The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At...The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At the same time,TP53 is the most frequently mutated gene in human cancers.Mutant p53 proteins lose wild-type p53 tumor suppression functions but acquire new oncogenic properties,among which are deregulating cell proliferation,increasing chemoresistance,disrupting tissue architecture,and promoting migration,invasion and metastasis as well as several other pro-oncogenic activities.The oncogenic p53 mutation Y220C creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation.This cavity accommodates stabilizing small molecules that have therapeutic values.The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein.In this review,we summarize approaches that target p53-Y220C,including reactivating this mutation with small molecules that bind Y220C to the hydrophobic pocket and developing immunotherapies as the goal for the near future,which target tumor cells that express the p53-Y220C neoantigen.展开更多
A case of hailstorm process occurring on 24 June 2006 in northwestern China was studied using satellite retrieval methodology. The particle effective radius (re) in the cloud tops was calculated by the reflectance in ...A case of hailstorm process occurring on 24 June 2006 in northwestern China was studied using satellite retrieval methodology. The particle effective radius (re) in the cloud tops was calculated by the reflectance in the 3.7 μm channel, and cloud-top microphysical properties were vividly represented using the RGB visual multispectral classification scheme. The microphysical zones of clouds and the processes of hail formation and develop-ment are inferred using the relations of cloud-top temperature (T) versus re for the tops of convective clouds. The results show that particle effective radius was smaller near the cloud base of hailstorm. There was a deep zone of diffusional droplet growth at the low level where the particles grew slowly with height, and there existed an evident area of small ice particles in the cloud top, suggesting the existence of a strong updraft in the clouds. The low glaciated temperature indicated a great depth from the cloud base to the glaciation height, which provided a deep layer of supercooled water for hail growth.展开更多
目的 观察原发性高血压患者室性心律失常易感性状况,并分析动态心电图P波离散度、T波峰-末(Tp-e)间期联合血压变异性对其预测效能。方法 纳入2020年6月至2022年6月医院126例原发性高血压患者为研究对象。入院时所有患者均接受动态心电...目的 观察原发性高血压患者室性心律失常易感性状况,并分析动态心电图P波离散度、T波峰-末(Tp-e)间期联合血压变异性对其预测效能。方法 纳入2020年6月至2022年6月医院126例原发性高血压患者为研究对象。入院时所有患者均接受动态心电图检查与血压变异性检查,记录P波离散度、Tp-e间期值,观察患者室性心律失常发生状况,并将其分为室性心律失常组与非室性心律失常组,分析动态心电图P波离散度、Tp-e间期联合血压变异性对原发性高血压患者室性心律失常易感性的预测效能。结果 126例原发性高血压患者中发生室性心律失常39例,占30.95%;室性心律失常组右心房横径(RAD)[(47.39±6.25)mm]长于非室性心律失常组[(40.37±6.74)mm],P波离散度[(42.82±8.14)ms]、Tp-e间期[(112.96±11.34)ms]、24 h舒张压标准差(24 h diastolic blood pressure standard deviation,24 h DPB-SD)[(13.79±5.22)mmHg]、24 h收缩压标准差(24 h systolic blood pressure standard deviation,24 h SBP-SD)值[(18.75±5.76)ms]高于非室性心律失常组[(36.16±7.28)ms、(99.23±12.61)ms、(9.78±4.36)mmHg、(14.03±5.17)mmHg](P<0.05);经点二列相关性分析显示,动态心电图P波离散度、Tp-e间期、血压变异性(24 h DPB-SD、24 h SBP-SD)值与原发性高血压患者发生室性心律失常呈正相关(r=0.276、0.463、0.207、0.293,P均<0.05);经logistic回归分析,结果显示,高P波离散度、高Tp-e间期、高24 h DPB-SD、高24 h SBP-SD是原发性高血压患者发生室性心律失常的危险因素(OR=1.112、1.095、1.199、1.177,P<0.05);ROC曲线结果显示,P波离散度、Tp-e间期、24 h DPB-SD、24 h SBP-SD预测原发性高血压患者发生室性心律失常的AUC分别为0.733(95%CI 0.635~0.830)、0.800(95%CI 0.723~0.877)、0.719(95%CI 0.621~0.817)、0.712(95%CI 0.614~0.810)、0.912(95%CI 0.863~0.961)。结论 动态心电图P波离散度、Tp-e间期联合血压变异性对原发性高血压患者室性心律失常易感性具有较高预测价值。展开更多
基金funded by the Ministry of Science and Higher Education of the Russian Federation(Grant No.075-15-2020-795 of 29.09.2020,unique project ID:RF-190220X0027).
