Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC₅₀ values and achieved picomolar DC₅₀ values and >99% of maximum degradation (D_max) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15 dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-MET^Y1230H and c-MET^D1228N mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.

Objective:To investigate multimodality imaging characteristics and clinical features of lymphomatosis cerebri (LC) and reasons for misdiagnosis,with the goal of potentially facilitating an early and accurate diagnosis for this often-missed disease.Methods:Clinical data and cerebral multimodality imaging findings from 11 patients with LC proven basing on pathology in the Affiliated Hospital of Guizhou Medical University from November 30, 2011 to December 28, 2020 were retrospectively extracted, analyzed, and reviewed in combination with the literatures.Results:The common presenting symptoms with subacute onset included cognitive decline (8/11), gait disturbance (9/11), and behavioral disturbance (5/11). Test of cerebrospinal fluid showed that the number of cells and the level of protein increased (8/10), the sugar content (2/10) and chloride (4/10) decreased. The imaging manifestations of 11 patients with LC were diffuse lesions of bilateral cerebral white matter in the both deep and lobar lesion distribution, involving the cerebral cortex and subcortical white matter in eight cases (8/11), basal ganglia in seven cases (7/11), thalamus in five cases (5/11), cerebellum in six cases and brain stem in six cases (6/11). All 11 patients showed equal or slightly low-density shadows on CT plain scan and slightly longer T 1WI and T 2WI signals on magnetic resonance imaging. Six cases (6/11) had no obvious enhancement in the early stage, and five cases and six follow-up cases showed heterogenous spots, patches, nodules or clusters of distinct enhancement. Diffusion-weighted imaging showed non restricted diffusion in nine (9/11) cases initially diagnosed, and restricted diffusion in two cases (2/11) and nine follow-up cases, which were hyperintense on diffusion-weighted imaging and hypointense on apparent diffusion coefficient maps. Five patients (5/5) presented a marked decrease in N-acetyl aspartic acid (NAA)/creatine (Cr) and increase in choline (Cho)/Cr on hydrogen proton magnetic resonance spectrum, including an increase in lipid/Cr in three cases. One case (1/3) showed no abnormal increase in lesion metabolism, and two cases (2/3) showed slightly increased uptake on positron emission tomography/CT. Conclusions:Diffuse bilateral cerebral lesions especially in deep and lobar region, without enhancement or with patchy enhancement, marked decrease in NAA/Cr and increase in Cho/Cr and Lip/Cr are suggestive of LC. Misdiagnosis may be mainly due to insufficient understanding and improper brain biopsy.

Objective:To explore the impact of occupational stress and shift work on the mental health of railway workers and provide a scientific basis for occupational health protection.Methods:In April 2019, stratified cluster sampling method was used to select 613 railway workers from Fuzhou railway as subjects. Job Content Questionnaire (JCQ) , Symptom Checklist-90 (SCL-90) , Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) were used to investigate railway workers' occupational stress and mental health conditions. The influencing factors of railway workers' mental health were analyzed.Results:The detection rates of mental health problems, anxiety and depression of railway workers were 40.5% (248/613) , 4.4% (27/613) and 9.0% (55/613) , respectively. There were 250 railway workers with occupational stress (40.78%) . There were statistically significant differences in the total scores of SCL-90 among different groups of working age and education background ( P<0.05) . And there were statistically significant differences in the SAS total scores among different groups of education background ( P<0.05) . The detection rates of mental health problems and anxiety in the night shift group were higher than that in the white shift group, and the differences were statistically significant ( P<0.05) . The detection rate of mental health problems in the group with occupational stress was higher than that in the group without occupational stress, and the difference was statistically significant ( P<0.05) . Logistic regression analysis found that night shift work was the main risk factor affecting railway workers' anxiety ( OR=2.38, 95 %CI: 1.04-5.46, P<0.05) . The results of interaction analysis showed that compared with the non-occupational stress+white shift group, the workers in the night shift+occupational stress group had the higher risk of mental health problems and anxiety ( OR=3.14, 95 %CI: 1.84-5.38; OR=4.29, 95 %CI: 1.36-13.54; P<0.05) . Conclusion:Night shift and occupational stress are the risk factors for the mental health of railway workers, and the interaction between night shift and occupational stress is the most harmful to the mental health of railway workers.

