BACKGROUND: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is a limited factor in the treatment of non-small-cell lung cancer (NSCLC) patients. Therefore, ongoing studies are trying to identify EGFR-TKIs-resistant mechanisms and to discover novel therapeutic strategies and targets for NSCLC treatment.METHODS: In the present study, the possibility of overcoming intrinsic gefitinib-resistance was examined by regulating the expression of AXL. A natural product-derived antitumor agent, yuanhuadine (YD) was employed to modulate the expression of AXL in the cells.RESULTS: Treatment with YD effectively downregulated AXL expression in AXL-overexpressed gefitinib-resistant H1299 cells. The combination of gefitinib and YD exhibited a synergistic grwoth-inhibitory activity in H1299 cells by downregulation of AXL expression.CONCLUSIONS: Based on these findings, AXL was found to be a promising therapeutic target to overcome the intrinsic resistance to gefitinib in NSCLC. Furthermore, YD is able to effectively regulate the expression of AXL and thus it may be applicable as a potential lead compound for the treatment of gefitinib-resistant NSCLC.
Carcinoma, Non-Small-Cell Lung ; Down-Regulation ; Drug Resistance ; Humans ; Lung Neoplasms ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor

Dysregulation of the Wnt pathway causes various diseases including cancer, Parkinson’s disease, Alzheimer’s disease, schizophrenia, osteoporosis, obesity and chronic kidney diseases. The modulation of dysregulated Wnt pathway is absolutely necessary. In the present study, we evaluated the anti-inflammatory effect and the mechanism of action of Wnt-C59, a Wnt signaling inhibitor, in lipopolysaccharide (LPS)-stimulated epithelial cells and macrophage cells. Wnt-C59 showed a dose-dependent anti-inflammatory effect by suppressing the expression of proinflammatory cytokines including IL6, CCL2, IL1A, IL1B, and TNF in LPS-stimulated cells. The dysregulation of the Wnt/β-catenin pathway in LPS stimulated cells was suppressed by WntC59 treatment. The level of β-catenin, the executor protein of Wnt/β-catenin pathway, was elevated by LPS and suppressed by Wnt-C59. Overexpression of β-catenin rescued the suppressive effect of Wnt-C59 on proinflammatory cytokine expression and nuclear factor-kappa B (NF-κB) activity. We found that the interaction between β-catenin and NF-κB, measured by co-immunoprecipitation assay, was elevated by LPS and suppressed by Wnt-C59 treatment. Both NF-κB activity for its target DNA binding and the reporter activity of NF-κB-responsive promoter showed identical patterns with the interaction between β-catenin and NF-κB. Altogether, our findings suggest that the anti-inflammatory effect of Wnt-C59 is mediated by the reduction of the cellular level of β-catenin and the interaction between β-catenin and NF-κB, which results in the suppressions of the NF-κB activity and proinflammatory cytokine expression.

Dysregulation of the Wnt pathway causes various diseases including cancer, Parkinson’s disease, Alzheimer’s disease, schizophrenia, osteoporosis, obesity and chronic kidney diseases. The modulation of dysregulated Wnt pathway is absolutely necessary. In the present study, we evaluated the anti-inflammatory effect and the mechanism of action of Wnt-C59, a Wnt signaling inhibitor, in lipopolysaccharide (LPS)-stimulated epithelial cells and macrophage cells. Wnt-C59 showed a dose-dependent anti-inflammatory effect by suppressing the expression of proinflammatory cytokines including IL6, CCL2, IL1A, IL1B, and TNF in LPS-stimulated cells. The dysregulation of the Wnt/β-catenin pathway in LPS stimulated cells was suppressed by WntC59 treatment. The level of β-catenin, the executor protein of Wnt/β-catenin pathway, was elevated by LPS and suppressed by Wnt-C59. Overexpression of β-catenin rescued the suppressive effect of Wnt-C59 on proinflammatory cytokine expression and nuclear factor-kappa B (NF-κB) activity. We found that the interaction between β-catenin and NF-κB, measured by co-immunoprecipitation assay, was elevated by LPS and suppressed by Wnt-C59 treatment. Both NF-κB activity for its target DNA binding and the reporter activity of NF-κB-responsive promoter showed identical patterns with the interaction between β-catenin and NF-κB. Altogether, our findings suggest that the anti-inflammatory effect of Wnt-C59 is mediated by the reduction of the cellular level of β-catenin and the interaction between β-catenin and NF-κB, which results in the suppressions of the NF-κB activity and proinflammatory cytokine expression.

