OBJECTIVE To systematically evaluate the efficacy and safety of tislelizumab in the treatment of advanced non- small cell lung cancer （NSCLC）. METHODS Computerized searches were conducted in PubMed， Embase， the Cochrane Library， CNKI， Wanfang and other Chinese and English databases to collect randomized controlled trials （RCTs） on tislelizumab for advanced NSCLC. The search period was from the establishment of the databases to December 2024. After strictly screening the literature， extracting data and conducting quality evaluations in accordance with the inclusion and exclusion criteria， a meta-analysis was performed using RevMan 5.3 and Stata 16.0 software. RESULTS A total of 18 RCTs involving 2 337 patients were included， with 1 283 in the experimental group and 1 054 in the control group. The meta-analysis results showed that the objective response rate [RR＝1.61， 95%CI （1.48， 1.75）， P＜0.000 01]， disease control rate [RR＝1.21， 95%CI （1.13， 1.29）， P＜0.000 01]， progression free survival [HR＝0.55， 95%CI （0.45， 0.66）， P＜0.000 01]， and overall survival [HR＝0.78， 95%CI（0.62， 0.97）， P＝0.03] were significantly better in the experimental group than in the control group. There was no statistically significant difference in the incidence of adverse reactions between the two groups [RR＝1.00， 95%CI （0.73， 1.37）， P＝1.00]； among the common adverse reactions， only the incidence of liver function impairment was significantly higher in the experimental group than in the control group [RR＝1.30， 95%CI （1.10， 1.54）， P＜0.01]. CONCLUSIONS Tislelizumab in combination with chemotherapy or targeted drugs significantly improves the efficacy in patients with advanced NSCLC without increasing the risk of adverse reactions overall. However， liver function should be closely monitored during treatment.

Ketone bodies have beneficial metabolic activities, and the induction of plasma ketone bodies is a health promotion strategy. Dietary supplementation of sodium butyrate (SB) is an effective approach in the induction of plasma ketone bodies. However, the cellular and molecular mechanisms are unknown. In this study, SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting enzyme in ketogenesis, to promote ketone body production in hepatocytes. SB administrated by gavage or intraperitoneal injection significantly induced blood ß-hydroxybutyrate (BHB) in mice. BHB production was induced in the primary hepatocytes by SB. Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis. However, the alteration was mostly observed in mitochondrial proteins with 41% down- and 65% up-regulation, respectively. Succinylation status of HMGCS2 protein was altered by a reduction at two sites (K221 and K358) without a change in the protein level. The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice. The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver. The effect was not associated with an elevation in NAD⁺/NADH ratio according to our metabolomics analysis. The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.
Mice ; Animals ; Butyric Acid/metabolism* ; Ketone Bodies/metabolism* ; Liver/metabolism* ; Hydroxybutyrates/metabolism* ; Down-Regulation ; Sirtuins/metabolism* ; Hydroxymethylglutaryl-CoA Synthase/metabolism*

Objective:To compare the spermatogenes response of human chorionic gonadotropin(HCG)combined with human menopausal gonadotropin(HMG)in patients with idiopathic hypogonadotropic hypogonadism(IHH)and congenital combined pituitary hormone deficiency(CCPHD), and to explore related factors.Methods:Clinical data of 90 IHH patients and 61 CCPHD patients from January, 2014 to November, 2018 were retrospectively analyzed. Spermatogenesis was compared between the two groups receiving combined gonadotropin therapy. The patients were then divided into two subgroups: spermatogenesis subgroup and nonspermatogenesis subgroup. Related factors of spermatogenesis after the combined gonadotropin therapy were investigated.Results:After the combined treatment of HCG/HMG for 3, 6, and 9 months, the patients with CCPHD revealed lower testicular sizes than those with IHH( P=0.004, 0.021 and 0.032, respectively). Compared with IHH patients, CCPHD patients had larger testicular volume increments( P<0.001), higher spermatogenesis rates( P=0.048), and shorter initial time for sperm appearance( P<0.001)after 24-month treatment. Multivariate logistic regression analysis showed that lower total cholesterol(TC)(IHH group: OR=5.508, 95% CI 1.110-27.326, P=0.037; CCPHD group: OR=4.068, 95% CI 1.077-15.371, P=0.039)was an independent risk factor of poorer spermatogenesis in patients with IHH and CCPHD. Conclusions:The patients with CCPHD demonstrate a better response to combined gonadotropin treatment than those with IHH. Lower TC is an independent risk factor for poor spermatogenesis of combined HCG/HMG therapy in patients with IHH or CCPHD.

