Analysis of the anti-T2DM components in dichloromethane fraction of Schisandra sphenanthera and its mechanism

Background:The type 2 diabetes mellitus(T2DM)pharmacodynamic study of various parts of Schisandra sphenanthera was conducted in the previous stage,and it was found that dichloromethane extracted part(SDP)had a significant hypoglycemic effect.Therefore,the components of SDP were analyzed,and the specific mechanism of its anti-T2DM was explored.Methods:We used a high-fat,high-sugar diet in combination with streptozotocin to induce a T2DM rat model,and the model rats were divided into two groups according to body weight and blood glucose.Triglyceride,oral glucose tolerance test,fasting blood glucose,low density lipoprotein cholesterol,superoxide dismutase,insulin,glycated hemoglobin,total cholesterol,nonesterified free fatty acids,alanine aminotransferase,high-density lipoprotein cholesterol,aspartate aminotransferase,malondialdehyde,and glutathione peroxidase were measured,organ indices were calculated,and pathological sections of pancreas and liver were observed.The 16S rRNA V3–V4 region of intestinal flora was sequenced to explore the effect of SDP on biochemical indicators and intestinal flora.Based on the above indicators,the anti-T2DM mechanism of SDP in Schisandra sphenanthera was analyzed.Results:After six weeks of administration,the biochemical indices of diabetic rats were diminished compared to the control group.And SDP could significantly increase the gut microbialα-diversity index,resulting in significant changes in the flora of T2DM rats,with increased richness and diversity,reduced harmful flora,and significantly back-regulated the levels of acetic acid,propionic acid,and butyric acid.Conclusion:SDP can improve the symptoms associated with elevated blood glucose,dyslipidemia,elevated fasting insulin levels,and damaged glucose tolerance in rats.SDP against T2DM may be through the control of intestinal flora to normalize and exert anti-diabetic effect;its main active components may be lignans and terpenoids.

Dipeptidyl peptidase-4 inhibitors and the risk of infection: A systematic review and meta-analysis of cardiovascular outcome trials

BACKGROUND Since adverse events during treatment affect adherence and subsequent glycemic control,understanding the safety profile of oral anti-diabetic drugs is imperative for type 2 diabetes mellitus(T2DM)therapy.AIM To evaluate the risk of infection in patients with T2DM treated with dipeptidyl-peptidase 4(DPP-4)inhibitors.METHODS Electronic databases were searched.The selection criteria included randomized controlled trials focused on cardiovascular outcomes.In these studies,the effects of DPP-4 inhibitors were directly compared to those of either other active anti-diabetic treatments or placebo.Six trials involving 53616 patients were deemed eligible.We calculated aggregate relative risks employing both random-effects and fixed-effects approaches,contingent upon the context.RESULTS The application of DPP-4 inhibitors showed no significant link to the overall infection risk[0.98(0.95,1.02)]or the risk of serious infections[0.96(0.85,1.08)],additionally,no significant associations were found with opportunistic infections[0.69(0.46,1.04)],site-specific infections[respiratory infection 0.99(0.96,1.03),urinary tract infections 1.02(0.95,1.10),abdominal and gastrointestinal infections 1.02(0.83,1.25),skin structure and soft tissue infections 0.81(0.60,1.09),bone infections 0.96(0.68,1.36),and bloodstream infections 0.97(0.80,1.18)].CONCLUSION This meta-analysis of data from cardiovascular outcome trials revealed no heightened infection risk in patients undergoing DPP-4 inhibitor therapy compared to control cohorts.

The anti-neoplastic effects of metformin modulate the acquired phenotype of fbroblast cells in the breast cancer-normal fbroblast co-culture system

