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PubMed2001

Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific guanine exchange factor pathways.

Approximately 50% of metastatic tumors contain Ras mutations. Ras proteins can activate at least three downstream signaling cascades mediated by the Raf-MEK-extracellular signal-regulated kinase family, phosphatidylinositol-3 (PI3) kinase, and Ral-specific guanine nucleotide exchange factors (RalGEFs). Here we investigated the contribution of RalGEF and ERK activation to the development of experimental metastasis in vivo and associated invasive properties in vitro. Each pathway contributes distinct properties to the metastatic phenotype. Following lateral tail vein injection, 3T3 cells transformed by constitutively active Raf or MEK produced lung metastasis that displayed circumscribed, noninfiltrating borders. In contrast, 3T3 cells transformed by Ras(12V,37G), a Ras effector mutant that activates RalGEF but not Raf or P13 kinase, formed aggressive, infiltrative metastasis. Dominant negative RalB inhibited Ras(12V,37G)-activated invasion and metastasis, demonstrating the necessity of the RalGEF pathway for a fully transformed phenotype. Moreover, 3T3 cells constitutively expressing a membrane-associated form of RalGEF (RalGDS-CAAX) formed invasive tumors as well, demonstrating that activation of a RalGEF pathway is sufficient to initiate the invasive phenotype. Despite the fact that Ras(12V,37G) expression does not elevate ERK activity, inhibition of this kinase by a conditionally expressed ERK phosphatase demonstrated that ERK activity was necessary for Ras(12V,37G)-transformed cells to express matrix-degrading activity in vitro and tissue invasiveness in vivo. Therefore, these experiments have revealed a hitherto-unknown but essential interaction of the RalGEF and ERK pathways to produce a malignant phenotype. The generality of the role of the RalGEF pathway in metastasis is supported by the finding that Ras(12V,37G) increased the invasiveness of epithelial cells as well as fibroblasts.

3T3 Cells↗
PubMed1995

Survival factors, intracellular signal transduction, and the activation of endonucleases in apoptosis.

Cell survival is normally mediated by factors in the extracellular environment, whereas genetic changes that constitutively activate intracellular survival pathways often occur in cancer. It is suggested that a Ras/Raf/MAP kinase-dependent pathway is critical for cell survival. Apoptosis results from loss of these survival factors or deregulation of survival pathways. If protein kinase cascades mediate survival, then it is likely that phosphatases mediate apoptosis. Potential targets for dephosphorylation include regulators of ion homeostasis as these have been implicated in the regulation of endonucleases associated with apoptosis. Survival factors also modulate anticancer drug response and understanding these pathways may improve therapy.

Animals↗
PubMed2002

Assessing clinical pathways use in a community hospital: it depends on what "use" means.

BACKGROUND: Many benefits have been associated with the use of clinical pathways, yet developing them can be costly, and implementing them is not always successful. A 300-bed Midwestern community hospital began a clinical pathways program in 1995, and by fall 1998, 15 pathways were in various stages of implementation, with 3 under development. Many challenges had been encountered, but hospital leaders were eager to find ways to increase pathway use. METHODS: A qualitative case study design was used to investigate four clinical pathways, two perceived as being "used" and two that were perceived as "not used". Each pathway was analyzed as a separate case, followed by cross-case analysis. Qualitative data were collected in 65 semistructured interviews with administrators, physicians, physicians' office staff, nurses, and allied health professionals at the hospital. Data were also collected through observation and document analysis. RESULTS: The two used pathways had been introduced as part of a larger change in care, whereas the two pathways not used had been introduced as stand-alone innovations. Confusing and inadequately developed aspects of the hospital's clinical pathways program included its purposes, the definition of pathway use, pathway procedures, accountability, education, and incentives. A new case management department, ongoing administrative support, and a sophisticated medical information system were viewed as supports for continued growth in the program. CONCLUSIONS: Implementation of clinical pathways was delayed and complicated by the varied perceptions of the program among stakeholders. Lack of clarity and consistency in how information about the program was communicated made it difficult for clinicians to develop a shared understanding of clinical pathways.

Attitude of Health Personnel↗
PubMed2000

Care pathways: an evaluation of their effectiveness.

This paper reports on a quasi-experimental case study of two care pathways--a midwifery-led maternity pathway and a breast disease pathway developed within one British National Health Service Trust. Of the aspects evaluated, those reported here are: a comparison of clinical care delivered before (the control group) and after the introduction of the two pathways; a comparison of patient satisfaction levels before (the control group) and after the introduction of the two pathways; and views of staff involved in the development and operation of the two pathways. The results are mixed. In the breast disease pathway five of 12 clinical indicators showed change, but only two of these showed statistically significant changes; three were considered of clinical significance but could not be tested statistically. In the maternity pathway, after allowing for the effect of gravid status, five of 10 indicators showed changes between the pre-pathway and pathway users and of these four showed statistically significant changes. Patient satisfaction levels showed little overall change--only 15% of the questions for breast disease and 9% for maternity showed any statistically significant change. However, both surveys indicated precise areas where a change resulting from the introduction of the pathway could be linked to an increase in satisfaction. The clinical staff interviewed highlighted many positive features of the tool (26/40 comments). The most frequently cited favourable comment was its ability to make staff focus on the clinical care they were providing and how this could be improved. It also highlighted some areas for concern, in particular the introduction of pathway documentation.

Attitude of Health Personnel↗