Objective:To evaluate the safety and feasibility of endovascular recanalization for non-acute internal carotid artery occlusion (NA-ICAO), and to propose a new angiographic classification.Methods:From April 2015 to October 2019, 95 consecutive patients with symptomatic NA-ICAO who received endovascular recanalization were retrospectively analyzed in Beijing Tiantan Hospital, Capital Medical University. All the patients were divided into four groups according to DSA: type Ⅰ, petrous segments were distally reconstituted by collateral vessels; type Ⅱ, cavernous segments were distally reconstituted by collateral vessels; type Ⅲ, ophthalmic segments were distally reconstituted by collateral vessels; type Ⅳ, communicating segments were distally reconstituted by collateral vessels. Study data including clinical characteristics, surgical details, lesion classification, recanalization rate and perioperative complications. For the counting data, the χ 2 test was used to compare between groups. For the quantitative data, the ANOVA was used for the normal distribution data, otherwise the Kruskal-Wallis H test was used. The primary safety outcome was any stroke or death within 30 days. Results:Among the 95 patients, 67 (70.53%) had successful recanalization. The recanalization rates of type Ⅰ－Ⅳ were 92.31% (36/39), 81.82% (18/22), 47.83% (11/23) and 18.18% (2/11) respectively (χ2=29.557, P<0.001). And the complication rates of the four types were 5.13% (2/39), 13.64% (3/22), 21.74% (5/23) and 9.10% (1/11) respectively. The incidence of perioperative ischemic stroke was 2.11% (2/95). No other serious stroke and death occurred. Conclusions:Endovascular recanalization may be feasible and safe for carefully selected patients with NA-ICAO and therefore represents an alternative treatment. The patients with type Ⅰ and Ⅱ lesions had higher recanalization rates, while the patients with type Ⅳ lesions had significantly lower recalculation rate. The new angiographic classification is conducive to the selection of suitable patients and difficulty in grading.

OBJECTIVETo investigate the effects of E2F-1 gene silencing on multidrug resistance of human gastric cancer SGC7901/DDP cells and its possible mechanisms.

METHODSGastric cancer SGC7901/DDP cells were seeded in 6 well plates and divided into three groups: the experimental group, blank control and the negative control groups. For the experimental group, the SGC7901/DDP cells were transfected with recombinant lentivirus vector (Lv-shRNA-E2F-1), while the negative control with an control lentiviral vector (Lv-shRNA-NC) and the blank control with no treatment. The E2F-1 protein level was analyzed by Western blot. MTT assay was used to detect the half maximal inhibitory concentration (IC50) of three chemotherapy drugs including adriamycin, 5-fluorouracil (5-Fu) and cisplatine (DDP) of the three cell groups. Flow cytometry (FCM) was used to detect the pump-out rate of adriamycin and apoptosis rate of the three cell groups. Semi-quantitative RT-PCR and Western blot were also used to detect the protein and mRNA levels of multidrug resistance-associated genes (MDR1, MRP) and apoptosis-related genes (c-Myc, Skp2, cyclinD1).

RESULTSThe expression of E2F-1 protein in the experimental group was significantly lower than that in the negative control and blank control groups (0.794 ± 0.033 vs. 1.487 ± 0.082 vs. 1.511 ± 0.084, P < 0.01). The IC50 of the three chemotherapy drugs (adriamycin, 5-Fu and cisplatine) in the experimental group was significantly lower than that of the negative control and blank control groups, respectively (P < 0.01). Compared with the negative control and blank control groups, the pump-out rate of adriamycin of the experimental group was significantly declined [(0.16 ± 0.01)% vs. (0.37 ± 0.01)% vs. (0.35 ± 0.02)%, P < 0.01]. However, the apoptosis rate of the experimental group was significantly higher than that of the negative control and blank control groups [(33.82 ± 1.26)% vs. (17.34 ± 0.81)% vs. (13.16 ± 1.06)%, P < 0.01]. The results of RT-PCR and Western blot assays showed that mRNA and protein expressions of five genes (MDR1, MRP, CyclinD1, c-Myc, Skp2) in the experimental group were significantly lower than that in the negative control and blank control groups, respectively (P < 0.01).

