Numerous c-mesenchymal-epithelial transition (c-MET) inhibitors have been reported as potential anticancer agents. However, most fail to enter clinical trials owing to poor efficacy or drug resistance. To date, the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed. In this study, we constructed the largest c-MET dataset, which included 2,278 molecules with different structures, by inhibiting the half maximal inhibitory concentration (IC₅₀) of kinase activity. No significant differences in drug-like properties were observed between active molecules (1,228) and inactive molecules (1,050), including chemical space coverage, physicochemical properties, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding (t-SNE) high-dimensional data. Further clustering and chemical space networks (CSNs) analyses revealed commonly used scaffolds for c-MET inhibitors, such as M5, M7, and M8. Activity cliffs and structural alerts were used to reveal "dead ends" and "safe bets" for c-MET, as well as dominant structural fragments consisting of pyridazinones, triazoles, and pyrazines. Finally, the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules, including at least three aromatic heterocycles, five aromatic nitrogen atoms, and eight nitrogen-oxygen atoms. Overall, our analyses revealed potential structure-activity relationship (SAR) patterns for c-MET inhibitors, which can inform the screening of new compounds and guide future optimization efforts.

Objective:To investigate the effects of ultrasound-guided thoracic paravertebral block on the changes of analgesic efficacy and inflammatory response in patients with multiple rib fractures.Methods:A retrospective case-control study was performed in 48 patients with multiple rib fractures admitted to 909th Hospital of Joint Logistics Support Force from July 2016 to December 2018. There were 30 males and 18 females, with the age range of 18-69 years[(41.1±10.4)years]. The number of fractured ribs was 3-9 (5.7±1.9). All patients were stabilized with the memory alloy embracing fixator. Thoracic paravertebral block group received ultrasound-guided thoracic paravertebral block and intravenous analgesia group received patient controlled intravenous analgesia, with 24 patients in each group. The visual analogue scale (VAS) was observed and recorded in the resting/cough state before induction of anesthesia(T1), and 1 h (T2), 6 h (T3), 24 h (T4) and 48 h (T5) after surgery. Blood samples were taken simultaneously from the vein for determination of plasma neutrophil elastase (NE), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) concentrations by ELISA method.Results:In the resting state, there was no significant difference between two groups in VAS at T1 ( P>0.05); the VAS in two groups at T2-T5 decreased significantly compared with T1 ( P<0.01); the VAS at T2-T4 in thoracic paravertebral block group [(3.4±0.7)points, (3.2±0.8)points, (3.1±0.7)points] was significantly lower than that in intravenous analgesia group [(4.8±0.9)points, (4.4±0.7)points, (3.9±0.8)points]( P<0.01 ). In the cough state, there was no significant difference between two groups in VAS at T1 ( P>0.05); the VAS at T2-T5 in intravenous analgesia group was all higher than 6 points[(7.7±1.0)points, (7.6±1.3)points, (7.4±1.2)points, (7.1±0.9)point], and was significantly higher than those in thoracic paravertebral block group [(3.6±0.7)points, (3.3±0.7)points, (3.2±0.6)points, (2.9±0.7)points] ( P<0.01). There was no significant difference between two groups in plasma levels of NE, TNF-α and IL-6 at T1 ( P>0.05). Their levels at T2 in two groups were significantly increased, but were decreased at T5 compared with those at T1 ( P<0.01). The plasma levels of NE, TNF-α and IL-6 were significantly lower in thoracic paravertebral block group at T2-T5 [NE: (65.5±19.0)ng/ml, (42.5±12.5)ng/ml, (26.3±9.3)ng/ml, (20.9±7.9)ng/ml; TNF-α: (8.7±1.9)pg/ml, (6.0±1.3)pg/ml, (3.9±0.9)pg/ml, (2.8±0.8)pg/ml; IL-6: (11.5±3.6)pg/ml, (6.7±1.8)pg/ml, (3.6±1.0)pg/ml, (2.5±0.7)pg/ml] than those in intravenous analgesia group[NE: (76.7±18.2)ng/ml, (51.4±15.1)ng/ml, (35.5±10.0)ng/ml, (28.6±9.0)ng/ml; TNF-α: (10.0±2.1)pg/ml, (6.8±1.5)pg/ml, (4.7±1.1)pg/ml, (3.6±1.0)pg/ml; IL-6: (16.2±4.2)pg/ml, (8.7±2.1)pg/ml, (5.7±1.2)pg/ml, (3.5±0.7)pg/ml] ( P<0.05 or 0.01). Conclusion:Compared with intravenous analgesia, ultrasound-guided thoracic paravertebral block can provide better analgesic effect, reduce the plasma levels of inflammatory cytokines that result from trauma and surgery, and down-regulate inflammatory response.

