The role of epigenetic therapies in colorectal cancer

Although developments in the diagnosis and therapy of colorectal cancer (CRC) have been made in the last decade, much work remains to be done as it remains the second leading cause of cancer death. It is now well established that epigenetic events, together with genetic alterations, are key events in initiation and progression of CRC. Epigenetics refers to heritable alterations in gene expression that do not involve changes in the DNA sequence. These alterations include DNA methylation, histone alterations, chromatin remodelers, and noncoding RNAs. In CRC, aberrations in epigenome may also involve in the development of drug resistance to conventional drugs such as 5-fluorouracil, oxaliplatin, and irinotecan. Thus, it has been suggested that combined therapies with epigenetic agents may reverse drug resistance. In this regard, DNA methyltransferase inhibitors and histone deacetylase inhibitors have been extensively investigated in CRC. The aim of this review is to provide a brief overview of the preclinical data that represent a proof of principle for the employment of epigenetic agents in CRC with a focus on the advantages of combinatorial therapy over single-drug treatment. We will also critically discuss the results and limitations of initial clinical experiences of epigenetic-based therapy in CRC and summarize ongoing clinical trials. Nevertheless, since recent translational research suggest that epigenetic modulators play a key role in augmenting immunogenicity of the tumor microenvironment and in restoring immune recognition, we will also highlight the recent developments of combinations strategies of immunotherapies and epigenetic therapies in CRC, summarizing preclinical, and clinical data to signify this evolving and promising field for CRC treatment.     

Epigenetic dysregulation in Epstein-Barr virus-associated gastric carcinoma: Disease and treatments

Epstein-Barr virus(EBV)-associated gastric carcinoma(EBVaGC)comprises nearly 10%of gastric carcinoma cases worldwide.Recently,it was recognised to have unique clinicopathologic characteristics,including male predominance,lower rates of lymph node involvement,and better prognosis.EBVaGC is further characterised by abnormal hypermethylation of tumour suppressor gene promoter regions,causing down-regulation of their expression.In the present review,we critically discuss the role of EBV in gastric carcinogenesis,summarising the role of viral proteins and microRNAs with respect to aberrant methylation in EBVaGC.Given the role of epigenetic dysregulation in tumourigenesis,epigenetic modifiers may represent a novel therapeutic strategy.     

Epigenetics of oral infection and inflammatory diseases—DNA methylation changes in infections and inflammation diseases

BackgroundEpigenetics involves alterations in gene expression that do not involve modifications in the DNA sequence, the memory of which can be passed down to the next generation in somatic cells. DNA methylation is an example of a mechanism that produces epigenetic changes. The purpose of this review is to summarize recent publications on DNA methylation in oral infections and inflammatory diseases, and to discuss its potential as a cause of disease and as a therapeutic target.HighlightSeveral types of oral bacteria and viruses may lead to DNA hypermethylation in oral tissues. Aberrant DNA hypermethylation is observed in oral inflammatory diseases, including chronic periodontitis, lichen planus, and radicular cysts.ConclusionSince epigenetic modifications are reversible, aberrant DNA methylation is a possible therapeutic target for such diseases. However, little is known about the epigenetics in oral inflammatory diseases, and further investigation is needed to elucidate the underlying mechanisms before epigenetic therapy can be used to treat oral inflammatory diseases.     

Effect of different combination of maternal and postnatal diet on adipose tissue morphology in male rat offspring

Purpose: Adipose tissue expansion can occur through several different ways and, under certain conditions, can be connected with chronic inflammation. TNF-α is one of the important cytokines involved in this process. Prolonged inflammation in obesity can lead to obesity-related insulin resistance and tissue dysfunction. The aim of our study was to investigate how different combination of maternal and postnatal diet affects offspring adipose tissue morphology and adipose tissue TNF-α expression.

Methods: Ten female Sprague Dawley rats, 9 weeks old, were randomly divided into two groups and fed either standard laboratory chow or food rich in saturated fatty acids during 6 weeks and then mated with the same male rat. After birth and lactation male rat offspring from both groups were divided into four subgroups depending on the diet they were fed until 22 weeks old. Samples of white adipose tissue were taken from the subcutaneous, epididymal, and perirenal fat pad. On tissue sections, histomorphometric analysis was conducted using CellProfiler program v 2.1.1, and immunohistochemical staining for TNF-α was performed.