Intracellular communications between breast cancer and fibroblast cells were reported to be involved in cancer proliferation,growth,and therapy resitance.The hallmarks of cancer fibroblast interactions,consisting of caveolin 1(Cav1)and mono-carboxylate ransporter 4(MCT4)(metabolic coupling markers),along with IL-6,TGFB,and lactate secretion,are considered robust biomarkers predicting recurrence and metastasis.In order to promote a novel phenotype in normal fibroblasts,we predicted that breast cancer cells could be able to cause loss of Cavl and increase of MCT4,as well as elevate IL 6 and TGF in nearby nomal fibroblasts.We created a co culture model using breast cancer(4T1)and normal fibroblast(NIH3T3)cell lines cultured under specific experimental conditions in order to directly test our theory.Moreover,we show that long-term co-culture of breast cancer cells and normal fibroblasts promotes loss of Cavl and gain of MCT4 in adjacent fibroblasts and increase lactate secretion.These results were validated using the monoculture of each group separately as a control.In this system,we show that me tformin inhibits IL-6 and TGFB secretion and re expresses Cavl in both cells.However,MCT4 and lactate stayed high after treatment with metformin.In conclusion,our work shows that co-culture with breast cancer cells may cause signifcant alterations in the phenotype and secretion of normal fibroblasts.Metformin,however,may change this state and affect fibroblasts'acquired phenotypes.Moreover,mitochondrial inhibition by metformin after 8 days of treatment,signi ficantly hinders tumor growth in mouse model of breast cancer.

溃疡性结肠炎患者血清Chemerin与Th9/Treg细胞失衡的相关性分析

目的探究溃疡性结肠炎(ulcerative colitis,UC)患者血清趋化素(Chemerin)水平与Th9/Treg细胞失衡的相关性。方法选取2020年11月至2021年11月于我院确诊为UC的患者85例(UC组)和健康体检者80名(对照组)。流式细胞术检测Th9/Treg的比例;采用ELISA法检测血清中IL-9、CRP、IL-10、IL-17的含量。统计学分析Chemerin表达与Mayo评分的相关性;与Th9、Treg、Th9/Treg以及相关细胞因子之间的相关性。结果UC组Chemerin水平和Mayo评分均显著高于对照组,UC患者重度组Chemerin水平和Mayo评分均显著高于中度组和轻度组,中度组显著高于轻度组(P<0.05);Chemerin表达与Mayo评分之间呈正相关(P<0.05);流式细胞术结果显示,UC患者血清中Th9/CD4+的比例显著升高,Treg/CD4+比例显著降低,Th9/Treg比例显著升高(P<0.05);UC组Treg比例以及IL-10水平显著低于对照组,Th9比例、Th9/Treg以及IL-9、CRP、IL-17水平显著高于对照组(P<0.05);UC患者重度组的Treg比例、IL-10水平显著低于中度组和轻度组,中度组显著低于轻度组(P<0.05);UC患者重度组的Th9比例、Th9/Treg、IL-9、CRP、IL-17水平显著高于中度组和轻度组,中度组显著高于轻度组(P<0.05);UC组患者血清Chemerin表达与Th9比例、Th9/Treg、CRP、IL-17、IL-9水平呈正相关,与Treg比例、IL-10水平呈负相关(P<0.05)。结论UC患者血清Chemerin水平与Th9/Treg细胞失衡有密切关系。

非小细胞肺癌不同胸腔积液严重程度及预后患者lncRNA MEG3表达及其与Th17/CD4^(+)T细胞的关系

目的:研究非小细胞肺癌(NSCLC)不同胸腔积液严重程度及预后患者lncRNA MEG3表达及其与Th17/CD4^(+)T细胞的关系。方法:选取2020年1月至2022年12月福建医科大学附属泉州第一医院收治的104例NSCLC恶性胸腔积液患者作为研究对象,根据胸腔积液量分为3组:少量胸腔积液组(35例)、中量胸腔积液组(42例)、大量胸腔积液组(27例)。根据患者疾病实际发展转归分为预后良好组(29例未出现复发和转移)和预后不良组(75例出现复发和转移)。另选取同期于福建医科大学附属泉州第一医院治疗的60例肺炎良性胸腔积液患者作为对照组。实时荧光定量PCR检测两组胸腔积液中MEG3表达。收集受试者外周静脉血,流式细胞术检测外周血Th17细胞、CD4^(+)T细胞比例,并计算Th17/CD4^(+)T。对比各组患者lncRNA MEG3及外周血Th17、CD4^(+)T细胞水平。Logistic回归分析NSCLC胸腔积液及预后的影响因素。结果:NSCLC组胸腔积液lncRNA MEG3表达及CD4^(+)T细胞百分比低于对照组,Th17细胞百分比、Th17/CD4^(+)T高于对照组(P<0.05)。大量胸腔积液组lncRNA MEG3表达及CD4^(+)T细胞百分比低于少量胸腔积液组、中量胸腔积液组,中量胸腔积液组lncRNA MEG3表达及CD4^(+)T细胞百分比低于少量胸腔积液组,大量胸腔积液组Th17细胞百分比、Th17/CD4^(+)T高于少量胸腔积液组、中量胸腔积液组,中量胸腔积液组Th17细胞百分比、Th17/CD4^(+)T高于少量胸腔积液组(P<0.05)。预后不良组lncRNA MEG3表达及CD4^(+)T百分比低于预后良好组,而Th17细胞百分比、Th17/CD4^(+)T高于预后良好组(P<0.05)。Logistic回归分析结果显示,lncRNA MEG3为NSCLC胸腔积液的保护因素,Th17/CD4^(+)T为危险因素(P<0.05);lncRNA MEG3为NSCLC预后的保护因素,Th17/CD4^(+)T为危险因素(P<0.05)。结论:NSCLC不同胸腔积液严重程度及预后患者lncRNA MEG3表达及Th17/CD4^(+)T不同,且lncRNA MEG3为NSCLC胸腔积液及预后的保护因素,Th17/CD4^(+)T为危险因素,可作为胸腔积液严重程度及预后诊断的有效生物标志物。