CONCLUSIONSE2F-1 gene silencing enhances the chemosensitivity of gastric cancer SGC7901/DDP cells to the chemotherapeutic drugs, directly or indirectly downregulated the expression of MDR1 and MRP, and finally reverses the multidrug resistance of the gastric cancer cells. The mechanism may be associated with the suppression of cyclinD1, c-Myc and Skp2.

ATP-Binding Cassette, Sub-Family B, Member 1 ; genetics ; metabolism ; Antibiotics, Antineoplastic ; pharmacology ; Antimetabolites, Antineoplastic ; pharmacology ; Antineoplastic Agents ; pharmacology ; Apoptosis ; Cell Line, Tumor ; Cisplatin ; pharmacology ; Cyclin D1 ; genetics ; metabolism ; Doxorubicin ; pharmacology ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; E2F1 Transcription Factor ; genetics ; metabolism ; Fluorouracil ; pharmacology ; Gene Silencing ; Genetic Vectors ; Humans ; Lentivirus ; genetics ; Multidrug Resistance-Associated Proteins ; genetics ; metabolism ; Proto-Oncogene Proteins c-myc ; genetics ; metabolism ; RNA, Messenger ; metabolism ; Recombinant Proteins ; genetics ; metabolism ; S-Phase Kinase-Associated Proteins ; genetics ; metabolism ; Stomach Neoplasms ; metabolism ; pathology ; Transfection

Objective To investigate the effects of caudal type homeobox 2 (Cdx2) silence on reservion of multi-drug resistance of gastric carcinoma cisplantin-resistant cell SGC7901/DDP.Methods Gastric carcinoma cisplantin-resistant cells SCG7901/DDP in the logarithmic phase were cultured in the plate,and were divided into the experimental group [gastric carcinoma cells of SGC7901/DDP were infected with a silent Cdx2-recombinanted lentiviral vector (pLL-Cdx2-shRNA)],the negative control group (gastric carcinoma cells of SGC7901/DDP were infected with empty lentiviral vector) and the blank control group (gastric carcinoma cells of SGC7901/DDP were not treated).The protein and mRNA expressions of Cdx2 and apoptosis related genes like c-myc,cyclin D1 and survivin were detected by the Western blot and reverse-transcription PCR,respectively.The sensitivity of the cells in the 3 groups to adriamycin,5-fluorouracil and cisplatium were assessed by MTT.The pump-out rate of adriamycin,cell cycle distribution and apoptosis of the 3 groups were analyzed using flow cytometry.All measurement data were expressed with mean ± standard deviation.Comparison among multi-groups was done by one-way analysis of variance,and comparison between 2 groups was done by SNK-q test.The enumeration data were analyzed using the chi-square test.Results The relative protein expression levels of Cdx2,c-myc,cyclin D1 and survivin were 0.187 ± 0.060,0.086 ± 0.004,0.016 ± 0.005 and 0.276 ± 0.012 in the experimental group,0.535 ± 0.033,0.379 ± 0.006,0.141 ± 0.003 and 0.672 ± 0.009 in the negative control group,and 0.567 ± 0.014,0.354 ± 0.004,0.162 ± 0.008 and 0.517 ± 0.313 in the blank control group,respectively.The relative protein expression levels of Cdx2,c-myc,cyclin D1 and survivin in the experimental group were significantly lower than those in the negative control group and the blank control group (F =247.385,3.353,597.882,98.628,P ＜0.05).The relative mRNA expression levels of Cdx2,c-myc,cyclin D1 and survivin were 0.184 ± 0.010,0.212 ± 0.022,0.045 ± 0.009 and 0.401 ± 0.027 in the experimental group,0.894 ± 0.056,0.538 ± 0.021,0.163 ±0.009 and 0.824 ± 0.016 in the negative control group,and 0.837 ±0.049,0.545 ±0.032,0.157 ±0.010 and 0.782 ±0.056 in the blank control group,respectively.The relative mRNA expression levels of Cdx2,c-myc,cyclin D1 and survivin in the experimental group were significantly lower than those in the negative control group and the blank control group (F =243.776,161.793,138.523,118.426,P ＜ 0.05).The IC50 values detected by MTT of adriamycin,5-flurouracile and cisplatin to gastroc carcinoma cisplantin-resistant cell SCG7901/DDP were (0.12 ± 0.05) mg/L,(0.52 ± 0.13) mg/L and (0.82 ± 0.13) mg/L in the experimental group,(0.33 ± 0.08) mg/L,(4.10.± 1.25) mg/L and (2.81 ± 0.50) mg/L in the negative control group,(0.39 ±0.15)mg/L,(4.05 ± 1.44) mg/L and (3.28 ± 1.03) rng/L in the blank control group,respectively.The pump-out rates of adriamycin of the experimental group,negative control group,and the blank control group were0.21％,0.37％ and 0.35％.Compared with the negative control group and the blank control group,the IC50values of adriamycin,5-fluorouracil and cisplatin in the experimental group were significantly increased,and thepump-out rate of adriamycin was significantly decreased (F =8.101,13.854,15.159,x2 =7.106,P ＜ 0.05).The ratios of cells in the G0/G1 phase were 17.87％,34.71％ and 37.20％ in the experimental group,negative control group and the blank control group,respectively.Compared with the negative control group and blank control group,the ratio of cells in the G0/Gt was significantly decreased (x2=1.055,P ＜ 0.05).The ratio of cells in the G2/M phase in the experimental group was 11.93％,and the apoptosis rate was 31.13％,which were significantly higher than the negative group (0.26％,16.58％) and the blank control group (0.35％,13.18％) (x2=2.249,11.030,P ＜ 0.05).Conclusions Silent Cdx2 can effectively enhance the sensitivity of the SGC7901/DDP cells and the intracellular accumulation concentration of the drugs.Silent Cdx2 can also reverse the multidrug resistance of the SGC7901/DDP cells.

