Qualitative study investigating the underlying motivations of healthy participants in phase I clinical trials.

Objectives: If patients are to reap the benefits of continued drug development, an understanding of why healthy participants take part in phase I clinical trials is imperative. The current study aimed to explore the nature of these underlying motivations which may, in turn, improve the overall participant experience and assist in the development of more effective recruitment and retention strategies.

Design: This study used a qualitative design based on the theory of planned behaviour.

Differential subcellular and extracellular localisations of proteins required for insulin-like growth factor- and extracellular matrix-induced signalling events in breast cancer progression.

Background: Cancer metastasis is the main contributor to breast cancer fatalities as women with the metastatic disease have poorer survival outcomes than women with localised breast cancers. There is an urgent need to develop appropriate prognostic methods to stratify patients based on the propensities of their cancers to metastasise. The insulin-like growth factor (IGF)-I: IGF binding protein (IGFBP):vitronectin complexes have been shown to stimulate changes in gene expression favouring increased breast cancer cell survival and a migratory phenotype.

Fasting increases serum bilirubin levels in clinically normal, healthy males but not females: a retrospective study from phase I clinical trial participants.

Aim: To examine if fasting affects serum bilirubin levels in clinically healthy males and females.

Methods: We used retrospective data from phase I clinical trials where blood was collected in either a fed or fasting state at screening and predosing time points and analysed for total bilirubin levels as per standard clinical procedures. Participants were clinically healthy males (n=105) or females (n=30) aged 18-48 inclusive who participated in a phase I clinical trial in 2012 or 2013.

Multiple types of data are required to identify the mechanisms influencing the spatial expansion of melanoma cell colonies.

Background: The expansion of cell colonies is driven by a delicate balance of several mechanisms including cell motility, cell-to-cell adhesion and cell proliferation. New approaches that can be used to independently identify and quantify the role of each mechanism will help us understand how each mechanism contributes to the expansion process. Standard mathematical modelling approaches to describe such cell colony expansion typically neglect cell-to-cell adhesion, despite the fact that cell-to-cell adhesion is thought to play an important role.

Quantifying the roles of cell motility and cell proliferation in a circular barrier assay.

Moving fronts of cells are essential features of embryonic development, wound repair and cancer metastasis. This paper describes a set of experiments to investigate the roles of random motility and proliferation in driving the spread of an initially confined cell population. The experiments include an analysis of cell spreading when proliferation was inhibited.

Stratum basale keratinocyte expression of the cell-surface glycoprotein CDCP1 during epidermogenesis and its role in keratinocyte migration.

Background: Epidermogenesis and epidermal wound healing are tightly regulated processes during which keratinocytes must migrate, proliferate and differentiate. Cell-to-cell adhesion is crucial to the initiation and regulation of these processes. CUB-domain-containing protein (CDCP)1 is a transmembrane glycoprotein that is differentially tyrosine phosphorylated during changes in cell adhesion and survival signalling, and is expressed by keratinocytes in native human skin, as well as in primary cultures.

Insulin-like growth factor-I:vitronectin complex-induced changes in gene expression effect breast cell survival and migration.

Recent studies have demonstrated that IGF-I associates with vitronectin (VN) through IGF-binding proteins (IGFBP), which in turn modulate IGF-stimulated biological functions such as cell proliferation, attachment, and migration. Because IGFs play important roles in transformation and progression of breast tumors, we aimed to describe the effects of IGF-I:IGFBP:VN complexes on breast cell function and to dissect mechanisms underlying these responses. In this study we demonstrate that substrate-bound IGF-I:IGFBP:VN complexes are potent stimulators of MCF-7 breast cell survival, which is mediated by a transient activation of ERK/MAPK and sustained activation of phosphoinositide 3-kinase/AKT pathways.

A chimeric vitronectin: IGF-I protein supports feeder-cell-free and serum-free culture of human embryonic stem cells.