FUZZY ROBUST H_∞ CONTROL OF UNCERTAIN NONLINEAR SYSTEM WITH TIME-DEALY

This paper addresses the problem of the fuzzy H ∞state feedback control for a class of uncertain nonlinear systems with time delay. The Takagi Sugeno (T S) mo del with time delay and parameter uncertainties is adopted for modeling of nonlinear system. The systematic design procedure for the fuzzy robust controller based on linear matrix inequality (LMI) is given. Some sufficient conditions are derived for the existence of fuzzy H ∞ state feedback controllers such that the closed loop system is asymptotically stable and the effect of the disturbance input on controlled output is reduced to a prescribed level. An example is given to demonstrate the effectiveness of the proposed method.

慢乙肝低病毒血症患者继续核苷(酸)类似物治疗的远期临床结局:一项系统评价和Meta分析

背景一线核苷(酸)类似物(nucleos(t)ide analogues,NAs)经治后发生低病毒血症(low-level viremia,LLV)的慢乙肝患者,继续使用NAs治疗的远期临床结局的研究尚缺乏.目的采用系统评价和Meta分析对慢乙肝经一线NAs治疗的LLV患者继续原NAs治疗和更换不同NAs治疗方案远期临床结局情况进行评价.方法经计算机检索PubMed、Embase、Web of Science、Cochrane Library数据库和中国知网(CNKI)、万方数据库,选取符合纳入标准的研究,使用R 4.3.1软件对纳入研究数据进行Meta分析.结果最终纳入11篇文献,涉及3153例慢乙肝LLV患者,其中7篇文献进行HBV DNA阴转率定量Meta分析,结果提示更换NAs方案组继续治疗24 wk[RR=4.23,95%CI(2.47,7.24),P<0.01]和48 wk[RR=2.90,95%CI(1.75,4.81),P<0.01]后HBV DNA阴转率明显高于继续原NAs方案组;纳入6篇文献进行HBeAg阴转率的定量Meta分析,更换NAs治疗方案组24 wk HBeAg阴转率高于继续原方案组[RR=2.31,95%CI(1.28,4.19),P<0.01],但48 wk两组HBeAg阴转率差异无统计学意义[RR=1.50,95%CI(0.88,2.54),P=0.13];纳入3篇文献进行终末期肝病发生率的定性系统评价,结果显示继续NAs治疗的LLV组患者远期终末期肝病发生率均高于维持病毒学应答(maintain virological response,MVR)组,差异均具有统计学意义(P<0.05).结论更换NAs治疗方案可提高慢乙肝LLV患者HBV DNA阴转率和HBeAg阴转率,但继续NAs方案治疗的慢乙肝LLV患者远期终末期肝病发生率较MVR患者高.

