The precise and rapid monitoring of multiple organ dysfunction is crucial in drug discovery. Traditional methods, such as pathological analysis, are often time-consuming and inefficient. Here, we developed a multiplexed near-infrared window two (NIR-II) fluorescent bioimaging method that allows for real-time, rapid, and quantitative assessment of multiple organ dysfunctions. Given that existing probes did not fully meet requirements, we synthesized a range of NIR-II hemicyanine dyes (HDs) with varying absorption and emission wavelengths. By modifying these dyes, we achieved high spatial and temporal resolution imaging of the liver, kidneys, stomach, and intestines. This method was further applied to investigate disorders induced by cisplatin, a drug known to cause gastric emptying issues along with liver and kidney injuries. By monitoring the metabolic rate of the dyes in these organs, we accurately quantified multi-organ dysfunction, which was also confirmed by gold-standard pathological analysis. Additionally, we evaluated the effects of five aristolochic acids (AAs) on multiple organ dysfunction. For the first time, we identified that AA-I and AA-II could cause gastric emptying disorders, which was further validated through transcriptomics analysis. Our study introduces a novel approach for the simultaneous monitoring of multi-organ dysfunction, which may significantly enhance the evaluation of drug side effects.

[摘 要] 目的：探究包被蛋白复合体β1亚基（COPB1）在食管鳞状细胞癌（ESCC）中的表达，及其对ESCC细胞恶性生物学行为的影响、作用机制及临床意义。方法：采用2014～2018年间在河北医科大学第四医院生物样本库中82例ESCC组织及癌旁组织，常规培养正常食管鳞状上皮细胞HEEC和食管癌细胞KYSE-150、KYSE-170、Eca109、TE1、KYSE-30、KYSE-450，用转染试剂将pcDNA3.1-vector（空载体）、pcDNA3.1-COPB1载体，si-NC和si-COPB1转染至KYSE-150、TE1细胞中，记为NC、COPB1-OE、si-NC和si-COPB1组。用数据库数据分析COPB1 mRNA在泛癌组织中的表达及其表达与免疫细胞浸润的关系，qPCR法检测ESCC组织和细胞中COPB1、PIK3CB、CD68、CD163、CD206、ARG1、IL-10 mRNA水平表达情况，WB法检测ESCC组织和各组细胞中的COPB1、PI3K、CD68、CD163、CD206、p-AKT蛋白表达，克隆形成实验和MTS实验检测各组细胞的增殖能力，划痕愈合实验和Transwell实验检测各组细胞的迁移和侵袭能力，免疫组织化学染色（IHC）法检测ESCC组织中COPB1和CD206蛋白表达。以人单核细胞白血病细胞（THP-1）构建巨噬细胞模型，用佛波酯（PMA）和IL-3和IL-4和ESCC细胞上清液诱导巨噬细胞转型，用qPCR和WB法检测CD68和CD206m RNA和蛋白的表达。结果：COPB1在泛癌组织和ESCC组织中均呈高表达且与淋巴结转移和TNM分期有关联（均P < 0.01），COPB1高表达的ESCC患者总生存期短（P < 0.05），COPB1是潜在的ESCC的诊断标志物。COPB1在KYSE-150和TE1细胞中也呈高表达（均P < 0.05），过表达或敲减COPB1可明显抑制或促进KYSE-150和TE1细胞的增殖能力、迁移和侵袭能力（均P < 0.05）。COPB1表达变化诱导的差异表达基因主要富集于PI3K/AKT通路（均P < 0.001）, COPB1可促进PI3K/AKT通路的活化（P < 0.05），COPB1高表达可导致M2型巨噬细胞浸润增加（P < 0.05），COPB1高表达促进TAM/M2极化（P < 0.05）。结论：COPB1在ESCC组织中呈高表达，其可激活PI3K/AKT通路及调控肿瘤免疫微环境促进 ESCC发生发展，COPB1有望成为ESCC诊断和预后的生物标志物及治疗靶点。

AIM: To quantify early changes of macular capillary parameters in type 2 diabetic patients using optical coherence tomography angiography(OCTA).METHODS: Retrospective case study. A total of 49 healthy subjects, 52 diabetic patients without retinopathy(noDR)patients, and 43 mild nonproliferative diabetic retinopathy(mNPDR)patients were recruited. Capillary perfusion density, vessel length density(VLD), and average vessel diameter(AVD)were calculated from macular OCTA images(3 mm×3 mm)of the superficial capillary plexus after segmenting large vessels and the deep capillary plexus. Parameters were compared among control subjects, noDR, and mNPDR patients. The area under the receiver operating characteristic curve estimated the abilities of these parameters to detect early changes of retinal microvascular networks.RESULTS: Significant differences were found in the VLD and AVD among the three groups(P<0.001). Compared with the control group, the noDR group had significantly higher AVD(P<0.05). VLD of both layers in patients of mNPDR group was significant decreased compared with that of noDR group(all P<0.01). Deep AVD had a higher area under the curve(AUC)of 0.796 than other parameters to discriminate the noDR group from the healthy group. Deep AVD had the highest AUC of 0.920, followed by that of the deep VLD(AUC=0.899)to discriminate the mNPDR group from the healthy group.CONCLUSIONS: NoDR patients had wider AVD than healthy individuals and longer VLD than mNPDR patients in both layers. When compared with healthy individuals, deep AVD had a stronger ability than other parameters to detect early retinal capillary impairments in noDR patients.

