BackgroundIn mammalian cells, Aurora serine/threonine kinases (Aurora A, B, and C) are expressed in a cell cycle-dependent fashion as key mitotic regulators required for the maintenance of chromosomal stability. Aurora-A (AURKA) has been proven to be an oncogene in a variety of cancers; however, whether its expression relates to patient survival and the association with radiotherapy remains unclear in non-small cell lung cancer (NSCLC).MethodsHere, we first analyzed AURKA expression in 63 NSCLC tumor samples by immunohistochemistry (IHC) and used an MTS assay to compare cell survival by targeting AURKA with MLN8237 (Alisertib) in H460 and HCC2429 (P53-competent), and H1299 (P53-deficient) cell lines. The radiosensitivity of MLN8237 was further evaluated by clonogenic assay. Finally, we examined the effect of combining radiation and AURKA inhibition in vivo with a xenograft model and explored the potential mechanism.ResultsWe found that increased AURKA expression correlated with decreased time to progression and overall survival (p = 0.0447 and 0.0096, respectively). AURKA inhibition using 100 nM MLN8237 for 48 h decreases cell growth in a partially P53-dependent manner, and the survival rates of H460, HCC2429, and H1299 cells were 56, 50, and 77%, respectively. In addition, the survival of H1299 cells decreased 27% after ectopic restoration of P53 expression, and the radiotherapy enhancement was also influenced by P53 expression (DER H460 = 1.33; HCC2429 = 1.35; H1299 = 1.02). Furthermore, tumor growth of H460 was delayed significantly in a subcutaneous mouse model exposed to both MLN8237 and radiation.ConclusionsTaken together, our results confirmed that the expression of AURKA correlated with decreased NSCLC patient survival, and it might be a promising inhibition target when combined with radiotherapy, especially for P53-competent lung cancer cells. Modulation of P53 function could provide a new option for reversing cell resistance to the AURKA inhibitor MLN8237, which deserves further investigation.
Acute ischemic stroke is one of the leading causes of death in developed countries and the most common cause of disability in adults worldwide. Despite advances in the understanding of stroke pathophysiology, therapeutic options remain limited. In this study, we explored the interaction of Shrm4 and the metabotropic gammaaminobutyric acid (GABA) receptors (GABA B) in ischemic stroke. A transient middle cerebral artery occlusion (MCAO) model was induced by filament insertion in Shrm4+/+ and wild-type C57BL/6J mice, followed by reperfusion for up to 7 days. Baclofen was administered was used to activate GABA B in vivo during reperfusion. Neurological deficits, motor and memory functions, and infarct volume were determined in the various mouse groups. Furthermore, we also developed an oxygenglucose deprivation (OGD) cell model in primary neurons to test Shrm4/GABA B interactions in vitro. Shrm4 was observed to decrease infarct volume and neuronal cell loss in penumbra, and rescue neurological deficits in MCAO mice. Notably, Shrm4 also increased pole climbing speed, reduced foot faults, and increased escape latency in the Morris water maze test, while reducing neuron autophagy through an 2 | YUAN et Al.
Background: This study aimed to determine the extent to which the survival outcomes of patients with N2-III non-small cell lung cancer (NSCLC) following surgery differ by histological subtype. Methods: Patients with N2-III NSCLC receiving surgery between 2010 to 2016 were included using the Surveillance, Epidemiology and End Results (SEER) database. Cox proportional hazards models were used to identify risk factors associated with overall survival (OS) and non-cancer mortality. The Kaplan-Meier method with log-rank tests was used to estimate survival. Propensity score matching (PSM) was used. Statistical significance was defined as P<0.05. Statistical analyses were done with IBM SPSS 23.0. Results: Ultimately, 2,501 patients with stage N2-III NSCLC receiving surgery were included: 1,891 (75.6%) patients had adenocarcinoma (AC), and 610 (24.4%) patients had squamous cell cancer (SCC). The percentages of patients with AC and SCC receiving chemotherapy and postoperative radiotherapy (PORT)were comparable. In multivariate analysis, histology remained a significant predictor for OS and non-cancer mortality after adjusting for other clinical factors (P<0.05). Based on clinical factors, 522 patients with SCC were ultimately matched with 518 patients with AC using PSM. The 5-year OS of SCC patients after matching was much worse than that of AC patients (36.3% vs. 41.5%; P=0.018), and the 5-year non-cancer mortality of SCC patients was much higher than that of AC patients (18.8% vs. 4.8%; P=0.001).Conclusions: Among patients with stage N2-III NSCLC following surgery, those with SCC had worse OS than those with AC, due to the higher percentage of patients dying from non-cancer causes.
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