Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.     

艾尔巴韦/格拉瑞韦治疗慢性丙型肝炎患者疗效初步观察

目的 初步探讨应用艾尔巴韦/格拉瑞韦治疗慢性丙型肝炎(CHC)患者的疗效。方法 2017年3月~2018年3月仙桃市第一人民医院感染病科收治的CHC患者82例,被随机分为对照组41例和观察组41例,分别给予聚乙二醇干扰素-α联合利巴韦林治疗和艾尔巴韦/格拉瑞韦治疗,两组均连续治疗24周。采用RT- PCR法检测血清 HCV RNA,采用全基因序列测定法行病毒基因分型。比较两组早期病毒学应答(EVR)、治疗结束时病毒学应答(ETVR)和持续病毒学应答(SVR)。结果 在治疗结束时,观察组血清丙氨酸氨基转移酶(ALT)水平为(47.9±19.7)U/L,显著低于对照组【(63.5±21.2)U/L,P<0.05】,天冬氨酸氨基转移酶(AST)水平为(55.5±22.3)U/L,显著低于对照组【(81.3±25.8)U/L,P<0.05】;观察组EVR、ETVR和SVR分别为48.8%、63.4%和70.7%,与对照组的41.5%、53.7%和65.8%比,无统计学差异(P>0.05);18例观察组非HCV Ⅰ型感染者EVR、ETVR和SVR分别为88.9%、94.4%和88.9%,显著高于同组23例HCV Ⅰ型感染者(分别为52.2%、60.9%和52.2%, P<0.05),而与对照组15例非HCV Ⅰ型感染者比,无统计学差异(分别为86.7%、93.3%和73.3%, P>0.05);观察组SVR₁₂为87.8%(36/41),显著高于对照组的73.2%(30/41,P<0.05)。结论 应用直接抗病毒(DAA)药物艾尔巴韦/格拉瑞韦治疗CHC患者近期疗效达到,但远期疗效似优于标准治疗方案, 值得临床进一步验证。     

外周血miR-150-5p、SOCS1 mRNA对类风湿关节炎“病”“证”诊断意义的初步探讨＊

目的 探讨类风湿关节炎患者外周血miR-150-5p、细胞因子信号抑制因子1（suppressor of cytokine signaling 1，SOCS1）mRNA的表达及对类风湿关节炎（Rheumatoid Arthritis，RA）疾病诊断、中医证型判断的意义。方法 纳入符合诊断标准的RA患者57例及健康对照组19例，根据《22个专业95个病种中医诊疗方案》有关RA的中医证候诊断标准，判断RA的中医证型。qPCR检测RA患者及健康对照组miR-150-5p、SOCS1mRNA的相对表达水平，同时检测血常规、肝功能、肾功能等常规指标。双荧光素酶分析方法判断两者是否存在靶向关系。统计分析miR-150-5p、SOCS1 mRNA对RA疾病的诊断意义及其与中医证型的相关性。结果 RA患者外周血miR-150-5p的相对表达水平下调，低于正常人群（t = -19.019，P < 0.05）；其表达水平随疾病活动度升高，有下降趋势；患者外周血SOCS1 mRNA的相对表达水平上调，低于正常人群（t = 5.333，P < 0.05）；其表达水平随疾病活动度升高，有上升趋势。MiR-150-5p与SOCS1 mRNA有靶向结合关系（P < 0.05）。通过AUC曲线比较，miR-150-5p的相对表达水平区分RA的敏感性及特异性分别为98.1%、92.1%（AUC = 0.972，P < 0.05）；SOCS1 mRNA的相对表达水平无法区分RA（AUC = 0.472，P > 0.05）。RA患者中miR-150-5p的相对表达水平低于3.06，RA患者风湿痹阻证、寒湿痹阻证的相对风险分别为8.33、250.00（P < 0.05）。结论 miR-150-5p、SOCS1 mRNA在RA患者中有差异性表达，且有靶向结合关系。miR-150-5p可能是RA的疾病诊断及中医风湿痹阻证、寒湿痹阻证证型诊断的潜在生物标志物。     

Clinicopathological features,diagnosis, and treatment of sessile serrated adenoma/polyp with dysplasia/carcinoma