Objective To explore the feasibility of harmonic waves analysis for observing morphological brain network changes in patients with depressive disorder(DD).Methods Whole brain 3D high resolution T1WI of 55 DD patients(DD group)and 46 normal controls(NC group)were acquired.Six kinds of morphological features brain network were constructed with FreeSurfer tool,including the number of brain region vertices,surface area,gray matter volume,average cortical thickness,Gaussian curvature and fold index.Laplace operator was applied to obtain common harmonic wave.The harmonic power of different morphological features and the gray matter volume in different brain regions were compared between groups.Results No significant difference of total harmonic energy was found between groups.The specific harmonic wave energies were significantly different between groups,including the number of brain region vertices corresponding to the 2nd,6th,15th,44th and 57th harmonic waves,surface area corresponding to the 2nd,6th,16th and 57th harmonic waves,gray matter volume corresponding to the 2nd,12th,13th,15th and 57th harmonic waves,average cortical thickness corresponding to the 2nd,19th,35th,36th and 44th harmonic waves,Gaussian curvature corresponding to the 34th,40th,54th and 57th harmonic waves,as well as fold index corresponding to the 5th,16th,21st and 57th harmonic waves.Gray matter volumes of transverse temporal gyrus in left hemisphere in DD group were significantly larger than that in NC group(t=2.900,P=0.004).Conclusion Harmonic waves analysis was feasible for observing morphological brain network changes in DD patients.

Objective:To investigate the efficacy and prognostic value of baseline 18F-FDG PET/CT metabolism parameters in patients with stage Ⅲ-Ⅳ lung adenocarcinoma before epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) monotherapy. Methods:From January 2012 to June 2020, 61 patients (19 males, 42 females; median age: 64 years) with stage Ⅲ-Ⅳ lung adenocarcinoma who underwent baseline 18F-FDG PET/CT imaging before EGFR-TKI monotherapy in 1 month in Beijing Hospital were retrospectively analyzed. The clinical data and metabolic parameters including SUV max, SUV max of lean body mass (SUL max), peak of SUV of lean body mass (SUL peak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the hottest lesions on PET were analyzed. Patients were followed up to obtain the efficacy evaluation, progression-free survival (PFS) and overall survival (OS). ROC curve analysis was performed to obtain the optimal cut-off value of metabolic parameters to predict disease remission and prognosis. Kaplan-Meier method, log-rank test and Cox proportional risk regression model were used to analyze the prognostic factors. Results:After EGFR-TKI monotherapy, 42.9%(24/56) patients were in disease remission. The optimal cut-off values for predicting disease remission of SUL peak, SUV max, SUL max, MTV, and TLG were 5.9, 13.1, 11.1, 10.6 ml and 99.6 g, respectively. The remission rates of patients with SUV max>13.1, MTV>10.6 ml and TLG>99.6 g were significantly higher than those of patients with SUV max≤13.1(51.2%(21/41) vs 