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Background@#and Purpose We performed a two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of genetically proxied AMP-activated protein kinase (AMPK) activation, which is the target of metformin, on functional outcome following ischemic stroke onset. @*Methods@#A total of 44 AMPK-related variants associated with HbA1c (%) were used as instruments for AMPK activation. The primary outcome was the modified Rankin Scale (mRS) score at 3 months following the onset of ischemic stroke, evaluated as a dichotomous variable (3–6 vs. 0–2) and subsequently as an ordinal variable. Summary-level data for the 3-month mRS were obtained from the Genetics of Ischemic Stroke Functional Outcome network, including 6,165 patients with ischemic stroke. The inverse-variance weighted method was used to obtain causal estimates. The alternative MR methods were used for sensitivity analysis. @*Results@#Genetically predicted AMPK activation was significantly associated with lower odds of poor functional outcome (mRS 3–6 vs. 0–2, odds ratio [OR]: 0.06, 95% confidence interval [CI]: 0.01–0.49, P=0.009). This association was maintained when 3-month mRS was analyzed as an ordinal variable. Similar results were observed in the sensitivity analyses, and there was no evidence of pleiotropy. @*Conclusion@#This MR study provided evidence that AMPK activation by metformin may exert beneficial effects on functional outcome following ischemic stroke.
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Objective:To study the expression and significance of long noncoding RNA (lncRNA) LINC00657 in diffuse-type adenocarcinoma of esophagogastric junction (AEG).Methods:RT-PCR was used to determine the expression of LINC00657 in AEG tissues and AEG patient-derived tumor cells (PDCs). The expression of E-cadherin in AEG tissues and PDCs was detected. The Kaplan-Meier method was used to evaluate the correlation of LINC00657 expression with the overall survival (OS) of patients.Results:LINC00657 was highly expressed in AEG tissues [(1.41±0.12) vs. (0.61±0.11), t=276.038, P<0.01] and PDCs, while E-cadherin was significantly down-regulated. The expression of LINC00657 was retated to tumor diamer, invassion depth, lymph node metastasis, TNM staging (all P<0.05) In Kaplan-Meier analysis, high levels of LINC00657 were associated with poor prognosis for patients with diffuse-type AEG. In addition, a significant inverse relationship was observed between LINC00657 and E-cadherin expression ( r=-0.529, P<0.001). Conclusions:Elevated expression of LINC00657 in diffuse-type AEG tissues is associated with poor prognosis and may confer a malignant phenotype upon tumor cells.
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Organoid models are used to study kidney physiology, such as the assessment of nephrotoxicity and underlying disease processes. Personalized human pluripotent stem cell-derived kidney organoids are ideal models for compound toxicity studies, but there is a need to accelerate basic and translational research in the field. Here, we developed an automated continuous imaging setup with the "read-on-ski" law of control to maximize temporal resolution with minimum culture plate vibration. High-accuracy performance was achieved: organoid screening and imaging were performed at a spatial resolution of 1.1 μm for the entire multi-well plate under 3 min. We used the in-house developed multi-well spinning device and cisplatin-induced nephrotoxicity model to evaluate the toxicity in kidney organoids using this system. The acquired images were processed via machine learning-based classification and segmentation algorithms, and the toxicity in kidney organoids was determined with 95% accuracy. The results obtained by the automated "read-on-ski" imaging device, combined with label-free and non-invasive algorithms for detection, were verified using conventional biological procedures. Taking advantage of the close-to-in vivo-kidney organoid model, this new development opens the door for further application of scaled-up screening using organoids in basic research and drug discovery.
