Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has recently attracted attention as a potential therapeutic agent in the treatment of cancer. We assessed the roles of p53, TRAIL receptors, and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (c-FLIP) in regulating the cytotoxic effects of recombinant TRAIL (rTRAIL) alone and in combination with chemotherapy [5-fluorouracil (5-FU), oxaliplatin, and irinotecan] in a panel of colon cancer cell lines. Using clonogenic survival and flow cytometric analyses, we showed that chemotherapy sensitized p53 wild-type, mutant, and null cell lines to TRAIL-mediated apoptosis. Although chemotherapy treatment did not modulate mRNA or cell surface expression of the TRAIL receptors death receptor 4, death receptor 5, decoy receptor 1, or decoy receptor 2, it was found to down-regulate expression of the caspase-8 inhibitor, c-FLIP. Stable overexpression of the long c-FLIP splice form but not the short form was found to inhibit chemotherapy/rTRAIL-induced apoptosis. Furthermore, siRNA-mediated down-regulation of c-FLIP, particularly the long form, was found to sensitize colon cancer cells to rTRAIL-induced apoptosis. In addition, treatment of a 5-FU-resistant cell line with 5-FU down-regulated c-FLIP expression and sensitized the chemotherapy-resistant cell line to rTRAIL. We conclude that TRAIL-targeted therapies may be used to enhance conventional chemotherapy regimens in colon cancer regardless of tumor p53 status. Furthermore, inhibition of c-FLIP may be a vital accessory strategy for the optimal use of TRAIL-targeted therapies.

The roles of thymidylate synthase and p53 in regulating Fas-mediated apoptosis in response to antimetabolites

Fas (CD95/Apo-1) is a member of the tumor necrosis factor receptor family. Receptor binding results in activation of caspase 8, leading to activation of proapoptotic downstream molecules. We found that expression of Fas was up-regulated >10-fold in MCF-7 breast and HCT116 and RKO colon cancer cell lines after treatment with IC(60) doses of 5-fluorouracil (5-FU) and raltitrexed (RTX). Combined treatment with the agonistic Fas antibody CH-11 and either 5-FU or RTX resulted in a highly synergistic induction of apoptosis in these cell lines. Similar results were obtained for another antifolate, Alimta. Induction of thymidylate synthase expression inhibited Fas induction in response to RTX and Alimta, but not in response to 5-FU. Furthermore, thymidylate synthase induction abrogated the synergy between CH-11 and both antifolates but had no effect on the synergistic interaction between 5-FU and CH-11. Inactivation of p53 in MCF-7 and HCT116 cell lines blocked 5-FU- and antifolate-mediated up-regulation of Fas. Furthermore, Fas was not up-regulated in response to 5-FU or antifolates in the p53-mutant H630 colon cancer cell line. Lack of Fas up-regulation in the p53-null and -mutant lines abolished the synergistic interaction between 5-FU and CH-11. Interestingly, synergy was still observed between the antifolates and CH-11 in the p53-null HCT116 and p53-mutant H630 cell lines, although this was significantly reduced compared with the p53 wild-type cell lines. Our results indicate that Fas is an important mediator of apoptosis in response to both 5-FU and antifolates.

The effect of type of hip protector and resident characteristics on adherence to use of hip protectors in nursing and residential homes - an exploratory study