3/15; χ2=4.37, P=0.037), MTV≤10.6 ml (9/12 vs 36.6%(15/41); χ2=5.53, P=0.019) and TLG≤99.6 g (10/13 vs 35.0%(14/40); χ2=6.96, P=0.008). The follow-up period for survival was 0.05-6.80 years, and 10.3%(6/58) patients had no disease progression, and 44.3%(27/61) patients died. The optimal cut-off values of SUL peak, SUV max, SUL max, MTV, and TLG for PFS were 11.2, 17.0, 13.7, 2.7 ml and 14.8 g, and those for OS were 5.6, 14.3, 8.8, 2.8 ml and 37.3 g, respectively. Patients with never-smoking, SUV max≤17.0 and SUL peak≤11.2 had longer PFS ( χ2 values: 3.87-7.37, all P<0.05); never-smoking history (hazard ratio ( HR)=2.29, 95% CI: 1.08-4.87, P=0.031) and SUL peak≤11.2 ( HR=2.67, 95% CI: 1.35-5.27, P=0.005) were independent predictors for PFS. Patients with stage Ⅲ+ ⅣA, SUV max≤14.3, SUL peak≤5.6, SUL max≤8.8 and TLG≤37.3 g had longer OS ( χ2 values: 5.78-8.83, all P<0.05); stage Ⅲ+ ⅣA ( HR=2.81, 95% CI: 1.08-7.32, P=0.034) and SUL max≤8.8 ( HR=9.66, 95% CI: 1.25-74.91, P=0.030) were independent predictors for OS. Conclusions:Baseline 18F-FDG PET/CT imaging has good prospect in clinical application in patients with stage Ⅲ-Ⅳ lung adenocarcinoma before EGFR-TKI monotherapy. The higher baseline metabolic activity of tumor in the 18F-FDG PET/CT, the higher remission rate. Smoking history and SUL peak are independent predictors for PFS; SUL max and stage are independent predictors for OS.

Objective:To investigate the value of left ventricular systolic synchrony assessed by gated myocardial perfusion imaging(GMPI)in predicting major adverse cardiovascular events(MACE)in elderly patients with coronary heart disease(CHD).Methods:In this retrospective study, clinical data from elderly patients who had completed a two-day assessment of resting-loading GMPI between September 2012 and February 2014 in Beijing Hospital were collected, including the summed stress score(SSS)for total ischemic burden, measured by GMPI, left ventricular ejection fraction(LVEF), peak filling rate(PFR), phase band width(PBW), phase standard deviation(PSD)and phase entropy(PE).Follow-up of MACE was conducted.Independent risk factors for MACE were analyzed using a multifactorial Cox proportional hazards regression model, and the cumulative MACE incidence was analyzed using the Kaplan-Meier survival curve.Results:A total of 427 subjects were enrolled, including 200(46.8%)men, with a mean age of 74.1±6.5(60-92)years and 323(75.6%)aged ≥ 70 years.The median follow-up time was 54.7 months.At the end of follow-up, MACE occurred in 47 patients(11.0%).Compared with the group without MACE, the incidences of hypertension, hyperlipidemia, and hyperuricemia were significantly higher( χ2=5.20, 5.62, 3.86, all P<0.05), LVEF and PFR were significantly lower( t=-5.51, -5.23, both P<0.001), and SSS, PSD, PBW, and PE were significantly higher( Z=4.78, t=5.14, 5.78, 5.62, all P<0.001)in the MACE group.The results of Cox proportional hazards regression model analysis suggested that age ≥ 70(hazard ratio: 2.57, 95% CI: 1.08-6.13), abnormal perfusion(hazard ratio: 2.60, 95% CI: 1.31-5.15), increased PSD(hazard ratio: 3.72, 95% CI: 1.72-8.05)and increased PE(hazard ratio: 4.09, 95% CI: 1.94-8.63)were independent risk factors for the occurrence of MACE(all P<0.05).Further analysis on 323 patients ≥ 70 years indicated that abnormal perfusion(hazard ratio: 2.96, 95% CI: 1.40-6.26), increased PSD(hazard ratio: 3.51, 95% CI: 1.56-7.89), and increased PE(hazard ratio: 4.49, 95% CI: 2.08-9.71)were independent risk factors for MACE( P<0.05 for all). Conclusions:Parameters of GMPI systolic synchrony analysis can very well identify the population at high risk of MACE in elderly patients with CHD.