Objective:To explore the impact of occupational stress and shift work on the mental health of railway workers and provide a scientific basis for occupational health protection.Methods:In April 2019, stratified cluster sampling method was used to select 613 railway workers from Fuzhou railway as subjects. Job Content Questionnaire (JCQ) , Symptom Checklist-90 (SCL-90) , Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) were used to investigate railway workers' occupational stress and mental health conditions. The influencing factors of railway workers' mental health were analyzed.Results:The detection rates of mental health problems, anxiety and depression of railway workers were 40.5% (248/613) , 4.4% (27/613) and 9.0% (55/613) , respectively. There were 250 railway workers with occupational stress (40.78%) . There were statistically significant differences in the total scores of SCL-90 among different groups of working age and education background ( P<0.05) . And there were statistically significant differences in the SAS total scores among different groups of education background ( P<0.05) . The detection rates of mental health problems and anxiety in the night shift group were higher than that in the white shift group, and the differences were statistically significant ( P<0.05) . The detection rate of mental health problems in the group with occupational stress was higher than that in the group without occupational stress, and the difference was statistically significant ( P<0.05) . Logistic regression analysis found that night shift work was the main risk factor affecting railway workers' anxiety ( OR=2.38, 95 %CI: 1.04-5.46, P<0.05) . The results of interaction analysis showed that compared with the non-occupational stress+white shift group, the workers in the night shift+occupational stress group had the higher risk of mental health problems and anxiety ( OR=3.14, 95 %CI: 1.84-5.38; OR=4.29, 95 %CI: 1.36-13.54; P<0.05) . Conclusion:Night shift and occupational stress are the risk factors for the mental health of railway workers, and the interaction between night shift and occupational stress is the most harmful to the mental health of railway workers.

Objective To study the clinical significance of globus pallidus signal intensity and the intensity ratio of globus pallidus and putamen (G/P ratio) on magnetic resonance T1WI for the early recognition of neonatal bilirubin encephalopathy.Method From January to December 2017,full-term neonates with hyperbilirubinemia admitted to the neonatology department of our hospital were enrolled in the case group,and full-term neonates without hyperbilirubinemia in the control group.The clinical data,globus pallidus T1WI signal intensity,G/P ratio and the follow-up data were collected.According to the level of hyperbilirubinemia,the neonates in the case group were further assigned into mild hyperbilirubinemia group (serum bilirubin:222 to ＜256 μmol/L),moderate hyperbilirubinemia group (serum bilirubin:256 to ＜342 μmol/L),and severe hyperbilirubinemia group (serum bilirubin:≥ 342 μmol/L).According to the injury score of ABE,the neonates with ABE were assigned into mild ABE group,moderate ABE group and severe ABE group.The correlation of globus pallidus T1WI and T2WI signal values,G/P ratio and the serum bilirubin level and ABE degree were analyzed;receiver operating characteristic (ROC) curve was drawn to explore the predictive value of the T1WI signal value and G/P ratio for the diagnosis of ABE;the changes of globus pallidus T1WI and T2WI signal values during the first 6 months after birth and the results of follow-up to 1 year after discharge were also analyzed.Result A total of 175 neonates were included in the case group (65 in the mild hyperbilirubinemia group,71 in the moderate hyperbilirubinemia group and 39 in the severe hyperbilirubinemia group) and 43 neonates in the control group.39 neonates were diagnosed as ABE (21 mild ABE,12 moderate ABE,and 6 severe ABE).The first T1WI signal value and G/P ratio of neonates in the severe hyperbilirubinemia group was higher than the moderate hyperbilirubinemia group,the mild hyperbilirubinemia group and the control group;the T1WI signal value and G/P ratio in the moderate hyperbilirubinemia group was higher than the mild hyperbilirubinemia group and the control group (P ＜ 0.05).No significant difference existed between the mild group and the control group(P ＞ 0.05).T2WI values showed no differences among neonates with different bilirubin levels (P ＞ 0.05).The first T1WI signal value and G/P ratio in the severe ABE group were significantly higher than the moderate and mild ABE group,and the moderate ABE group higher than the mild ABE group (P ＜ 0.05).The ROC curve indicated the optimal cut-off value of T1WI signal and G/P ratio were 628 and 1.38,respectively.Among all the 175 neonates,9 had a decrease in T1WI signal value and an increase in T2WI signal value at 6 months after birth.After 1 year of follow-up visits,7 children were finally diagnosed as chronic bilirubin encephalopathy.All these children had increased signal intensity on T1WI in the acute phase,plus a decreased T1WI signal and an increased T2WI signal in 1 ～ 6 months after birth.Conclusion The globus pallidus T1WI signal and G/P ratio are closely related to the serum bilirubin level and ABE severity.If T1WI signal value ＞ 628 or G/P value ＞ 1.38,ABE should be considered.The T1WI signal value and G/P ratio play important roles as indicators for the early recognition of neonatal bilirubin encephalopathy.