TELEPERM-ME 闭环控制模块中调节算法的剖析

主要对西门子ＴＥＬＥＰＥＲＭ－ＭＥ闭环控制模块６ＤＳ１４１２中的调节算法功能块ＲＥＫ进行了剖析，以便进一步了解Ｔ－ＭＥＤＣＳ闭环控制系统的设计方法及设计技巧，从而能够更好地开发和应用Ｔ－ＭＥ系统．

1例气管重度狭窄病人全身麻醉下经硬质气管镜置入Montgomery T管术后的护理

总结1例气管切开术后气道重度狭窄病人在全身麻醉下行经硬质气管镜气管上段置入Montgomery T管治疗术的护理经验。护理要点包括制定出术后风险预警评估方案及预警阳性事件的紧急处理规范;气道湿化管理及非零负压浅层探索式吸痰的方法;术后康复功能锻炼;心理支持干预。经过多学科专业的规范化治疗和精心护理,病人于术后第9天复查支气管镜效果良好,术后第10天顺利出院,出院后连续随访3个月,情况良好。

双靶点嵌合抗原受体-T细胞治疗复发难治多发性骨髓瘤患者疗效和安全性的Meta分析

背景嵌合抗原受体(CAR)-T细胞免疫疗法已在多发性骨髓瘤(MM)中取得较好的疗效,最常见的靶点为B细胞成熟抗原(BCMA)。单靶点CAR-T细胞免疫疗法的缺点是会导致疾病抵抗和复发,可能与抗原逃逸有关。为此,改进开发了双靶点CAR-T细胞治疗复发难治多发性骨髓瘤(RRMM),此方面尚缺乏系统的临床分析。目的对RRMM患者应用双靶点CAR-T细胞免疫疗法治疗的有效性及安全性进行Meta分析。方法计算机检索PubMed、Embase、Cochrane Library、Web of Science、中国知网、万方数据知识服务平台、维普网7个数据库中有关双靶点CAR-T细胞治疗RRMM的单组率研究,检索时限为建库至2023-02-06。由2名研究人员使用自制的数据表单来提取收集数据,并采用非随机对照试验方法学评价指标进行文献质量评价。采用R Studio软件进行数据分析。结果共纳入9篇文献,包括200例既往接受过多线治疗的RRMM患者。双靶点CAR-T细胞疗法根据不同靶点可分为4类:BCMA+CD19、BCMA+CD38,BCMA+跨膜剂与钙调节亲环素配体的相互作用者(TACI)、BCMA+人信号淋巴细胞激活分子家族成员7(CS1),其中BCMA+CD19靶点的研究较多。根据输注形式不同CAR-T细胞疗法可分为4类:双特异性CAR-T细胞、联合或序贯输注两种不同CAR-T细胞、双顺反子结构、共转导。Meta分析显示,双靶点CAR-T细胞治疗RRMM的总缓解率(ORR)为90.0%(95%CI=0.849~0.943),完全缓解率(CRR)为54.6%(95%CI=0.416~0.673),微小残留病(MRD)阴性率为75.6%(95%CI=0.489~0.952),髓外病变(EMD)总缓解率为55.1%(95%CI=0.234~0.851),最后一次随访时的复发率为29.7%(95%CI=0.141~0.454),最后一次随访时的生存率为75.6%(95%CI=0.554~0.915),3~4级细胞释放因子综合征(CRS)发生率为16.4%(95%CI=0.094~0.245),神经毒性(ICANS)发生率为4.0%(95%CI=0~0.120)。敏感性分析提示结果稳定。Egger's检验结果显示,ORR(P=0.03)及EMD总缓解率(P=0.02)提示存在一定的偏倚风险;CRR(P=0.53)、MRD阴性率(P=0.79)、最后一次随访时的复发率(P=0.71)、生存率(P=0.98)、3~4级CRS发生率(P=0.90)、ICANS发生率(P=0.30)提示不存在发表偏倚。结论双靶点CAR-T细胞免疫治疗RRMM显示出良好的疗效和安全性,未来需要多中心、大样本、更长随访期的研究来进一步评估其疗效和安全性。

