Hepatocellular carcinoma(HCC)is one of the most common tumor types and remains a major clinical challenge.Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC.However,few mitophagy inhibitors have been approved for clinical use in humans.Pyrimethamine(Pyr)is used to treat infections caused by protozoan parasites.Recent studies have reported that Pyr may be beneficial in the treatment of various tumors.However,its mechanism of action is still not clearly defined.Here,we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis.Mechanistically,Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells.In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29(SNAP29)-vesicle-associated membrane protein 8(VAMP8)interaction.Moreover,Pyr acted synergistically with sorafenib(Sora)to induce apoptosis and inhibit HCC proliferation in vitro and in vivo.Pyr enhances the sensitivity of HCC cells to Sora,a common chemotherapeutic,by inhibiting mitophagy.Thus,these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor.Notably,Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

Objective:To develop an imaging-assisted diagnostic tool for schizophrenia based on multimodal magnetic resonance imaging and artificial intelligence techniques.Methods:Three independent datasets were utilized. For each subject, four brain structural metrics including grey matter volume (GMV), white matter volume (WMV), cortical thickness (CT) and deformation-based morphometry (DBM) indicators were extracted from the structural magnetic resonance imaging (sMRI) data, and three brain functional metrics including amplitude of low frequency fluctuation (ALFF), regional homogeneity (ReHo) and functional connectivity (FC) were extracted from the functional magnetic resonance imaging (fMRI) data. To distinguish patients with schizophrenia and healthy controls, single-metric classification models and multi-metrics-fusion classification models were trained and tested using a within-dataset and a between-dataset cross-validation strategy.Results:The results of within-dataset cross-validation showed that the highest accuracy of the single-metric classifications for schizophrenia diagnosis was 86.18% (FC), while the multi-metric-fusion classifications could reach an accuracy of 90.21%. The results of between-datasets cross-validation showed that the highest accuracy of the single-metric classifications for schizophrenia diagnosis was 69.02% (ReHo), while the multi-metric-fusion classifications could reach an accuracy of 71.25%.Conclusion:The functional metrics generally outperforms the structural metrics for the classification between patients with schizophrenia and heathy controls. Additionally, fusion of multi-modal brain imaging metrics can improve the classification performance. Specifically, the fusion of CT, DBM, WMV, FC and ReHo demonstrates the highest classification accuracy, which is a potential tool for imaging-assisted diagnosis of schizophrenia.

Objective: To determine the relationship between volume of epicardial adipose tissue (EAT) and atrial fibrillation (AF) . Methods: A total of 207 patients who hospitalized in the Department of Cardiology, Nantong University Affiliated Hospital from January 2016 to June 2018 were included in this study. They were divided into two groups, including AF group (n=125) and sinus rhythm group (n=82). The AF group included 80 paroxysmal AF (PAF) and 45 persistent AF (PeAF) patients. Total EAT and left atrial EAT (LA-EAT) volume were measured using 256 rows of multi-slice spiral CT in all patients. Echocardiographic derived left ventricular ejection fraction (LVEF) and left atrial diameter (LAD) were analyzed. Hospholipase A2 and blood lipids were examined in all patients. The baseline data and EAT volume of all groups were compared. The multivariate logistic regression was used to analyze the risk factors related to the occurrence of AF. The correlation between total EAT volume and LA-EAT volume and LAD were analyzed by Pearson correlation. Result: The volume of total EAT in patients with sinus rhythm, AF, PAF and PeAF were (92.2±32.1), (136.0±46.0), (134.2±46.3) and (140.1±52.6)cm³, respectively. The volume of LA-EAT in patients with sinus rhythm, AF, PeAF and PAF were (27.1±7.5), (39.2±19.2), (35.9± 17.0) and (45.1±21.5)cm³, respectively. Total EAT and LA-EAT volume were significantly larger in PAF and PeAF groups than in sinus rhythm group (all P<0.01). The LA-EAT volume was larger in PeAF group than in PAF group (P<0.01), but total EAT volume was similar between two groups (P>0.05). Logistic regression analysis showed that total EAT volume (OR=1.202, 95%CI 1.083-1.334, P=0.001), LA-EAT volume (OR=1.051, 95%CI 1.003-1.101, P=0.037) and LAD (OR=1.019, 95%CI 1.005-1.032, P=0.006) were the independent related factors of AF. Pearson correlation analysis showed that the total EAT volume was positively correlated with LAD (r=0.466, P<0.01) and LA-EAT volume was positively correlated with LAD (r=0.290, P<0.01). Conclusion The volume of total EAT and LA-EAT measured by 256-row multi-slice spiral CT is significantly correlated with the incidence of AF.

