探讨定量构效关系模型在药物及其杂质毒性预测方面的应用

随着定量构效关系（QSAR）模型从二维至多维的不断发展,它被越来越广泛地应用于各个领域,同时也为药品的监管提供了新的参考方案。QSAR模型对于杂质的毒性预测可应用于药品的研发和质量控制过程,有利于控制药品的安全风险,缩减企业的研发成本。QSAR模型的应用程序也在不断优化,以确保QSAR模型可以不断地适用于新药及未知杂质的毒性研究。本文从QSAR模型的建模基础及发展历程出发,对近年来该模型在药物及其杂质毒性预测方面的应用研究报道进行了归纳总结。     

Polymorphism analysis of Glutathione S-transferase A1 in patients with hematological diseases and its effect on GST enzyme activity

Glutathione S-transferases (GSTs) are important drug-metabolizing enzymes that catalyze the binding of glutathione (GSH) to electrophilic substances. GST has genetic polymorphism, and the enzyme activity of GST affects the metabolism of certain drugs in vivo. In the present day, we investigated the GST enzyme activity and GSTA1 gene polymorphism in 170 patients with hematological diseases and explored their relationship. The GSTA1 gene polymorphism of the patient was analyzed by PCR- restriction fragment length polymorphism (PCR-RFLP) technique, and the base sequences of the four mutation sites (-631, -567, -69, and -52) in the promoter region were determined by DNA-Sequencer. The patient's GST enzyme activity was calculated by measuring the rate at which it catalyzed the reaction between 1-chloro-2,4-dinitrobenzene (CDNB) and GSH. The average GST enzyme activities of males and females were 5.20±0.13 and 5.17±0.12 nmol/min/mL, respectively, and the difference was not significant (P = 0.91). The frequencies of genotypes GSTA1*A*A (wild genotype), GSTA1*A*B (heterozygous genotype), and GSTA1*B*B (homozygous mutant genotype) were 75.3%, 22.9%, and 1.8%, respectively. Alleles GSTA1*A and *B were distributed at 86.8% and 13.2%, respectively. The genotype frequency distribution between males and females was no significant difference by Pearson’s chi-square test (P = 0.743). The average GST activity of the heterozygous mutant genotype (4.83±0.76 nmol/min/mL) was lower than the wild genotype (5.34±1.26 nmol/min/mL, P = 0.018), and higher than that of the homozygous mutant genotype (3.32±0.07 nmol/min/mL, P = 0.022). These findings might help us improve the individualized treatment of patients with hematological diseases in the future and promote the development of precision medicine for blood diseases.     

Comparative study on main compounds in Ginkgo biloba L. base on mathematical statistics

In this paper, an HPLC-DAD-ELSD method was developed to determine main 20 components of Ginkgo bilobaL. leaves from different ages and sources, including six flavonol glycosides, five terpene lactones and nine organic acids. Using statistics method and establishing relevant mathematics models, the measured data has proceeded correlation analysis, principal component analysis, and regression statistics and the results showed generalityand specific characteristics. We defined p-hydroxybenzoicacid, catechinic, KRcG and ginkgolide A as characteristic indexes representing commonnessand specialityof Ginkgo biloba L. leaf. The four characteristic indexes can reflect the quality of Ginkgo biloba L. leaf, and the internal relations between them are significant.The contents of other compounds could define the quantity relation with characteristic markers. It simplified the approach of quality control, and provided a basis for quality control of Ginkgo biloba L.     

MR扩散加权成像纹理分析鉴别肝硬化背景下不典型强化的小肝癌和增生结节

目的探讨基于磁共振扩散加权成像(DWI)的纹理分析鉴别诊断肝硬化不典型强化小肝癌(sHCC)和增生结节(DNs)的价值。方法回顾性分析术前MRI动态增强不典型强化、手术标本病理学证实的单发肝硬化结节(≤2 cm)患者59例的资料,其中不典型强化sHCC 37例,DNs 22例。分析病灶的DWI信号特征,测量病灶的平均表观扩散系数(ADC)值、病灶与肝实质ADC比值。采用MaZda软件手工勾画感兴趣区,提取病灶DWI的纹理参数,采用Fisher系数、分类错误概率联合平均相关系数、交互信息三者联合的方法选择30个最佳纹理参数集合。使用原始数据分析、主要成分分析、线性判别分析和非线性判别分析进行纹理分类。采用独立样本t检验比较sHCC与DNs组间ADC值、ADC比值的差异,计数资料(或率)的比较采用χ2检验。采用ROC曲线分析评估诊断效能。结果DWI高信号鉴别不典型强化sHCC与DNs的灵敏度、特异度及准确度分别为94.6%(35/37)、68.2%(15/22)及84.7%(50/59)。不典型强化sHCC的ADC比值显著低于DNs,差异存在统计学意义(t=2.99,P=0.002);诊断不典型强化sHCC的灵敏度、特异度及准确度分别为73.0%(27/37)、72.7%(16/22)及72.9%(43/59)。DWI纹理分析诊断不典型强化sHCC的灵敏度、特异度及准确度为94.6%(35/37)、95.5%(21/22)及94.9%(56/59)。DWI纹理分析的诊断效能(AUC=0.94)显著高于DWI高信号(AUC=0.81)及ADC比值(AUC=0.72)。结论基于DWI的纹理分析可以鉴别肝硬化背景下不典型强化的小肝癌和增生结节,其效能优于定性及定量DWI。     

Analysis of the myoelectric characteristics of genioglossus in REM sleep and its improvement by CPAP treatment in OSA patients

Sleep and Breathing - To reveal the characteristics of genioglossus (GG) activation in moderate and severe obstructive sleep apnea (OSA) patients during rapid eye movement (REM) sleep compared with...     

