3,600 research outputs found

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

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    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

    Barnes Hospital Bulletin

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    https://digitalcommons.wustl.edu/bjc_barnes_bulletin/1164/thumbnail.jp

    Corporate social responsibility and global standardization: sustainable environmental management in the chemical industry

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    Corporate social responsibility and sustainable development are issues that been in the forefront of corporate strategy for several decades. The increase in the power of environmental groups, the ease of cross border information flow, and the rising concern of the public with regards to global impact of environmental issues are motivating factors resulting in the establishment of environmental management systems. Many multinational chemical companies, threatened with the possibility of the establishment of new, stricter, environmental laws, are actively working to demonstrate their corporate social responsibility while operating in a global market with regards to developing and implementing voluntary programs to handle the increasingly important issues surrounding environmental responsibility and global sustainability. The integration of the environmental management system into the corporate vision, mission and strategic plan is demonstrated with the ultimate goal of changing corporate culture in the companies which have the power to affect international environmental policies.chemical industry, corporate social responsibility, environmental management system, global sustainability.

    The Spanish savings banks and the competitive cooperation model (1928-2002)

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    This paper explores the relationship between the nature of Spanish Savings banks and the extent of their market success during the twentieth century. It deals with the key factors that have made so good a performance possible, such as: their ability to promote private saving, to cooperate with government economic policy, to adapt to changing circumstances, to operate in particular geographical areas, and to cooperate with one another. Finally, the paper deals with this last factor in depth. The competitive cooperation model is used to explain the outstanding role of the Spanish Confederation of Savings Banks in making the strategic alliance among the Spanish savings banks possible
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