Objective:To explore the effects of genistein-3'-sodium sulfonate (GSS) on on motor function and brain autophagy levels in Parkinson disease (PD) model mice.Methods:Forty C57BL/6J mice were randomly divided into control group, model group, low-dose GSS group (0.15 mg/kg), medium-dose GSS group (0.50 mg/kg) and high-dose GSS group (1.50 mg/kg), with 8 mice in each group.Mice in the model group and the high, medium, and low-dose GSS groups were injected intraperitoneally with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine to establish the PD mouse model, then mice in high, medium and low-close GSS group were intraperitoneally injected with corresponding doses of GSS (once a day for 21 days). The mice in model group were injected with equal volume 0.9% sodium chloride solution(once a day for 21 days), while the control group mice were fed normally.After 21 days, the motor and cognitive abilities of mice were evaluated by gait analysis, open field test, rotarod test, and modified Y maze test.Western blot was used to detect the expression levels of LC3-Ⅱ and Beclin-1 proteins in the cerebral cortex and striatum tissues of mice.SPSS 26.0 software was used for data analysis.One-way ANOVA was used for normal distribution data comparison among multiple groups, and LSD test was used for further pairwise comparisons, while Kruskal-Wails H test was used for non normal distribution data comparison. Results:(1) Gait analysis showed that there were statistically significant differences in the stride length of left forelimb, left hindlimb, right hindlimb( F=5.93, 6.21, 3.78, all P<0.01) and regularity index( H=14.409, P<0.01). The regularity index of the model group mice was lower than that of the control group ( P<0.05), and the regularity indexes of the low, medium, and high-dose GSS groups were all higher than that of the model group (all P<0.05). (2)In the open field test, there were statistically significant differences in the total distance and speed of movement among the 5 groups ( F=5.49, 5.49, both P<0.01). The total distance and speed of movement in the model group were both lower than those in the control group (both P<0.05). The total distance and speed of movement in the medium-dose GSS group( (2 395.57±319.35) cm, (7.98±1.06) cm/s) and high-dose GSS group ((2 386.51±396.00) cm, (7.95±1.32) cm/s) were higher than those of the model group ((1 863.31±278.96) cm, (6.21±0.93) cm/s) and the low-dose GSS group ((1 956.90±297.15) cm, (6.52±0.99) cm/s) (all P<0.05). (3) In the rotarod test and modified Y maze test, there were significant differences in latency to fall and residence time among the 5 groups ( F=58.41, 9.90, both P<0.01). The latency to fall and residence time of model group were lower than those of control group (both P<0.05), while those in the medium-dose and high-dose GSS groups were higher than those in the model group and low-dose GSS group (all P<0.05). (4) Western blot results showed that there were significant differences in the expression levels of LC3-Ⅱ/LC3-Ⅰ ratio ( F=8.17, 15.47, both P<0.01)and Beclin-1 protein( F=29.07, 20.54, both P<0.01) in cerebral cortex and striatum among the five groups.The LC3-Ⅱ/LC3-Ⅰ ratio and Beclin-1 protein levels in the cerebral cortex ((0.51±0.14), (0.46±0.06)) and striatum ((0.58±0.09), (0.55±0.10)) of the model group were lower than those in the control group (cerebral cortex: (1.00±0.10), (1.00±0.05), striatumm: (1.00±0.06), (1.00±0.25), all P<0.01). The LC3-Ⅱ/LC3-Ⅰratio and Beclin-1 protein in the medium-dose GSS group were higher than those in the model group, low-dose and high-dose GSS groups in both cerebral cortex and striatum (all P<0.05). The level of Beclin-1 of cerebral cortex in model group was lower than those in various doses of GSS group(all P<0.05). There were no statistically significant differences of Beclin-1 protein levels between the model group mice and various doses of GSS groups in striatum (all P>0.05). Conclusion:GSS can improve the motor and cognitive functions of PD model mice, and the mechanism may be related to the upregulation of autophagic activity in the cerebral cortex and striatum of mice.

Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta, tau, and α-synuclein aggregates in neurodegenerative diseases. However, due to the complex structure and ambiguous pathogenic species of the misfolded proteins, a universal approach to remove the misfolded proteins remains unavailable. Here, we found that a polyphenol, α-mangostin, reprogrammed metabolism in the disease-associated microglia through shifting glycolysis to oxidative phosphorylation, which holistically rejuvenated microglial surveillance capacity to enhance microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins. Nanoformulation of α-mangostin efficiently delivered α-mangostin to microglia, relieved the reactive status and rejuvenated the misfolded-proteins clearance capacity of microglia, which thus impressively relieved the neuropathological changes in both Alzheimer's disease and Parkinson's disease model mice. These findings provide direct evidences for the concept of rejuvenating microglial surveillance of multiple misfolded proteins through metabolic reprogramming, and demonstrate nanoformulated α-mangostin as a potential and universal therapy against neurodegenerative diseases.

