La(iii) biodistribution profiles from intravenous and oral dosing of two lanthanum complexes, La(dpp)3 and La(XT), and evaluation as treatments for bone resorption disorders.

Trivalent lanthanum (La3+) has the potential to treat bone resorption disorders (such as osteoporosis) by eliciting a bone-building response in the cells which control skeletal remodelling. Because La3+ suffers from extremely poor intestinal absorption, specifically designed chelators are required in order that a biologically active form of lanthanum can be administered orally. Two such chelators, 1,2-dimethyl-3-hydroxy-4-pyridinone (Hdpp) and bis-{[bis(carboxymethyl)amino]methy}phosphinic acid (H5XT), have previously been the subjects of extensive physical, in vitro, and in vivo testing as the tris- and mono-lanthanum(iii) complexes La(dpp)3 and La(XT), respectively. In this manuscript, we expand upon those studies to include 4-week intravenous (IV) and oral La3+ biodistribution profiles, which show that the metal ion initially accumulates in the liver followed by preferential redistribution and retention by bone. Of the two compounds, La(XT) demonstrates the more favourable in vivo characteristics, therefore dose-dependent oral biodistribution studies were carried out with this complex. These show drug saturation above a dose of 100 mg kg-1 day-1, so liver histology was performed in order to assess any potential toxicity. Finally, we improve upon the physical characterization of La(dpp)3 to include a single crystal X-ray structure, which exhibits an 8-coorindate La3+ centre with two bound water molecules, and a disordered exoclathrate-type hydrogen bonded network.

Harnessing the bone-seeking ability of Ca(II)-like metal ions in the treatment of metastatic cancer and resorption disorders.

Metal ions are naturally retained by skeletal tissues in living systems because of their high affinity for the hydroxyapatite-like mineral matrix that makes up cortical bone. This is particularly true for metal ions that bear a close resemblance to calcium(ii) (such as the lanthanides or alkaline earth metals), and in a few key cases this targeting ability has been exploited in order to develop medicinal agents that are intended to treat bones which have become diseased. In this review, we focus on two areas where this has been particularly effective: first is in the diagnosis and therapy of metastatic bone cancer, in which radioactive metal ions including (99m)Tc, (153)Sm, and (223)Ra are used to image, alleviate, and ablate harmful cancerous legions with good specificity versus healthy tissues; second is the use of trivalent lanthanides to treat osteoporosis, an emerging concept which has gathered significance over the last 15 years, and is now entering preclinical trials with carefully designed systems.

Regulation of osteosarcoma cell lung metastasis by the c-Fos/AP-1 target FGFR1.

Osteosarcoma is the most common primary malignancy of the skeleton and is prevalent in children and adolescents. Survival rates are poor and have remained stagnant owing to chemoresistance and the high propensity to form lung metastases. In this study, we used in vivo transgenic models of c-fos oncogene-induced osteosarcoma and chondrosarcoma in addition to c-Fos-inducible systems in vitro to investigate downstream signalling pathways that regulate osteosarcoma growth and metastasis. Fgfr1 (fibroblast growth factor receptor 1) was identified as a novel c-Fos/activator protein-1(AP-1)-regulated gene. Induction of c-Fos in vitro in osteoblasts and chondroblasts caused an increase in Fgfr1 RNA and FGFR1 protein expression levels that resulted in increased and sustained activation of mitogen-activated protein kinases (MAPKs), morphological transformation and increased anchorage-independent growth in response to FGF2 ligand treatment. High levels of FGFR1 protein and activated pFRS2α signalling were observed in murine and human osteosarcomas. Pharmacological inhibition of FGFR1 signalling blocked MAPK activation and colony growth of osteosarcoma cells in vitro. Orthotopic injection in vivo of FGFR1-silenced osteosarcoma cells caused a marked twofold to fivefold decrease in spontaneous lung metastases. Similarly, inhibition of FGFR signalling in vivo with the small-molecule inhibitor AZD4547 markedly reduced the number and size of metastatic nodules. Thus deregulated FGFR signalling has an important role in osteoblast transformation and osteosarcoma formation and regulates the development of lung metastases. Our findings support the development of anti-FGFR inhibitors as potential antimetastatic therapy.

In vivo study and thermodynamic investigation of two lanthanum complexes, La(dpp)3 and La(XT), for the treatment of bone resorption disorders.

Bone density diseases such as osteoporosis affect a significant number of people worldwide. Lanthanide ions are functional mimics of calcium ions, able to substitute for Ca2+ in the bone mineral component, hydroxyapatite (HAP). Bone undergoes a continuous remodelling cycle and lanthanides can affect this cycle, exerting a positive influence on bone mineral. We have been engaged in efforts to find new lanthanide containing complexes as active agents for treatment of these diseases and have identified two lead compounds, 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (Hdpp) and a phosphinate-EDTA derivative, bis[[bis(carboxymethyl)amino]-methyl]phosphinate (H5XT). In this paper, we report in vivo data for the first time for the two lead compounds. The pharmacokinetics of La(dpp)3 suggest the complex is rapidly cleared from plasma. We demonstrate that La3+ accumulates in the bone following IV dose of either La(dpp)3 or La(XT) and we have investigated the influence of each chelating ligand on the incorporation of La3+ into HAP using ITC and HAP-binding studies.

