Mapping a Circular RNA-microRNA-mRNA-Signaling Regulatory Axis That Modulates Stemness Properties of Cancer Stem Cell Populations in Colorectal Cancer Spheroid Cells.

Spheroidal cancer cell cultures have been used to enrich cancer stem cells (CSC), which are thought to contribute to important clinical features of tumors. This study aimed to map the regulatory networks driven by circular RNAs (circRNAs) in CSC-enriched colorectal cancer (CRC) spheroid cells. The spheroid cells established from two CRC cell lines acquired stemness properties in pluripotency gene expression and multi-lineage differentiation capacity. Genome-wide sequencing identified 1503 and 636 circRNAs specific to the CRC parental and spheroid cells, respectively. In the CRC spheroids, algorithmic analyses unveiled a core network of mRNAs involved in modulating stemness-associated signaling pathways, driven by a circRNA-microRNA (miRNA)-mRNA axis. The two major circRNAs, hsa_circ_0066631 and hsa_circ_0082096, in this network were significantly up-regulated in expression levels in the spheroid cells. The two circRNAs were predicted to target and were experimentally shown to down-regulate miR-140-3p, miR-224, miR-382, miR-548c-3p and miR-579, confirming circRNA sponging of the targeted miRNAs. Furthermore, the affected miRNAs were demonstrated to inhibit degradation of six mRNA targets, viz. ACVR1C/ALK7, FZD3, IL6ST/GP130, SKIL/SNON, SMAD2 and WNT5, in the CRC spheroid cells. These mRNAs encode proteins that are reported to variously regulate the GP130/Stat, Activin/Nodal, TGF-ß/SMAD or Wnt/ß-catenin signaling pathways in controlling various aspects of CSC stemness. Using the CRC spheroid cell model, the novel circRNA-miRNA-mRNA axis mapped in this work forms the foundation for the elucidation of the molecular mechanisms of the complex cellular and biochemical processes that determine CSC stemness properties of cancer cells, and possibly for designing therapeutic strategies for CRC treatment by targeting CSC.

WITHDRAWN: Eradication of Helicobacter pylori for non-ulcer dyspepsia.

BACKGROUND: Helicobacter pylori (H pylori) is the main cause of peptic ulcer disease. The role of H pylori in non-ulcer dyspepsia is less clear. OBJECTIVES: To determine the effect of H pylori eradication on dyspepsia symptoms in patients with non-ulcer dyspepsia. SEARCH STRATEGY: Trials were identified through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and keywords, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and with pharmaceutical companies. SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing drugs to eradicate H pylori with placebo or other drugs known not to eradicate H pylori for patients with non-ulcer dyspepsia. DATA COLLECTION AND ANALYSIS: Data were collected on individual and global dyspeptic symptom scores, quality of life measures and adverse effects. Dyspepsia outcomes were dichotomised into minimal/resolved versus same/worse symptoms. MAIN RESULTS: Twenty one randomised controlled trials were included in the systematic review. Eighteen trials compared antisecretory dual or triple therapy with placebo antibiotics +/- antisecretory therapy, and evaluated dyspepsia at 3-12 months. Seventeen of these trials gave results as dichotomous outcomes evaluating 3566 patients and there was no significant heterogeneity between the studies. There was a 10% relative risk reduction in the H pylori eradication group (95% CI = 6% to 14%) compared to placebo. The number needed to treat to cure one case of dyspepsia = 14 (95% CI = 10 to 25). A further three trials compared Bismuth based H pylori eradication with an alternative pharmacological agent. These trials were smaller and had a shorter follow-up but suggested H pylori eradication was more effective than either H2 receptor antagonists or sucralfate in treating non-ulcer dyspepsia. AUTHORS' CONCLUSIONS: H pylori eradication therapy has a small but statistically significant effect in H pylori positive non-ulcer dyspepsia. An economic model suggests this modest benefit may still be cost-effective but more research is needed.

WITHDRAWN: Psychological interventions for non-ulcer dyspepsia.