Objective To investigate the influencing factors for acute multiple vessels occlusion(MVO)and its impact on the prognosis of patients with anterior circulation acute large vessel occlusion stroke(ALVOS)who achieved successful recanalization after endovascular treatment(EVT).Methods Patients with anterior circulation ALVOS who received successful EVT at the Yijishan Hospital of Wannan Medical College between July 2015 and April 2023 were retrospectively analyzed.Baseline data,including age,sex,onset-to-puncture time(OTP),onset-to-recanalization time(OTR),medical history(including atrial fibrillation,diabetes,hypertension),alcohol and smoking history,admission blood pressure(systolic and diastolic),Alberta stroke program early CT score(ASPECTS),National Institutes of Health stroke scale(NIHSS)score,trial of Org 10172 in acute stroke treatment(TOAST)classification(atherosclerotic type,cardioembolic type,and other etiology types),and 90-day modified Rankin scale(mRS)score were collected.Collateral circulation was assessed based on the degree of contrast agent reflux observed in the occluded arterial supply area during delayed DSA,and patients were classified into poor and good collateral circulation groups.Malignant cerebral edema was defined as a midline shift of ≥5 mm on the follow-up CT scan performed on day 3 post-surgery.The primary endpoint(efficacy indicator)was the 90-day mRS score,with mRS score≤ 2 considered as a good prognosis and mRS score＞2 considered as a poor prognosis.The secondary endpoint(safety indicator)was the 90-day mortality rate.All patients were divided into MVO and non-MVO groups based on whether they had single or multiple intracranial vessel occlusions.Acute MVO was defined as the detection of acute occlusion of other large or medium vessels,in addition to the main vessels(internal carotid artery or M1/M2 segments of the middle crebral artery[MCA]),in CT angiography,MR angiography,or DSA,resulting in ischemia in brain regions distinct from the main occlusion area.Factors that showed statistically significant differences in univariate analysis were further analyzed using multivariate Logistic regression to identify the risk factors for the occurrence of acute MVO and the factors associated with the prognosis of ALVOS patients.Results A total of 846 patients with ALVOS were included,with ages ranging from 26 to 94 years(mean age[69±11]years).The proportion of male patients was 57.2％(484/846).The median admission ASPECTS was 8(7,9)and the median admission NIHSS score was 14(12,18).The incidence of malignant cerebral edema at 3 days post-surgery was 13.4％(112/835),and the 90-day mortality rate was 19.1％(162/846).(1)Among the 846 ALVOS patients,810(95.7％)were in the non-MVO group and 36(4.3％)were in the MVO group.Univariate analysis showed significant differences between the MVO and non-MVO groups in terms of atrial fibrillation,malignant cerebral edema,admission ASPECTS,admission NIHSS scores,TOAST classification,collateral circulation,rate of complete recanalization,and 90-day poor prognosis rate(all P＜0.05).However,there was no statistically significant difference in 90-day mortality between the two groups(P=0.193).Multivariate Logistic regression analysis showed that TOAST classification of cardioembolic type(OR,16.089,95％CI 1.835-141.061,P=0.012)and other etiology types(OR,9.768,95％CI 1.078-88.540,P=0.043)were associated with the occurrence of MVO.(2)Among the 846 ALVOS patients,445 had a good prognosis at 90days,and 401 had a poor prognosis.Univariate analysis showed that,compared to the good prognosis group,the poor prognosis group had a lower proportion of males and smokers,and a higher proportion of patients with older age,higher baseline systolic blood pressure,hypertension,diabetes,and atrial fibrillation(all P＜0.01).Additionally,the poor prognosis group had higher admission NIHSS scores(P＜0.01),lower admission ASPECTS,lower rates of good collateral circulation and complete recanalization,higher rates of malignant cerebral edema and MVO,and statistically significant differences in TOAST classification distribution(all P＜0.01).Multivariate Logistic regression analysis showed that MVO was associated with poor 90-day prognosis in ALVOS patients after EVT(OR,3.368,95％CI 1.149-9.878,P=0.027).Furthermore,older age(OR,1.045,95％CI 1.025-1.066),diabetes(OR,1.719,95％CI 1.080-2.734),higher baseline systolic blood pressure(OR,1.012,95％CI 1.004-1.019),lower admission ASPECTS(OR,0.746,95％CI 0.674-0.826),higher admission NIHSS score(OR,1.115,95％CI 1.070-1.162),without immediate postoperative complete recanalization(OR,0.413,95％CI 0.290-0.592),poor collateral circulation(OR,0.594,95％CI 0.415-0.851),and malignant cerebral edema(OR,6.191,95％CI 3.026-12.670)were all associated with poor 90-day prognosis after EVT in ALVOS patients(all P＜0.05).Conclusions The TOAST classification of cardioembolic type and other etiology types is associated with MVO.MVO is a risk factor for poor outcomes after successful EVT in ALVOS patients.

