Faecal microRNAs as a non-invasive tool in the diagnosis of colonic adenomas and colorectal cancer: A meta-analysis.

MicroRNAs (miRNAs) are proposed as potential biomarkers for the diagnosis of numerous diseases. Here, we performed a meta-analysis to evaluate the utility of faecal miRNAs as a non-invasive tool in colorectal cancer (CRC) screening. A systematic literature search, according to predetermined criteria, in five databases identified 17 research articles including 6475, 783 and 5569 faecal-based miRNA tests in CRC, adenoma patients and healthy individuals, respectively. Sensitivity, specificity, positive/negative likelihood and diagnostic odds ratios, area under curve (AUC), summary receiver operator characteristic (sROC) curves, association of individual or combinations of miRNAs to cancer stage and location, subgroup, meta-regression and Deeks' funnel plot asymmetry analyses were employed. Pooled miRNAs for CRC had an AUC of 0.811, with a sensitivity of 58.8% (95% confidence interval [CI]: 51.7-65.5%) and specificity of 84.8% (95% CI: 81.1-87.8%), whilst for colonic adenoma, it was 0.747, 57.3% (95% CI: 40.8-72.3%) and 76.1% (95% CI: 66.1-89.4%), respectively. The most reliable individual miRNA was miR-21, with an AUC of 0.843, sensitivity of 59.3% (95% CI: 26.3-85.6%) and specificity of 85.6% (95% CI: 72.2-93.2%). Paired stage analysis showed a better diagnostic accuracy in late stage CRC and sensitivity higher in distal than proximal CRC. In conclusion, faecal miR-21, miR-92a and their combination are promising non-invasive biomarkers for faecal-based CRC screening.

Disease activity indices in coeliac disease: systematic review and recommendations for clinical trials.

OBJECTIVE: Although several pharmacological agents have emerged as potential adjunctive therapies to a gluten-free diet for coeliac disease, there is currently no widely accepted measure of disease activity used in clinical trials. We conducted a systematic review of coeliac disease activity indices to evaluate their operating properties and potential as outcome measures in registration trials. DESIGN: MEDLINE, EMBASE and the Cochrane central library were searched from 1966 to 2015 for eligible studies in adult and/or paediatric patients with coeliac disease that included coeliac disease activity markers in their outcome measures. The operating characteristics of histological indices, patient-reported outcomes (PROs) and endoscopic indices were evaluated for content and construct validity, reliability, responsiveness and feasibility using guidelines proposed by the US Food and Drug Administration (FDA). RESULTS: Of 19 123 citations, 286 studies were eligible, including 24 randomised-controlled trials. Three of five PROs identified met most key evaluative criteria but only the Celiac Disease Symptom Diary (CDSD) and the Celiac Disease Patient-Reported Outcome (CeD PRO) have been approved by the FDA. All histological and endoscopic scores identified lacked content validity. Quantitative morphometric histological analysis had better reliability and responsiveness compared with qualitative scales. Endoscopic indices were infrequently used, and only one index demonstrated responsiveness to effective therapy. CONCLUSIONS: Current best evidence suggests that the CDSD and the CeD PRO are appropriate for use in the definition of primary end points in coeliac disease registration trials. Morphometric histology should be included as a key secondary or co-primary end point. Further work is needed to optimise end point configuration to inform efficient drug development.

MicroRNA-20a in human faeces as a non-invasive biomarker for colorectal cancer.

OBJECTIVE: Detection of microRNA (miRNA) aberrations in human faeces is a new approach for colorectal cancer (CRC) screening. The aim of this study was to characterise miR-20a in faeces as a non-invasive biomarker for diagnosis of CRC. RESULTS: miR-20a expression was significantly higher in the 40 CRC tumours compared to their respective adjacent normal tissues (P = 0.0065). Levels of miR-20a were also significantly higher in faecal samples from CRC patients (P < 0.0001). The area under receiver operating characteristic (AUROC) curve for miR-20a was 0.73, with a sensitivity of 55% and specificity of 82% for CRC patients compared with controls. No significant difference in the level of miR-20a was found between patients with proximal, distal, and rectal cancer. The use of antibiotics did not influence faecal miR-20a levels. PATIENTS AND METHODS: miR-20a was selected from an expression microarray containing 667 miRNAs. Further verification of miR-20a was performed in 40 pairs of primary CRC tissues, as well as 595 faecal samples (198 CRCs, 199 adenomas, and 198 healthy controls) using TaqMan probe based quantitative Real-Time PCR (qRT-PCR). CONCLUSIONS: Faecal-based miR-20a can be utilised as a potential non-invasive biomarker for CRC screening.