Objectives: To investigate the factors influencing the acceptability of hip protectors to residents of nursing and residential homes, especially the effect of hip protector type, and resident characteristics. Design: A randomised controlled trial with 12 weeks follow-up. Participants were randomised to receive either Safehips or HipSaverTM hip protectors. Setting/Participants: 109 residents aged 61 to 98 years from seven residential homes and two nursing homes in Northern Ireland. Main outcome measures: Percentage day-time use of the hip protectors over 12 weeks and ongoing use at 12 weeks. Results: 42% (119/285) of residents invited to enter the studyagreed to take part, and 109 started to wear the hip protectors. 43.1% (47/109) were still using them at 12 weeks. Mean percentage day-time use for all residents during 12 weeks was 48.6%. There was no significant difference in percentage day-time use (p=0.40), or use at 12 weeks (p=0.56) between the residents wearing Safehips and HipSaverTM protectors. Greater percentage daytime use of hip protectors was associated with being resident in a home for the elderlymentallyinfirm (75.1%, pp0.0005), having a low (12 or less) Barthel score (61.1%, pp0.0005), and having been injured in a fall in the last 12 months (57.3%, p=0.012). Conclusions: The type of hip protector appeared to make no difference to their continued use by residents. Residents with a historyof a fall and those who are physicallyand mentallyincapacitated appear to be more likelyto wear hip protectors. These residents, who are at high risk of falling, are also highlydependent on nursing staff. Efforts to increase hip protector use in residential and nursing home should focus on staff, who are in the best position to advise and influence residents and their relatives.

A model for developing, implementing and evaluating a strategy to improve nursing and midwifery care

Background: Health care organizations world wide are faced with the need to develop and implement strategic organizational plans to meet the challenges of modern health care. There is a need for models for developing, implementing and evaluating strategic plans that engage practitioners, and make a measurable difference to the patients that they serve. This article describes the development of such a model to underpin a strategy for nursing and midwifery in an acute hospital trust. An integrated model: The processes for strategy development (values clarification, critical companionship and focus groups) are discussed, together with the development of processes for implementation, based upon a modification of the PARIHS (Promoting Action on Research Implementation in Health Services) conceptual framework. Finally, the methods for evaluating the strategy (a pre-test/post-test approach measuring the quality of nursing care, the degree to which the organization supports professional nursing care, the leadership styles of ward managers, and patient satisfaction with care) are described. Conclusion: The model is offered as one that may be of use to others who wish to develop an integrated approach to strategic change; an approach in which the development, implementation and evaluation of strategic plans are informed by the core values of nurses and midwives.

Factors affecting adherence to use of hip protectors amongst residents of nursing homes - A correlation study

Background: Hip protectors are protective pads designed to cover the greater trochanter and attenuate or disperse the force of a fall sufficiently to prevent a hip fracture. Promising results from randomised controlled trials in nursing homes have resulted in hip protectors being widely recommended in the health care literature and in national guidelines. Objectives: The objectives of the study were to identify characteristics of individual residents, and the organisational features of the homes in which they live, which may affect adherence to wearing hip protectors. Design: An observational, correlation study designed to identify factors related to adherence. Setting: Forty nursing and residential homes in the UK. Participants: 1346 residents of the homes who were not confined to bed and with no pressure sore on the hip. Methods: The introduction of an evidence-based policy to offer Safehips hip protectors to residents free of charge and with support from a nurse facilitator. Adherence to wearing the hip protectors was observed over 72 weeks. Results: Initial acceptance of the hip protectors was 37.2%. Continued adherence was 23.9% at 24 weeks; 23.2% at 48 weeks; and 19.9% at 72 weeks. Greater adherence was associated with the following individual resident characteristics: a greater degree of dependency (95% CI 1.39 - m3.78) and cognitive impairment (95% CI 1.01 - 2.98); being male rather than female (95% CI 1.06 - 2.48). Greater adherence was also associated with the following organisational characteristics of homes: fewer changes of senior manager during the study period (95% CI 1.01 - 8.51), and being resident in a home with a resident profile showing a greater proportion of residents with a higher degree of dependency (95% CI 1.04 - 1.27). There was wide a variation in the degree of success in implementation between homes (adherence of 0 - 100% at 24 weeks). Conclusions: Those implementing a policy of introducing hip protectors into nursing and residential homes should consider targeting residents with cognitive impairment. Such residents are at greater risk of hip fracture and appear to be more likely to continue wearing hip protectors. Those charged with implementing changes inpractice or policy should consider how the context for implementation can be optimised to increase the likelihood of success.