Synthesis and biological evaluation of quinoxaline derivatives as tubulin polymerization inhibitors that elevate intracellular ROS and triggers apoptosis via mitochondrial pathway

A series of novel quinoxaline derivatives were synthesized and evaluated for their antiproliferative activity in three human cancer cell lines. Compound 12 exhibited the most potent antiproliferative activity with IC₅₀ in the range of 0.19–0.51 μM. The compound inhibited tubulin polymerization and disrupted the microtubule network, leading to G2/M phase arrest. Furthermore, compound 12 induced ROS production and malfunction of mitochondrial membrane potential. Compound 12 led to cancer cells apoptosis in a dose‐dependent manner. Western blot analysis showed that compound 12 induced up‐regulation of p21 and affected the expression of cell cycle‐related proteins. The binding mode was also probed by molecular docking.     

牙线牵引辅助内镜黏膜下剥离术治疗胃角黏膜病变的疗效（含视频）

目的 探讨牙线牵引辅助内镜黏膜下剥离术（endoscopic submucosal dissection, ESD）治疗胃角黏膜病变的疗效。方法 回顾性分析2015年1月—2018年12月厦门大学附属第一医院内镜中心收治的127例胃角黏膜病变患者病例资料。根据术中手术方法,将患者分为牙线牵引辅助ESD组（牵引组,n=51）和传统ESD组（传统组,n=76）,同时把41例胃角纤维化病例也分为牵引组(n=23)和传统组(n=18)。对比分析手术时间、整块切除率、治愈性切除率及出血、肌层损伤、穿孔等不良事件发生率等指标。结果 牵引组与传统组病例年龄、性别、病变大小及病变形态差异无统计学意义（P＞0.05）。牵引组手术时间较传统组明显缩短[（65.4±36.5） min比(103.5±43.2) min,P=0.012],病变整块切除率[100.00%(51/51)比90.79%(69/76),P=0.026]及治愈性切除率均更高[94.12%(48/51)比81.58%(62/76),P=0.042],且剥离过程中肌层损伤[5.88%(3/51)比25.00%（19/76）,P=0.010]及术中出血更少[47.06%（24/51）比82.89%（63/76）,P=0.010]。传统组2例(2.63%)纤维化病例穿孔,牵引组无穿孔病例,穿孔发生率差异无统计学意义（P=0.243）。在胃角纤维化病例中,牵引组手术时间较传统组明显缩短[（81.4±29.3） min比(119.3±37.6） min,P=0.010],病变整块切除率[100.00%（23/23）比72.22%(13/18）,P=0.007]及治愈性切除率均更高[95.65%(22/23)比72.22%(13/18),P=0.035],且剥离过程中肌层损伤[8.70%(2/23)比72.22%(13/18）,P=0.001]及术中出血更少[78.26%(18/23)比100.00%(18/18),P=0.035]。结论 牙线牵引辅助ESD治疗胃角黏膜病变及有纤维化的胃角病变安全有效,与传统ESD相比,手术时间更短,治愈率更高,不良事件发生率更低。     

中国早期胃癌筛查流程专家共识意见 在广东地区的应用

目的探讨“中国早期胃癌筛查流程专家共识意见”在广东地区胃癌风险人群中的应用价值。方法纳入2018年3月—2019年3月在广东地区进行早期胃癌筛查的居民,采用量化的新型胃癌筛查评分系统进行胃癌初筛,根据初筛结果将患者分为高危组、中危组和低危组,比较各组精查胃镜下早期胃癌、癌前疾病、癌前病变的检出率,统计学分析采用卡方检验。结果完成精查胃镜检查共545例,其中高危组32例,中危组184例,低危组329例。精查胃镜结果显示,早期胃癌检出率方面,高危组(12.5%)>中危组(1.1%)>低危组(0),差异有统计学意义（χ2＝41.85,P<0.01）;癌前疾病检出率方面,高危组(60.9%)>中危组(52.4%)>低危组(34.3%),差异有统计学意义（χ2＝18.00,P<0.01）;癌前病变检出率分别为17.9%、8.8%及8.8%,差异无统计学意义（χ2＝2.58,P＝0.28）。内镜病变检出阳性率组间比较,高危组(71.9%)>中危组(57.1%)>低危组(40.1%),差异有统计学意义（χ2＝21.54,P<0.01）。结论“中国早期胃癌筛查流程专家共识意见”在广东地区胃癌风险人群的早期胃癌及癌前疾病筛查中具有较好的应用价值。     