OBJECTIVE: To explore the correlation between endothelial microparticles(EMPs) and subacute 1,2-dichloroethane(1,2-DCE) toxic encephalopathy. METHODS: A total of 24 patients with subacute 1,2-DCE toxic encephalopathy were selected as the case group, and 24 healthy individuals were selected as the control group using a convenient sampling method. Blood plasma was collected from the fasting venous blood of patients in these two groups, and the level of EMPs in the plasma was detected by flow cytometry. RESULTS: The levels of plasma EMPs of patients in the control group and the case group were(692.0±174.4) ×10~3/L and(839.8±155.8) ×10~3/L respectively. The levels of plasma EMPs in patients with mild, moderate and severe case subgroups were(691.6±101.9) ×10~3/L,(900.6±46.6) ×10~3/L and(1 026.8±69.8)×10~3/L respectively. The EMPs level of patients in the case group was higher than that of the control group(P<0.01). The level of EMPs in the moderate and severe case subgroups was higher than that of the control group and mild case subgroup(P<0.01). CONCLUSION: Endothelial injury was found in patients with subacute 1,2-DCE toxic encephalopathy and endothelial injury is related to the severity of poisoning.

Objective:To investigate the clinical value of ankle-brachial index (ABI) in evaluating vascular cognitive dysfunction (VCI) in the elderly.Methods:According to the mini mental state examination (MMSE) and Montreal cognitive assessment (MoCA), 200 elderly inpatients from May 2016 to February 2018 in our hospital were selected. MoCA scale was used to evaluate the cognitive function of the patients. The patients were divided into cognitive dysfunction group ( n=110) and cognitive normal group ( n=90). The clinical data of the two groups were analyzed and compared. The correlation between ABI and MMSE, MOCA and clinical indicators was observed. The receiver operating characteristic (ROC) curve of ABI value to the predictive value of VCI in the elderly was drawn. Results:⑴ There was no significant difference between the two groups in terms of gender, the first fasting blood glucose value in hospital and the situation of diabetes, hypertension and hyperlipidemia ( P>0.05); there was significant difference in age, low-density lipoprotein cholesterol (LDL-C) level, history of small cerebral vessels and ABI between the two groups ( P<0.05). ⑵ Logistic regression analysis showed that ABI was the related factor of VCI in the elderly ( P<0.01). ⑶ Pearson correlation analysis showed that MMSE score was positively correlated with ABI ( r=0.887, P<0.01), MOCA score was positively correlated with ABI ( r=0.843, P<0.01). ⑷ The area under ROC curve of ABI prediction value for VCI in the elderly was (0.965±0.01) [95% CI (0.945, 0.985), P<0.01]. When ABI ≤0.9, the sensitivity and specificity were 88.2%, 91.1% respectively; the accuracy and the yordan index were 89.5% and 0.793. Conclusions:⑴ ABI is an influencing factor of VCI in the elderly and is positively correlated with the severity of cognitive impairment in patients. ⑵ ABI has a high predictive value for VCI of the elderly, and ABI≤0.9 can be used as an early warning factor for VCI of the elderly.