Sessile serrated adenoma/polyps (SSA/Ps) are early precursor lesions in the serrated neoplasia pathway, which results in BRAF‐mutated colorectal carcinomas with not only high levels of microsatellite instability but also microsatellite stable. SSA/Ps with advanced histology, including cytological dysplasia or minimally invasive carcinomas, are important lesions because SSA/Ps are considered major contributors to “interval cancers” and these lesions can rapidly become dysplastic or invasive carcinomas. Clinicopathologically, SSA/Ps with dysplasia or invasive carcinoma were associated with advanced age, female sex, and proximal colon. Although SSA/Ps with submucosal invasive carcinoma were smaller and invaded less deeply into the submucosal layer than conventional tubular adenomas with submucosal invasive carcinoma, SSA/Ps with submucosal invasive carcinoma frequently had a mucinous component and exhibited a higher potential for lymphatic invasion and lymph node metastasis. In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, may help accurately diagnose SSA/Ps with advanced histology. Removal of SSA/Ps with dysplasia or invasive carcinoma was recommended. Endoscopic treatment such as endoscopic mucosal resection or endoscopic submucosal dissection is useful for those lesions. However, surgical resection with lymph node dissection might be indicated when SSA/Ps with invasive carcinoma are endoscopically suspected, because these have the high risk of lymph node metastasis. Greater awareness may promote further research into improving the detection, recognition, and complete resection rates of SSA/Ps with dysplasia or invasive carcinoma and reduce the interval cancer rates.     

产前分娩预演对初产妇自然分娩成功率及产后并发症的影响

[目的]探讨产前分娩预演对初产妇自然分娩成功率和产后并发症的影响.[方法]收集2016年9月至2018年10月在本院妇产科分娩的初产妇86例,按产前分娩教育方式分为观察组(n=42)和对照组(n=44).对照组孕妇产前接受常规产前健康教育课程培训,观察组在对照组的基础上进行分娩预演实践.比较两组自我效能感量表(GSES)、抑郁自评量表(SDS)和焦虑自评量表(SAS)评分及自然分娩成功率和产后并发症发生率等.[结果]与对照组相比,观察组分娩总产程和第一、二、三明显缩短;新生儿窒息率和产后SDS、SAS评分均明显降低;自然分娩成功率、GSES评分均明显提高,其差异均有统计学意义(P<0.05).观察组产后出血、感染、尿潴留、乳汁淤积发生率及总并发症发生率均低于对照组(P<0.05).[结论]采用常规产前健康教育培训结合产前分娩预演实践的产前管理方式,可有效提高初产妇自然分娩成功率,缩短产程,减少产后并发症的发生,值得临床推广应用.     

依维莫司联合全反式维甲酸逆转急性早幼粒细胞白血病细胞耐药的研究

目的探讨依维莫司联合全反式维甲酸(简称维甲酸)逆转急性早幼粒细胞白血病(APL)细胞株NB4-R1耐药的作用。方法应用CD11b染色流式细胞术及硝基四唑氮蓝(NBT)还原实验检测两药联合应用对细胞分化的影响, 流式细胞术检测细胞周期情况, Annexin V/PI双染色检测细胞凋亡情况, 蛋白质印迹法检测自噬相关蛋白微管结合蛋白轻链3(LC3)、Beclin 1及早幼粒白血病-维甲酸受体融合蛋白(PML-RARα)、磷酸化核糖体S6激酶(P-P70S6K)、磷酸化4E结合蛋白1(P-4E-BP1) 等表达水平。结果与维甲酸组比较, 联用组能诱导耐药细胞株NB4-R1细胞的分化, 并将细胞增殖阻止在G ₁期而对细胞凋亡无明显影响。100 nmol/L依维莫司组、1μmol/L维甲酸组、联用组、对照组NB4-R1细胞培养48 h后分化百分率分别为(2.29±0.57)%、(17.06±2.65)%、(54.47±4.91)%、(2.54±0.53)%; 处于G ₁期的细胞百分率分别为(35.20±11.97)%、(33.54±6.25)%、(53.70±8.73)%、(27.40±6.01)%; 四组细胞凋亡细胞百分率分别为(2.30±0.14)%、(2.25±0.21)%、(2.40±0.28)%、(1.95±0.07)%。与维甲酸组比较, 联用组mTOR信号通路下游的P70S6K、4E-BP1分子磷酸化水平下降, LC3-II和Beclin 1的表达上调, 且能部分降解融合蛋白PML-RARα。 结论依维莫司联合维甲酸能诱导NB4-R1细胞分化, 且能阻滞细胞周期而不致细胞凋亡, 其机制可能与依维莫司联合维甲酸抑制mTOR信号通路激活自噬作用从而降解PML-RARα蛋白有关。