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Humains , Rein , Organoïdes , Cellules souches pluripotentesRésumé
Objective:To investigate the relationship between caspase activation and recruitment domain 8 ( CARD8) gene rs2043211 polymorphism and the age of onset for large artery atherosclerosis (LAA) stroke in Chinese Han population. Methods:Based on Nanjing Stroke Registry Program, patients with LAA stroke from January 2010 to December 2014 were included retrospectively and genotyped. Grouping according to different genetic models, the age distribution among different genotypes were compared, and Kaplan-Meier curve was used to compare the age-related cumulative non-onset frequency of the patients with different genotypes.Results:A total of 738 patients were admitted and 717 (97.15%) were successfully genotyped and included in the study. There were no significant differences in age, sex, body mass index, hypertension, diabetes, hyperlipidemia, smoking and drinking history among the genotype groups. Patients with T allele had earlier onset under codominant model (AA genotype: 61.68 years, 95% confidence interval [ CI] 59.92-63.45 years; AT genotype: 60.51 years, 95% CI 59.41-61.60 years; TT genotype: 60.44 years, 95% CI 58.96-61.92 years). Kaplan-Meier curve analysis showed that there was a significant difference in the age-related cumulative non-onset frequency between patients with different genotypes (log-rank test, P=0.041). Similar results in the female was observed in the stratified analysis (log-rank test, P=0.001). Conclusions:T allele of CARD8 rs2043211 is associated with the early age of onset of large artery atherosclerosis stroke in Chinese Han population, especially in female patients.
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Objective Mean platelet volume (MPV) and Red Blood Cell Distribution Width (RDW) have been demonstrated to be associated with deep vein thrombosis (DVT).However,their role in the prediction of pulmonary embolism (PE),which is a major complication of DVT,are still unclear.Therefore,we investigated the association of MPV and RDW values with acute PE in patients with DVT.Methods A case-control study was conducted in patients hospitalized in emergency department of Beijing Friendship Hospital from November 2006 to June 2016.The study included three groups:patients with DVT and PE (PE group,n =96),patients with DVT without PE (non PE group,n =95),and control group (No DVT,No PE,n =96).Results (1) MPV was significantly higher in all DVT patients than that in control group (9.8 ±0.5 vs7.8 ±0.6,P ＜0.05;8.6±0.6 vs7.8 ± 0.6,P＜0.05) and MPV was significantly higher in DVT patients with PE than that in DVT patients without PE [(9.8 ± 0.5) fL,(8.6 ± 0.6) fL] (P ＜ 0.05).(2) The percentage of patients with RDW ＞ 14.5％ was significantly higher in PE group and non PE group than that in control group (52.1％ vs 20.8％),and (45.3 ％ vs 20.8％) (P ＜ 0.05).(3) In logistic analysis,MPV is an independent risk factor for PE patients (OR:22.18,95％ CI:9.36-53.16,P ＜0.01),the area under receiver operating characteristic (ROC) curve is 0.91,and the best critical value is 9.15 fL.The incidence of PE in patients with MPV ＞ 9.15 fL and MVP ＜ 9.15 fL was 75.6％ vs 15％ respectively,with statistically significance (P ＜ 0.05).Conclusions Combining use of RDW and MPV may be used as an early assessment of venous thromboembolism.MPV ＞ 9.15 fL suggests that patients may have PE.
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Objective To investigate the relationship between osteoprotegerin ( OPG ) gene polymorphisms and susceptibility to large-artery atherosclerotic stroke ( LAA ). Methods A total of 1 010 patients with LAA registered in Nanjing Stroke Registry Program between August 2013 and May 2017 were retrieved, and 1 121 healthy residents were selected as controls. Two single nucleotide polymorphisms of rs2073617 and rs3134069 of OPG gene were genotyped by SNPscan technique. Multivariate logistic regression analysis was used to analyze the relationship between rs2073617/rs3134069 and susceptibility to LAA. Results Multivariate logistic regression analysis indicated that the rs3134069 C allele (odds ratio [OR] 1.39, 95%confidence interval [CI] 1.13-1.71; P=0.002) and its corresponding CC/CA genotype (OR 1.43, 95% CI 1.14-1.80; P=0.002) were the independent risk factors for LAA. Stratification analysis showed that this association was more pronounced in the subgroups of olderly (≥60 years), those with hypertension, smoking or without diabetes and hyperlipidemia. In addition, haplotype analysis showed that G-C haplotype of rs2073617/rs3134069 was also an independent risk factor for LAA onset (OR 1.36, 95% CI 1.10-1.68; P=0.005). Conclusion OPG gene polymorphisms are associated with the susceptibility to LAA.