Objective To explore the accuracy and clinical application value of artificial intelligence(AI)-based coronary computed tomography angiography(CCTA)in the evaluation of coronary artery stenosis in patients with acute coronary syndrome(ACS).Methods Fifty-four patients with suspected ACS who underwent CCTA examination and invasive coronary angiography(ICA)within 72 h were retrospectively selected.The CCTA images of all patients were processed by AI(AI group)and manual post-pro-cessing(manual group),respectively.The image quality,work efficiency and detection rate of coronary artery stenosis were compared between AI group and manual group.With ICA results as the gold standard,the sensitivity,specificity,positive predictive value,negative predictive value and accuracy of AI in the diagnosis of ACS patients with coronary artery stenosis(≥50％)in CCTA were analyzed,and the consistency of AI and ICA examination results was tested.Results The image quality of CCTA in AI group(grade Ⅰ 27.8％)was better than that in manual group(grade Ⅰ 14.8％),but there was no statistical difference between the two groups(X2=2.707,P＞0.05).The average diagnosis time of AI group(89.67 s±33.21 s)was significantlyshorter than that of manual group(813.33 s±301.84 s)and the difference was statistically significant(t=-17.512,P＜0.001),and the average time gain rate was 88.97％.There was no statistical difference in the detection rate of coronary artery stenosis(≥50％)between AI group and manual group(x2=0.003,P＞0.05).The sensitivity,specificity,positive predictive value,negative predictive value,and accuracy of AI in diagnosis of ACS were 87.60％,96.44％,80.30％,97.92％,and 95.19％,respectively,which were significantly consistent with the results of ICA examina-tion(Kappa=0.810,P＜0.05).Conclusion AI-assisted diagnosis can correctly identify the coronary artery tree with better image,significantly shorten the diagnosis time of CCTA in ACS patients with high accuracy,and can provide a strong basis for the early treat-ment of patients with acute chest pain.