OBJECTIVETo investigate the effects of E2F-1 gene silencing on the chemosensitivity of human gastric cancer SGC-7901/DDP cells to cisplatin and explore the underlying mechanism.

METHODSGastric cancer SGC-7901/DDP cells were transfected with the recombinant lentivirirus vector Lv-shRNA-E2F-1 for E2F-1 gene silencing, with cells transfected with the control recombinant lentivirirus vector Lv-shRNA-NC as the negative control. MTT assay was used to evaluate cisplatin chemosensitivity of the cells, and the cell apoptosis rate and cell cycle distribution were detected by flow cytometry. The mRNA and protein expressions of E2F-1 and apoptosis-related genes (survivin and Bcl-2) were detected by RT-PCR and Western blotting.

RESULTSMTT assay showed that the IC50 of cisplatin was significantly lowered in Lv-shRNA-E2F-1-transfected cells compared with the negative and blank control cells (P<0.05). Lv-shRNA-E2F-1 transfection caused significant cell cycle arrest in G0/G1 phase and induced obvious cell apoptosis. Compared with Lv-shRNA-NC group and the blank control group, Lv-shRNA-E2F-1 group showed significantly lowered expressions of E2F-1 mRNA by 45.0% and 41.3% and E2F-1 protein by 66.7% and 70.5%, survivin mRNA by 30.3% and 28.7% and survivin protein by 56.5% and 53.6%, and Bcl-2 mRNA by 76.6% and 76.8% and Bcl-2 protein by 74.6% and 79.9%, respectively. No significant difference was found in the measurements between Lv-shRNA-NC group and the blank control group (P>0.05).

CONCLUSIONE2F-1 gene silencing can enhance cisplatin chemosensitivity of gastric cancer SGC-7901/DDP cells possibly by down-regulating survivin and Bcl-2 expressions, suggesting the value of E2F-1 as a new chemotherapeutic target for gastric cancer.