The Forkhead Box M1 protein regulates BRIP1 expression and DNA damage repair in epirubicin treatment.

FOXM1 is implicated in genotoxic drug resistance but its role and mechanism of action remain unclear. Here, we establish that γH2AX foci, indicative of DNA double-strand breaks (DSBs), accumulate in a time-dependent manner in the drug-sensitive MCF-7 cells but not in the resistant counterparts in response to epirubicin. We find that FOXM1 expression is associated with epirubicin sensitivity and DSB repair. Ectopic expression of FOXM1 can increase cell viability and abrogate DSBs sustained by MCF-7 cells following epirubicin, owing to an enhancement in repair efficiency. Conversely, alkaline comet and γH2AX foci formation assays show that Foxm1-null cells are hypersensitive to DNA damage, epirubicin and γ-irradiation. Furthermore, we find that FOXM1 is required for DNA repair by homologous recombination (HR) but not non-homologous end joining (NHEJ), using HeLa cell lines harbouring an integrated direct repeat green fluorescent protein reporter for DSB repair. We also identify BRIP1 as a direct transcription target of FOXM1 by promoter analysis and chromatin-immunoprecipitation assay. In agreement, depletion of FOXM1 expression by small interfering RNA downregulates BRIP1 expression at the protein and mRNA levels in MCF-7 and the epirubicin-resistant MCF-7 Epi(R) cells. Remarkably, the requirement for FOXM1 for DSB repair can be circumvented by reintroduction of BRIP1, suggesting that BRIP1 is an important target of FOXM1 in DSB repair. Indeed, like FOXM1, BRIP1 is needed for HR. These data suggest that FOXM1 regulates BRIP1 expression to modulate epirubicin-induced DNA damage repair and drug resistance.

Life-span development: a review of theory and practice for families with chronically ill members.

While the family's primacy in the patient's adaptation to chronic illness increasingly is being recognized by health professionals and social scientists, the reverse side of the coin, that is, the impact of chronicity on the family, has received little attention. A life-span development perspective is used to enrich the more traditional frameworks employed to study family development and also as a unifying framework from which to view the impact of illness on individual family members and the family as a unit. A review of selected literature reveals a profile of families most at risk for serious disruption in situations involving chronic illness. Propositions suggesting interventions directed at patients and families experiencing chronicity are derived.

Gender differences in sleep patterns for early adolescents.

PURPOSE: To describe gender differences in self-reported sleep disturbances and daytime sleepiness in an urban sample of early adolescents (11-14 years of age). METHODS: One hundred and forty-four racially diverse sixth- to eighth-grade students responded to an investigator-developed sleep questionnaire. Variables included school night and weekend sleep patterns as well as factors that influence sleep and daytime sleepiness, such as sleep/wake routine and alcohol and caffeine consumption. RESULTS: Boys consumed significantly more caffeinated beverages than girls, but this did not correlate with self-reports of waking after sleep onset. Caffeine intake was significantly related to self-reported parasomnias. Significant gender differences were found for self-reports of daytime sleepiness. There were also large variations between weekday and weekend sleep schedules. Weekday wakeup time for boys was significantly later compared to girls. Those who reported consumption of alcohol during the past week were likely to fall asleep in the classroom before lunch. Girls, who awakened earlier than boys on school days, were more likely to report falling asleep on the way home from school. CONCLUSIONS: These descriptive data support the need for further investigation into the relationship between caffeine intake and parasomnias, as well as into the observed gender differences.

African-American families with chronically ill children: oversights and insights.

From a critical review of the literature concerning African-American families' management and care of children having chronic illness, we concluded that information on culture-related experiences in such families remains seriously deficient. To present an accurate picture of African-American life as these families manage a child with a chronic illness, more comprehensive and detailed descriptions of family caregiving styles and other experiences are needed.

Perceptions of the mammography experience.

The 1993 projections for breast cancer indicate a morbidity of 183,000 women with a mortality rate of 18%. Mammography is one of three approaches available for the early detection of breast cancer. However, underutilization has been reported and attributed to pain associated with the procedure, the expense to the consumer, and lack of referral by physicians. Other reasons for the low utilization rates include fears on the part of the woman of a positive diagnosis, radiation, and a possible mastectomy. This study provides an analysis of the responses of a convenience sample of 272 women, aged 30-90 years, to two open-ended questions about the mammography experience. The words and phrases women used to describe the mammography experience and the sensations experienced in their breasts during mammography were subjected to content analysis. The results of this study suggest that the word descriptors women use to describe their experience during mammography are highly individualistic and may not be totally captured by numeric or descriptive rating scales of pain intensity.