Objective To explore the association of the magnitude of systolic blood pressure reduction(SBPr)with post-procedure 24 h symptomatic intracranial hemorrhage(sICH)and 90-day clinical outcomes in patients with successful endovascular thrombectomy(EVT).Methods Consecutively registered patients with EVT caused by anterior circulation large vessel occlusion stroke(LVOS)in the First Affiliated Hospital of Wannan Medical College(Yijishan Hospital)between July 2015 and April 2023 and patients with successful reperfusion were analyzed.Demographic data,medical history(hypertension,diabetes),the trial of Org 10172 in acute stroke treatment(TOAST)classification,the baseline National Institutes of Health Stroke Scale(NIHSS)score and the baseline Alberta stroke early CT(ASPECT)score of patients were collected.And procedure related parameters(including time from onset to puncture,time from onset to reperfusion,occluded site[internal carotid artery,M1 segment of middle cerebral artery,M2 segment of middle cerebral artery],collateral circulation status[determined based on preoperative occluded angiography showing the range of collateral circulation in the occluded vessel area,defined as good collateral circulation with a reflux range of ≥ 50％and poor collateral circulation with a reflux range of＜50％]),immediate postoperative reperfusion status(evaluated using the modified thrombolysis for cerebral infarction[mTICI]grading,successful reperfusion defined as mTICI grading of 2b-3),24 hours sICH,and 90 days clinical outcomes(evaluated using the modified Rankin scale score at 90days after EVT,with a score ≤ 2indicating a good prognosis and a score＞2indicating a poor prognosis).SBPr was defined as(baseline SBP-mean SBP)/baseline SBP x 100％.According to the the magnitude of SBPr,SBPr is divided into 5 categories(＜-10％,-10％-10％,＞10％-20％,＞20％-30％and＞30％).Based on the clinical outcomes at 90 days and the occurrence of sICH at 24 hours after EVT,patients were divided into a good prognosis group and a poor prognosis group,as well as an sICH group and a non-sICH group.The relationship between SBPr and postoperative 90 days clinical prognosis or sICH was analyzed using a binary Logistic regression model.Subgroup analysis was conducted based on a history of hypertension(yes and no),continuous intravenous hypotensive therapy(yes and no),baseline ASPECT scores(3-5 and 6-10),and collateral circulation status(good and bad).Using a restricted cubic plot to depict the relationship between SBPr and sICH and clinical prognosis at 90days.Results(1)In total,731 patients were included.The median age was 71(62,77)years and 424(58.0％)were men.The median baseline NIHSS score was 14(12,18),the median baseline ASPECT was 9(7,10),405(55.4％)patients achieved 90-day modified Rankin scale score 0-2,and 35 patients(4.8％)developed sICH.(2)Multivariate analysis showed that the older age(OR,1.036,95％CI 1.017-1.056),the higher baseline NIHSS score(OR,1.095,95％CI1.049-1.144),the lower baseline ASPECT score(OR,0.704,95％CI 0.636-0.780),diabetes(OR,1.729,95％CI 1.084-2.758),bad collateral circulation(good collateral circulation vs.bad collateral circulation,OR,0.481,95％CI 0.332-0.696)and SBPr＞30％(SBPr-10％-10％as a reference,OR,2.238,95％CI 1.230-4.071),the higher the risk of poor clinical outcomes at 90 days(all P＜0.05).Continuous intravenous hypotensive therapy is a risk factor for postoperative 24 h sICH(OR,2.278,95％CI 1.047-4.953;P=0.038),while SBPr 20％-30％is associated with a lower risk of postoperative 24 h sICH(SBPr-10％-10％as a reference,OR,0.362,95％CI0.131-0.998;P=0.049).(3)The restrictive cube plot shows that there is a U-shaped relationship between SBPr after EVT and poor clinical outcomes at 90 days,while there is a nearly linear relationship with the occurrence of sICH.The more SBP reduction,the lower the incidence of sICH.(4)In the subgroup analyses,in the non-hypertension history and the good collateral circulation group,SBPr＞30％has a higher risk of poor clinical outcomes compared to SBPr-10％-10％(OR and 95％CI were 2.921[1.000-8.528]and 2.363[1.078-5.183],respectively,with P=0.05 or P＜0.05);After EVT,the group receiving continuous intravenous hypotensive therapy and the baseline ASPECT score 6-10 groups showed a significant correlation between SBPr＞30％and poor clinical outcomes at 90 days(SBPr-10％-10％as a reference,OR and 95％CI were 2.646[1.168-5.993]and 2.481[1.360-4.527],respectively,with P＜0.05).The correlation between SBPr and lower incidence of sICH was only found in the subgroup of poor collateral circulation(SBPr-10％-10％as a reference,SBPr＞20％-30％:OR,0.133,95％CI 0.027-0.652;SBPr＞30％:OR,0.104,95％CI 0.013-0.864;all P＜0.05).Conclusions Among patients who achieved successful reperfusion with EVT,SBPr might be related to a worse functional outcome at 90 days and sICH 24 h after operation.However,the relationship may exhibit significant heterogeneity across different subgroups.Baseline ASPECT score,history of hypertension,collateral circulation,and the use of continuous venous hypertension after EVT have been highlighted in individualized blood pressure management after EVT.