恶性肿瘤中免疫检查点抑制剂与甲状腺功能异常风险的Meta分析

目的 Meta分析免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)治疗引起恶性肿瘤患者发生甲状腺功能异常的风险。方法 检索从建库至2022年10月15日Pub Med、Embase、Cochrane Library、中国知网及万方医学网中关于恶性肿瘤ICIs治疗的相关不良反应研究。根据纳入与排除标准筛选文献,提取研究数据,采用Stata 12.0软件进行Meta分析。结果 共纳入32项随机对照试验,其中使用程序性细胞死亡蛋白1(programmed cell death protein-1,PD-1)、程序性细胞死亡配体1(programmed cell death ligand-1,PD-L1)、细胞毒性T淋巴细胞相关蛋白4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)抑制剂单药治疗分别为17篇、6篇、3篇,两种ICIs联合使用为8篇。Meta分析显示,ICIs单药治疗引起恶性肿瘤患者发生甲状腺功能减退(RR=9.04,95%CI为7.21~11.33)、甲状腺功能亢进(RR=10.83,95%CI为6.96~16.90)、甲状腺炎(RR=7.61,95%CI为2.99~19.37)的风险明显高于对照组。PD-1(RR=8.61,95%CI为6.47~11.46)、PD-L1(RR=6.75,95%CI为4.33~10.52)、CTLA-4(RR=7.12,95%CI为3.16~16.08)和联合应用(RR=52.56,95%CI为13.15~210.12)引起的甲状腺功能减退的风险比对照组均升高。与单一ICIs比较,ICIs联合使用引起甲状腺功能减退(RR=1.77,95%CI为1.41~2.22)及甲状腺功能亢进(RR=3.79,95%CI为2.42~5.96)的风险进一步升高。结论 ICIs治疗引起恶性肿瘤患者甲状腺功能异常的风险明显升高,以发生甲状腺功能减退的风险最高,其次是甲状腺功能亢进和甲状腺炎。与ICIs单药比较,ICIs联合使用可进一步升高风险。

ROBUST CONTROL OF A CLASS OF NONLINEAR SYSTEM WITH TIME-VARYING PAR AMETRIC UNCERTAINTIES

A class of triangular non li near system with disturbances which has unknown multiplicative time varying par ametric uncertainties in each virtual control is treated by a backstepping techn ique. The controller designed for all admissible uncertainties can guarantee tha t all states of its closed loop system are uniformly bounded. The robust contro ller design algorithm and a sufficient condition of the system stability are giv en. In addition, the closed loop system has an ISS property when the multiplica tive time varying parametric uncertainties are viewed as inputs to the system. Thus, this design provides a way to prevent a destabilizing effect of the multip licative time varying parametric uncertainties. Finally, simulational example i s given and simulational result shows that the controller exhibits effectiveness and excellent robustness.

Spectrophotometric Determination of Lodine in Soils by Chloramine T-Tetrabase System

Optimized the experimental conditions of determination of trace iodine in soil in chloramine T-Tetrabase system, and analysis the national standards material, the results showed that the measured values was to be identical with recommended values with a detection limit of 0.16 μg/g, and the relative standard deviation was less than 8%, the whole process was short in time and simple, so it was applicable to the determination of trace iodine in batches.

Secondary metabolites of mulberry leaves exert anti-lung cancer activity through regulating the PD-L1/PD-1 signaling pathway

Lung cancer ranks the top of malignancies that cause cancer-related deaths worldwide.The leaves of Morus alba L are traditional Chinese medicine widely applied in respiratory diseases.Our previous work has demonstrated the anti-lung cancer effect of secondary metabolites of mulberry leaf,but their mechanism of action has still not fully elucidated.We synthesized Moracin N(MAN)-Probe conjugated with alkyne to label lung cancer cells and identified protein targets by chemical proteomic analysis.MAN and its probe exerted similar growth-inhibitory effect on human lung cancer cells.Chemical proteomic results showed that MAN targeted the programmed death ligand 1(PD-L1)checkpoint pathway and T cell receptor(TCR)signaling pathway,indicating its immune-regulatory function.Cell-free surface plasmon resonance(SPR)results showed the direct interaction of MAN with PD-L1 protein.Molecular docking analysis demonstrated that MAN bound to E158 residue of PD-L1 protein.MAN downregulated the expression levels of PD-L1 in a time-and dose-dependent manner and disrupted the PD-L1/programmed death 1(PD-1)binding,including other secondary metabolites of mulberry leaves Guangsangon E(GSE)and Chalcomoracin(CMR).Human peripheral blood mononuclear cells(PBMCs)co-cultured with MAN-treated A549 cells,resulting in the increase of CD8^(+)GZMB^(+)T cells and the decrease of CD8^(+)PD-1^(+)T cells.It suggested that MAN exerts anti-cancer effect through blocking the PD-L1/PD-1 signaling.In vivo,MAN combined with anti-PD-1 antibody significantly inhibited lung cancer development and metastasis,indicating their synergistic effect.Taken together,secondary metabolites of mulberry leaves target the PD-L1/PD-1 signaling,enhance T cell-mediated immunity and inhibit the tumorigenesis of lung cancer.Their modulatory effect on tumor microenvironment makes them able to enhance the therapeutic efficacy of immune checkpoint inhibitors in lung cancer.

