OBJECTIVE To investigate the potential mechanism of the effect of ginkgo flavone aglycone （GA） against doxorubicin （DOX）-induced cardiotoxicity. METHODS The male ICR mice were randomized into control group （CON group）， model group （DOX group） and GA+DOX group （GDOX group）， with 12 mice in each group. The DOX group was injected with DOX solution at a dose of 3 mg/kg via tail vein every other day， and the GDOX group was given GA suspension intragastrically at a dose of 100 mg/kg every day+DOX solution at a dose of 3 mg/kg via tail vein every other day， for 15 consecutive days. After the end of administration， the serum levels of aspartate aminotransferase（AST）， creatine kinase（CK）， creatine kinase isoenzyme（CK- MB） and lactate dehydrogenase（LDH） in mice were detected in each group. Based on the metabolomics method， UHPLC-Q- Exactive Orbitrap HRMS method was used； based on principal component analysis （PCA） and orthogonal partial least squares- discriminant analysis （OPLS-DA）， the differentially expressed metabolites （DEMs） were screened using the criteria of variable importance in the projection≥1， fold change of peak area＞1 and P＜0.05； biological analysis was conducted based on databases such as HMDB and PubChem. RESULTS Compared with CON group， serum levels of AST， CK， CK-MB and LDH were increased significantly in DOX group （P＜0.05）； compared with DOX group， the serum levels of the above indicators （except for CK-MB） were decreased significantly in GDOX group （P＜0.05）. PCA and OPLS-DA showed that myocardial tissue samples of CON group， DOX group and GDOX group were isolated completely. After database matching， 37 common DEMs were identified， among which 17 DEMs were significantly up-regulated in the DOX group and significantly down- regulated in the GDOX group， and 8 DEMs were significantly down-regulated in the DOX group and significantly up-regulated in the GDOX group； pathway enrichment involved the biosynthesis of unsaturated fatty acids， arachidonic acid metabolism， linoleic acid metabolism， taurine and hypotaurine metabolism； the key metabolites in the above pathways included docosahexaenoic acid， arachidonic acid， phosphatidylcholine （16∶0/18∶3） and taurine. CONCLUSIONS GA may regulate the biosynthesis of unsaturated fatty acids， arachidonic acid metabolism and other metabolic pathways by acting on the core metabolites such as docosahexaenoic acid and arachidonic acid， thus alleviating the cardiotoxic effects of DOX.

Objective: To study the anatomical features of the distal humerus in Chinese healthy adults. Methods: A total of 121 cases of normal elbow joint CT images were selected from the picture archiving and communication system (PACS), and reconstructed and measured on the AW4.5 workstation. Coronal plane and horizontal plane were determined by flexion-extension (FE) axis and humeral shaft, while the sagittal plane was perpendicular to the FE axis. The angle between the axis of humerus medullary cavity and the FE axis of elbow (H-FE angle) was measured on the coronal plane. The capitellar height (CH), lateral trochlear height (LTH), trochlear height (TH) and medial trochlear height (MTH) were measured on four different sagittal planes. The capitellar width (CW), capitellar depth (CD), anterior lateral trochlear width (ALTW), posterior lateral trochlear width (PLTW), trochlear width (TW), anterior medial trochlear width (AMTW), posterior medial trochlear width (PMTW), trochlear depth (TD), anterior lateral trochlear depth (ALTD), posterior lateral trochlear depth (PLTD), anterior medial trochlear depth (AMTD), posterior medial trochlear depth (PMTD), and distal humeral width (W) were measured on the horizontal plane. The gender differences in measured parameters, correlations between data, and differences in H-FE angle from 90° were analyzed. Results: In male, CH was 21.5± 1.3 mm, CW 17.5±1.1 mm, CD 10.8±0.9 mm, TW 25.1±2.2 mm, TH 17.3±1.5 mm, TD 17.5±1.4 mm, ALTW 7.7±1.2 mm, PLTW 12.5±1.6 mm, AMTW 12.4±1.6 mm, PMTW 9.8±2.0 mm, ALTD 10.0±0.8 mm, PLTD 16.3±1.4 mm, AMTD 12.9±1.4 mm, PMTD 13.2±1.4 mm, LTH 20.6±1.3 mm, MTH 25.0±2.4 mm, W 42.6±2.5 mm. The above parameters in female was 18.7±1.1 mm, 15.3±1.1 mm, 9.5±0.6 mm, 21.7±1.5 mm, 15.4±1.7 mm, 