This study was aimed to analyze the formulas and classify the treatment of chronic kidney disease (CKD) by Dr. Huang Chunlin based on the data mining method. A total of 63 CKD outpatients' medical records by Dr. Huang were collected. And 226 formulas prescribed in the medical records were put in the Traditional Chinese Medicine Inheritance Support System (TCMISS). Data mining techniques were applied in the study of as-sociation rule mining algorithm and complex system entropy cluster, the usage frequency and the correlation of each single Chinese medicinal in order to sort out the prescription pattern of CKD. The results showed that to for-tify the spleen and tonify the kidney were found to be the basic method of CKD treatment . Through the applica-tion of TCMISS, the Chinese medicinals used in Dr. Huang's CKD treatment were Astragalus root, Eucommia, Epimedium, Cuscuta, Agastache, Danshen Root, Ligustrum. It was concluded that the TCMISS is of great value in the summarization of clinical experiences of well-known TCM doctors.

Objective To survey on satisfaction degree of preventive medicine undergraduates on tutorial system and to improve the effects of tutorial system.Methods Totally 73 students of preventive medicine,who would graduate in 2012,were asked to fill the questionnaires by themselves.Main contents of questionnaires include effects,satisfaction score,expectations and reality benefits,requirements for the tutors and problems of the tutorial system.Chi-square was used to test the differences between expectations and reality benefits and the significance level was set as P ＜ 0.05.Results More than half of the students thought that the effect of tutorial system was general while 43.8％students thought good and excellent.Percentages of satisfaction score over 50,over 80 and over 90 were 75.3％,41.1％ and 12.3％,respectively.Statistical analysis shown that the real benefits from research activities were more than expectation (P ＜ 0.001),while the real benefits from tutor's academic encouragement,job guidance and life values were lower than expectation (P =0.026,P =0.003,P =0.010).Students expected to have more opportunities with the professors in the future.However,there were 17.8％ students hardly attended the activities of tutorial system,in which lack of understanding of tutorial system was the main reason and without enough time was another reason.Conclusions Students basically satisfies with tutorial system and the satisfaction degree needs to be improved.Roles of tutorial system should be fully strengthened by the management department,tutors and students.

Objective To evaluate the hematological adverse events of sunitinib in treatment of advanced renal cell carcinoma.Methods Forty-four male patients and 18 female patients were included in this study.They were all with metastatic renal cell carcinoma and received sunitinib treatment at the dose of 50 mg daily in repeated 6 weeks cycle (4 weeks on and 2 weeks off).Toxicity was assessed every cycle with tumor assessments every 2 cycles via CT or PET-CT.Results Fifty patients (80.6％) had experienced treatment-related hematotoxicity,including leucocytopenia,anemia and thrombocytopenia.Severe hematological adverse events ( grade 3 -4 ) occured in 18 patients ( 29.0％ ) and slight events ( grade 1 - 2 ) in others (51.6％).Most of the hematological adverse events were manageable and reversible and treatment-changes (dose reduction,interruption) were necessary in severe cases.Almost half of the dose reduction (9/21,42.9％ ) were owing to hematotoxicity.Conclusions Sunitinib of 50 mg dose on schedule 4/2 is effective and well-tolerated in advanced renal carcinoma patients.Hematological adverse events are frequent in Chinese patients and can be controlled well.