c-FLIP: A Key Regulator of Colorectal Cancer Cell Death

c-FLIP is an inhibitor of apoptosis mediated by the death receptors Fas, DR4 and DR5 and is expressed as long (c-FLIPL) and short (c-FLIPS) splice forms. We found that siRNA-mediated silencing of c-FLIP induced spontaneous apoptosis in a panel of p53 wild-type, mutant and null colorectal cancer (CRC) cell lines and that this apoptosis was mediated by caspase 8 and FADD. Further analyses indicated the involvement of DR5 and/or Fas (but not DR4) in regulating apoptosis induced by c-FLIP siRNA. Interestingly, these effects were not dependent on activation of DR5 or Fas by their ligands TRAIL and FasL. Overexpression of c-FLIPL, but not c-FLIPS, significantly decreased spontaneous and chemotherapy-induced apoptosis in HCT116 cells. Further analyses with splice form-specific siRNAs indicated that c-FLIPL was the more important splice form in regulating apoptosis in HCT116, H630 and LoVo cells, although specific knock down of c-FLIPS induced more apoptosis in the HT29 cell line. Importantly, intra-tumoral delivery of c-FLIP-targeted siRNA duplexes induced apoptosis and inhibited the growth of HCT116 xenografts in Balb/c SCID mice. In addition, the growth of c-FLIPL overexpressing CRC xenografts was more rapid than control xenografts, an effect that was significantly enhanced in the presence of chemotherapy. These results indicate that c-FLIP inhibits spontaneous death ligand-independent, death receptor-mediated apoptosis in CRC cells and that targeting c-FLIP may have therapeutic potential for the treatment of colorectal cancer.

Effect of ternary phosphate-based glass compositions on osteoblast and osteoblast-like prolferation, differentiation and death in vitro

There is currently a need to expand the range of graft materials available to orthopaedic surgeons. This study investigated the effect of ternary phosphate based glass (PBG) compositions on the behaviour of osteoblast and osteoblast-like cells. PBGs of the formula in mol% P2O5 (50)-CaO (50-X)-Na2O (X), where X was either 2, 4, 6, 8 or 10 were produced and their influence on the proliferation, differentiation and death in vitro of adult human bone marrow stromal cells (hBMSCs) and human fetal osteoblast 1.19 (HFOB 1.19) cells were assessed. Tissue culture plastic (TCP) and hydroxyapatite (HA) were used as controls. Exposure to PBGs in culture inhibited cell adhesion, proliferation and increased cell death in both cell types studied. There was no significant difference in %cell death between the PBGs which was significantly greater than the controls. However, compared to other PBGs, a greater number of cells was found on the 48 mol% CaO which may have been due to either increased adherence, proliferation or both. This composition was capable of supporting osteogenic proliferation and early differentiation and supports the notion that chemical modification of the glass could to lead to a more biologically compatible substrate with the potential to support osteogenic grafting. Realisation of this potential should lead to the development of novel grafting strategies for the treatment of problematic bone defects.

The death blow to unlimited liability in Victorian Britain: The City of Glasgow failure

In 1878, one of Britain's largest banks, the City of Glasgow Bank, collapsed, leaving a huge deficit between its assets and liabilities. As this bank, similar to many other contemporary British banks, had unlimited liability, its failure was accompanied by the bankruptcy of the vast majority of its stockholders. It is generally believed that the collapse of this depository institution revealed the extent to which ownership in large joint-stock banks had been diffused to investors of very modest means. It is also believed that the failure resulted in bank shareholders dumping their shares unto the market. Our evidence, garnered from ownership records, trading data, and stock prices, offers no support for these widely held beliefs. © 2007 Elsevier Inc. All rights reserved.

An Unkind Cut: Circumcision, Death and the Impact of Irish Health Policy on Asylum Seekers

Healthcare and the wider social determinants of health are the keystone of a number of complex progressive social justice issues that evoke complex emotions. As the demography of Ireland rapidly changes, the practices and expectations of some asylum seekers presents new opportunities for the providers of health service provision and reform. This paper looks at some of the emotions evoked in health care issues and draws on observations and interviews from empirical fieldwork carried out for the Health Research Board. The research was conducted both in the Adelaide and Meath Hospital, incorporating the National Children’s Hospital, Tallaght and in a number of refugee reception centres in Ireland. At one level honouring faith choices within a healthcare setting is a societal acknowledgement made to people at their most vulnerable, that the potent and cathartic transformative rituals they value are significant in mediating and managing their emotions - at another level, it is a practical and a symbolic communication of a statutory commitment to inter-culturalism and community cohesion..

Factor markets in England before the Black Death

Modern English factor markets originated during the two centuries of active commercialization that preceded the Black Death. An active labour market was established by the late twelfth century. Evolution of a land market followed the legal reforms of the 1170s and 1180s, which created legally secure and defensible property rights in land. These rights stimulated growth of a capital market, since land became a security against which credit could be obtained. Nevertheless, none of these nascent factor markets functioned unconstrained and each became embedded in legal, tenurial, and institutional complexities and rigidities which it took later generations centuries to reform.