凋亡相关因子和肿瘤坏死因子-α介导的细胞凋亡及白介素-19、白介素-10在高原慢性肺心病发病中的作用

目的 探讨凋亡相关因子（Fas/Apo-1）和肿瘤坏死因子-α（TNF-α）介导的细胞凋亡及白介素-19（IL-19）、白介素-10（IL-10）在高原慢性阻塞性肺疾病（COPD）合并慢性肺心病（CCP）发病机制中的作用.方法 采用双抗体夹心ABC-ELISA法测定60例高原COPD合并CCP急性加重期患者（急性加重组）和稳定期57例患者（稳定组）血清Fas/Apo-1、TNF-α、IL-19、IL-10浓度;测定1 s用力呼气容积（FEV1％）占预计值百分比（FEV1％pred）、动脉血氧分压（PaO2）和动脉血二氧化碳分压（PaCO2）,并与30例当地健康人（健康组）进行比较.结果 急性加重组和稳定组患者血清Fas/Apo-1、TNF-α、IL-19浓度和PaCO2[分别为（46.89±6.18） pg/ml、（18.37±3.26） ng/ml、（285.52±38.71） pg/ml、（56.36±5.28） mmHg和（37.25±4.82） pg/ml、（13.34±2.5） ng/ml、（166.12±32.45） pg/ml、（43.05±4.43）mmHg]显著高于健康组[分别为（30.44 ±4.16） pg/ml、（9.26±2.01）ng/ml、（86.59±20.91）pg/ml],血清IL-10浓度、FEV1％pred、PaO2[分别为（37.29±6.88） pg/ml、（33.19 ±5.45）、（35.22±5.26） mmHg和（55.36±7.62） pg/ml、（51.33±5.27）、（47.63±5.50） mmHg]显著低于健康组[（30.67±2.91）mmHg、（65.68±7.06） pg/ml、（72.15±5.23）、（68.08±529） mmHg]（均P＜0.01）,急性加重组与稳定组比较亦有非常显著性差异（均P＜0.01）.急性加重组血清Fas/Apo-1、TNF-α、IL-19与FEV1％pred、PaO2显著负相关（分别r=-0.525、-0.498、-0.603和-0.536、-0.528、-0.463,均P＜0.01）,与PaCO2显著正相关（分别r=0.533、0.562、0.498,均P＜0.01）;IL-10与FEV1％pred、PaO2显著正相关（分别r=0.476、0.563,均P＜0.01）,与PaCO2显著负相关（r=-0.525,P＜0.01）.结论 高原COPD合并CCP患者Fas/Apo-1和TNF-α表达上调介导细胞凋亡异常,Fas/Apo-1、TNF-α、IL-19和IL-10可能共同参与了气道慢性炎症反应.     

Narrow band imaging: Application for early‐stage gastrointestinal neoplasia

Narrow‐band imaging (NBI) is an imaging technique for endoscopy using optical filters to narrow the bandwidth of spectral transmittance. Through this narrow spectrum, NBI contrasts surface structure and microvascular architecture of various lesions. In this article we focus on the application of NBI for early‐stage neoplasia in the esophagus, stomach and colon with a three‐step strategy of endoscopic diagnosis: (i) the detection of abnormality; (ii) the differentiation between non‐neoplasia and neoplasia; and (iii) staging for tumor extension and depth of invasion.     

不同临床分型的新型冠状病毒肺炎患者影像学表现

目的 探讨不同临床分型的新型冠状病毒肺炎（COVID-19）的影像学表现。方法 回顾性分析71例COVID-19患者的电子计算机断层扫描（computed tomography,CT）影像资料,分析普通型与重型及危重型患者的临床特点、影像学特点、优势分布以及出现好转时间,并进行统计学分析。结果 71例患者中,轻型12例,普通型45例,重型及危重型14例。临床表现方面,重型及危重型（6/14,42.9%;4/14,28.6%）伴乏力、胸闷及呼吸困难较轻型（0;0）及普通型（2/45,4.4%;0）明显,差异有统计学意义（P值分别为0.001,0.002）;普通型（30/45,66.7%）、重型及危重型（9/14,64.3%）C反应蛋白升高较轻型（2/12,16.7%）明显,差异有统计学意义（P=0.005）。CT表现,病变累及范围超过3个肺叶数：重型及危重型（13/14,92.9%）明显高于普通型（26/45,57.8%）;重型及危重型（12/14,85.7%）病变分布于两肺外周及中心多于普通型（20/45,44.4%）;病变表现为实变、病变内伴小叶间隔增厚,重型及危重型均多于普通型;以上表现两组相比,差异均有统计学意义（P值分别为0.036、0.007、0.004、0.002）。对22例患者进行随访,CT表现达高峰及病情出现好转多发生在发病10 d后（40.9%,45.5%）。结论 普通型与重型及危重型COVID-19患者胸部CT在发病部位、病变密度、实变程度等方面具有不同特征,多数COVID-19患者多在发病10 d后好转。