Purpose: We aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)–mutated patients with or without concomitant alterations. Materials and Methods: This multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non–small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR–tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint. Results: The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment. Conclusion EGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Objective:To clarify the effects of bortezomib combined with or without siramesine on the proliferation of multiple myeloma cell lines, the expression changes of transcription factor EBC (TFEB) nuclear translocation and the level of autophagy, and to provide basis for further exploring the regulation mechanism of transcription factor TFEB on autophagy.Methods:The multiple myeloma cell lines RPMI8226 and U266 were cultured in vitro, and the multiple myeloma cells were treated with a certain concentration of bortezomib and siramesine. The changes of cell proliferation inhibition were detected by CCK-8 method. Real time PCR and Western blot were used to detect the relative expression of TFEB, autophagy-related factor LC3B, Beclin1, p62, LAMP1 mRNA and protein.Results:As the concentration of bortezomib increased and the duration of action increased, the proliferation inhibition rates of the two cell lines gradually increased ( P<0.05) . The combination of the two drugs has a synergistic inhibitory effect on the proliferation of the above-mentioned multiple myeloma cell lines ( P<0.05) . In the blank control group, single drug group, and combination drug group, the relative expression of TFEB mRNA and protein in the cytoplasm decreased sequentially ( P<0.05) , and the relative expression of TFEB mRNA and protein in the nucleus increased sequentially ( P<0.05) . The relative expression of autophagy-related factors LC3B, Beclin1, LAMP1 mRNA and protein increased sequentially, and the relative expression of p62 mRNA and protein decreased sequentially ( P<0.05) . Conclusion:Bortezomib and siramesine can synergistically inhibit the growth of multiple myeloma cells, which is related to the increased autophagy expression in multiple myeloma cell lines and the expression of TFEB with nuclear translocation is also enhanced.

Objective:To investigate the incidence of and risk factors for osteoporosis in patients with pemphigus treated with systemic glucocorticoids, and to analyze the current status of prevention and treatment of osteoporosis.Methods:Clinical data were collected from 101 inpatients with pemphigus treated in Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College from January 2014 to January 2019, and these patients were divided into osteoporosis group ( n= 21) and non-osteoporosis group ( n= 80) according to their bone mineral density (BMD) values. Correlations of osteoporosis with patients′ general information, treatment duration and cumulative dose of glucocorticoids, application of immunosuppressive agents, diabetes mellitus, hypertension, hyperlipidemia, smoking, outdoor activity and other factors were analyzed, and the application status of calcium supplements, vitamin D and bisphosphonates was also analyzed. Enumeration data were compared by using chi-square test, measurement data were compared by using t test, and multiple factors influencing osteoporosis were analyzed by using non-conditional Logistic regression analysis. Results:Logistic regression analysis showed that age ( P= 0.001, OR= 1.08, 95% CI: 1.03- 1.14) and cumulative dose of glucocorticoids ( P<0.001, OR= 1.72, 95% CI: 1.18- 2.52) were risk factors for the occurrence of osteoporosis, while outdoor activity ( P<0.001, OR= 0.04, 95% CI: 0.01- 0.21) was a protective factor. Moreover, 13 (61.9%) patients in the osteoporosis group and 16 (21.6%) patients in the non-osteoporosis group received combination treatment with calcium supplements, vitamin D and bisphosphonates. Conclusions:Pemphigus patients treated with systemic glucocorticoids are prone to develop osteoporosis. Older age, cumulative dose of glucocorticoids may be risk factors for osteoporosis in patients with pemphigus, while outdoor activity may be a protective factor. The prevention and treatment of osteoporosis in pemphigus patients are still not standardized.

Objective: To study the mutation of ENG, ACVRL1, and SMAD4 genes in one of a family of hereditary hemorrhagic telangiectasia (HHT) and explore its molecular pathogenesis. Methods: A family spectrum of a patient with a clinical diagnosis of HHT was surveyed. Peripheral blood samples from proband and their eldest were collected, and ENG, ACVRL1 and SMAD4 gene analysis was performed by chip capture high-throughput sequencing. The mutation detected was verified by Sanger. Results: 9 of the 71 family members were diagnosed with HHT with the main manifestation of recurrent nasal bleeding. Genetic analysis showed that the proband and the eldest son of ENG gene exon 9 frameshift mutation: c.1502-1503insGG (p.Gly501GlyfsX18) , and mutations in ACVRL1 and SMAD4 genes were not detected. Conclusion The frameshift mutation c.1502-1503insGG (p.Gly501GlyfsX18) of the ENG gene is the genetic basis for the pathogenesis of this HHT family.

Objective To observe the effect of PIF1 knockdown on cell growth and cell cycle arrest induced by ionizing radiation.Methods HeLa cell lines that consistently down-regulated PIF1 were prepared by the lentivirus granules interfering technology and confirmed by real-time PCR and Western blotting.The effect of down-regulation of PIF1 on cell growth and cell cycle arrest induced by ionizing radiation was evaluated by cell counting and flow cytometry.Results HeLa cell lines consistently down-regulating PIF1 were established.The growth of HeLa that down-regulated PIF1 was inhibited greatly after 4 Gy of γ-ray irradiation.There was little cell proliferation until the 5th day post 4 Gy γ-ray.Moreover, the S phase block and G2/M phase block of PIF1 knock-downed cell lines were significantly delayed after 8 Gy γ-ray irradiation.Conclusion Knockdown of PIF1 can significantly enhance the radiation sensitivity and delayes the S phase block and G 2 /M phase block induced by ionizing radiation.