高原地区结肠镜检查质量临床观察及干预对策分析

目的分析高原环境对结肠镜检查质量的影响。方法收集2016年1月—2018年5月在青海省人民医院完成结肠镜检查且结果无异常的450例健康体检者资料。根据患者居住地区海拔高度,分为对照组（海拔>1 500~<2 500 m,120例）、高海拔组（海拔2 500~<3 500 m,170例）、超高海拔组（海拔3 500~<5 500 m,160例）,分析进镜时间、退镜时间、结肠清洁率、盲肠达镜率、镜检过程中腹痛腹胀症状等指标与海拔的关系。结果对照组、高海拔组和超高海拔组平均进镜时间为9.23 min、17.69 min和24.51 min,多元回归分析发现,高海拔组比对照组平均延长8.20 min,超高海拔组比对照组平均延长15.11 min（P<0.001）。对照组、高海拔组和超高海拔组平均退镜时间为7.17 min、7.28 min和7.93 min,多元回归分析发现,高海拔组与对照组比较差异无统计学意义（P>0.05）,但超高海拔组相比对照组延长了0.76 min（P<0.001）。对照组、高海拔组和超高海拔组的肠道清洁优良率分别为41.7%（50/120）、17.6%（30/170）和12.5%（20/160）,Logistic回归分析发现,高海拔组比对照组肠道清洁程度下降一个等级的可能性增加1.96倍,超高海拔组比对照组肠道清洁程度下降一个等级的可能性增加8.76倍（P<0.001）。对照组、高海拔组和超高海拔组盲肠达镜率分别为91.7%（110/120）、85.9%（146/170）和81.2%（130/160）,高海拔组与对照组比较差异无统计学意义（P>0.05）,超高海拔组与对照组比较差异有统计学意义（OR=0.38,95%CI：0.17~0.82,P=0.015）。随着患者居住地海拔升高,结肠镜检查中患者腹痛、腹胀等症状逐渐加重,3组间差异有统计学意义（P<0.05）。结论高原地区结肠镜检查质量低,检查前选择性干预可提高高原地区结肠镜检查质量。     

Design and optimize N‐substituted EF24 as effective and low toxicity NF‐κB inhibitor for lung cancer therapy via apoptosis‐to‐pyroptosis switch

As NF‐κB signaling pathway is constitutively activated in lung cancer, targeting NF‐κB has a potential for the treatment. EF24 has been proved to be a NF‐κB inhibitor with good antitumor activity, while whose toxicity possibly became one of the obstacles to enter into clinical application. In order to find high efficiency and low toxicity NF‐κB inhibitors, EF24 was modified and 13d was screened out. It was proved that 13d possessed an effective combination of inhibiting NF‐κB pathway and showing lower cytotoxicity on normal cells as well as less toxicity in acute toxicity experiment compared with the lead compound of EF24. In addition, 13d was found to inhibit cell vitality, arrest cell cycle in G2/M phase, promote cell apoptosis, and suppress the xenograft tumor growth. Furthermore, 13d was elucidated to induce pyroptosis developing from apoptosis, which was associated with the inhibition of NF‐κB. Taken together, it was suggested that 13d was a potent antitumor agent.     

