The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma

Cholangiocarcinoma (CCA) is an aggressive cancer with high resistance to chemotherapeutics. CCA is enriched in cancer stem cells, which correlate with aggressiveness and prognosis. FXR, a member of the metabolic nuclear receptor family, is markedly down-regulated in human CCA. Our aim was to evaluate, in primary cultures of human intrahepatic CCA (iCCA), the effects of the FXR agonist obeticholic acid (OCA), a semisynthetic bile acid derivative, on their cancerogenic potential. Primary human iCCA cell cultures were prepared from surgical specimens of mucinous or mixed iCCA subtypes. Increasing concentrations (0–2.5 μM) of OCA were added to culture media and, after 3–10 days, effects on proliferation (MTS assay, cell population doubling time), apoptosis (annexin V-FITC/propidium iodide), cell migration and invasion (wound healing response and Matrigel invasion assay), and cancerogenic potential (spheroid formation, clonogenic assay, colony formation capacity) were evaluated. Results: FXR gene expression was downregulated (RT-qPCR) in iCCA cells vs normal human biliary tree stem cells (p < 0.05) and in mucinous iCCA vs mixed iCCA cells (p < 0.05) but was upregulated by addition of OCA. OCA significantly (p < 0.05) inhibited proliferation of both mucinous and mixed iCCA cells, starting at a concentration as low as 0.05 μM. Also, CDCA (but not UDCA) inhibited cell proliferation, although to a much lower extent than OCA, consistent with its different affinity for FXR. OCA significantly induced apoptosis of both iCCA subtypes and decreased their in vitro cancerogenic potential, as evaluated by impairment of colony and spheroid formation capacity and delayed wound healing and Matrigel invasion. In general, these effects were more evident in mixed than mucinous iCCA cells. When tested together with Gemcitabine and Cisplatin, OCA potentiated the anti-proliferative and pro-apoptotic effects of these chemotherapeutics, but mainly in mixed iCCA cells. OCA abolished the capacity of both mucinous and mixed iCCA cells to form colonies when administered together with Gemcitabine and Cisplatin. In subcutaneous xenografts of mixed iCCA cells, OCA alone or combined with Gemcitabine or Cisplatin markedly reduced the tumor size after 5 weeks of treatment by inducing necrosis of tumor mass and inhibiting cell proliferation. In conclusion, FXR is down-regulated in iCCA cells, and its activation by OCA results in anti-cancerogenic effects against mucinous and mixed iCCA cells, both in vitro and in vivo. The effects of OCA predominated in mixed iCCA cells, consistent with the lower aggressiveness and the higher FXR expression in this CCA subtype. These results, showing the FXR-mediated capacity of OCA to inhibit cholangiocarcinogenesis, represent the basis for testing OCA in clinical trials of CCA patients

Personality Testing in the Church of Scientology: \ud Implications for Outcome Research\ud

Many fields of modern society require scientific proof of effectiveness before new methods can be widely accepted, as in clinical trials for new drugs, educational evaluation for teaching approaches, and outcome studies for psychological interventions. Previous outcome studies on the results from Scientology services are reviewed and found to be inconclusive. The paper is devoted to the question of whether the existing data base of several thousand case histories could be used for outcome studies. The existing data contain personality test scores on the Oxford Capacity Analysis (OCA) administered before and after scientology services. A detailed analysis of the OCA demonstrates that it was derived from the Johnson Temperament Analysis (JTA), a psychological test of poorly documented validity, by paraphrasing its items, copying its scoring weights and transforming its test norms, with some alterations. It was concluded that the OCA is presently unsuitable for outcome studies, but that this situation could change if additional research could demonstrate that the OCA had validities comparable to other personality tests. For future use, it is recommended that an entirely new version of the OCA be constructed with completely original items, simplified scoring weights, and empirically derived norms, and that its validity and reliability be demonstrated prior to implementation.Scientology, outcomes, OCA, Oxford Capacity Analysis, validatio

Assessing the Endogeneity of OCA Conditions in EMU

The academic and political discussion about which countries met the conditions for joining EMU was decisively influenced by the Frankel and Rose (1997) hypothesis concerning endogenous OCA properties. The answer to their question "Is EMU more justifiable ex post than ex ante?" was a definite yes in their ex ante analysis. Our ex post examination of the euro's first decade, however suggests that the hypothesis does not hold for some countries. This paper utilizes panel data estimation techniques to compute OCA indices that help assess the OCA endogeneity hypothesis and signal current external and fiscal imbalances.Optimum currency areas; OCA index; Monetary union.

Obeticholic acid for the treatment of primary biliary cholangitis in adult patients: clinical utility and patient selection.

Primary biliary cholangitis (PBC), previously known as primary biliary "cirrhosis", is a rare autoimmune liver disease characterized by the hallmark autoantibodies to mitochondrial antigens and immune-mediated destruction of small bile duct epithelial cells leading to cholestasis and cirrhosis. Surprisingly, while immune modulators have not been effective in the treatment of PBC, supplementation with the hydrophilic bile acid (BA) ursodeoxycholic acid (UDCA) has been demonstrated to slow the disease progression. However, a significant minority of PBC patients do not have a complete response to UDCA and remain at risk of continued disease progression. Although the mechanisms of action are not well understood, UDCA provided proof of concept for BA therapy in PBC. Obeticholic acid (OCA), a novel derivative of the human BA chenodeoxycholic acid, is a potent agonist of the nuclear hormone receptor farnesoid X receptor, which regulates BA synthesis and transport. A series of clinical trials of OCA in PBC, primarily in combination with UDCA, have established that OCA leads to significant reductions in serum alkaline phosphatase that are predicted to lead to improved clinical outcomes, while dose-dependent pruritus has been the most common adverse effect. On the basis of these studies, OCA was given conditional approval by the US Food and Drug Administration with plans to establish the long-term clinical efficacy of OCA in patients with advanced PBC

On one-way cellular automata with a fixed number of cells

We investigate a restricted one-way cellular automaton (OCA) model where the number of cells is bounded by a constant number k, so-called kC-OCAs. In contrast to the general model, the generative capacity of the restricted model is reduced to the set of regular languages. A kC-OCA can be algorithmically converted to a deterministic finite automaton (DFA). The blow-up in the number of states is bounded by a polynomial of degree k. We can exhibit a family of unary languages which shows that this upper bound is tight in order of magnitude. We then study upper and lower bounds for the trade-off when converting DFAs to kC-OCAs. We show that there are regular languages where the use of kC-OCAs cannot reduce the number of states when compared to DFAs. We then investigate trade-offs between kC-OCAs with different numbers of cells and finally treat the problem of minimizing a given kC-OCA

The Endogeneity of optimum currency area criteria, intraindustry trade and EMU enlargement

This paper tests an endogeneity hypothesis of optimum currency area (OCA) criteria (Frankel and Rose, 1998) on a cross-section of OECD countries between 1990 and 1999. The findings indicate that convergence of business cycles relates to intra-industry trade, but has no direct relation between business cycles and bilateral trade intensity. As far as intra-industry trade is positively correlated with trade intensities, this result confirms the OCA endogeneity hypothesis. The endogeneity of OCA linkage criteria implies extensive business cycle harmonization between CEECs and EU countries in the medium term.optimum currency area; EMU; trade; business cycle; CEECs