Prospective histomorphometric and DXA evaluation of bone remodeling in imatinib-treated CML patients: evidence for site-specific skeletal effects.

CONTEXT: Imatinib is a tyrosine kinase inhibitor that has been successfully used to treat Philadelphia chromosome-positive chronic myeloid leukemia (CML) and Kit(+) gastrointestinal stromal tumors. We have previously shown that imatinib therapy is associated with an increase in trabecular bone volume. OBJECTIVE: In the present study, we performed a prospective analysis of bone indices in imatinib-treated CML patients to determine the mechanism responsible for this altered bone remodeling. DESIGN, PATIENTS, AND INTERVENTION: This study assessed the effects of high-dose (600 mg/d) imatinib on bone parameters in newly diagnosed chronic-phase Philadelphia chromosome-positive CML patients (n = 11) enrolled in the TIDEL II study. At baseline and after 6, 12, and 24 months of treatment, serum markers of bone remodeling were quantitated, dual-energy x-ray absorptiometry analysis of bone mineral density (BMD) was carried out, and a bone biopsy was collected for histological and micro-computed tomography analysis. RESULTS: Our studies show that the increase in trabecular bone volume and trabecular thickness after imatinib treatment was associated with a significant decrease in osteoclast numbers, accompanied by a significant decrease in serum levels of a marker of osteoclast activity. In contrast, osteoblast numbers were not altered by up to 24 months of imatinib treatment. Notably, we also found that imatinib caused a site-specific decrease in BMD at the femoral neck. CONCLUSIONS: These data suggest that imatinib therapy dysregulates bone remodeling, causing a generalized decrease in osteoclast number and activity that is not counterbalanced by a decrease in osteoblast activity, leading to increased trabecular bone volume. Further long-term investigations are required to determine the causes and consequences of the site-specific decrease in BMD at the femoral neck.

Phenoxodiol, an experimental anticancer drug, shows potent antiangiogenic properties in addition to its antitumour effects.

Phenoxodiol (2H-1-benzopyran-7-0,1, 3-[4-hydroxyphenyl], PXD) is a synthetic analogue of the naturally-occurring plant isoflavone and anticancer agent, genistein. PXD directly induces mitotic arrest and apoptosis in most cancer cells and is currently undergoing clinical trials, as a chemotherapeutic in ovarian and prostate cancers. We show here that PXD also exhibits potent antiangiogenic properties. Thus, it inhibited endothelial cell proliferation, migration and capillary tube formation and inhibited expression of the matrix metalloproteinase MMP-2, a major matrix degrading enzyme. Importantly, we demonstrate that PXD is functional in vivo since it inhibited the extent of capillary tube invasion in an in vivo model of angiogenesis. We show that phenoxodiol inhibits hallmarks of endothelial cell activation, namely TNF or IL-1 induced E-selectin and VCAM-1 expression and IL-8 secretion. However, PXD had no effect on unstimulated endothelial cells. We also describe that PXD inhibits the lipid kinase sphingosine kinase, which recently has been implicated in endothelial cell activation and angiogenesis as well as oncogenesis. Thus, our results suggest that PXD may be an effective anticancer drug targeting the two drivers of tumour growth--the proliferation of the tumour cells themselves and the angiogenic and inflammatory stimulation of the vasculature.

Role of protein kinase Czeta in thrombin-induced endothelial permeability changes: inhibition by angiopoietin-1.

Endothelial cell leakiness is regulated by mediators such as thrombin, which promotes endothelial permeability, and anti-inflammatory agents, such as angiopoietin-1. Here we define a new pathway involved in thrombin-induced permeability that involves the atypical protein kinase C isoform, PKCzeta. Chemical inhibitor studies implicated the involvement of an atypical PKC isoform in thrombin-induced permeability changes in human umbilical vein endothelial cells. Thrombin stimulation resulted in PKCzeta, but not the other atypical PKC isoform, PKClambda, translocating to the membrane, an event known to be critical to enzyme activation. The involvement of PKCzeta was confirmed by overexpression of constitutively active PKCzeta, resulting in enhanced basal permeability. Dominant-negative PKCzeta prevented the thrombin-mediated effects on endothelial cell permeability and inhibited thrombin-induced activation of PKCzeta. Rho activation does not appear to play a role, either upstream or downstream of PKCzeta, as C3 transferase does not block thrombin-induced PKCzeta activation and dominant-negative PKCzeta does not block thrombin-induced Rho activation. Finally, we show that angiopoietin-1 inhibits thrombin-induced PKCzeta activation, Rho activation, and Ca(++) flux, thus demonstrating that the powerful antipermeability action of angiopoietin-1 is mediated by its action on a number of signaling pathways induced by thrombin and implicated in permeability changes.

Role of a paediatric nurse in primary care 2: research findings.

This article is the second of a two-part article that presents the findings of a study focusing on the role and function of two qualified children's nurses, each working within a different primary healthcare team (PHCT). The first part described the variation in settings for community paediatric nurses, the paucity of literature discussing the role of a paediatric nurse working as a member of a PHCT, the application of a research methodology that incorporated practitioner values and experience, the application of naturalist inquiry and the use of a formative evaluation strategy which enabled the researcher to be involved in directing and supporting the research nurses with the data collection (Vol 11(22): 1452-60). This second part focuses on the findings and discussions where it was demonstrated that qualified children's nurses working in community setting contributes to raising the overall support and quality of care for a whole range of conditions currently perceived as low profile. There was evidence that these nurses catered for unmet needs and were, at times, functioning as nurse practitioners and on occasions as advanced practitioners. These findings may contribute as a catalyst for change in informing the development of children's nursing services as part of the Children's National Service Framework.

Role of a paediatric nurse in primary care 1: research issues.

This study, which looked at the potential for the role of a paediatric nurse in primary care, was a tripartite partnership arrangement with Community Health Sheffield NHS Trust, the University of Sheffield and the Children's Hospital Sheffield. The study focused on the role and function of two qualified children's nurses each working within a different primary healthcare team (PHCT). It was important to allow the role to evolve without undue pressure, so that members of the PHCT could work with the nurses to establish what would be the most useful and relevant tasks to be carried out by the team. The methodological problems posed in this type of study where little was known about how a children's nurse would work in a PHCT resulted in exploring the concept of a formative evaluation process. The major data source and contribution to the evaluation were the nurses' reflective accounts of their role and function as members of the PHCT. Case studies written in the form of reflective diaries provided a self-critical approach to the record of tasks undertaken and explained why the service was taken up. Five constructions emerged: duplication and perceived threats to established nursing roles within the PHCT; improved care of children in PHCT settings; the nature of support for children and families; working as a nurse practitioner; and meeting unmet need. A clear need was demonstrated for a qualified children's nurse working in a community setting to raise the overall support and quality of care for a whole range of conditions which are currently low profile. There was evidence that these nurses met unmet need and were, at times, functioning as nurse practitioners and at times as advanced practitioners. This article, the first of two parts, focuses on the methods used and the associated problems. The second part will present the findings and discussions of the research.