初始T1值及细胞外容积分数对心脏淀粉样变的诊断价值:Meta分析

目的 采用Meta分析方法探讨初始T1值及细胞外容积分数(extracellular volume fraction,ECV)对心脏淀粉样变性(cardiac amyloidosis,CA)的诊断价值。材料与方法检索数据库PubMed、 Embase、 Cochrane Library、 Web of Science、Wanfang Database、CBM、VIP及CNKI中有关探讨初始T1值及ECV对CA诊断价值的文献,检索时间为从建库开始至2022年11月。由2名研究者单独完成文献筛选,提取纳入文献的相关资料并进行质量评估。应用Revman 5.3、Stata 16.0和Meta-Disc1.4软件进行偏倚风险评价和统计分析,进行异质性、发表偏倚分析。使用敏感性分析验证Meta分析结果的稳定性与可靠性。结果 最终纳入文献12篇,共1 045例患者。Meta分析显示初始T1值诊断CA的合并敏感度(sensitivity,Sen)、特异度(specificity,Spe)、阳性似然比(positive likelihood ratio,PLR)、阴性似然比(negative likelihood ratio,NLR)、诊断比值比(diagnostic odds ratio,DOR)、曲线下面积(area under the curve,AUC)和95%置信区间(confidence interval,CI)分别为86%(95%CI:82%~89%)、86%(95%CI:80%~91%)、6.2(95%CI:4.2~9.3)、0.16(95%CI:0.12~0.22)、38(95%CI:19~75)、0.92(95%CI:0.90~0.94);ECV诊断CA的Sen合并、Spe合并、PLR合并、NLR合并、DOR合并、AUC分别为90%(95%CI:83%~94%)、90%(95%CI:83%~94%)、8.8 (95%CI:5.3~14.6)、0.11 (95%CI:0.07~0.19)、79 (95%CI:38~162)、0.95 (95%CI:0.93~0.97)。结论 初始T1值和ECV对CA具有较高的诊断价值,可为CA的早期诊断提供影像学依据。

Correlative factors of poor prognosis and abnormal cellular immune function in patients with Alzheimer’s disease

BACKGROUND Alzheimer’s disease(AD)is a serious disease causing human dementia and social problems.The quality of life and prognosis of AD patients have attracted much attention.The role of chronic immune inflammation in the pathogenesis of AD is becoming more and more important.AIM To study the relationship among cognitive dysfunction,abnormal cellular immune function,neuroimaging results and poor prognostic factors in patients.METHODS A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November 2020.Collect cognitive dysfunction performance characteristics,laboratory test data and neuroimaging data from medical records within 24 h of admission,including Mini Mental State Examination Scale score,drawing clock test,blood T lymphocyte subsets,and neutrophils and lymphocyte ratio(NLR),disturbance of consciousness,extrapyramidal symptoms,electroencephalogram(EEG)and head nucleus magnetic spectroscopy(MRS)and other data.Multivariate logistic regression analysis was used to determine independent prog-nostic factors.the modified Rankin scale(mRS)was used to determine whether the prognosis was good.The correlation between drug treatment and prognostic mRS score was tested by the rank sum test.RESULTS Univariate analysis showed that abnormal cellular immune function,extrapyramidal symptoms,obvious disturbance of consciousness,abnormal EEG,increased NLR,abnormal MRS,and complicated pneumonia were related to the poor prognosis of AD patients.Multivariate logistic regression analysis showed that the decrease in the proportion of T lym-phocytes in the blood after abnormal cellular immune function(odd ratio:2.078,95%confidence interval:1.156-3.986,P<0.05)was an independent risk factor for predicting the poor prognosis of AD.The number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score(r=0.578,P<0.05).CONCLUSION The decrease in the proportion of T lymphocytes may have predictive value for the poor prognosis of AD.It is recommended that the proportion of T lymphocytes<55%is used as the cut-off threshold for predicting the poor prog-nosis of AD.The early and continuous drug treatment is associated with a good prognosis.

