Next generation histone deacetylase inhibitors: the answer to the search for optimized epigenetic therapies?

Introduction: HDAC inhibitors have demonstrated potent anticancer activities in preclinical and clinical studies. Currently, two drugs (SAHA and romidepsin) have gained the FDA approval for the treatment of cutaneous T-cell lymphoma. Clinical efficacy of HDAC inhibitors has been observed in advanced hematological malignancies, while response in other cancers has been in most cases unpredictable and often rather limited. The search for new molecules with the potential to overcome the limitations of the first HDAC inhibitors has become a primary goal in the field of epigenetic drug discovery as well as drugs acting on other chromatin modifying enzymes.

Areas covered: The article shortlists seven new HDAC inhibitors that have recently entered clinical studies as representative examples of next generation drugs. The most recently published preclinical profile is reviewed, together with the first clinical data for these compounds. The article then focuses on challenges faced during the progress of first generation HDAC inhibitors and analyzes whether these new compounds are likely to provide a solution to the existing issues and needs.

Expert opinion: Next generation HDAC inhibitors have the ‘best-in-class’ potential, particularly regarding potency and in vivo exposure. However, several issues remain unresolved. For example, none of the presented compounds appears to have a significantly different selectivity profile towards various HDAC isoforms and, thus, none of them may provide a further elucidation between the toxicity seen in more advanced HDAC inhibitors and isoform selectivity. Additionally, a need for a continuous effort on target validation is seen as a necessary requirement for further progress in the field.     

2型糖尿病发病进程中血清微小核糖核酸-103表达的临床意义

目的 探讨血清微小核糖核酸(miRNA)-103在2型糖尿病(T2DM)前期、新诊断的T2DM以及糖尿病并发症患者中的表达水平及临床意义.方法 选取70例研究对象,其中20例为糖耐量正常的个体(NGT组),18例为糖调节受损患者(prediabetes组),18例为新诊断的T2DM并无明显并发症患者(T2DM组),14例为T2DM并发症患者(T2DM伴并发症组).所有诊断均符合美国糖尿病学会(ADA)糖尿病诊断与分型标准中的诊断标准.应用荧光定量实时逆转录聚合酶链反应(PR-PCR)法评价各组受试者血清miRNA-103的表达水平.结果 Pre-diabetes组、T2DM组以及T2DM并发症组血清样本中miR-NA-103水平显著高于NGT组(P ＜0.05);T2DM组血清样本中miRNA-103水平显著高于pre-diabetes组(P＜0.05),而miR-NA-103在T2DM伴并发症组与T2DM组血清中的表达差异无统计学意义(P＞0.05).结论 血清miRNA-103有可能用于诊断及预测糖尿病的敏感的生物标志物,对于鉴别高风险患者具有至关重要的意义.     

miRNA-30 b纳米粒转染对甲状腺未分化癌细胞系TA -K 细胞生物学特性的影响

目的：研究miRNA-30b纳米粒对甲状腺未分化癌细胞株TA-K细胞的生物学特性的影响。方法转染不同浓度的miRNA-30b纳米粒进入TA-K细胞中,通过流式法检测TA-K细胞凋亡情况,后通过生物信息学预测miR-NA-30b的生物学靶点,并通过RT-PCR及Western Blot方法验证。结果发现转染了miRNA-30b纳米粒后,TA-K细胞的凋亡显著增加,而生物信息学显示miRNA-30b可靶向作用于Survivin,后经RT-PCR及Western blot 法证实Sur-vivin确实是miRNA-30b的生物学靶点。结论 miRNA-30b可以通过作用Survivin促进TA-K细胞的凋亡,这一现象也为将来甲状腺未分化癌的临床治疗提供了新的思路。     

The biology,function, and applications of exosomes in cancer

Exosomes are cell-derived nanovesicles with diameters from 30 to 150 nm, released upon fusion of multivesicular bodies with the cell surface. They can transport nucleic acids, proteins, and lipids for intercellular communication and activate signaling pathways in target cells. In cancers, exosomes may participate in growth and metastasis of tumors by regulating the immune response, blocking the epithelial–mesenchymal transition, and promoting angiogenesis. They are also involved in the development of resistance to chemotherapeutic drugs. Exosomes in liquid biopsies can be used as non-invasive biomarkers for early detection and diagnosis of cancers. Because of their amphipathic structure, exosomes are natural drug delivery vehicles for cancer therapy.     

高危型HPV阳性宫颈癌患者miRNA-34a-5p的表达及临床意义

目的　探讨高危型人乳头状瘤病毒（high risk-human papilloma virus, HR-HPV）阳性宫颈癌患者组织及血清中微小RNA（microRNA, miRNA）-34a-5p的表达及其对宫颈癌的诊断价值。方法　将100例HR-HPV阳性宫颈癌患者（宫颈癌组）、70例宫颈上皮内瘤变（cervical intraepithelial neoplasia, CIN）患者（CIN组）、70例HR-HPV阳性子宫良性病变或者HPV单纯阳性的健康体检者（对照组）作为研究对象。采集上述研究对象的血清标本及70例行手术治疗的宫颈癌组患者癌组织及癌旁组织。使用实时荧光定量PCR技术测定组织及血清中miRNA-34a-5p水平,并分析miRNA-34a-5p与宫颈癌临床、病理指标的关联及血清miRNA-34a-5p对宫颈癌的诊断价值。结果　①对照组血清中miRNA-34a-5p的相对表达量高于CIN组和宫颈癌组：（0.933±0.097）vs.（0.554±0.099）vs.（0.369±0.099）,差异有统计学意义（F=741.401,P=0.000）;宫颈癌组患者术前血清中miRNA-34a-5p相对表达量低于术后1周,差异有统计学意义（t=8.305,P=0.000）。有无淋巴结转移和有无远处转移的宫颈癌患者血清中miRNA-34a-5p相对表达量的差异有统计学意义（P均＜0.05）。②宫颈癌组患者癌旁组织中miRNA-34a-5p的相对表达量高于癌组织,差异具有统计学意义（t=40.313,P=0.000）。③宫颈癌组患者癌组织中的miRNA-34a-5p表达水平与血清中的表达水平呈正相关（r=0.908,P=0.000）。④以0.508为miRNA-34a-5p相对表达量的最佳临界值诊断宫颈癌,其灵敏度为83.6%,特异度为79.4%,AUC为0.860,95%置信区间为0.803～0.917。结论　HR-HPV阳性宫颈癌患者癌组织和血清中miRNA-34a-5p表达下调,对宫颈癌诊断及预后监测具有一定的参考价值。     