Objective To explore the relationship between the expression of transcription factor ⅡB-related factor 1 (Brf1) and the prognosis of non-small cell lung cancer (NSCLC).Methods Collected 96 cases of NSCLC Surgical specimens and clinical data of patients from January 2013 to August 2015 in our hospital.First of all,we compared the expression of Brf1 in NSCLC tissues and adjacent lung tissues by Western blot and RT-qPCR.Then,Immunohistochemistry was used to detect the expression of Brf1 in NSCLC tissues,and analysis of the relationship between Brf1 expression level and clinical case characteristics.Survival curves were plotted using the Kaplan-Meier method and Log-rank test and multivariate Coxv regression analysis were performed.Results Western blot and RT-qPCR results showed that the expression of Brf1 in NSCLC tissues was significantly higher than that in adjacent lung tissues (P ＜0.01).The positive expression rate of Brf1 in 96 cases of NSCLC was 72.9％.The Brf1 expression level was higher in the poorly differentiated group than in the moderately-highly differentiated group(Mean Rank 62.33 ＞ 43.89,Z =-2.914,P =0.004),and the lymph node metastasis group was higher than the non-metastasis group(Mean Rank 60.34 ＞ 42.58,Z =-3.055,P =0.002),which was independent of patient gender,age,smoking status,tumor size,TNM stage,and pathological type (P ＞0.05).Single-factor survival analysis by Log-rank test showed that the survival rate of Brf1 positive expression group was lower than that of the negative group (x2 =7.560,P ＜0.01).Multivariate analysis of Cox regression model found that Brf1 positive expression (HR =2.043,95％ CI:1.082-3.860) was an independent observational index that affects the prognosis of patients with NSCLC.Conclusion Brf1 is overexpressed in NSCLC tissues,and Brf1 negative expression has a good clinical prognosis,suggesting that Brf1 may be one of the indicators of malignant degree and prognosis of NSCLC.

Objective To investigate the effect of perioperative secondary thoracotomy on the risk of thrombosis in patients with thoracic trauma.Methods A retrospective case control study was conducted on the clinical data of 175 patients with thoracic trauma who underwent thoracotomy from January 2000 to December 2016.According to whether the patients underwent secondary thoracotomy,they were divided into secondary thoracotomy group (36 cases) and the control group (139 cases).In the secondary thoracotomy group,there were 25 males and 11 females,with age of (65.4 ± 5.5) years and thoracic abbreviated injury score (AIS) of (3.8 ±0.6) points.In the control group,there were 98 males and 41 females,with the age of (64.6 ±5.3)years and thoracic AIS of (3.7 ±0.8)points.The ICU stay,thoracic drainage,bed rest time,and the incidence of thrombosis in two groups were compared,and the levels of endothelin (ET-1),D-dimer aggregation and platelet were measured.Logistic regression analysis was used to analyze the impact of secondary thoracotomy on the risk of thrombosis.Results Compared with the control group,patients in the secondary thoracotomy group had longer ICU stay [(4.2 ± 1.4) d ∶(1.8± 1.0)d](P＜0.01),more thoracic drainage [(1 550 ±250)ml ∶ (635 ± 184)ml] (P＜0.01),and longer bed rest time [(5.4 ± 1.6) days ∶ (1.5 ± 0.9) days] (P ＜ 0.01).There were significant differences in levels of ET-1 and D-dimer aggregation between two groups (P＜0.01).There was significant difference in platelet count after 5 days (P ＜ 0.01).Twelve cases of deep venous thrombosis (33％) occurred in the secondary thoracotomy group,of which six cases died of thrombus related complications.Eight cases (5.7％) of deep venous thrombosis occurred in the control group,all of which recovered (P ＜ 0.05).In multivariate analysis,ET-1 (OR =7.46,95％ CI 4.53-11.06,P ＜ 0.05),D-dimer aggregation (OR =4.28,95％ CI 2.65-8.37,P ＜ 0.05),and platelet count (OR =1.13,95 ％ CI 0.56-1.98,P ＜ 0.05) were independent risk factors for thrombosis events.Conclusions Perioperative secondary thoracotomy increases the risk of thrombotic events.ICU hospitalization,thoracic drainage,and bed time are associated with thrombosis events.ET-1,D-dimer aggregation,and platelet count are independent risk factors for thrombosis events.