文摘The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At the same time,TP53 is the most frequently mutated gene in human cancers.Mutant p53 proteins lose wild-type p53 tumor suppression functions but acquire new oncogenic properties,among which are deregulating cell proliferation,increasing chemoresistance,disrupting tissue architecture,and promoting migration,invasion and metastasis as well as several other pro-oncogenic activities.The oncogenic p53 mutation Y220C creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation.This cavity accommodates stabilizing small molecules that have therapeutic values.The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein.In this review,we summarize approaches that target p53-Y220C,including reactivating this mutation with small molecules that bind Y220C to the hydrophobic pocket and developing immunotherapies as the goal for the near future,which target tumor cells that express the p53-Y220C neoantigen.
基金supported jointly by Chinese Ministry of Science and Technology (Grant 2005DIB3J099)Science Foundation of Shaanxi Province (Grant 2007D11)
文摘A case of hailstorm process occurring on 24 June 2006 in northwestern China was studied using satellite retrieval methodology. The particle effective radius (re) in the cloud tops was calculated by the reflectance in the 3.7 μm channel, and cloud-top microphysical properties were vividly represented using the RGB visual multispectral classification scheme. The microphysical zones of clouds and the processes of hail formation and develop-ment are inferred using the relations of cloud-top temperature (T) versus re for the tops of convective clouds. The results show that particle effective radius was smaller near the cloud base of hailstorm. There was a deep zone of diffusional droplet growth at the low level where the particles grew slowly with height, and there existed an evident area of small ice particles in the cloud top, suggesting the existence of a strong updraft in the clouds. The low glaciated temperature indicated a great depth from the cloud base to the glaciation height, which provided a deep layer of supercooled water for hail growth.