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Objective@#To investigate the clinical value of multimodal navigation-based virtual reality (MNVR) in the needle biopsy of intracranial eloquent lesions.@*Methods@#From January 2016 to January 2017, 20 patients with intracranial deep-seated lesions involving eloquent brain areas underwent MNVR-aided needle biopsy at Department of Neurosurgery, People′s Liberation Army General Hospital. Preoperatively, MNVR was used to propose and revise the biopsy planning. Intraoperatively, navigation helped trajectory avoid the eloquent structures. Intraoperative MRI (iMRI) was performed to prove the biopsy accuracy and detect the intraoperative complications. Perioperative neurological status, iMRI findings, intraoprative complications, surgical outcome and pathological diagnosis were recorded. Wilcoxon rank-sum test was conducted to compare the preoperative and postoperative neurological scores.@*Results@#MNVR helped revised 45%(9/20) initial biopsy trajectories, which would probably injury the nearby eloquent structures. Navigation helped biopsy trajectories spare the eloquent structures during the operation. No statistical difference was found between postoperative and preoperative neurological status, despite all the lesions were adjacent to eloquent areas. Additionally, 20 patients totally received 21 iMRI scanning. iMRI helped revise incorrect biopsy site in one case and detected intraoperative hemorrhage in another case, both of cases were treated immediately and effectively. No MNVR related adverse events and complications occurred.@*Conclusions@#MNVR-aided needle biopsy of intracranial eloquent lesions is a safe, novel and efficient biopsy modality. This technique is helpful to reduce the incidence of surgery related neurological deficits.
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Objective To evaluate the changes of CEA,CA19-9,CA72-4 of patients with advanced adenocarcinoma of the esophagogastric junction (AEGJ) who received ultra-early precise hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) with paclitaxel (PTX) after radical surgery.Methods From Jul 2014 to Dec 2015 postoperative advanced AEGJ patients were divided to receive ultraearly precise HIPEC (87 cases,HIPEC group) and conventional therapy group (85 cases) in early stage after radical surgery.Serum levels of CEA,CA19-9 and CA72-4 were examined on preoperative day 1 and postoperative day 9.Results On post-op day 9,the level of CEA,CA19-9 and CA72-4 was (2.8 ± 1.3)ng/ml,(22 ±8)IU/ml,(4.1 ± 1.9)IU/ml in HIPEC group,while that was (3.4 ± 1.2)ng/ml,(25 ±11) IU/ml,(4.8 ± 2.1) IU/ml in control group respectively (t =2.453,P =0.015;t =2.241,P =0.026;t =2.154,P =0.033).Conclusion Ultra-early PTX-based HIPEC with advanced AEGJ after radical surgery lowers serum tumor makers of CEA,CA19-9,CA72-4,reducing body's tumor burden.
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Objective To investigate the effect of long non-coding RNA HOX transcript antisense RNA ( lncRNA HOTAIR ) on the cell proliferation, radiosensitivity and apoptosis of the rectal adenocarcinoma cell lines SW480 and HCT116 in vitro. Methods The expression levels of lncRNA HOTAIR in the rectal adenocarcinoma cell lines ( SW480 and HCT116 ) were assessed by real-time quantitative PCR (RT-qPCR).Silencing of HOTAIR by RNA interference was performed to explore its roles in cell proliferation,radiosensitivity and apoptosis. After treatment with irradiation at a gradient dose,the cell viability was measured and the rate of cell apoptosis was tested. Results Compared with the human rectal epithelial cell lines,the expression of lncRNA HOTAIR was significantly higher in the rectal adenocarcinoma cell lines. The colonic assay demonstrated that the sensitizing enhancement ratios ( SERs) were 1. 58 and 1. 33 for the cells transfected with HOTAIR siRNA in SW480 and HCT116 cell line compared with the control isRNA transfection group. In vitro silencing of lncRNA HOTAIR could enhance the apotosis rate and radiosensitivity of the rectal adenocarcinoma cell line SW480. Conclusion The expression level of lncRNA HOTAIR is correlated with the cellular radiosensitivity, which is probably a parameter for predicting the radiosensitivity of rectal adenocarcinoma cells. Radiotherapy combined with HOTAIR-siRNA can significantly inhibit the cell proliferation,induce cell apoptosis and enhance the radiosensitivity.
