Expert consensus document:Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted

Up-regulation and Cytoprotective Role of Epithelial Multidrug Resistance-associated Protein 1 in Inflammatory Bowel Disease

MRP1 (multidrug resistance-associated protein 1) is well known for its role in providing multidrug resistance to cancer cells. In addition, MRP1 has been associated with both pro- and anti-inflammatory functions in nonmalignant cells. The pro- inflammatory function is evident from the fact that MRP1 is a high affinity transporter for cysteinyl-leukotriene C-4 (LTC4), a lipid mediator of inflammation. It remains unexplained, however, why the absence of Mrp1 leads to increased intestinal epithelial damage in mice treated with dextran-sodium sulfate, a model for inflammatory bowel disease (IBD). We found that MRP1 expression is induced in the inflamed intestine of IBD patients, e. g. Crohn disease and ulcerative colitis. Increased MRP1 expression was detected at the basolateral membrane of intestinal epithelial cells. To study a putative role for MRP1 in protecting epithelial cells against inflammatory cues, we manipulated MRP1 levels in human epithelial DLD-1 cells and exposed these cells to cytokines and anti-Fas. Inhibition of MRP1 (by MK571 or RNA interference) resulted in increased cytokine- and anti-Fas-induced apoptosis of DLD-1 cells. Opposite effects, e. g. protection of DLD-1 cells against cytokine- and anti-Fas-induced apoptosis, were observed after recombinant MRP1 overexpression. Inhibition of LTC4 synthesis reduced anti-Fas-induced apoptosis when MRP1 function was blocked, suggesting that LTC4 is the pro- apoptotic compound exported by epithelial MRP1 during inflammation. These data show that MRP1 protects intestinal epithelial cells against inflammation-induced apoptotic cell death and provides a functional role for MRP1 in the inflamed intestinal epithelium of IBD patients

Potential biomarkers of infertility associated with microbiome imbalances

PROBLEM: The aim of this study was to investigate the possible relationship between vaginal/rectal microbiome disbalances and miRNA expression with infertility. METHOD OF STUDY: Observational, exploratory, preliminary study. A total of 287 multiple IVF failure infertile patients were recruited. Twenty fertile women, not IVF failure, were recruited as the control group. Swab samples were collected from the vagina and rectum. Microbial composition by NGS and miRNA expression by real-time PCR of vaginal and rectal samples was measured. Immunometabolic markers from blood (insulin, vitamin D, LDL-cholesterol, ANA, TPO, Tg, and ASCA antibodies) and saliva (sIgA) were analyzed. RESULT(S): Infertile patients showed a lower bacterial richness and increased Firmicutes/Bacteroidetes ratio at rectal level and an increased Lactobacillus brevis/Lactobacillus iners ratio in vaginal samples regarding the fertile group. In the same rectal swab samples, we found that miR-21–5p, which is associated with tight junction disruption and yeast overgrowth, is upregulated and that miR-155–5p, which is associated with inflammation, is overexpressed in the unexplained infertile group (*p < .05). These deregulated miRNAs were also upregulated in the vaginal samples from the same patients (*p < .05). CONCLUSION: miRNAs could be potential biomarkers of the inflammatory impact of microbiome disbalances in unexplained infertile women