Variations of shear-wave splitting parameters in the source region of the 2023 Türkiye doublet earthquakes

In this study,the shear-wave splitting parameters of local seismic events from the source regions of the 2023 Türkiye MW7.7 and MW7.6 doublet earthquakes(event 1 and event 2,respectively)were measured from June 1,2022,to April 25,2023,and their spatiotemporal characteristics were analyzed.The results revealed clear spatial and temporal differences.Spatially,the dominant fast-wave polarization direction at each station shows a strong correlation with the direction of the maximum horizontal principal compressive stress,as characterized by focal mechanism solutions of seismic events(MW≥3.5)near the station.The dominant fast-wave polarization direction and the regional stress field also showed a strong correlation with the intermovement of the Arabian Plate,African Plate,and Anatolian Block.Along the Nurdagi-Pazarcik fault zone,the seismic fault of event 1,stations closer to the middle of the fault where the mainshock occurred exhibited notably greater delay times than stations located towards the ends of the fault and far from the mainshock.In addition,the stations located to the east of the Nurdagi-Pazarcik fault and to the north of the Sürgüfault also exhibited large delay times.The spatial distribution of shear-wave splitting parameters obtained from each station indicates that the upper-crust anisotropy in the source area is mainly controlled by the regional stress field,which is closely related to the state of the block motion.During the seismogenic process of the MW7.7 earthquake,more stress accumulated in the middle of the Nurdagi-Pazarcik fault than at either end of the fault.Under the influence of the MW7.7 and MW7.6 events,the stress that accumulated during the seismogenic process of the earthquake doublet may have migrated towards some areas outside the aftershock intensive area after the earthquakes,and the crustal stress and its adjustment range near the outer stations increased significantly.With the exception of two stations with few effective events,all stations showed a consistent change in shear-wave splitting parameters over time.In particular,each station showed a decreasing trend in delay times after the doublet earthquakes,reflecting the obvious intensification of crustal stress adjustment in the seismogenic zone after the doublet earthquakes.With the occurrence of the earthquake doublet and a large number of aftershocks,the stress accumulated during the seismogenic process of the doublet earthquakes is gradually released,and then the adjustment range of crustal stress is also gradually reduced.

分泌型PD-1抗体可提高c-Met CAR-T细胞对胰腺癌细胞的杀伤作用

目的设计并制备能够分泌PD-1抗体和靶向c-Met的CAR-T细胞,以消除肿瘤对CAR-T细胞的免疫抑制作用,从而提高CAR-T细胞对胰腺癌的治疗效果。方法采用Kaplan-Meier Plotter、GEPIA和Timer2.0生物信息学数据库,分析c-Met在胰腺癌中的表达、生存期及免疫浸润。免疫组化检测胰腺癌临床样本c-Met和PD-L1表达,流式细胞术验证胰腺癌细胞Aspc-1 c-Met和PD-L1表达通过基因编辑将PD-1分泌型抗体和HIS标签连接至2代c-Met CAR分子后,构建PD-1/c-Met CAR质粒并包被慢病毒,慢病毒感染至活化T细胞内,通过流式细胞技术检测CAR-T阳性率和细胞亚群;Western blotting检测分泌型PD-1抗体在细胞上清液中的存在;体外功能试验中,通过LDH释放实验检测CAR-T对靶细胞的杀伤效率,CCK-8检测靶细胞存在下PD-1抗体对CAR-T增殖的促进作用。ELISA检测PD-1/c-Met CAR-T和c-Met CAR-T活化后细胞因子的分泌量。结果生信分析结果显示,胰腺癌组织c-Met表达高于正常组织(P<0.01);c-Met表达水平与胰腺癌患者生存期呈负相关(P<0.01)。c-Met的表达可能与多种免疫细胞浸润成正相关。免疫组化结果显示,胰腺癌c-Met和PD-L1表达均高于癌旁组织(P<0.01);流式细胞术结果显示,Aspc-1细胞c-Met和PD-L1表达量为90.7%和57.7%,琼脂糖凝胶电泳显示成功制备四代PD-1/c-Met CAR分子;流式细胞术和Western blotting显示,成功构建PD-1/c-Met CAR-T且PD-1抗体可顺利分泌。体外功能验证中LDH结果显示,PD-1/c-Met CART对肿瘤细胞杀伤效率在效靶比为20:1时高于c-Met CAR-T(P<0.01);CCK-8实验结果显示,靶细胞刺激72 h后增殖效率高于c-Met CAR-T(P<0.01);ELISA结果显示,PD-1/c-Met CAR-T分泌的细胞因子IL-2和TNF-α高于c-Met CAR-T(P<0.01)。结论PD-1抗体分泌型c-Met CAR-T可成功构建,并在体外胰腺癌细胞上显示出优于c-Met CAR-T肿瘤杀伤效率和增殖效率。