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Objective To evaluate T lymphocyte changes in esophagogastric junction adenocarcinoma (AEGJ) patients receiving early hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) after radical resection.Methods 98 AEGJ cases were randomized into postoperative early paclitaxel HIPEC group (50 cases) and surgery only group (48 cases).The changes in TLC,CD3 +,CD4 +,CD8 + and CD4 + CD25 + were examined by using flow cytometry on the preoperaive d1,and on the postoperative d 9.Results There were significant differences in cellular ratios of TLC,CD3 +,CD4 +,CD8 + and CD4 + CD25 + between the two groups on postoperative d 9 [(1.85 ± 0.36) × 109/L,(1.28 ± 0.28) ×109/L,t=8.727,P＜0.001;76％ ±6％,65％ ±6％,t =8.680,P＜0.001;57％ ±8％,41％ ± 7％,t =10.246,P ＜0.001:20％ ±7％,25％ ±6％,t =4.037,P ＜0.001;4.2％ ±1.8％;6.7％ ± 2.0％,t =6.548,P ＜ 0.001].Conclusion Postoperative early HIPEC using paclitaxel improves the celluar immune activity of T cell subsets in advanced AEGJ patients.
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<p><b>OBJECTIVE</b>To investigate the predictive value of P53, Ki-67, HER2 protein detection in neoadjuvant chemotherapy for adenocarcinoma of gastroesophageal junction (AGEJ).</p><p><b>METHODS</b>Preoperative biopsy specimens and clinical data of 72 patients of locally advanced Siewert II AGEJ between June 2010 and December 2013 were reviewed. All the patients received SOX scheme neoadjuvant chemotherapy, and were divided into effective group (complete response plus partial response) and ineffective group (stable disease plus progressive disease). Expressions of above 3 proteins were detected by immunohistochemistry in all the patients before neoadjuvant chemotherapy. The relationship between various proteins and efficacy of chemotherapy was analyzed by univariate and logistic multivariate regression analyses.</p><p><b>RESULTS</b>All the 72 patients successfully completed 2 cycles of SOX neoadjuvant chemotherapy, among them, 5 cases (6.9%) with complete response, 30 cases (41.7%) with partial response, 31 cases (43.1%) with stable disease, 6 cases (8.3%) with progressive disease, including 35 cases in effective group and 37 cases in ineffective group. Compared with ineffective group, the positive expression rate of P53 was significantly reduced (25.0% vs. 45.9%, P=0.020), and that of Ki-67 significantly increased (77.1% vs. 43.2%, P=0.003), however, there was no significant difference in the expression rate of HER2 between the two groups (P>0.05). Multivariate analysis showed that Ki-67 was the independent predictive factor for the efficacy of neoadjuvant chemotherapy (P=0.015). Spearman rank correlation showed that Ki-67 expression was positively correlated with HER2 expression (r=0.259, P=0.028), but P53 expression was not correlated with Ki-67 or HER2 (r=0.140, 0.042, P=0.240, 0.725, respectively).</p><p><b>CONCLUSIONS</b>SOX neoadjuvant chemotherapy is safe and effective for AGEJ, especially for patients with depressed expression of P53 and elevated expression of Ki-67, which both may be used as reference for the prediction of chemotherapy efficacy. There is no correlation between P53 and Ki67 proteins, so combined detection may improve the predictive value.</p>
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Humains , Adénocarcinome , Diagnostic , Traitement médicamenteux , Tumeurs de l'oesophage , Diagnostic , Traitement médicamenteux , Jonction oesogastrique , Anatomopathologie , Immunohistochimie , Antigène KI-67 , Métabolisme , Traitement néoadjuvant , Récepteur ErbB-2 , Métabolisme , Induction de rémission , Protéine p53 suppresseur de tumeur , MétabolismeRésumé