Objective To determine the relationship between volume of epicardial adipose tissue (EAT) and atrial fibrillation (AF). Methods A total of 207 patients who hospitalized in the Department of Cardiology, Nantong University Affiliated Hospital from January 2016 to June 2018 were included in this study. They were divided into two groups, including AF group (n=125) and sinus rhythm group (n=82). The AF group included 80 paroxysmal AF (PAF) and 45 persistent AF (PeAF) patients. Total EAT and left atrial EAT (LA?EAT) volume were measured using 256 rows of multi?slice spiral CT in all patients. Echocardiographic derived left ventricular ejection fraction (LVEF) and left atrial diameter (LAD) were analyzed. Hospholipase A2 and blood lipids were examined in all patients. The baseline data and EAT volume of all groups were compared. The multivariate logistic regression was used to analyze the risk factors related to the occurrence of AF. The correlation between total EAT volume and LA?EAT volume and LAD were analyzed by Pearson correlation. Result The volume of total EAT in patients with sinus rhythm, AF, PAF and PeAF were (92.2 ± 32.1), (136.0 ± 46.0), (134.2 ± 46.3) and (140.1 ± 52.6)cm3, respectively. The volume of LA?EAT in patients with sinus rhythm, AF, PeAF and PAF were (27.1±7.5), (39.2±19.2), (35.9± 17.0) and (45.1±21.5)cm3, respectively. Total EAT and LA?EAT volume were significantly larger in PAF and PeAF groups than in sinus rhythm group (all P<0.01). The LA?EAT volume was larger in PeAF group than in PAF group (P<0.01), but total EAT volume was similar between two groups (P>0.05). Logistic regression analysis showed that total EAT volume ( OR=1.202, 95%CI 1.083-1.334, P=0.001), LA?EAT volume ( OR=1.051, 95%CI 1.003-1.101, P=0.037) and LAD ( OR=1.019, 95%CI 1.005-1.032, P=0.006) were the independent related factors of AF. Pearson correlation analysis showed that the total EAT volume was positively correlated with LAD (r=0.466, P<0.01) and LA?EAT volume was positively correlated with LAD (r=0.290, P<0.01). Conclusion The volume of total EAT and LA?EAT measured by 256?row multi?slice spiral CT is significantly correlated with the incidence of AF.