BACKGROUND: Studies have also shown that non-ulcer dyspepsia (NUD) patients have higher scores of anxiety, depression, neurotism, chronic tension, hostility, hypochondriasis and tendency to be more pessimistic when compared with the community controls. However, the role of psychological interventions in NUD remains uncertain. OBJECTIVES: This review aims to determine the effectiveness of psychological interventions including psychotherapy, psychodrama, cognitive behavioural therapy, relaxation therapy and hypnosis in the improvement of either individual or global dyspepsia symptom scores and quality of life scores in patients with NUD. SEARCH STRATEGY: Trials were identified by searching the Cochrane Controlled Trials Register (Issue 3-1999), MEDLINE (1966-99), EMBASE (1988-99), PsycLIT (1987-1999) and CINAHL (1982-99). Bibliographies of retrieved articles were also searched and experts in the field were contacted. Searches were updated on 10 December 2002 and 21 January 2004. The searches were re-run on 24 January 2005 and 9 January 2006 and no new trials were found SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-randomised studies assessing the effectiveness of psychological interventions (including psychotherapy, psychodrama, cognitive behavioural therapy, relaxation therapy and hypnosis) for non-ulcer dyspepsia (NUD) were identified. DATA COLLECTION AND ANALYSIS: Data collected included both individual and global dyspepsia symptom scores and quality of life (QoL) scores. MAIN RESULTS: We identified only four trials each using different psychological interventions; three presented results in a manner that did not allow synthesis of the data to form a meta-analysis. All trials suggested that psychological interventions benefit dyspepsia symptoms and this effect persists for one year. However, all trials used statistical techniques that adjusted for baseline differences between groups. This should not be necessary for a randomised trial that is adequately powered suggesting that the sample size was too small. Unadjusted data was not statistically significant. The other problems of psychological intervention included low recruitment and high drop out rate, which has been shown to be greater in patients receiving group therapy. AUTHORS' CONCLUSIONS: There is insufficient evidence from this review to confirm the efficacy of psychological intervention in NUD.

Intravenous immunoglobulin for the treatment of severe, refractory, and recurrent Clostridium difficile diarrhea.

PURPOSE: Clostridium difficile diarrhea is common in elderly patients and leads to prolonged hospitalization. Patients with severe or recurrent Clostridium difficile diarrhea have poor antitoxin antibody responses. Intravenous immunoglobulin has been advocated in these patients. This study was designed to assess the response of patients with refractory, recurrent, or severe Clostridium difficile diarrhea to intravenous immunoglobulin. METHODS: Retrospective review (November 2003-January 2005) of 14 patients with severe, refractory, recurrent Clostridium difficile diarrhea treated with intravenous immunoglobulin (Flebogamma, 150-400 mg/kg) from 264 Clostridium difficile toxin-positive patients. RESULTS: Median age was 79 (range, 54-91) years. Median length of symptoms before intravenous immunoglobulin was 29 (range, 3-90) days. Patients received a median of three (range, 1-5) courses of vancomycin or metronidazole before intravenous immunoglobulin. All had hypoalbuminemia (median, 22 g/l; range, 18-33) and raised C-reactive protein (median, 47 mg/l; range, 25-255) at time of infusion. The median white cell count was 15.3 x 10(9)/liters (range, 4-24). Eight patients had evidence of pancolitis on abdominal imaging, suggesting severe Clostridium difficile diarrhea. All patients tolerated intravenous immunoglobulin without side effects. Nine (64 percent) responded with bowels normalizing in a median of ten (range, 2-26) days; one patient received two doses. One patient had a partial response from two doses but died two months later after a recurrence. The other four patients died of other causes within three weeks of infusion. CONCLUSIONS: Intravenous immunoglobulin may be effective for severe, refractory, or recurrent Clostridium difficile diarrhea after failed conventional treatment.

A systematic review of psychological therapies for nonulcer dyspepsia.

OBJECTIVES: We conducted a systematic review to determine the effectiveness of psychological interventions including psychodrama, cognitive behavioral therapy, relaxation therapy, guided imagery, or hypnosis in the improvement of dyspepsia symptoms in patients with nonulcer dyspepsia (NUD). DESIGN: Trials were identified through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL, and PsycLIT, using appropriate subject headings and text words and searching bibliographies of retrieved articles. All randomized controlled trials (RCTs) or quasi-randomized studies were eligible. RESULTS: The four eligible trials all used different psychological interventions including applied relaxation therapy, psychodynamic psychotherapy, cognitive therapy, and hypnotherapy. Trials did not present data in a form that could be synthesized. All reported an improvement in the dyspepsia symptom scores at the end of treatment and at 1 yr in the intervention arm compared with controls. All studies only achieved statistically significant results through adjusting for baseline differences between groups. This reflects the small sample sizes of the trials. There were also problems with assumptions made in the statistical analyses used to achieve statistical significance. The studies highlighted problems with recruitment and compliance. CONCLUSIONS: There was insufficient evidence on the efficacy of psychological therapies in NUD. This emphasizes the need for appropriately powered well-designed trials in this area.