Objective There is little research on the relationship of gene polymorphism of CYP2C19 and clopidogrel response after percutaneous transluminal angioplasty and stenting ( PTAS) in patients with ischemic cerebrovascular disease.The study aimed to investigate the relationship between gene polymorphism and high on-treatment platelet reactivity ( HTPR ) after PTAS and 6 months of regular dual antiplatelet administration in patients. Methods A total of 145 Chinese patients treated with PTAS in our de-partment from January 2011 to March 2014 were enrolled in this study.According to the gene sequencing, patients were divided into wild-type group(CYP2C19*1/*1,69 cases) and mutation group(heterozygous mutation CYP2C19*1/*2 and homozygous mutation CYP2C19*2/*2, 76 cases).Patients received a 100mg/d aspirin and 75mg/d clopidogrel maintenance dose (MD) as dual anti-platelet therapy after PTAS.The clopidogrel inhibition effect was measured by thrombelastography ( TEG) system 6 months after PTAS. Routine cerebral artery digital subtraction angiography was applied to evaluate whether there was restenosis in stent and logistic regres-sion analysis was used to analyze the influential factors of HTPR after PTAS and clopidogrel adminstration. Results After 6 months'regular administration of clopidogrel after PTAS, the platelet adenosine diphosphate ( ADP ) receptor inhibition rates in wild-type group, heterozygous mutation and homozygous mutation group were respectively (58.43 ±21.98)%, (47.80 ±22.93)%, (37.53 ± 21.84)%.The platelet ADP receptor inhibition rate was significantly decreased compared with wild-type group(P=0.001).Carriers of at least one CYP2C19 loss-of-function ( LOF) allele had a higher frequency of clopidogrel HTPR (35.5% vs17.4 % for patients with and without LOF alleles, respectively;P=0.014) .Using multivariate logistic regression analysis, the carriage of CYP2C19 LOF alleles was an independent predictor of the post-procedure HTPR (OR=2.356, 95% CI:1.053-5.272, P=0.037).The rate of ISR was remarkably higher in patients with at least one CYP2C19*2 alleles compared with wild-type patients(11.8%vs 1.4%, P=0.019) . Conclusion In patients with ischemic cerebrovascular disease, the CYP2C19 LOF allele had significant impact on post-procedure clopidogrel HTPR and the prognosis of ISR after PTAS.
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Objective To explore the significance of shock index in the early assessment of patients with severe sepsis and septic shock.Methods A retrospective study of 100 patients with severe sepsis and septic shock admitted in the Emergency Department of the Beijing Friendship Hospital from September 2011 to August 2013 was carried out.According to the 28-day outcome,all patients were divided into survival group (n =48) and death group (n =52).Shock index of patients was calculated at admission (SI1) and 2 hours after resuscitation (SI 2).Results (1) The SI1 and SI2 (1.5 ± 0.05),(1.2 ± 0.04) in the death group were significantly higher than those (1.3 ± 0.08),(0.9 ± 0.05),in the survival group (P ＜ 0.01) ; (2) AUC of SI1 and SI2 of death group were 0.7075 and 0.8894,respectively.The SI2 showed higher sensitivity (80.3％) and specificity (78.4％) compared to SI1.The optimal cut-off point for SI2 was ≥ 1.Conclusions SI2 may potentially be utilized as a reliable predictor for death in patients with septic shock and severe sepsis in an emergency department.