OBJECTIVE:To develop a method for simultaneous determination of carbamazepine,venlafaxine,rosiglitazone and nifedipine in human plasma.METHODS:UPLC-MS/MS method was adopted to determine plasma sample after precipitated with methanol (containing 0.1％ formic acid) using pioglitazone hydrochloride as internal standard.The determination was performed on Waters ACQUITY UPLC HSS C18 column with mobile phase consisted of aqueous solution containing 0.01％ formic acid-methanol containing 0.01％ formic acid (gradient elution) at the flow rate of 0.3 mL/min.The column temperature was 50 ℃,and sample size was 5 μL.ESI was used for positive ion scanning by multi reaction monitoring mode.The ion pairs for quantitative analysis were m/z 237.00 to 194.05 (carbamazepine),m/z 278.20 to 58.10 (venlafaxine),m/z 358.08 to 135.04 (rosiglitazone),m/z 347.15 to 315.17 (nifedipine),m/z 357.09 to 134.06 (internal standard).RESULTS:The liner ranges of carbamazepine,venlafaxine hydrochloride,rosiglitazone hydrochloride and nifedipine were 2.00-2 000.00 (r=0.995 9,n=5),2.12-2 120.00(r=0.990 5,n=5),2.00-2 000.00(r=0.991 5,n=5) and 2.04-1 020.00(r=0.991 0,n=5) ng/mL;the minimum detection limits were 0.200,0.106,0.100,1.020 ng/mL,respectively.RSDs of inter-day and intra-day were less than 15％.The absolute values of RE were less than 15％.The extraction recoveries were 65.66％-96.36％ (RSD％ ＜15％,n=5),and matrix effects ranged 80.99％-114.33％.The plasma concentrations of carbamazepine in 2 epileptic patients were (1 500.41 ± 169.11),(1 159.01 ±59.24) ng/mL(RSD were 11.27％,5.60％,n=3).The plasma concentrations of nifedipine in 2 hypertensive patients were (14.68 ±1.92),(21.18 ± 3.59)ng/mL (RSD were 16.98％,13.10％,n=3).CONCLUSIONS:The method is simple,specific,sensitive,accurate and suitable for the monitoring of plasma concentration and pharmacodynamic study of above drugs.

Objective To study the clinical effect of diversion treatment for complex anal fistula.Methods A total of 60 patients with complex anal fistula were enrolled in this study were divided into control group and experimental group according to the random number table method,with 30 cases per group.All patients were given routinely imaging examination and other related checks,and the intestine tract was cleaned in the morning of the operative day.The control group were treated with low anal fistula resection,while the experimental group with diversion treatment.The efficacy of treatment,postoperative anal function,wound healing time and pain were compared between the two groups.Results The total effective rate in the experimental group was higher than that in the control group (P ＜ 0.05).The Wexner score of the anus function in the experimental group was lower than that in the control group at 1,7,14 and 21 d after the operation,and the differences were statistically significant (P ＜ 0.05).The wound healing time,VAS score on 14thpostoperative day,intraoperative wound area and postoperative scar size were lower in the experimental group than that in the control group (P ＜ 0.05).Conclusion Diversion treatment for complex anal fistula has significant efficacy,faster postoperative wound healing,and it can effectively relieve clinical symptoms and signs,improve anal function,reduce body pain,so it is worthy of clinical promotion.

Objective To study the clinical effect of diversion treatment for complex anal fistula.Methods A total of 60 patients with complex anal fistula were enrolled in this study were divided into control group and experimental group according to the random number table method,with 30 cases per group.All patients were given routinely imaging examination and other related checks,and the intestine tract was cleaned in the morning of the operative day.The control group were treated with low anal fistula resection,while the experimental group with diversion treatment.The efficacy of treatment,postoperative anal function,wound healing time and pain were compared between the two groups.Results The total effective rate in the experimental group was higher than that in the control group (P ＜ 0.05).The Wexner score of the anus function in the experimental group was lower than that in the control group at 1,7,14 and 21 d after the operation,and the differences were statistically significant (P ＜ 0.05).The wound healing time,VAS score on 14thpostoperative day,intraoperative wound area and postoperative scar size were lower in the experimental group than that in the control group (P ＜ 0.05).Conclusion Diversion treatment for complex anal fistula has significant efficacy,faster postoperative wound healing,and it can effectively relieve clinical symptoms and signs,improve anal function,reduce body pain,so it is worthy of clinical promotion.