c-Met作为嵌合抗原受体T(CAR-T)细胞治疗结肠癌靶点的生物信息学预测及验证

目的探索细胞间充质上皮转化因子(c-Met)作为嵌合抗原受体T(CAR-T)细胞治疗结肠癌有效靶点的可能性。方法通过生物信息学方法分析c-Met在结肠腺癌(COAD)中的特异性表达及其临床意义;使用免疫组织化学验证结肠癌临床患者肿瘤组织中c-Met的表达,采用流式细胞术检测HCT116结肠癌细胞株中c-Met的表达;使用慢病毒感染人外周血单个核细胞(PBMC)中原代T细胞,制备靶向c-Met的二代CAR-T细胞,并观察c-Met CAR-T细胞对HCT116细胞的抑制效果。结果免疫组织化学与生物信息学显示c-Met在COAD中高表达,其中相对低表达的患者生存预后较好,在正常结肠组织中低表达或不表达。流式细胞术显示c-Met在HCT116细胞中也高表达。c-Met CAR-T细胞能够靶向表达抗原的肿瘤细胞,并且在抗原刺激下,CAR-T细胞特异性增殖,起到杀伤癌细胞与释放白细胞介素2(IL-2)和γ干扰素(IFN-γ)的生物学作用。结论c-Met有成为COAD潜在治疗靶点的潜能;c-Met CAR-T细胞在体外对结肠癌细胞具有抑制作用。

Long-term outcomes after endoscopic removal of malignant colorectal polyps:Results from a 10-year cohort

BACKGROUND Choosing an optimal post-polypectomy management strategy of malignant colorectal polyps is challenging,and evidence regarding a surveillance-only strategy is limited.AIM To evaluate long-term outcomes after endoscopic removal of malignant colorectal polyps.METHODS A single-center retrospective cohort study was conducted to evaluate outcomes after endoscopic removal of malignant colorectal polyps between 2010 and 2020.Residual disease rate and nodal metastases after secondary surgery and local and distant recurrence rate for those with at least 1 year of follow-up were invest-igated.Event rates for categorical variables and means for continuous variables with 95%confidence intervals were calculated,and Fisher’s exact test and Mann-Whitney test were performed.Potential risk factors of adverse outcomes were RESULTS In total,135 lesions(mean size:22.1 mm;location:42%rectal)from 129 patients(mean age:67.7 years;56%male)were enrolled.The proportion of pedunculated and non-pedunculated lesions was similar,with en bloc resection in 82%and 47%of lesions,respectively.Tumor differentiation,distance from resection margins,depth of submucosal invasion,lymphovascular invasion,and budding were reported at 89.6%,45.2%,58.5%,31.9%,and 25.2%,respectively.Residual tumor was found in 10 patients,and nodal metastasis was found in 4 of 41 patients who underwent secondary surgical resection.Univariate analysis identified piecemeal resection as a risk factor for residual malignancy(odds ratio:1.74;P=0.042).At least 1 year of follow-up was available for 117 lesions from 111 patients(mean follow-up period:5.59 years).Overall,54%,30%,30%,11%,and 16%of patients presented at the 1-year,3-year,5-year,7-year,and 9-10-year surveillance examinations.Adverse outcomes occurred in 9.0%(local recurrence and dissemination in 4 patients and 9 patients,respectively),with no difference between patients undergoing secondary surgery and surveillance only.CONCLUSION Reporting of histological features and adherence to surveillance colonoscopy needs improvement.Long-term adverse outcome rates might be higher than previously reported,irrespective of whether secondary surgery was performed.