15.6±1.5 mm, 6.8±1.3 mm, 10.7±1.4 mm, 10.6±1.4 mm, 8.5±1.4 mm, 8.9±0.8 mm, 14.5±1.1 mm, 11.4±1.1 mm, 11.5±1.0 mm, 18.1±1.4 mm, 21.6±1.4 mm and 37.0±1.8 mm, respectively. All the above anatomical parameters in men were larger than those in women with statistically significant difference (P<0.05). However, the H-FE angle (male: 87.4°±3.5°, female 87.8°±3.3°), CW/CH (male: 0.8±0.1, female: 0.8±0.1), TW/CW (male: 1.4±0.2, female: 1.4±0.1), MTH/LTH (male: 1.2±0.1, female: 1.2±0.1), AMTW/TW (male: 0.5±0.1, female: 0.5±0.1), PMTW/TW (male: 0.4±0.1, female: 0.4±0.1), ALTW/TW (male: 0.3±0.0, female: 0.3±0.1), PLTW/TW (male: 0.5±0.1, female: 0.5±0.1) were not statistically different between male and female groups (P>0.05). All measurements except for the H-FE angle had a positive correlation with the articular width (0.335≤r≤0.928, P<0.05). The difference between the angle of the H-FE axis (87.6°±3.4°) and 90° was statistically significant (t=-7.287, P<0.05). Conclusion The size of the distal humerus in male is larger than that in female without difference in shape. Distal humerus width can be used as an indicator to measure the size of the distal humerus. The humeral shaft is more biased toward the radial side.

Objective: To investigate the aggravation of pancreatic tissue injury in rats with acute hypertriglyceridemic pancreatitis and the possible role of NADPH oxidase (NOX). Methods: Thirty SPF rats were randomly (random number)divided into five groups: N group, H group, NLAP group, HLAP group and HAPO group. AMY, TG, TC and FFA levels were detected. The pathological changes of pancreas were observed under light microscope and the ultrastructural changes of pancreatic acinar cells were observed by TEM. Serum levels of MDA, SOD, IL-1β, TNF-α and LDH were detected. The expression of NOX4, p-Akt and p-GSK3β in pancreas was detected by immunofluorescence, and the expression of NF-κB and TNF-α in pancreas was detected by immunohistochemistry. Results: Intraperitoneal injection of P-407 could significantly increase the levels of serum TG, TC and FFA in rats. After acute pancreatitis induced by L-Arg, the levels of serum AMY in the NLAP and HLAP groups were significantly increased, while Apocynin could significantly decrease the level of serum AMY. Compared with the NLAP group, the pathological injury of pancreatic tissue in the HLAP group was more serious, the level of inflammatory mediators was significantly increased, and the cell necrosis was more serious. After inhibiting NOX, the activation of Akt/GSK3β pathway was regulated and the pancreatic injury was improved. Conclusion In HTGP, NOX aggravates pancreatic injury by regulating the activation of Akt/GSK3 β pathway. Inhibition of NOX expression can play a protective role in pancreas injury of HTGP..

Objective: To analyze the spatial distribution of brain metastases in EGFR-mutant lung cancer and the risk of hippocampal metastasis. Methods: Patients with lung cancer brain metastases diagnosed and treated in the Shanghai Cancer Center Fudan University from 2006 to 2016 were enrolled. The brain metastasis with positive mutation of EGFR gene was screened. The magnetic resonance images of the patients were reviewed and the distribution characteristics of brain metastasis were analyzed. Results: A total of 920 lung cancer patients with brain metastases were screened, 266 of whom had EGFR gene mutation detection, and 131(49%) were identified as EGFR gene mutations. Excluding 17 patients who did not have a head magnetic resonance examination in our hospital, a total of 114 patients and 738 lesions were enrolled in this study. The proportion of brain metastases distributed in each brain region was 22.8%, 19.5%, 22.0%, 13.4%, 3.3%, 16.7%, and 2.2% for frontal, temporal, parietal, occipital lobe, insula, cerebellum, and brainstem, respectively. The number of metastases and cases located in the hippocampus, <5 mm from the hippocampus, <10 mm from the hippocampus, and<15 mm from the hippocampus were 6(0.8%), 10(1.3%), 11(1.4%), and 14(1.8%), 5 cases (4.4%), 8 cases (7.0%), 9 cases (7.9%), and 11 cases (9.6%), respectively. Conclusion EGFR-mutant lung cancer brain metastasis is low risk in the hippocampus and its surrounding 15 mm.