文摘目的 观察原发性高血压患者室性心律失常易感性状况,并分析动态心电图P波离散度、T波峰-末(Tp-e)间期联合血压变异性对其预测效能。方法 纳入2020年6月至2022年6月医院126例原发性高血压患者为研究对象。入院时所有患者均接受动态心电图检查与血压变异性检查,记录P波离散度、Tp-e间期值,观察患者室性心律失常发生状况,并将其分为室性心律失常组与非室性心律失常组,分析动态心电图P波离散度、Tp-e间期联合血压变异性对原发性高血压患者室性心律失常易感性的预测效能。结果 126例原发性高血压患者中发生室性心律失常39例,占30.95%;室性心律失常组右心房横径(RAD)[(47.39±6.25)mm]长于非室性心律失常组[(40.37±6.74)mm],P波离散度[(42.82±8.14)ms]、Tp-e间期[(112.96±11.34)ms]、24 h舒张压标准差(24 h diastolic blood pressure standard deviation,24 h DPB-SD)[(13.79±5.22)mmHg]、24 h收缩压标准差(24 h systolic blood pressure standard deviation,24 h SBP-SD)值[(18.75±5.76)ms]高于非室性心律失常组[(36.16±7.28)ms、(99.23±12.61)ms、(9.78±4.36)mmHg、(14.03±5.17)mmHg](P<0.05);经点二列相关性分析显示,动态心电图P波离散度、Tp-e间期、血压变异性(24 h DPB-SD、24 h SBP-SD)值与原发性高血压患者发生室性心律失常呈正相关(r=0.276、0.463、0.207、0.293,P均<0.05);经logistic回归分析,结果显示,高P波离散度、高Tp-e间期、高24 h DPB-SD、高24 h SBP-SD是原发性高血压患者发生室性心律失常的危险因素(OR=1.112、1.095、1.199、1.177,P<0.05);ROC曲线结果显示,P波离散度、Tp-e间期、24 h DPB-SD、24 h SBP-SD预测原发性高血压患者发生室性心律失常的AUC分别为0.733(95%CI 0.635~0.830)、0.800(95%CI 0.723~0.877)、0.719(95%CI 0.621~0.817)、0.712(95%CI 0.614~0.810)、0.912(95%CI 0.863~0.961)。结论 动态心电图P波离散度、Tp-e间期联合血压变异性对原发性高血压患者室性心律失常易感性具有较高预测价值。
文摘目的研究长链非编码RNA(long non-coding RNA,LncRNA)LINC01137在非小细胞肺癌(nonsmall cell lung cancer,NSCLC)免疫逃逸中的生物学功能及其潜在的调节机制。方法采集24例健康志愿者和24例NSCLC患者血液样本,并收集NSCLC肿瘤组织和癌旁组织检测LINC01137水平。利用Starbase数据库预测LINC01137与miR-22-3p的结合位点,荧光素酶报告基因分析进行验证。采用A549细胞来源的外泌体和/或sh-LINC01137干扰序列转染A549细胞,检测细胞增殖和侵袭能力;收集转染后的细胞上清液培养CD8^(+)T细胞,检测CD8^(+)T细胞耗竭标志物干扰素-γ(interfereron-γ,IFN-γ)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、颗粒霉素B(granzyme B)和白细胞介素-2(interleukin-2,IL-2)水平,以及PD-1+Tim3^(+)CD8^(+)T细胞百分比。采用外泌体和/或miR-22-3p模拟物(miR-22-3p mimic)转染CD8^(+)T细胞,检测PD-1蛋白水平。结果与癌旁组织相比,NSCLC肿瘤组织中LINC01137表达(3.357±0.548 vs 1.011±0.371)明显升高;与健康志愿者相比,NSCLC患者外周血LINC01137表达(3.216±0.342 vs 1.007±0.313)亦明显升高,差异具有统计学意义(t=-17.367,-17.147,均P<0.001)。肿瘤组织LINC01137表达与外周血中LINC01137表达呈正相关(r=0.755,P<0.05)。在A549细胞来源的外泌体中LINC01137显著富集。与Exo+sh-NC组相比,Exo+sh-LINC01137组细胞活力(65.852%±4.715%vs 100.153%±11.934%)及细胞侵袭(21.464%±3.481%vs 43.126%±1.447%)能力显著降低,差异具有统计学意义(t=4.630,9.953,均P<0.01)。NSCLC患者外周血中LINC01137表达和CD8^(+)T细胞百分比呈负相关(r=-0.520,P<0.05)。与Exo+sh-NC组相比,Exo+sh-LINC01137组IFN-γ(3865.314±543.852 pg/ml vs 1786.971±105.982 pg/ml),TNF-α(4631.930±510.715pg/ml vs 1973.242±379.623pg/ml),Granzyme B(3876.496±312.438pg/ml vs 1879.439±287.584pg/ml)和IL-2 mRNA水平(3.286±0.437 vs 1.015±0.314)升高,PD-1+Tim3^(+)CD8^(+)T细胞百分比(7.680%±2.185%vs 18.952%±3.216%)降低,差异具有统计学意义(t=-6.497,-7.237,-8.146,-7.310,5.021,均P<0.01)。miR-22-3p是LINC01137的靶基因。与Exo+NC mimic组相比,Exo+miR-22-3p组PD-1蛋白水平(0.384±0.087 vs 1.003±0.147)显著降低,差异有统计学意义(t=6.277,P<0.01)。结论NSCLC患者肿瘤组织及外周血中LINC01137表达显著上调;NSCLC细胞来源的外泌体中LINC01137通过靶向CD8^(+)T细胞中miR-22-3p并抑制其表达,诱导CD8^(+)T细胞耗竭,促进NSCLC细胞免疫逃逸。