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Objective ToinvestigatetherelationshipbetweenmuscleRASoncogenehomolog (MRAS)genepolymorphismandyoungpatientswithischemicstroke.Methods Atotalof243young patients with ischemic stroke from Nanjing Stroke Registry Program from December 2009 to October 2012 were enrolled retrospectively. At the same time,512 age-and sex-matched healthy controls were selected. The polymorphisms of MRAS genes rs3755751 and rs9289559 loci were analyzed by the modified multiplex PCR-ligase detection reaction assay. The genotype of each locus and the allele frequencies were analyzed and compared. Results (1)The frequencies of AA,AG and GG genotypes for rs3755751 in the stroke group (n=243)were 7. 4%(n=18),37. 0%(n=90),and 55. 6%(n=135),respectively. There were no significant differences compared with those (6. 4%[n=18],36. 9%[n=189]and 56. 6%[n=190]) in the control group (n=512)(P>0. 05). The frequencies of AA,AG and GG genotypes for rs9289559 in stroke group were 7. 0 (n=17)%,42. 0%(n=102),and 51. 0%(n=124),respectively. There were no significant differences compared with 6. 1%,(n=31)37. 9%(n=194),and 56. 1%(n=287)in the control group (P>0. 05). (2)Further construction of an effect model (AA vs. AG+GG and GG vs. AG+AA),there was no significant difference between the stroke group and the control group (P >0. 05 ). Analyzing the effects of different genotypes on plasma lipid levels showed that the high-density lipoprotein cholesterol level of the GG genotype subgroup in the young ischemic stroke group was significantly higher than that rs3755751 of the AG +AA genotype subgroup (OR,6. 80,95%CI 2.18-21.27, P=0. 001 ). Conclusions MRAS gene polymorphism may have no significant correlation with the genetic susceptibility in young patients with ischemic stroke. Polymorphism of rs3755751 may be correlated with the level of serum high-density lipoprotein cholesterol.
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Objective To investigate the relationship between the carotid calcification and the prognosis in patients with ischemic stroke. Methods A total of 522 patients with non-cardiac ischemic stroke registered in the Nanjing Stroke Registry Program (NSRP )from December 2009 to October 2012 were enrolled. All patients underwent head and neck CT angiography (CTA). The original data of CT scan were transmitted into the Siemens workstation. Calcium score measurement was performed using the same reconstruction conditions and Agatston calcium score to measure calcification score. The patients were divided into no (0),mild (0
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Stroke is a class of complex diseases,and it is the result of the combined action of environmental and genetic factors.With the development of molecular biology techniques,a large number of candidate genes associated with stroke and susceptibility loci have been identified.This article reviews the recent progress in research on the genetics of different subtypes of ischemic stroke.
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Objective To explore the role of BNP (B-type natriuretic peptide) in the early assessment of patients with acute pulmonary embolism (PE).MethodsEighty-six patients hospitalized in Beijing Friendship Hospital from November 2005 to June 2010 diagnosed as acute PE were studied retrospectively.The differences of BNP and other indicators and the relationship of BNP and right ventricular and right atrial pressure gradient value ( RV-RA PG) were compared between two groups divided by whether right ventricular dysfunction exists or not.imilarly,the differences of BNP and other indictors were compared between the two groups divided by complications exists or not.ResultsIn the right ventricular dysfunction group and control group,BNP was ( 1356.8 ±675.4) pg/ml and ( 103.8 ±51.4) pg/ml,respectively,and the differences are significant.BNP and RV-RA PG had a significant correlation (γ =0.824,P ＜0.01 ) by Linear correlation analysis.BNP had a reliable diagnostic power for right ventricular dysfunction ( AUC 0.907).In the group with complications and none -complication group,BNP value was ( 1356.8 ±675.4)pg/mlvs.(103.8 ±51.4) pg/ml,and pH value was (7.372 ±3.7) vs.(7.446 ±3.5),and the differences were all significant ( P ＜ 0.05 ). Conclusions BNP has important significance in early predicting the occurring,severity and prognosis of congestive heart failure caused by acute pulmonary embolism; pH of the early arterial blood gas has positive significance for early diagnose and treatment and predicting the severity and prognosis of patients suffering acute pulmonary embolism.