Objective To explore the protective mechanism of glycogen synthase kinase-3β(GSK-3β) inhibitor TDZD-8 on acute necrotizing pancreatitis (ANP) associated kidney injury in rats. Methods SPF male Wistar rats were randomly divided into four groups (n = 20): sham operation group (Sham group), ANP model group, TDZD-8 intervention group and TDZD-8 control group. The rat ANP model was prepared by retrograde injection of 5% sodium taurocholate into the bile duct; the same volume of normal saline was injected into the pancreatic duct of the Sham group. The TDZD-8 intervention group and the TDZD-8 control group were injected with GSK-3β inhibitor TDZD-8 (1 mL/kg) via the femoral vein 30 minutes before the model or sham operation; the ANP model group and the Sham group were injected equal volume of 10% dimethyl sulfoxide (DMSO). Rats in each group were sacrificed at 12 hours after operation to measure the serum amylase (AMY), blood lipase (LIPA), serum creatinine (SCr) and blood urea nitrogen (BUN) levels and to observe the pathological changes of pancreatic tissues and kidney tissues. Ultrastructural change of renal cells was analyzed by transmission electron microscopy. Serum interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels were evaluated by enzyme linked immunosorbent assay (ELISA). The activation of nuclear factor-κB p65 (NF-κB p65) was evaluated by immunohistochemistry assay. The protein expressions of GSK-3β, phospho-GSK-3β (Ser 9), tumor necrosis factor -α (TNF-α), inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1) and interleukin-10 (IL-10) in the kidney were determined by Western Blot. Results Compared with the Sham group, the serum and inflammatory factors levels of the ANP model group were significantly increased, the pathological damage of the pancreas and kidney tissues were severe, the histopathological score was significantly increased, the expression of NF-κB p65 was enhanced in the nucleus of the kidney tissue, and the expressions of GSK-3β, TNF-α, ICAM-1 and iNOS were significantly enhanced, and the expressions of p-GSK-3β(Ser 9) and IL-10 were significantly attenuated. Compared with the ANP model group, TDZD-8 pretreatment significantly reduced serum and inflammatory factor levels in the ANP model group [AMY (kU/L): 5.60±0.30 vs. 10.07±0.34, LIPA (U/L): 1 111.0±110.8 vs. 2 375.0±51.1, SCr (μmol/L): 47.38±1.48 vs. 72.50±2.43, BUN (mmol/L): 17.6±1.0 vs. 26.0±1.0, IL-1β (ng/L):195.90±5.50 vs. 332.40±38.29, IL-6 (ng/L): 246.10±26.74 vs. 385.30±32.19, all P < 0.01]; pathological damage of pancreas and kidney tissue (histopathological score: 7.1±0.4 vs. 12.1±0.3, 301.2±7.5 vs. 433.5±13.8, both P < 0.01) and ultrastructural damage of renal cells were alleviated; the expression of NF-κB p65 in the nucleus was significantly decreased; the expression of p-GSK-3β(Ser 9) was significantly increased, and blocking GSK-3β activity could inhibit the expressions of TNF-α, ICAM-1, iNOS and increase the expression of IL-10, while the expression of GSK-3β in renal tissues was not statistically significant. There were no significant differences between the TDZD-8 control group and the Sham group. Conclusions Blockade of GSK-3βactivity by TDZD-8 exerts the protective effect against kidney injury by inhibiting the inflammation signaling pathway in ANP. It can alleviate histopathological and ultrastructural changes in kidney injury, which protection mechanism is mediated by NF-κB and its related inflammatory mediators.

