Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.     

长链非编码RNA CBR3-AS1在胆管癌中的表达及其临床意义

目的:探讨长链非编码RNA CBR3-AS1(lncRNA CBR3-AS1)在胆管癌(CCA)中表达状态及其临床意义。方法:用qRT-PCR检测lncRNA CBR3-AS1在CCA组织与癌旁组织以及CCA细胞与正常胆管上皮细胞中的表达,分析lncRNA CBR3-AS1表达与CCA患者临床病理参数及生存率的关系。将胆管癌细胞分别转染lncRNA CBR3-AS1过表达质粒(过表达组)、阴性对照质粒(对照组)及lncRNA CBR3-AS1沉默序列(沉默组),用MTT实验与Transwell实验检测各组细胞的增殖与侵袭能力。结果:lncRNA CBR3-AS1的表达在胆管癌组织中明显高于癌旁组织,在胆管癌细胞系中明显高于正常胆管上皮细胞(均P0.01)。lncRNA CBR3-AS1表达与CCA患者淋巴结转移、TNM分期和术后复发明显有关(P0.05)。lncRNA CBR3-AS1高表达患者总生存率明显低于lncRNA CBR3-AS1低表达患者(P=0.004)。lncRNA CBR3-AS1表达(P=0.020)与TNM分期(P=0.014)是影响CCA患者总生存率的独立危险因素。与对照组CCA细胞比较,过表达组CCA细胞增殖与侵袭能力明显增高,沉默组CCA细胞增殖与侵袭能力明显降低(均P0.05)。结论:lncRNA CBR3-AS1在胆管癌中表达升高,升高的lncRNA CBR3-AS1与CCA的恶性临床病理特征及患者的不良预后密切相关。     

Non-coding RNAs: Regulators of glioma cell epithelial-mesenchymal transformation

GBM (glioblastoma multiforme) is the most malignant form of glioma and is the most commonly occurring primary malignant brain tumour. GBM is difficult to completely excise, resulting in an extremely high recurrence rate. The occurrence of an aggressive glioma phenotype depends on EMT (epithelial-mesenchymal transformation), in which epithelial cells transform into mesenchymal cells by losing their cell-cell adhesion and polarity. NcRNAs (non-coding RNAs) play a significant role in the cellular progression from a normal phenotype to a cancerous phenotype. Recently, many studies have shown that there are two essential regulatory ncRNAs, miRNAs (microRNAs) and lncRNAs, which are closely related to EMT. In this review, we conducted a comprehensive investigation of the dysregulated lncRNAs and miRNAs in gliomas with particular attention to the function and regulatory mechanisms of several important lncRNAs and miRNAs, and we discussed their roles as glioma diagnostic and prognostic biomarkers and their potential clinical applications as therapeutic targets.     

The potential of circulating cell free RNA as a biomarker in cancer

Introduction: It is now clear that circulating cell-free ribonucleic acids (ccfRNAs), including messenger RNA (mRNA) and miRNA, are potential cancer biomarkers. As ccfmiRNA is relatively more stable than ccfmRNA, research should concentrate on developing novel methods to preserve the stability of ccfmRNA and standardization of the protocol which includes extraction, detection, and multicenter validation.

Areas covered: This literature review concentrates on the potential of ccfRNA being used as a biomarker in cancer, with special focus on mRNAs and microRNAs (miRNAs).

Expert opinion: With the advancement of high-throughput technologies such as RNA sequencing, a panel of biomarkers will be used for the diagnosis, prognosis and therapeutic monitoring of cancer patients. In order to achieve this important target, bioinformatics education to pathologists, scientists, and technologists in molecular diagnostic laboratories is essential. Moreover, the panel of these new ccfRNAs biomarkers has to obtain approval or clearance from an authority such as the US Food and Drug Administration (FDA), and the standard of utilizing these new protocols has to be recognized via accreditation exercise. Therefore, there is still a long way to go before an extensively use of ccfRNA biomarkers in cancer patients can be realized.     

Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases

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沉默环状RNA hsa_circ_0001785表达对乳腺癌MDA-MB-231细胞增殖、迁移及侵袭能力的影响

目的:探究环状RNA（circRNA）hsa_circ_0001785在乳腺癌组织和细胞中的表达变化及其对乳腺癌细胞增殖、迁移和侵袭能力的影响。方法:qRT-PCR实验检测hsa_circ_0001785在乳腺癌组织和乳腺癌细胞（MDA-MB-231和SK-BP-3）中的相对表达水平；CCK-8和克隆形成实验检测沉默或上调表达hsa_circ_0001785对MDA-MB-231细胞活性和克隆形成能力的影响；划痕愈合实验和Transwell侵袭实验检测沉默或上调表达hsa_circ_0001785对MDA-MB-231细胞迁移及侵袭能力的影响。结果:hsa_circ_0001785在乳腺癌组织中的相对表达水平明显高于癌旁组织，hsa_circ_0001785在MDA-MB-231和SK-BP-3细胞中的相对表达水平明显高于人乳腺上皮细胞MCF10A。在MDA-MB-231细胞沉默hsa_circ_0001785，MDA-MB-231细胞的活性和克隆形成能力明显降低，迁移距离显著减少，侵袭能力也明显下降。而在MDA-MB-231细胞中上调表达hsa_circ_0001785，MDA-MB-231细胞的活性和克隆形成能力显著升高，迁移距离明显升高，侵袭能力也明显升高。结论:hsa_circ_0001785在乳腺癌组织和乳腺癌细胞（MDA-MB-231和SK-BP-3）中的表达水平明显升高；沉默hsa_circ_0001785显著抑制乳腺癌MDA-MB-231细胞的增殖、迁移和侵袭能力，而上调表达hsa_circ_0001785明显促进乳腺癌MDA-MB-231细胞的增殖、迁移和侵袭能力。     

PRNCR1在前列腺癌诊断及预后的价值

目的 探讨前列腺癌非编码RNA1（PRNCR1）在前列腺癌早期诊断及预后的价值。方法 选取2012年1月至2015年10月在本院诊治前列腺癌患者45例、良性前列腺增生患者88例，进行PRNCR1检验。结果 PRNCR1 检验的灵敏度84.4%（38/45）、特异度90.9%（80/88）、阳性预测值82.6%（38/46）、阴性预测值92.0%（80/87)、符合率88.7%（118/133），PRNCR1在前列腺癌组织中含量高于癌旁组织和良性前列腺增生组织，差异有统计学意义（P<0.05）。两年内转移、复发、肿瘤死亡患者30例，其PRNCRA表达量高于两年内无转移、复发、死亡的患者（15例），差异有统计学意义（P<0.05）。结论 PRNCR1表达在诊断前列腺癌有价值，PRNCR1高表达与患者预后不良有关。