Objective To detect the expressions of Lingo-1 and myelin associated protein in the white matter and hippocampus of ovariectomized rats after short-term estrogen replacement therapy in order to explore the possible mechanisms for the effects of estrogen on the brain myelin sheaths and cognitive function.Methods 24 middleaged (9-12 months) female Sprague-Dawley (SD) rats were bilaterally ovariectomized (OVX) and randomly divided into vehicle replacement (OVX+Veh) group and estrogen replacement (OVX+E) group.After one month ERT,The spatial learning and memory ability of all rats were assessed with Morris water maze.Then,10 rats were randomly selected from each group.The ultrastucture of myelin sheaths in the cerebral white matter and hippocampus were observed,and the protein expression of MBP and Lingo-1 were investigated with Western blot and immunohistochemical staining.Results The escape latencies of OVX+E rats in navigation test were significantly shorter than that of OVX+Veh rats(P＜0.05).The myelin sheaths in the white matter and hippocampus of OVX+Veh rats showed obviously degeneration.In the OVX+E group,the expression of MBP in the white matter and hippocampus was significantly higher than that of OVX+Veh group(P＜0.05),however,the expression of Lingo-1 was significantly lower than that of OVX +Veh group (P＜ 0.05).Conclusions One-month ERT has significant beneficial effects on the spatial learning capacity and myelin sheaths in the white matter and hippocampus.The protective effects may be related to estrogen-induced downregulation of the Lingo-1 expression in the white matter and hippocampus of rats.

Objective: To explore the peri-operative application of GLP-1 analogue and insulin on myocardial perfusion and clinical prognosis in patients of acute ST segment elevation myocardial infarction (STEMI) with stress-induced hyperglycemia. Methods: Our research was a prospective single center randomized control study. A total of 114 consecutive STEMI patients received percutaneous coronary intervention (PCI) within 12h of onset were enrolled, the patients had no diabetes while blood glucose ≥11.1mmol/L at immediate admission. Based on random number table, the patients were divided into 2 groups: Observation group, the patients received GLP-1 analogue, n=59 and Control group, the patients received insulin, n=55. The post-operative myocardial perfusion, indicators of myocardial damage and cardiac function, myocardial infarct area (MIA) and myocardial salvage index (MSI) were compared between 2 groups. The patients were followed-up for 6 months to record the incidence of major adverse cardiovascular events (MACE). Results: At peri-operative period, compared with Control group, Observation group had decreased peak values of creatine kinase isoenzyme (CK-MB) and troponin T (cTnT), P<0.05. At 6 months post-operation, compared with Control group, Observation group showed increased myocardial perfusion and left ventricular ejection fraction (LVEF), P<0.05, reduced MIA (15±12) g vs (20±14) g, P<0.05 and 12% elevated MSI as (0.64±0.13) vs (0.56±0.12), P<0.001. The MACE incidence was similar between 2 groups, P=0.217. Conclusion: In STEMI patients with stress-induced hyperglycemia, peri-operative application of GLP-1 analogue may safely regulate blood glucose, improve cardiac perfusion and function, reduce MIA; while it had no influence on myocardial perfusion at peri-operative period and no impact on MACE occurrence at 6 months post-operation.

Objective:To compare the changes of marginal bone resportion between immediate implantation and delayed implantation after 12 to 24 months of definitive prostheses finished.Methods:41 patients were recruited and divided into immediate implant placement group(n =20) and delayed implant placement group(n =21).All implants were evaluated via radiograph after surgery,6 months after implantion,1 year and 2 years after prostheses placement respectively,the height of marginal bone was measured 6 month after implation,1 year and 2 years after prostheses placement.Results:After 6 month,1 year and 2 year the mesial marginal bone attachement (MBA) of immediate implant placement group increased by (1.35 ± 1.12),(2.16 ± 1.73) and (2.53 ± 1.65) mm,the distal by (1.46 ± 1.17),(1.94 ± 1.16) and (2.32 ± 1.68) mm,respectively (among the 3 time points of examination,P ＜ 0.05).As for the delayed implantation group,in the mesial area MBA increased by (-0.52 ± 0.47),(-0.69 ± 0.58) and (-0.97 ± 0.78) mm,in the distal area by (-0.46 ± 0.44),(-0.60 ± 0.45) and (-0.72 ± 0.63) mm (among 3 time points,P ＞ 0.05).Conclusion:Immediate implantation is superior to delayed implantation for marginal bone attachement of dental implant.