Objective To observe the dose-response relationship of the GSK-3β inhibitor TDZD-8 in severe acute pancreatitis (SAP) associated kidney injury in rats. In order to identify the most effective class of GSK-3β inhibitor and its effective and reasonable safe dose in SAP associated kidney injury model in rats by comparing three kinds of frequently-used GSK-3β inhibitor TDZD-8, lithium chloride (LiCL), SB216763 in this model. Methods Totally 96 SPF male Wistar rats were randomly(random number) divided into 8 groups (n=12): sham operation group (SO group), severe acute pancreatitis group (SAP group), TDZD-8 pretreatment groups (TD group, marked TD1, TD2, TD3 and TD4 group, respectively) at different dosage (0.25, 0.5, 1.0 and 2.0 mg/kg), LiCL pretreatment groups (L group, 40 mg/kg), and SB216763 pretreatment group (SB group, 1 mg/kg). SAP model was induced by retrograde infusion of 5％ sodium taurocholate into the biliopancreatic duct. Rats in each group were sacrificed at 12 h after operation. Then the mortality, quantity of ascites, serum AMY, Cr, BUN and ALT were recorded, and the pathological changes of pancreatic tissues and kidney tissues were observed. Results Compared with the SO group, the levels of ascites, serum AMY, Cr, BUN, ALT and pancreatic and renal pathologic score in the SAP group were all significantly increased (P<0.05). Compared with the TD1 group, quantity of ascites, serum AMY, Cr, BUN,ALT and pancreatic tissue pathological grading were reduced in different degrees in the TD2, TD3 and TD4 groups with statistically significant difference (P<0.05); ALT values were reduce in different degrees in the TD2 and TD3 groups as compared with the SAP group (P<0.05), while ALT value in the TD4 group was similar to that in the SAP group; compared with the TD2 group, all the indexes in the TD3 group were significant better (P<0.05); Compared with TD3 group (the best group in TD group), the levels of ascites and serum ALT in the L group and SB group had no significant difference (P>0.05), but the levels of AMY, Cr, BUN, ALT, pancreatic and renal pathologic score were significantly reduced in the TD3 group than those in the L and SB groups (P<0.05); compared with the SB group, the values of Cr, BUN, pancreatic and renal pathologic score in the L group were lower (P<0.05). GSK-3βprotein expression in all groups showed no obvious difference (P>0.05), while p-GSK-3β ser9 protein expression in the SAP group was lower than that in the SO group (P<0.05), and p-GSK-3β ser9 protein expression in the TD3, L and SB groups were stronger than that in the SAP group. Among them, p-GSK-3βser9 protein expression was highest in the TD3 group, followed by the L group, finally the SB group, and the differences were statistically significant (P<0.05). Conclusions Among the three different GSK-3βinhibitors, TDZD-8 is the most effective GSK-3β inhibitor for SAP associated with kidney injury in rats. The GSK-3β inhibitor TDZD-81 mg/kg administered intravenously is safe, effective and optimal dosage for attenuating the severity of severe acute pancreatitis associated with kidney injury.

Objective To explore the prognostic value of sarcopenia in patients undergoing pancreati-coduodenectomy.Method Clinicopathologic data and follow-up information of 116 patients undergoing pancre-aticoduodenectomy at Renmin Hospital of Wuhan University between March 2011 and August 2016 were collected for statistical analysis.Results Among the 116 patients,the prevalence of sarcopenia was 42.2％ (n =49).When compared to the rest of the patients who did not have sarcopenia,the sarcopenia group had longer recovery time [(17.33±6.54) d vs.(13.46±9.32) d,P=0.013] and increased risk of complications (complications in general,59.2％ vs.38.8％,x2 =4.714,P =0.030;Clavien-Dindo ≥ 3:26.5％ vs.10.4％,x2 =5.130,P=0.024).Both the Kaplan-Meier survival analysis (P＜0.05) and the Cox proportional hazard model (overall survival:hazard ratio =2.285,95％ CI =1.521-3.431;recurrence-free survival,hazard ratio =2.167,95％ CI=1.445-3.248) indicated sarcopenia as the risk factor for poorer overall survival and recurrence-free survival.Conclusions Sarcopenia was an independent predictor of poor prognosis for patients undergoing pancreaticoduodenectomy.Patients with sarcopenia had higher risk of developing complications after surgery and lower overall survival rate and recurrence-free survival rate.

