RESUMEN
Patients with non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs) inevitably exhibit drug resistance, which diminishes therapeutic effects. Nonetheless, the molecular mechanisms of TKI resistance in NSCLC remain obscure. In this study, data from clinical and TCGA databases revealed an increase in DNMT3A expression, which was correlated with a poor prognosis. Using NSCLC organoid models, we observed that high DNMT3A levels reduced TKI susceptibility of NSCLC cells via upregulating inhibitor of apoptosis proteins (IAPs). Simultaneously, the DNMT3Ahigh subset, which escaped apoptosis, underwent an early senescent-like state in a CDKN1A-dependent manner. Furthermore, the cellular senescence induced by TKIs was observed to be reversible, whereas DNMT3Ahigh cells reacquired their proliferative characteristics in the absence of TKIs, resulting in subsequent tumour recurrence and growth. Notably, the blockade of DNMT3A/IAPs signals enhanced the efficacy of TKIs in DNMT3Ahigh tumour-bearing mice, which represented a promising strategy for the effective treatment of NSCLC.
RESUMEN
Gefitinib is a potent inhibitor of EGFR and represents the front-line treatment for non-small cell lung cancer (NSCLC) therapeutics. However, NSCLC patients are prone to develop acquired resistance through as yet, undefined mechanisms of resistance. Here, we investigated the role of COX-2 during gefitinib resistance in NSCLC cells and revealed its underlying mechanism(s) of action. We report the upregulation of COX-2 in gefitinib-resistant NSCLC tissues and cells, which is associated with poor prognosis. In vitro assays in NSCLC cells (PC9/GR) showed that COX-2 facilitates gefitinib resistance in NSCLC cells through its effects on P-gp, MRP1, and BCRP, and cancer cell migration and invasion. In vivo, COX-2 silencing could repress tumor growth. We found that the overexpression of COX-2 enhances the transcription of MMP-2, MMP-7, and MMP-9 which mediates PI3K-AKT activation. In summary, we demonstrate that COX-2 mediates the gefitinib resistance of NSCLC cells through its interaction with EGFR and the PI3K-AKT axis. This highlights COX-2 as a novel molecular target for NSCLC.
RESUMEN
This study aimed to evaluate the relationship between gut probiotic flora and nonalcoholic fatty liver disease in a diet-induced rat model, and to compare the effects of two different probiotic strains on nonalcoholic fatty liver disease. Forty male Sprague-Dawley rats were randomized into 4 groups for 12 weeks: control (standard rat chow), model (fat-rich diet), Lactobacillus (fat-rich diet plus Lactobacillus acidophilus), and Bifidobacterium (fat-rich diet plus Bifidobacterium longum) groups. Probiotics were provided to rats in drinking water (10(10)/ml). Gut bifidobacteria and lactobacilli were obviously lower at weeks 8 and 10, respectively, in the model group compared with the control group. Supplementation with Bifidobacterium significantly attenuated hepatic fat accumulation (0.10 ± 0.03 g/g liver tissue) compared with the model group (0.16 ± 0.03 g/g liver tissue). However, there was no improvement in intestinal permeability in either the Lactobacillus or the Bifidobacterium group compared with the model group. In all 40 rats, the hepatic total lipid content was negatively correlated with gut Lactobacillus (r = -0.623, p = 0.004) and Bifidobacterium (r = -0.591, p = 0.008). Oral supplementation with probiotics attenuates hepatic fat accumulation. Further, Bifidobacterium longum is superior in terms of attenuating liver fat accumulation than is Lactobacillus acidophilus.
RESUMEN
OBJECTIVE: To compare the prevalence rates of metabolic syndrome (MS) in obese children, according to three commonly used 'Pediatric MS definitions': (1) the International Diabetes Federation (IDF), (2) Cook, et al, and(3)da Silva, et al, in order to choose an appropriate one for the Chinese obese children. It was also intended to assess the variances of American or Chinese cutoff values on MS prevalence. METHODS: A retrospective study was performed in obese children from Obesity Outpatient Service Program from January 2004 to December 2008. Subjects were eligible if they met the following criteria: (1) aged 7 to 18 years, (2) with no following conditions as hereditary endocrine or metabolic diseases, secondary obesity, hepatic or renal disease, using medication that alters blood pressure or glucose or lipid metabolism etc., (3) data were complete on the variables of interest. Height, weight and waist circumference, systolic and diastolic blood pressure, fasting lipid profiles, blood sugar and insulin were measured. Insulin resistance was evaluated by homeostasis model assessment (HOMA). American or Chinese cutoff values were used to identify central obesity and hypertension. The prevalence rates of MS under three definitions were calculated and compared by Kappa test to determine the degree of agreement. RESULTS: 136 patients with 103 males and 33 females were enrolled in the study. According to the American cutoff value, 19.2%, 34.6%, 52.9% of the subjects were classified as MS under definitions of IDF, Cook, et al, da Silva, et al respectively, matching well with 19.2%, 43.4%, 58.1% when the Chinese cutoff value was used (Kappa = 1, 0.79, 0.90). The degrees of agreement according to the Kappa statistics between Cook, et al and da Silva, et al (0.52, American cutoff value/0.51, Chinese cutoff value) were better than the others (0.24 - 0.4). Children who were diagnosed as MS under the definitions of Cook, et al. or da Silva, et al. appeared to have had serious insulin resistance when compared to those without MS. CONCLUSION: Prevalence of the metabolic syndrome appeared to be high among the obese pediatric outpatients, which was probably due to the definition being chosen. The use of definitions provided by Cook, et al and da Silva, et al might be more suitable for MS diagnosis in obese children in the outpatient department, if insulin resistance was under consideration. Both American and Chinese cutoff value could be used for MS diagnosis in the Chinese obese children.