The therapeutic use of human embryonic stem (hES) cells is severely limited by safety concerns regarding their culture in media containing animal-derived or nondefined factors and on animal-derived feeder cells. Thus, there is a pressing need to develop culture techniques that are xeno-free, fully defined, and synthetic. Our laboratory has discovered that insulin-like growth factor (IGF) and vitronectin (VN) bind to each other resulting in synergistic short-term functional effects in several cell types, including keratinocytes and breast epithelial cells.

Long-term economic growth stimulus of human capital preservation in the elderly.

Health care is a crucial factor in US economic growth, because growing health care costs have made US corporations less competitive than their counterparts in countries where central governments assume most of those costs. In this paper we illustrate a second, possibly more powerful, effect of health care expenditures on the long term pace of US economic growth, i.e.

Serum-free primary human fibroblast and keratinocyte coculture.

Research has shown that the inclusion of a fibroblast cell support layer is required for the isolation and expansion of primary keratinocytes. Recent advances have provided keratinocyte culture with fibroblast-free alternatives. However, these technologies are often undefined and rely on the incorporation of purified proteins/components.

Production of cell-cell signalling molecules by bacteria isolated from human chronic wounds.

Aim: To (i) identify chronic wound bacteria and to test their ability to produce acyl-homoserine-lactones (AHLs) and autoinducer-2 (AI-2) cell-cell signalling molecules and (ii) determine whether chronic wound debridement samples might contain these molecules.

Methods And Results: Partial 16S rRNA gene sequencing revealed the identity of 46 chronic wound strains belonging to nine genera. Using bio-reporter assays, 69.

Purification and characterization of heparan sulfate from human primary osteoblasts.

Heparan sulfate (HS) is a linear, highly variable, highly sulfated glycosaminoglycan sugar whose biological activity largely depends on internal sulfated domains that mediate specific binding to an extensive range of proteins. In this study we employed anion exchange chromatography, molecular sieving and enzymatic cleavage on HS fractions purified from three compartments of cultured osteoblasts-soluble conditioned media, cell surface, and extracellular matrix (ECM). We demonstrate that the composition of HS chains purified from the different compartments is structurally non-identical by a number of parameters, and that these differences have significant ramifications for their ligand-binding properties.

NIH funding trajectories and their correlations with US health dynamics from 1950 to 2004.

To determine optimal future National Institutes of Health (NIH) funding levels, the longitudinal correlation of the level of investment in NIH research with population changes in the risk of specific diseases should be analyzed. This is because NIH research is the primary source of new therapies and treatments for major chronic diseases, many of which were viewed as relatively untreatable in the 1950s. NIH research is also important in developing preventative and screening strategies to support public health interventions.

[Investigation of disability prevalence in men and women of advanced age].

Disability prevalence among men and women are investigated using NLTCS surveys conducted in 1982, 1984, 1989, 1994 and 1999 in the US population, on persons older than 65 years, and data from LSADT surveys conducted in 1995, 1997, 1999 and 2001 in the population of the Danish Twins Registry, on persons older than 75 years. In both surveys women are more disabled than men. The probability of becoming disabled and surviving is higher for women than men.

Cohort changes in active life expectancy in the U.S. elderly population: experience from the 1982-2004 National Long-Term Care Survey.

Objectives: To understand declines in chronic disability prevalence in the U.S. elderly population, we examined cohort changes in active life expectancy, a health measure relating population disability and longevity dynamics.

Association between APOE epsilon 2/epsilon 3/epsilon 4 polymorphism and disability severity in a national long-term care survey sample.

Background: early studies reported controversial findings on association of apolipoprotein E (APOE) polymorphism with disability.

Objective: to analyse sex-specific associations of APOE genotypes with impairments in (instrumental) activities of daily living [(I)ADL] and mortality.

Design: population-based 1999 National Long Term Care Survey (NLTCS) of the US older (65+) individuals.

Health-protective and adverse effects of the apolipoprotein E epsilon2 allele in older men.