Design,synthesis, and biological evaluation of target water‐soluble hydroxamic acid‐based HDACi derivatives as prodrugs

Four compounds T1 , T2 , T3 , and T4 were designed and synthesized as Vorinostat and Belinostat derivatives being the target water‐soluble prodrugs. The water solubility of Vorinostat derivatives, T1 and T2 , exhibited 400‐ to 600‐fold higher than that of Vorinostat, and Belinostat derivatives, T3 and T4 , showed 600‐ to 750‐fold higher than that of Belinostat. Four compounds were evaluated for their inhibitory activities against tumor cell lines HT‐29 and Hut‐78 in the absence or presence of β‐D‐glucuronidase. The inhibitory effects of T1 and T2 were comparable to Vorinostat in the presence of β‐D‐glucuronidase, but were higher than 10 μM in the absence of β‐D‐glucuronidase. Therefore, T1 and T2 are promising candidates for in vivo investigations with high potential to be the target water‐soluble prodrugs. IC₅₀ values of Belinostat derivatives T3 and T4 were not affected by β‐D‐glucuronidase, but T3 and T4 had the excellent cell proliferation inhibition on Hut‐78.     

Blood-based biomarkers for early detection of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma(ESCC) is a common malignant tumor of the digestive system worldwide, especially in China. Due to the lack of effective early detection methods, ESCC patients often present at an advanced stage at the time of diagnosis, which seriously affects the prognosis of patients. At present,early detection of ESCC mainly depends on invasive and expensive endoscopy and histopathological biopsy. Therefore, there is an unmet need for a noninvasive method to detect ESCC in the early stages. With the emergence of a large class of non-invasive diagnostic tools, serum tumor markers have attracted much attention because of their potential for detection of early tumors. Therefore, the identification of serum tumor markers for early detection of ESCC is undoubtedly one of the most effective ways to achieve early diagnosis and treatment of ESCC.This article reviews the recent advances in the discovery of blood-based ESCC biomarkers, and discusses the origins, clinical applications, and technical challenges of clinical validation of various types of biomarkers.     

葡萄糖转运体9基因 rs3733591（C>T）的单核苷酸多态性与我国汉族人群原发性痛风发病的相关性研究

目的探讨葡萄糖转运体9（SLC2A9）基因 rs3733591（C>T）的单核苷酸多态性（SNPs）与我国汉族人群痛风发病及血尿酸水平的相关性,并分析其多态性与痛风患者、健康体检者 PBMCs SLC2A9 mRNA 表达的相关性。方法①采用 TaqMan?探针法检测痛风组（297例原发性痛风性关节炎患者）和健康对照组（211名健康体检者） rs3733591（C>T）位点的基因型,χ2检验比较2组基因型及等位基因分布频率,计算比值比（OR）及95%可信区间（95%CI）。②采用实时荧光定量-PCR（RT-qPCR）法检测46例间歇期痛风患者及40名健康对照组 PBMCs SLC2A9 mRNA 的表达水平,非参数检验比较各组变量间的差异,并分析与 rs3733591（C>T）多态性的相关性。结果 rs3733591（C>T）位点的 TT 基因型在痛风组的分布频率显著低于健康对照组（37.7%与48.3%,P=0.017）,携带 TT 基因型的个体罹患痛风的相对风险OR 为0.647（95%CI：0.452~0.925）。而等位基因 T 在痛风组中的分布频率为60.9%,显著低于健康对照组的69.2%（χ2=7.324,P=0.007）,携带等位基因 T 的个体罹患痛风的相对风险 OR 为0.695（95%CI：0.533~0.905）;等位基因 C 在痛风组中的分布频率为39.1%,显著高于健康对照组的30.8%（χ2=1.440,P<0.05）。痛风组中携带 TC 基因型个体的外周血单个核细胞 SLC2A9 mRNA 的表达水平显著高于携带 TT 基因型者,而痛风组及健康对照组携带其他基因型的个体 SLC2A9 mRNA 的表达差异无统计学意义（P>0.05）。有痛风石（30例）痛风患者与无痛风石（190例）痛风患者的基因型及等位基因分布频率差异无统计学意义（P>0.05）。结论本研究提示 SLC2A9基因 rs3733591（C>T）位点的多态性可能与我国汉族人群原发性痛风的易感性相关,而与痛风患者痛风石形成无关;等位基因 C 可能为痛风发病的风险因子,而 TT 基因型及 T 等位基因可能对痛风发病具有保护作用;其多态性可能通过影响 SLC2A9基因的转录表达水平来参与痛风的发病。