Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) positively affect the initial control of non-small cell lung cancer (NSCLC). Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful treatment. However, the mechanisms that control the resistance of EGFR-TKIs remain largely unknown. RNA structures have widespread and crucial functions in many biological regulations; however, the functions of RNA structures in regulating cancer drug resistance remain unclear. Here, the psoralen analysis of RNA interactions and structures (PARIS) method is used to establish the higher-order RNA structure maps of EGFR-TKIs-resistant and -sensitive cells of NSCLC. Our results show that RNA structural regions are enriched in untranslated regions (UTRs) and correlate with translation efficiency (TE). Moreover, yrdC N⁶-threonylcarbamoyltransferase domain containing (YRDC) promotes resistance to EGFR-TKIs. RNA structure formation in YRDC 3' UTR suppresses embryonic lethal abnormal vision-like 1 (ELAVL1) binding, leading to EGFR-TKI sensitivity by impairing YRDC translation. A potential therapeutic strategy for cancer treatment is provided using antisense oligonucleotide (ASO) to perturb the interaction between RNA and protein. Our study reveals an unprecedented mechanism through which the RNA structure switch modulates EGFR-TKI resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; ErbB Receptors/metabolism* ; GTP-Binding Proteins/therapeutic use* ; Lung Neoplasms/genetics* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; RNA ; RNA-Binding Proteins/genetics* ; Tyrosine Kinase Inhibitors/therapeutic use*

Objective To investigate the effects of enteral nutrition added with glutamine on the incidences of gastrointestinal complications,intestinal mucosal barrier function and inflammatory responses in patients with acute severe traumatic brain injury (sTBI).Methods A prospective case control study was made on 107 patients with sTBI hospitalized from January 2016 to June 2017.The patients were divided into experimental group added with glutamine (n =54) and control group without glutamine (n =53) according to the random number table.The general data of the patients were recorded.After treatment,the incidences of gastrointestinal complications in both groups were compared.The serum levels of intestinal mucosal barrier function indices,namely,diamine oxidase (DAO),Dlactate acid,and intestinal fat acid binding protein (I-FABP) were evaluated by enzymology spectrophotometer method.Meanwhile,the serum levels of C-reactive protein (CRP),tumor necrosis factor-α (TNF-α),and interleukin-6 (IL-6) were also tested with enzyme-linked immunosorbent assay (ELISA).Glasgow coma scale (GCS),acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ),and hospital stay in both groups were compared.Results The two group were comparable with respect to gender,age,injury reasons,body mass index,preoperative GCS,preoperative APACHE Ⅱ,injury type and injury time (P ＞ 0.05).The experimental group had lower incidences of stress ulcer,gastric retention and diarrhea compared with the control group 14 days after treatment (P ＜ 0.05).Within 14 days after treatment,the serum levels of DAO,D-lactate acid and I-FABP were significantly decreased in the experimental group at days 7 and 14 after treatment (P ＜ 0.05).The serum levels of CRP,TNF-α and IL-6 in the experimental group were significantly decreased after treatment (P ＜ 0.05).The experimental group had better prognosis compared with the control group (P ＜ 0.05),with higher GCS scores [(9.3 ± 0.7) points vs.(8.2 ± 0.7) points],lower APACHE Ⅱ scores [(15.3 ± 1.1) points vs.(17.7 ± 1.2) points] at day 14,and shorter hospital stay [(19.1 ± 2.2) days vs.(25.3 ± 2.4) days] (P ＜ 0.01).Conclusions Enteral nutrition added with glutamine can effectively reduce the incidence of gastrointestinal complications,as well as alleviate the intestinal mucosal barrier function damage and the inflammatory responses at early stage after sTBI,which possibly improves prognosis.

Objective To investigate the effect of enteral microecopharmaceutics nutrition supplement (EMN) on incidence of ventilator associated pneumonia complications,inflammatory responses,and prognoses in patients with severe traumatic brain injury (sTBI) undergoing ventilator therapy.Methods From January 2016 to September 2017,70 patients with sTBI were randomly divided into an experimental group (EMN supplement,n=35) and a control group (n=35).Early enteral nutrition was given to patients from both groups,and bifidobacterium viable capsule was given to patients from the experimental group.Glasgow Coma Scale (GCS) scores,acute physiological and chronic health evaluation (APACHE) II scores,number of white blood cells (WBC),proportion of neutrophil (N),and serum levels of procalcitonin (PCT) and C-reactive protein (CRP) were compared between the two groups on admission and 14 d after treatment.The incidence of VAP and clinical pulmonary infection scale (CPIS) scores,pulmonary function,mechanical ventilation time and hospital stays were compared 14 d after treatment.Results The incidence of VAP in the experimental group (n=17,51％) 14 d after EMN supplement was significantly lower as compared with that in the control group (n=22,63％,P＜0.05).Meanwhile,VAP patients from the experimental group had significantly lower CPIS scores as compared with patients from control group (P＜0.05).Ventilator weaning was achieved in 29 patients from experimental group (83％) and 24 patients from control group (69％),with significant difference (P＜0.05);ventilator weaning patients from the experimental group had significantly improved lung function as compared with ventilator weaning patients from control group (P＜0.05).WBC number,N proportion,and serum PCT and CRP levels in the experimental group were significantly smaller/decreased as compared with those in the control group (P＜0.05).As compared with patients from control group,patients from the experimental group had significantly higher GCS scores (8.35±0.51 vs.9.48±0.48,P＜0.05) and significantly lower APACHE II scores (12.58±0.78 vs.14.68±0.97,P＜0.05).Conclusion EMN supplement can effectively reduce the VAP incidence,alleviate the degree of infection and inflammatory response in patients with sTBI undergoing ventilator therapy,therefore,improve the prognosis;this method is worth of promotion.