Apoptosis ; Cell Cycle ; Cell Line, Tumor ; drug effects ; Cisplatin ; pharmacology ; Down-Regulation ; E2F1 Transcription Factor ; genetics ; metabolism ; Gene Silencing ; Genetic Vectors ; Humans ; Inhibitor of Apoptosis Proteins ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; RNA, Messenger ; RNA, Small Interfering ; Stomach Neoplasms ; metabolism ; pathology ; Transfection

Objective To investigate the effects of E2F-1 gene silencing on the chemosensitivity of human gastric cancer SGC-7901/DDP cells to cisplatin and explore the underlying mechanism. Methods Gastric cancer SGC-7901/DDP cells were transfected with the recombinant lentivirirus vector Lv-shRNA-E2F-1 for E2F-1 gene silencing, with cells transfected with the control recombinant lentivirirus vector Lv- shRNA- NC as the negative control. MTT assay was used to evaluate cisplatinchemosensitivity of the cells, and the cell apoptosis rate and cell cycle distribution were detected by flow cytometry. The mRNA and protein expressions of E2F-1 and apoptosis-related genes (survivin and Bcl-2) were detected by RT-PCR and Western blotting. Results MTT assay showed that the IC50 of cisplatinwas significantly lowered in Lv-shRNA-E2F-1-transfected cells compared with the negative and blank control cells (P<0.05). Lv-shRNA-E2F-1 transfection caused significant cell cycle arrest in G0/G1 phase and induced obvious cell apoptosis. Compared with Lv-shRNA-NC group and the blank control group, Lv-shRNA-E2F-1 group showed significantly lowered expressions of E2F-1 mRNA by 45.0%and 41.3%and E2F-1 protein by 66.7%and 70.5%, survivin mRNA by 30.3%and 28.7%and survivin protein by 56.5%and 53.6%, and Bcl-2 mRNA by 76.6%and 76.8% and Bcl-2 protein by 74.6% and 79.9%, respectively. No significant difference was found in the measurements between Lv-shRNA-NC group and the blank control group (P>0.05). Conclusion E2F-1 gene silencing can enhance cisplatinchemosensitivity of gastric cancer SGC-7901/DDP cells possibly by down-regulating survivin and Bcl-2 expressions, suggesting the value of E2F-1 as a new chemotherapeutic target for gastric cancer.

Objective To investigate the effects of E2F-1 gene silencing on the chemosensitivity of human gastric cancer SGC-7901/DDP cells to cisplatin and explore the underlying mechanism. Methods Gastric cancer SGC-7901/DDP cells were transfected with the recombinant lentivirirus vector Lv-shRNA-E2F-1 for E2F-1 gene silencing, with cells transfected with the control recombinant lentivirirus vector Lv- shRNA- NC as the negative control. MTT assay was used to evaluate cisplatinchemosensitivity of the cells, and the cell apoptosis rate and cell cycle distribution were detected by flow cytometry. The mRNA and protein expressions of E2F-1 and apoptosis-related genes (survivin and Bcl-2) were detected by RT-PCR and Western blotting. Results MTT assay showed that the IC50 of cisplatinwas significantly lowered in Lv-shRNA-E2F-1-transfected cells compared with the negative and blank control cells (P<0.05). Lv-shRNA-E2F-1 transfection caused significant cell cycle arrest in G0/G1 phase and induced obvious cell apoptosis. Compared with Lv-shRNA-NC group and the blank control group, Lv-shRNA-E2F-1 group showed significantly lowered expressions of E2F-1 mRNA by 45.0%and 41.3%and E2F-1 protein by 66.7%and 70.5%, survivin mRNA by 30.3%and 28.7%and survivin protein by 56.5%and 53.6%, and Bcl-2 mRNA by 76.6%and 76.8% and Bcl-2 protein by 74.6% and 79.9%, respectively. No significant difference was found in the measurements between Lv-shRNA-NC group and the blank control group (P>0.05). Conclusion E2F-1 gene silencing can enhance cisplatinchemosensitivity of gastric cancer SGC-7901/DDP cells possibly by down-regulating survivin and Bcl-2 expressions, suggesting the value of E2F-1 as a new chemotherapeutic target for gastric cancer.