Objective:To investigate the influence of P27RF-Rho mRNA gene silencing in the drug sensitivity of 5-fluorouracil(5-Fu)to the liver cancer SMMC cell line,and to provide theoretical basis for the treatment of advanced liver cancer.Methods:The P27RF-Rho RNAi vector was constructed and the P27RF-Rho gene silencing lentivirus were used to infect the SMMC7721 cells.Western blotting method was used to detect the gene silencing effect.The SMMC7721 cells were divided into Scramble-siRNA group, 5-Fu group, P27RF-Rho siRNA group and P27RF-Rho siRNA + 5-Fu group.Western blotting was used to detect the transfection efficiency of RNAi.MTT method was used to detect the cell growth in various groups.Scratching test was used to detect the migration ability of cells in various groups.Transwell experiment were used to detect the invasion ability of cells in various groups.The expressions of P27 and RhoC protein were detected by Western blotting method.Results:P27RF-Rho RNAi lentiviral vector was successfully constructed.The Western blotting results showed that the expression of P27RF-Rho protein in P27RF-Rho siRNA group was decreased compared with 5-Fu group and Scramble-siRNA group(P<0.05).Compared with other three groups, the growth speed of the cells in P27RF-Rho siRNA + 5-Fu group was significantly decreased(P<0.05).The migration ability of the cells in P27RF-Rho siRNA + 5-Fu group was significantly lower than those in other three groups (P<0.01);the average number of cells passing through the Transwell microporous membrane was significantly less than those in other three groups (P<0.01).The Western blotting analysis results showed that the expression level of P27 protein in the cells in P27RF-Rho siRNA + 5-Fu group was significantly higher than those in other three groups(P<0.05);the expression level of RhoC protein was significantly lower than those in other three groups(P<0.05).Conclusion:P27RF-Rho gene silencing can significantly enhance the drug sensitivity of 5-Fu to SMMC7721 cells.

Objective To observe the changes of tissue morphology and ultrastructure of kidney in the rat model of acute necrotizing pancreatitis (ANP),and to investigate the protein expression of glycogen synthase kinase-3β(GSK-3β) and phosphorylated GSK-3βin renal tissue.Methods Sixty SPF male SD rats were randomly divided into 5 groups (n =12 for each group) according to random number method,including control group,ANP 3 h,6 h,12 h,24 h groups.ANP model was established by retrograde infusion of 5％ sodium taurocholate solution into the biliopancreatic duct.Rats were sacrificed at corresponding time points to collect pancreatic and left renal tissue.Serum amylase (AMY),lipase (LIPA),creatinine (Cr) and urea nitrogen (BUN) levels were detected.Pancreatic and renal tissues were routinely pathologically examined.Rephrocytes' ultrastructure changes were observed by projection electron microscope.GSK-3β protein expression and phosphorylated GSK-3β(p-GSK-3β) in kidney tissue were quantified by Western-blot.Results Serum AMY,LIPA,Cr,Bun and pathological scores for pancreatic and renal tissues in ANP groups were obviously higher than those in control group,which increased gradually with the progress of pancreatitis.In ANP rats,it was observed that the microvilli on the surface of the epithelial cells of renal tubules were swelling and irregularly arranged,the nucleus was condensed and broken,the nuclear chromatin was condensed and separated from the nuclear membrane,the mitochondria was condensed,swelling and vacuolated.The expression levels of GSK-3β protein in the renal tissue of the control group and ANP 3 h,6 h,12 h,24 h groups were 0.702± 0.044,0.876± 0.017,0.872± 0.034,0.855± 0.035 and 0.852± 0.032,respectively.The expression levels of p-GSK-3β were 0.626 ± 0.029,0.790 ± 0.029,0.616 ± 0.021,0.448 ±0.028 and 0.439 ± 0.017.GSK-3β protein expression was higher in ANP group than in control group,and the difference was statistically significant (all P ＜ 0.05).But there was no statistically significant difference at different time points in ANP group.p-GSK-3β protein expression increased at 3 h after modeling,and then gradually decreased.p-GSK-3β protein expression was higher in ANP 3 h group than control group and other ANP groups,which in ANP 12 h,24 h group was obviously lower than control group and ANP 3 h,6 h group,and the difference was statistically significant (P ＜ 0.05).Conclusions GSK-3β expression in the kidney of ANP rats began to increase at 3 h after modeling and maintain a high level.p-GSK-3β was transiently increased at 3 h after modeling and then gradually decreased to a level obviously lower than control group.It indicated that these changes may play a crucial role in ANP associated kidney injury.