An evaluation of the intervention against smoking in the multiple risk factor intervention trial

The results of the Multiple Risk Factor Intervention Trial showed no significant difference in mortality from coronary heart disease between intervention and control groups despite an apparent success of the intervention against cigarette smoking. A reanalysis of the published data indicates that the effectiveness of the smoking intervention may have been overestimated. The researchers counted those who smoked pipes or cigars at screen as nonsmokers and attempted to classify cigarette smokers who switched to pipes or cigars during the trial as successes whether or not they continued to inhale the smoke. It is unreasonable to assume a priori that inhaling pipe or cigar smoke is less dangerous than cigarette smoke. Moreover, attempting to include pipe and cigar smokers, who may have been inhaling smoke, among the successes makes biochemical validation of claims of abstinence overly lenient. When levels of serum thiocyanate are used to obtain an objective index of smoking reduction, it appears that the effect of intervention was considerably smaller than has been reported, and failed to reach design goals over the first 4 years. This could help to explain the disappointing mortality results.     

D101大孔树脂纯化鸡骨草总黄酮的研究

探讨 D101大孔吸附树脂纯化鸡骨草总黄酮的工艺条件。以吸附率和解吸率为考查指标,通过单因素实验对影响树脂动态吸附和解吸条件进行考察。最佳工艺条件为：上样浓度3 mg•mL-1,上样流速3 BV•h-1;洗脱剂为80%的乙醇溶液,pH值6.0,洗脱流速3.5 BV•h-1,洗脱剂用量2 BV。鸡骨草黄酮纯度由原来的17.95%提高到52.80%。D101大孔树脂对鸡骨草黄酮类物质有较好的纯化效果,该工艺简单可行。     

miR-101在宫颈癌组织中的表达及其临床意义

目的:探讨miR-101在宫颈癌组织中的表达及与宫颈癌临床病理特征的关系。方法:应用逆转录实时荧光定量聚合酶链反应(RT-PCR)检测40例宫颈癌组织miR-101水平,以30例子宫肌瘤患者作为正常对照,探讨其表达与宫颈癌临床病理特征的关系。结果:与正常宫颈组织比较,miR-101在宫颈癌组织中表达下调(0.54±0.32)倍,差异有统计学意义(P<0.05)。不同病理分级、间质浸润深度、淋巴结转移宫颈癌患者miR-101表达水平分别比较差异均具有统计学意义(P<0.05),而不同年龄、临床分期、肿瘤直径、绝经与否的宫颈癌患者miR-101表达水平分别比较差异均无统计学意义(P>0.05)。结论:miR-101的表达与宫颈癌的发生、转移和侵袭能力有关,可作为治疗及评价预后的参考指标,并可为肿瘤靶向治疗提供新靶点。     

Smokers have varying misperceptions about the harmfulness of menthol cigarettes: national survey data

Objective : To describe the prevalence of menthol use and perceptions of relative harmfulness among smokers in an ethnically diverse population where tobacco marketing is relatively constrained (New Zealand). Methods : The New Zealand (NZ) arm of the International Tobacco Control Policy Evaluation Survey (ITC Project) utilises the NZ Health Survey (a national sample). From this sample we surveyed adult smokers, with Wave 2 (n=923) covering beliefs around menthol cigarettes. Results : Agreement with the statement that “menthol cigarettes are less harmful than regular cigarettes” was higher in smokers who were: older, Māori, Pacific, Asian, financially stressed and had higher levels of individual deprivation. Most of these associations were statistically significant in at least some of the logistic regression models (adjusting for socio‐economic and smoking beliefs and behaviour). In the fully‐adjusted model this belief was particularly elevated in Pacific smokers (adjusted odds ratio [aOR] = 7.36, 95% CI = 1.92 – 28.27) and also in menthol smokers (aOR = 4.58, 95% CI = 1.94–10.78). Most smokers in this study (56%), and especially menthol smokers (73%), believed that menthols are “smoother on your throat and chest”. Conclusion : Various groups of smokers in this national sample had misperceptions around the relative harmfulness of menthols, which is consistent with most previous studies. Implications : This evidence, along with a precautionary approach, supports arguments for enhanced regulation of tobacco marketing and tobacco ingredients such as menthol.     

黄芪注射液中黄芪总皂苷的含量测定

目的：建立黄芪注射注中黄芪总皂苷含量测定的新方法。方法：采用大孔吸附树脂吸附分离,以5％得草醛冰醋酸溶液和高氯酸为显色剂,比色法测定,测定波长为536nm。结果：在10－50μg.ml^-1浓度范围内,线性关系良好,平均回收率为98．04％,RSD＝1．7％。结论：方法简便,结果可靠。