without significant difference (P ¼ 0.204). OS adjusted by propensity score favored the afatinib group with a significant difference (P ¼ 0.018). Subgroup analysis with propensity score showed that patients with L858R and without brain metastasis had superior survival benefit with afatinib compared with osimertinib (P < 0.001). Conclusions: TD-TKI in the afatinib group was not significantly prolonged compared with the osimertinib group in the practical data. In the exploratory analysis of patients with L858R-mutated non-small-cell lung cancer without brain metastasis, afatinib showed more benefit in OS over osimertinib.
Epithelial-mesenchymal transition (EMT), which involves the persistent loss of epithelial markers and expression of mesenchymal markers, is assumed to have a critical role in not only tissue development during embryogenesis but also central mechanisms that enhance the invasive and metastatic ability of cancer cells. Twist has been identified to play an essential role in EMT-mediated tumor invasion and metastasis. Although recent studies suggest that twist expression levels in tissue specimens of lung cancer might be associated with prognosis, the expression of twist in lung cancer cells itself and its effect have not been fully evaluated. Here, we evaluated twist expression and its effect on phenotype alteration in lung cancer cell lines. Twist expression varied among human lung cancer cell lines. The lung cancer cell lines with high twist expression also tended to show a high vimentin/E-cadherin ratio, which was supported by a migration assay, in which high twist expression gave rise to high cell motility. Furthermore, in comparison to control cells, the lung cancer cells with ectopic expression of twist showed a significant phenotype alteration through EMT and an increasing ability to migrate in vitro, in part, due to a tenfold increase in matrix metalloproteinases activity and almost a 60% increase in modulation of focal adhesion kinase activity, although a contribution of microRNA appeared unlikely in our study. Our present analysis of twist expression in lung cancer provide clues to comprehensive understanding of the mechanisms, by which metastasis often develops in lung cancer.
Abstract. Objectives: Advances in the field of cardiopulmonary resuscitation have led to an increasing number of patients initially surviving sudden cardiac arrest. Unfortunately, most of these patients do not recover from the resultant anoxic brain insult. Several animal and human trials have suggested that post-resuscitative brain hypothermia may improve neurologic recovery after cardiopulmonary arrest. Present cooling methods are slow, induce only brain surface cooling, or result in systemic hypothermia. The authors tested the hypothesis that unilateral hypothermic carotid bypass would induce bilateral brain cooling without evoking systemic hypothermia or hemodynamic instability. Methods: Anesthetized, ventilated common swine (n = 6, 24-37 kg) underwent right femoral and carotid artery bypass cannulation. Central and peripheral hemodynamic parameters were recorded every 2 minutes throughout the procedure. Thermodynamic parameters included bilateral frontal lobe, bilateral nasopharyngeal, pulmonary artery, and rectal temperatures. Hypothermic femoral-carotid bypass was accomplished by drawing blood from the right femoral artery, cooling it to 24ЊC, and returning it to the right carotid artery at a flow rate of 5 mL/kg/min for 30 minutes. Results: With initiation of cooling, brain temperatures dropped rapidly from baseline of 37.2ЊC to 30.6ЊC (right frontal lobe) and 33.1ЊC (left frontal lobe) at 30 minutes. Pulmonary artery and rectal temperatures also decreased, but never reached mild hypothermic levels (34ЊC). There was no significant change in any hemodynamic parameters during brain cooling. Conclusions: Femoral-carotid hypothermic bypass rapidly induced a state of selective brain hypothermia without causing systemic hypothermia or hemodynamic instability. Key words: hypothermia; brain; resuscitation; bypass; cerebral ischemia. ACADEMIC EMERGENCY MEDICINE 2001; 8:303-308 I NCREASING numbers of patients experiencing out-of-hospital cardiac arrest are surviving to hospital admission as a result of improvements in resuscitation techniques.1-3 Unfortunately, most of these patients fail to recover to their previous functional status. [4][5][6] Present therapy during the post-resuscitative period remains largely suppor- tive and directed at preventing further anoxic insult and cardiovascular instability.Recent evidence from both laboratory and human trials suggests that post-resuscitative brain hypothermia may improve functional outcome of survivors from out-of-hospital cardiac arrest. [7][8][9][10][11]
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