Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated. METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro. RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism. CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA.

MicroRNAs and extracellular vesicles in cholangiopathies.

Cholangiopathies encompass a heterogeneous group of disorders affecting biliary epithelial cells (i.e. cholangiocytes). Early diagnosis, prognosis and treatment still remain clinically challenging for most of these diseases and are critical for adequate patient care. In the past decade, extensive research has emphasized microRNAs (miRs) as potential non-invasive biomarkers and tools to accurately identify, predict and treat cholangiopathies. MiRs can be released extracellularly conjugated with lipoproteins or encapsulated in extracellular vesicles (EVs). Research on EVs is also gaining attention since they are present in multiple biological fluids and may represent a relevant source of novel non-invasive biomarkers and be vehicles for new therapeutic approaches. This review highlights the most promising candidate miRs and EV-related biomarkers in cholangiopathies, as well as their relevant roles in biliary pathophysiology. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. RESEARCH STRATEGY: PubMed search (April 2017) was done with the following terms: "microRNA", "miRNA", "miR", "extracellular vesicles", "EV", "exosomes", "primary biliary cholangitis", "primary biliary cholangitis", "PBC", "primary sclerosing cholangitis", "PSC", "cholangiocarcinoma", "CCA", "biliary atresia", "BA", "polycystic liver diseases", "PLD", "cholangiopathies", "cholestatic liver disease". Most significant articles in full-text English were selected. The reference lists of selected papers were also considered.

Evaluation of a small organ procurement organization in the Basque country, Spain.

A limited supply of organs is the main obstacle for organ transplantation. The shortage reflects not only a shortage of donors but also a failure to make use of existing donors. The Basque Country Transplant Coordination Team is an organ procurement organization that operates in the Basque country, an area of 7260 km2 with 2.1 million inhabitants. From January 1, 1990, to December 31, 1995, the number of potential cadaveric organ donors found by the team increased, to 70 donors per million inhabitants in 1995. Since 1993, the organization has had more than 30 donors per million persons and has procured more than 90 cadaveric organs, including more than 60 cadaveric kidneys, per million persons. Because of these rates, the team coordinated 61.7 cadaveric kidney transplants per million persons during 1995. This paper describes some characteristics of the Basque organ procurement organization that might explain these results.

[Yersiniosis in a general hospital in the Basque country (1984-1989). Clinical and epidemiological aspects]. / Yersiniosis en un hospital general del País Vasco (1984-1989). Aspectos clínico-epidemiológicos.

BACKGROUND: The features of the diseases caused by Yersinia have not been properly evaluated in the Basque Country. The present study was performed to assess the incidence and consequences of this infection. METHODS: 51 cases of Yersinia infection in a general hospital during the period 1984-1989 were reviewed. Clinical, epidemiological, microbiological, and therapeutic data and the hospital stay were evaluated. RESULTS: 62% of patients were males with a mean age of 16 +/- 19.4 years. Most came from urban areas. 40% of cases developed in winter and 32% in summer. The presenting features were: acute gastroenteritis (66%), pseudoappendicitis (10%), sepsis (4%), lymphadenopathy (2%) and others (18%). 40% of the patients had significant underlying diseases, and 16% had complications attributable to the infection. The microbiological diagnosis was made by stool culture in 88%. 96% corresponded to Yersinia enterocolitica (biotype 4), serogroup 0: 3 (93%). Yersinia pseudotuberculosis was isolated from the culture of a cervical lymph node in one patient. In the Yersinia enterocolitica strains the most common antibiotic resistances were to ampicillin (87%), cephalotin (81%), ticarcillin (75%), mezlocillin (43%) and piperacillin (43%). The mean hospital stay was 6.1 +/- 12.2 days and it was significantly shorter in children (3.3 +/- 6.1%) than in the adult population (10.9 +/- 17.4) (p less than 0.05). It was longer in patients with underlying diseases (13.3 +/- 17.8 vs 3.3 +/- 5.6) (p less than 0.005). CONCLUSIONS: Our patient population had male and urban predominance. Most infections were caused by Yersinia enterocolitica and presented as acute gastroenteritis, without differences between winter and summer. We point out to the relationship between Yersinia infection, abnormalities in iron metabolism and immunosuppression. There were few complications of the infection. The mean hospital stay was directly correlated with age and underlying diseases.