Results: Greater mean surface area of subcutaneous and epididymal adipocytes was found in groups of male rat offspring with altered diet. In perirenal adipose tissue, the highest number of adipocytes was measured in the group where both mother and offspring were fed a high-fat diet. Adipocyte staining intensity for TNF-α did not differ significantly between the groups.

Conclusions: Together with our previously published data, our results lead to the conclusion that alteration of postnatal diet can lead to TNF-α and adipocyte morphology changes.     

《中医药法》持有人传承使用权的若干问题探讨

《中医药法》明确规定了持有人的传承使用权,但该法并未对持有人范围以及持有人所享有的传承使用权属性进行规定。文章通过对持有人的概念进行分析,阐述持有人与传承人关系,确定持有人范畴,并进而论述传承使用权的私权属性,克服中医药传统知识单一公权力保护传承存在的制度缺陷。     

基于数据挖掘对治疗口疮的成方制剂的用药规律分析*

目的分析治疗口疮的成方制剂的剂型、功能主治、组方用药规律及核心组合，为临床治疗口疮的辨证用药及新药研发提供参考。方法 收集《中华人民共和国卫生部药品标准·中药成方制剂》(以下简称《中药成方制剂》)、《中华人民共和国药典：2015年版》(以下简称2015年版《中国药典》)中治疗口疮的成方制剂的名称、处方、剂型、功能与主治，录入Microsoft Excel及中医传承辅助平台(V2.5)，统计用药频次；运用Apriori算法及关联规则对处方核心组合进行统计分析(支持度为10%，置信度100%)；采用熵聚类算法统计2-3个不同成分间的关联系数(支持度为8，惩罚度为2)；根据无监督的熵层次聚类法提取内在核心组合和新方组合。结果 挖掘得出86种成方制剂及其处方，以丸剂、散剂、片剂等多见，包含药物148味，使用频次较高为冰片、甘草、大黄、黄芩等，药物四气五味以苦寒为主，主要归肺胃心脾经，治疗证型较多为热毒炽盛证、热毒攻喉证等，常用核心配伍包括“黄芩-大黄”“黄连-甘草”等，挖掘得出新方组合“珍珠-川贝母-灯心草-天花粉-没药”等4首。结论 利用数据挖掘分析治疗口疮的成方制剂的组方规律，由核心药物组合成新方，可为临床辨证使用及研发治疗口疮成方制剂、新药提供依据和参考。     

Detection and reporting of RB1 promoter hypermethylation in diagnostic screening

Background: RB1 gene screening aids clinical management and genetic counselling in retinoblastoma families. Here we present epigenetic changes identified during routine molecular RB1 screening of tumor and blood samples. Complications in interpreting RB1 methylation are discussed.

Materials and Methods: Screening for RB1 promoter hypermethylation was carried out by Methylation Specific PCR (MS-PCR) after bisulphite modification of DNA. The cohort consisted of 315 tumors, and 204 blood samples, from 497 retinoblastoma patients (22 patients had both blood and tumor screened).

Results: 11.4% of retinoblastoma tumors had promoter hypermethylation. It was not routinely detected in blood samples, or in tumors with two other oncogenic RB1 changes. One blood sample had promoter hypermethylation due to an X;13 translocation. One tumor had low level methylation as well as two other oncogenic changes. Histopathological analysis of a small subset of age-matched tumors was similar regardless of promoter hypermethylation status.

Conclusions: Promoter hypermethylation was detected in 11.4% of the retinoblastoma tumors and should be tested for in routine RB1 screening programmes. Constitutional samples are not expected to display RB1 hypermethylation. In a small proportion of cases it may not be possible to use this somatic change in patient management.     

祁宝玉教授继承与发扬古籍的经验

祁宝玉教授擅长治疗诸多疑难眼病,并取得了良好的疗效.本文记述了祁老在中医古籍继承与发扬方面的学术经验,即“由博转约”和“提炼引申”.