Objectives: To reexamine a health-protective role of the common apolipoprotein E (APOE) polymorphism focusing on connections between the APOE epsilon2-containing genotypes and impairments in instrumental activities of daily living (IADLs) in older (> or = 65) men and women and to examine how diagnosed coronary heart disease (CHD), Alzheimer's disease, colorectal cancer, macular degeneration, and atherosclerosis may mediate these connections.

Design: Retrospective cross-sectional study.

Setting: The unique disability-focused data from a genetic subsample of the 1999 National Long Term Care Survey linked with Medicare service use files.

Recent declines in chronic disability in the elderly U.S. population: risk factors and future dynamics.

As U.S. life expectancy has increased, questions arise as to how the quality of health and functioning in the elderly population has changed.

Disruption of heparan and chondroitin sulfate signaling enhances mesenchymal stem cell-derived osteogenic differentiation via bone morphogenetic protein signaling pathways.

Cell surface heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans have been implicated in a multitude of biological processes, including embryonic implantation, tissue morphogenesis, wound repair, and neovascularization through their ability to regulate growth factor activity and morphogenic gradients. However, the direct role of the glycosaminoglycan (GAG) sugar-side chains in the control of human mesenchymal stem cell (hMSC) differentiation into the osteoblast lineage is poorly understood. Here, we show that the abundant cell surface GAGs, HS and CS, are secreted in proteoglycan complexes that directly regulate the bone morphogenetic protein (BMP)-mediated differentiation of hMSCs into osteoblasts.

Isolation of a native osteoblast matrix with a specific affinity for BMP2.

During their commitment and differentiation toward the osteoblast lineage, mesenchymal stem cells secrete a unique extracellular matrix (ECM) that contains large quantities of glycosaminoglycans (GAGs). Proteoglycans (PGs) are major structural and functional components of the ECM and are composed of a core protein to which one or more glycosaminoglycan sugar chains (GAGs) attach. The association of BMP2, a member of the TGF-beta super-family of growth factors, and a known heparin-binding protein, with GAGs has been implicated as playing a significant role in modulating the growth factor's in vitro bioactivity.

Glycosaminoglycan and growth factor mediated murine calvarial cell proliferation.

Understanding the complex mechanisms underlying bone remodeling is crucial to the development of novel therapeutics. Glycosaminoglycans (GAGs) localised to the extracellular matrix (ECM) of bone are thought to play a key role in mediating aspects of bone development. The influence of isolated GAGs was studied by utilising in vitro murine calvarial monolayer and organ culture model systems.

Labor force participation and human capital increases in an aging population and implications for U.S. research investment.

The proportion of the United States labor force >/=65 years of age is projected to increase between 2004 and 2014 by the passing of age 65 of the large post-World War II baby boom cohorts starting in 2010 and their greater longevity, income, education, and health [Toossi M (2005) Mon Labor Rev 128(11):25-44]. The aging of the U.S.

Health-based population forecasting: effects of smoking on mortality and fertility.

A microsimulation model, allowing one to forecast short- and long-term population changes conditional on the prevalence of a risk factor in a population, is presented. In this model, population changes result from the aggregation of changes in individual event histories, which, in turn, result from mortality and infertility rates recalculated in accordance with their known relative risks in population groups exposed to a risk factor. Smoking, being the most widespread and influential preventable public health risk factor, is chosen to demonstrate the abilities of the model to forecast the population effects of different hypothetical smoking prevalences.

Medicare cost effects of recent U.S. disability trends in the elderly: future implications.

Objective: The authors examine how trends in disability prevalence and in inflation-adjusted per capita, per annum Medicare costs, 1982 to 1999 and 1989 to 1999, affected total Medicare costs projected to 2004 and 2009.

Method: To describe disability trends, the authors applied grade of membership analyses to 27 measures of disability from the 1982 to 1999 National Long Term Care Surveys (NLTCS). This identified seven disability profiles for which individual scores were calculated.