Objective To explore the effects of rosiglitazone (ROSI),a peroxisome proliferator-activated receptors-gamma (PPAR-γ) ligand,on hyperlipidemia in rats with severe acute pancreatitis (SAP) associated with lung injury.Methods A total of 120 male SD rats received intragastric administration of high fat diet for two weeks to induce experimental hyperlipemia.The hyperlipidemic rats were randomly (random number) divided into six groups:hyperlipidemia (HL) group (n =20),hyperlipidemia with SAP (HP) group (n =20),hyperlipidemia with rosiglitazone intervention (HRP) group (n =20),hyperlipidemia with rosiglitazone and antagonist to rosiglitazone (HRGP) group (n =20),rosiglitazone control (HR) group (n =20) and antagonist control (HG) group (n =20).The SAP was induced by a retrograde infusion of 5％ sodium tauroholate into bile-pancreatic duct,and the SAP was established in HP group,HRP group and HRGP group.In HL group,HR group and HG group,equivalent volume of normal saline was used instead of sodium taurocholate.In HRP group and HR group,ROSI (6 mg/kg) was administered via the femoral vein 1 hour prior to the administration of sodium taurocholate.In HRGP group,GW9662 (0.3 mg/kg),an antagonist to PPRA-gamma,was given via the femoral vein 30 min prior to the administration of ROSI.In HG group,only GW9662 (0.3 mg/kg) was given via the left femoral vein 30 min prior to pretend SAP modeling.Rats from each group were sacrificed by exsanguination 12 h after SAP modeling.Blood samples were taken from all subjects to measure serum amylase (AMY),total cholesterol (TC),triglycerides (TG),Successive sections of the paraffin embedded tissue from pancreas and lung were taken for pathological examination with hematoxylin-eosin (HE) staining.Histopathological changes of pancreatic and pulmonary tissues observed under light microscope were evaluated.In pulmonary tissue,nuclear factor-kappa B (NF-κB) p65 expression was assayed by immunohistochemistry.Intercellular adhesion molecule (ICAM-1) protein and tumor necrosis factor-α (TNF-γ) protein levels were studied using Western blot analysis.Results The serum levels of TC and TG in HL group and HP group were significantly higher than those in HR group and HRP group (1.24 ± 0.28,1.14 0.08 vs.0.41 ±0.17,0.58±0.12;14.86±1.47,12.42±0.96 vs.6.52±2.04,7.36±0.95,allP＜ 0.05);The levels of serum AMY,W/D ratio,pancreas pathologic score,lung pathologic score,expression of NF-κB p65,ICAM-1 and TNF-α in pancreas in the HP group and HRGP group were significantly higher than those in HL group,HR group,and HG group (6 501.9 ±3 770.0,5 922.2 ±925.9 vs.1 139.3 ± 35.6,1 070.8 ±67.0,1 012.4 ±94.7;3.14±0.16,3.06±0.12vs.1.81 ±0.13,1.76±0.23,1.83 ± 0.18;all P ＜0.05);Compared with the HP group and HRGP group,the levels of serum AMY,TC and TG were significantly decreased in HR group and HRP group,ameliorating pancreas and lung pathological damage,and down-regulating the expression of NF-κB p65,ICAM-1 and TNF-α in pulmonary tissue (all P ＜ 0.05).While there were no statistically significant differences in above biomarkers between HP group and HRGP group (all P ＞ 0.05).Conclusions Our study demonstrates that ROSI exerts anti-hyperlipidemic effect and anti-inflammatory effect on hyperlipidemia in rats with sodium taurocholate-induced severe acute pancreatitis associated with lung injury by inhibiting NF-κB and down-regulating the expression of TNF-α and ICAM-1.