Adolescents completing cancer therapy: meaning, perception, and coping.

PURPOSE/OBJECTIVES: To explore and describe adolescents' experiences and associated changes in coping strategies during the time period from three to six months before cancer therapy completion to six months after completion. DESIGN: Exploratory, descriptive, longitudinal, qualitative design using grounded theory techniques. SETTING: Pediatric oncology outpatient clinics in the San Francisco Bay area and British Columbia. SAMPLE: 13 adolescents undergoing cancer therapy. METHODS: Semistructured interview conducted at four points in time (three to six months prior to completion of chemotherapy, at time of completion, three months after completion, and six months after completion). Subjects' responses were tape-recorded, transcribed verbatim, and analyzed using constant comparative techniques. FINDINGS: Themes emerged from the data in three categories: meaning and perception of the experience of completing cancer therapy (task accomplishment, movement toward a normal life); coping strategies before completion of therapy (positive thinking, not thinking about treatments, "busy-ness," reinterpretation, and "philosophical stance"); and coping strategies after completion of therapy (negotiation, cognitive reliving, selective forgetting). CONCLUSIONS: Completion of cancer therapy is an event that is uniquely perceived by adolescents, and they employ different coping strategies before and after completion. IMPLICATIONS FOR NURSING PRACTICE: Knowledge of adolescents' experiences of completing chemotherapy will assist nurses in offering support to the patient as well as to the parents who must support their child. Further longitudinal studies with larger samples are needed, as are studies comparing and contrasting the views of the adolescents and the parents.

A Delphi study of pediatric oncology nurses' facilitative behaviors.

Using a classic Delphi methodology, this study identified the nursing behaviors and interventions that oncology nurses rated as most important in facilitating the patient's, parents', and siblings' coping efforts with the effects of disease and treatment. Random selection of 300 pediatric oncology nurses resulted in a final sample of 69 nurses who completed all 3 rounds of the Delphi. The majority of the nurses were younger than 35 years of age, had less than 10 years of experience, were educated with at least a bachelor's degree, and practiced in an all-oncology setting. Twenty-eight facilitative behaviors were identified for the child with cancer, 25 for the parents, and 25 for the siblings. Results of this study support previous research on patient, parent, and sibling coping.

The phenomenon of hand holding as a coping strategy in adolescents experiencing treatment-related pain.

The purpose of this study was to understand the phenomenon of hand holding as a coping strategy used by adolescents to deal with treatment-related pain. The convenience sample consisted of 20 adolescents whose ages were 11 to 19 years: 10 had cancer and 10 had renal disease (this served as the comparison group). Using a descriptive design, a semistructured interview was conducted with each adolescent. To supplement and support interview data, structured observations were conducted as adolescents underwent painful treatments (eg, blood draws, shunt placement, peripheral chemotherapy, lumbar punctures, and bone marrow aspirations). Data were analyzed using descriptive statistics and qualitative analytic techniques similar to those delineated by Strauss and Corbin. The results of this study indicated that subjects in both the cancer and the renal disease group perceived hand holding to be a very effective coping strategy in ameliorating treatment-related pain. Overwhelmingly the patients preferred to hold their mother's hand. When the mother was unavailable, they preferred to hold a specific nurse's hand. Hand holding functioned to reduce tension associated with impending treatments, as a source of distraction, and as a source of security. Accordingly, adolescents' subjective experience of treatment-related pain was reduced when they felt more secure, less tense, and were distracted.

What teachers want to know about students with cancer.

This article reports the results of a survey of classroom teachers in elementary and high schools in the San Francisco Bay Area. The teachers were asked to respond to questions about their informational needs and concerns related to students in their classroom who were diagnosed with cancer or receiving cancer treatment. Findings indicated that classroom teachers perceive themselves to be ill prepared to address the needs of the student with cancer. Specific concerns clustered around information deficits regarding the students' physiological and physical vulnerability, physical limitations/alterations following treatment, psychological responses to cancer treatment, and peer interactions. Utilizing data from the survey, a conceptual approach and collaborative intervention scheme were developed.

Application of the life-span developmental perspective to nursing research with adolescents.

Phenomena of interest to nurse researchers include the responses of persons across the life span to changes in their lives related to conditions of health and illness. The topic of this article is the life span stage known as adolescence, and the article is grounded in the premise that questions related to the effects of chronic illness at different points in the adolescent life course (i.e., early, middle, and late adolescence) are best studied from a life-span developmental perspective. First, the traditional developmental theories, the commonly held world views from which they emerged, and their relative contributions to research with adolescents are reviewed. The life-span developmental perspective is then discussed, with particular emphasis on its usefulness in guiding research aimed at answering questions that address change in the behavioral responses of adolescents to conditions of health and illness.