Objective To expand the influence and promotion effect of the grassroots health demonstration base of appropriate technology at county level,explore the practice model for full coverage.Methods Four consortium and eight units in the county were engaged into the whole process,the whole cycle,synchronous implementation;the promotion practices were divided into different stages with different focuses based on priority setting;Stratified training,classified promotion strategies were involved to carry out the appropriate technology for all 11 items covered.Results The technical promotion training,technical promotion applications were completed with full coverage in the county,gained high satisfaction from both medical staff and public.Enhanced the technology radiation ability,also the base's annual development was increasing year by year.Conclusions The base construction full coverage promotion experiences can be shared and learned by other areas which aims for the promotion of fit health techniques.

OBJECTIVETo examine the associations of apparent diffusion coefficient (ADC) value from MR diffusion-weighted imaging (DWI) with Ki-67 expression and differentiation grade in gastric cancer.

METHODSImages and pathologic data of 68 gastric cancer patients between September 2013 and February 2015 in Affiliated Changshu Hospital of Soochow University were analyzed retrospectively. The expression of Ki-67 antigen in cancer tissue sample was determined by immunohistochemistry. Ki-67 labeling index(LI) was calculated to divide the cases into low Ki-67 group(Ki-67 LI <50%) and high Ki-67 group (Ki-67 LI ≥ 50%). Associations of ADC value with differentiation grade and Ki-67 LI were examined.

RESULTSMean ADC value of low Ki-67 LI group was significantly higher than that of high Ki-67 LI group [(0.977 ± 0.100) × 10(-3) mm(2)/s vs. (0.859 ± 0.064) × 10(-3) mm(2)/s, P=0.000]. The ADC value was negatively correlated with Ki-67 LI (r=-0.685, P=0.000). Mean ADC value of well differentiated adenocarcinoma, moderately differentiated adenocarcinoma, poorly differentiated adenocarcinoma, and signet-ring cell carcinoma was (1.124 ± 0.080) × 10(-3) mm(2)/s, (0.950 ± 0.064) × 10(-3) mm(2)/s, (0.899 ± 0.091) × 10(-3) mm(2)/s, and (0.894 ± 0.081) × 10(-3) mm(2)/s respectively. Difference of ADC value among differentiation grades was significantly different (F=11.405, P=0.000). Difference of ADC value between well differentiated adenocarcinoma and non-well differentiated adenocarcinoma was significantly different(P=0.000).

CONCLUSIONADC value is associated with differentiation grade and Ki-67 LI of gastric cancer, which may be used as a noninvasive predictor for evaluating the proliferation and differentiation grade of gastric cancer.

Objective: To investigate the relationship between serum levels of high sensitivity cardiac troponin T (hs-cTnT) and the severity of coronary lesions in patients with stable coronary artery disease (SCAD). Methods: A total of 450 SCAD patients with coronary angiography (CAG) conifrmed diagnosis in our hospital were studied, and serum levels of hs-cTnT were examined at 3 days prior CAG in all patients. Based on tertiles of Gensini score, the patients were divided into 3 groups: Low score group,n=153 patients with Gensini score<14, Intermediate score group, n=145 patients with Gensini score at 14-28 and High score group,n=152 patients with Gensini score>28. The relationships between Gensini score and hs-cTnT levels were analyzed among 3 groups. The optimal cut-off value of hs-cTnT for predicting high Gensini score and the need of revascularization were studied by ROC curve, the relationships between hs-cTnT and high Gensini score, the need of revascularization were further detected by Logistic regression analysis. Results: The median values (25%-75%) of hs-cTnT in Low score group, Intermediate score group and High score group were 6.72 (4.20, 8.93) pg/ml, 7.90 (5.74, 12.68) pg/ml and 14.99 (10.26, 24.30) pg/ml respectively, allP<0.01. ROC curve analysis indicated that the area under curve (AUC) of hs-cTnT for predicting high Gensini score was 0.837 (95% CI 0.803-0.874), for the need of revascularization was 0.772 (95% CI 0.728-0.817); the best cut-off value of hs-TnT for predicting high Gensini score was 10.04 pg/ml and for the need of revascularization was 8.56 pg/ml. Logistic regression analysis suggested that with adjusted age, gender, the history of hypertension, diabetes, smoking, blood levels of creatinine, LDL-C and hs-CRP, hs-cTnT was still an independent predictor for high Gensini score (OR=1.13, 95% CI 1.06-1.20,P<0.001) and for the need of revascularization (OR=1.19, 95% CI 1.14-1.24,P<0.001). Conclusion: Serum level of hs-cTnT has been related to severity of coronary lesions in SCAD patients, hs-cTnT might be used as one of the pre-operative predictor for severe coronary disease and for the need of revascularization.