PUROPOSE: Surgical critically ill patients require adequate nutrition support and the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) guidelines recommend low non-protein calorie:nitrogen ratio (NPC:N ratio, 70~100) for critically ill pateints. In this study, we assess the current use of early parenteral nutrition of surgical critically ill patients and analyze the clinical significance of NPC:N. METHODS: This is a retrospective study of critically ill adult patients who remained in the intensive care unit (ICU) for over 3 days and could not receive enteral nutrition for the first 7 days. Data on parenteral intake of patients were collected from electronic medical records. Association of NPC:N scores with clinical outcome (length of ICU stay, length; of hospital stay, duration of ventilation, and mortality) were analyzed using Pearson correlation and multiple regression. RESULTS: The study included 72 cases, average parenteral calorie intake was 14.6 kcal/kg/day and protein intake was 0.5 g/kg/day. We assessed the NPC:N scores to determine the patients' NPC:N for the first 7 days in ICU close to the A.S.P.E.N guidelines. NPC:N scores showed weak negative correlation with length of hospital stay and duration of mechanical ventilation (r=-0.259, P=0.028; r=-0.495, P=0.001). Multiple regression adjusted with APACHE (Acute Physiology and Chronic Health Evaluation) II score, age, and body mass index showed correlation of higher NPC:N score with decreased length of hospital stay and shorter duration of ventilation (P=0.0001, P=0.035, respectively). However, length of ICU stay and mortality within 60 days showed no significant correlation with NPC:N scores. CONCLUSION: Parenteral calories and protein intakes of critically ill patients in ICU were lower in comparison to A.S.P.E.N. recommendation in this study. Low NPC:N scores might be related to shorter length of hospital stay, duration of mechanical ventilation. Consultation of a nutritional support team could have a positive effect in providing appropriate nutrition support.
Adult ; APACHE ; Body Mass Index ; Critical Illness* ; Electronic Health Records ; Enteral Nutrition ; Humans ; Intensive Care Units ; Length of Stay ; Mortality ; Nitrogen* ; Nutritional Support ; Parenteral Nutrition* ; Physiology ; Protein-Energy Malnutrition ; Respiration, Artificial ; Retrospective Studies ; Ventilation

Variability in rapid response system (RRS) characteristics based on the admitted wards is unknown. We aimed to compare differences in the clinical characteristics of RRS activation between patients admitted to medical versus surgical services. We reviewed patients admitted to the hospital who were detected by the RRS from October 2012 to February 2014 at a tertiary care academic hospital. We compared the triggers for RRS activation, interventions performed, and outcomes of the 2 patient groups. The RRS was activated for 460 patients, and the activation rate was almost 2.3 times higher for surgical services than that for medical services (70% vs. 30%). The triggers for RRS activation significantly differed between patient groups (P = 0.001). They included abnormal values for the respiratory rate (23.2%) and blood gas analysis (20.3%), and low blood pressure (18.8%) in the medical group; and low blood pressure (32.0%), low oxygen saturation (20.8%), and an abnormal heart rate (17.7%) in the surgical group. Patients were more likely classified as do not resuscitate or required intensive care unit admission in the medical group compared to those in the surgical group (65.3% vs. 54.7%, P = 0.045). In multivariate analysis, whether the patient belongs to medical services was found to be an independent predictor of mortality after adjusting for the modified early warning score, Charlson comorbidity index, and intervention performed by the RRS team. Our data suggest that RRS triggers, interventions, and outcomes greatly differ between patient groups. Further research is needed to evaluate the efficacy of an RRS approach tailored to specific patient groups.