Integrative identification of Epstein-Barr virus-associated mutations and epigenetic alterations in gastric cancer.

BACKGROUND & AIMS: The mechanisms by which Epstein-Barr virus (EBV) contributes to the development of gastric cancer are unclear. We investigated EBV-associated genomic and epigenomic variations in gastric cancer cells and tumors. METHODS: We performed whole-genome, transcriptome, and epigenome sequence analyses of a gastric adenocarcinoma cell line (AGS cells), before and after EBV infection. We then looked for alterations in gastric tumor samples, with (n = 34) or without (n = 100) EBV infection, collected from patients at the Prince of Wales Hospital, Chinese University of Hong Kong (from 1998 through 2004), or the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (from 1999 through 2006). RESULTS: Transcriptome analysis showed that infected cells expressed 9 EBV genes previously detected in EBV-associated gastric tumors and 71 EBV genes not previously reported in gastric tumors. Ten viral genes that had not been reported previously in gastric cancer but were expressed most highly in EBV-infected cells also were expressed in primary EBV-positive gastric tumors. Whole-genome sequence analysis identified 45 EBV-associated nonsynonymous mutations. These mutations, in genes such as AKT2, CCNA1, MAP3K4, and TGFBR1, were associated significantly with EBV-positive gastric tumors, compared with EBV-negative tumors. An activating mutation in AKT2 was associated with reduced survival times of patients with EBV-positive gastric cancer (P = .006); this mutation was found to dysregulate mitogen-activated protein kinase signaling. Integrated epigenome and transcriptome analyses identified 216 genes transcriptionally down-regulated by EBV-associated hypermethylation; methylation of ACSS1, FAM3B, IHH, and TRABD increased significantly in EBV-positive tumors. Overexpression of Indian hedgehog (IHH) and TraB domain containing (TRABD) increased proliferation and colony formation of gastric cancer cells, whereas knockdown of these genes reduced these activities. We found 5 signaling pathways (axon guidance, focal adhesion formation, interactions among cytokines and receptors, mitogen-activated protein kinase signaling, and actin cytoskeleton regulation) to be affected commonly by EBV-associated genomic and epigenomic alterations. CONCLUSIONS: By using genomic, transcriptome, and epigenomic comparisons of EBV infected vs noninfected gastric cancer cells and tumor samples, we identified alterations in genes, gene expression, and methylation that affect different signaling networks. These might be involved in EBV-associated gastric carcinogenesis.

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.

Management of chronic hepatitis B infection: current treatment guidelines, challenges, and new developments.

Chronic hepatitis B (CHB) virus infection is a global public health problem, affecting more than 400 million people worldwide. The clinical spectrum is wide, ranging from a subclinical inactive carrier state, to progressive chronic hepatitis, cirrhosis, decompensation, and hepatocellular carcinoma. However, complications of hepatitis B virus (HBV)-related chronic liver disease may be reduced by viral suppression. Current international guidelines recommend first-line treatment of CHB infection with pegylated interferon, entecavir, or tenofovir, but the optimal treatment for an individual patient is controversial. The indications for treatment are contentious, and increasing evidence suggests that HBV genotyping, as well as serial on-treatment measurements of hepatitis B surface antigen and HBV DNA kinetics should be used to predict antiviral treatment response. The likelihood of achieving a sustained virological response is also increased by extending treatment duration, and using combination therapy. Hence the paradigm for treatment of CHB is constantly evolving. This article summarizes the different indications for treatment, and systematically reviews the evidence for the efficacy of various antiviral agents. It further discusses the shortcomings of current guidelines, use of rescue therapy in drug-resistant strains of HBV, and highlights the promising clinical trials for emerging therapies in the pipeline. This concise overview presents an updated practical approach to guide the clinical management of CHB.

Hypoxia-inducible factor-1 as a therapeutic target in cancer.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that immortalizes tumors by inducing key genes in cancer biology, including angiogenesis, glycolysis, invasion, and metastasis. Overexpression of HIF-1α is thus associated with resistance to cancer chemotherapy and increased patient mortality in several cancer phenotypes. In the present review, we summarize the role of intratumoral hypoxia and bioactive lipids in enhancing HIF-1 activity, critically discussing the potential for HIF-1α inhibitors in cancer chemotherapy. Considering preclinical studies, HIF-1 inhibitors appear to have antitumor effects and thus represent a novel therapeutic strategy.