Role of wnts in prostate cancer bone metastases

Prostate cancer (CaP) is unique among all cancers in that when it metastasizes to bone, it typically forms osteoblastic lesions (characterized by increased bone production). CaP cells produce many factors, including Wnts that are implicated in tumor-induced osteoblastic activity. In this prospectus, we describe our research on Wnt and the CaP bone phenotype. Wnts are cysteine-rich glycoproteins that mediate bone development in the embryo and promote bone production in the adult. Wnts have been shown to have autocrine tumor effects, such as enhancing proliferation and protecting against apoptosis. In addition, we have recently identified that CaP-produced Wnts act in a paracrine fashion to induce osteoblastic activity in CaP bone metastases. In addition to Wnts, CaP cells express the soluble Wnt inhibitor dickkopf-1 (DKK-1). It appears that DKK-1 production occurs early in the development of skeletal metastases, which results in masking of osteogenic Wnts, thus favoring osteolysis at the metastatic site. As metastases progress, DKK-1 expression decreases allowing for unmasking of Wnt's osteoblastic activity and ultimately resulting in osteosclerosis at the metastatic site. We believe that DKK-1 is one of the switches that transitions the CaP bone metastasis activity from osteolytic to osteoblastic. Wnt/DKK-1 activity fits a model of CaP-induced bone remodeling occurring in a continuum composed of an osteolytic phase, mediated by receptor activator of NFkB ligand (RANKL), parathyroid hormone-related protein (PTHRP) and DKK-1; a transitional phase, where environmental alterations promote expression of osteoblastic factors (Wnts) and decreases osteolytic factors (i.e., DKK-1); and an osteoblastic phase, in which tumor growth-associated hypoxia results in production of vascular endothelial growth factor and endothelin-1, which have osteoblastic activity. This model suggests that targeting both osteolytic activity and osteoblastic activity will provide efficacy for therapy of CaP bone metastases. J. Cell. Biochem. 97: 661–672, 2006. © 2005 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49527/1/20735_ftp.pd

Identification and implementation of potential energy efficiency programs in Indian Country: Working paper series--04-03

The strongest recommendation stemming from the Air Pollution Prevention forum of the Western Regional Air Partnership (WRAP) was for tribes to develop and implement energy plans. This paper provides a discussion of the benefits of any such plan and itemized a variety of components of any said plan. A brief discussion of the WRAP is presented is the framework of improving air quality. Based on the background of Jacobs (2000) and Smith (2000), the primary and secondary benefits of energy efficiency plans are then discussed. Then a series of specific recommendations are itemized. These include tribally sponsored programs, collaborative opportunities, and tribal leadership programs

Recommendations for reducing energy consumption and improving air quality through energy efficiency in Indian Country: Working paper series--04-04

The strongest recommendation stemming from the Air Pollution Prevention forum of the Western Regional Air Partnership (WRAP) was for tribes to develop and implement energy plans. This paper provides a discussion of the benefits of any such plan and itemized a variety of components of any said plan. A brief discussion of the WRAP is presented is the framework of improving air quality. Based on the background of Jacobs (2000) and Smith (2000), the primary and secondary benefits of energy efficiency plans are then discussed. Then a series of specific recommendations are itemized. These include tribally sponsored programs, collaborative opportunities, and tribal leadership programs

Economic analysis of energy efficiency measures: Tribal case studies with The Confederated Salish and Kootenai Tribes of The Flathead Reservation, The Pascua Yaqui Tribe, and The Yurok Tribe: Working paper series--04-02

The best way to reduce air pollution from the production of electricity is not to produce it in the first place. This paper presents three cases studies explaining how energy efficiency programs can be beneficial to tribes from a purely cost-saving basis, The Yurok, Flathead and Pascua Yaqui Reservations graciously provided an opportunity to investigate energy efficiency for their tribes. In each case the consumption of electricity was reduced such that a positive net present value was present following an initial capital investment. In the case of the irrigation systems on the Flathead Reservation, the savings were substantial even though no explicit savings of water was accounted for. It is estimated that tribes can reduce electricity costs by 10-50% by following energy efficiency programs. Many programs can be very simple involving small upfront capital outlays, such as changing light bulbs or installing motion sensors. The Yurok case showed a return of 7.5% after simply changing bulbs and the Pasqua Yaqui case showed a possible return of 10-80%. Other tribes could make similar investments and realize similar benefits in addition to improved air quality. The strongest recommendation from the Air Pollution Prevention Forum to tribes was to develop an energy plan. These cases show that some fairly simple analysis can make a plan very beneficial

Economic evaluation of ‘Men on the Move’, a ‘real world’ community-based physical activity programme for men

Background Physical activity (PA) interventions capable of producing health benefits cost effectively are a public health priority across the Western world. ‘Men on the Move’ (MOM), a community-based PA intervention for men, demonstrated significant health benefits up to 52-weeks (W) post-baseline. This article details the economic evaluation of MOM with a view to determining its cost-effectiveness as a public health intervention to be rolled out nationally in Ireland. Methods Cost-effectiveness was determined by comparing the costs (direct and indirect) of the programme to its benefits, which were captured as the impact on quality-adjusted life-years (QALYs). For the benefits, cost–utility analysis was conducted by retrospectively adapting various health-related measures of participants to generate health states using Brazier et al.’s (2002) short form-6D algorithm. This in turn allowed for ‘utility measures’ to be generated, from which QALYs were derived. Results Findings show MOM to be cost-effective in supporting an ‘at risk’ cohort of men achieves significant improvements in aerobic fitness, weight loss and waist reduction. The total cost per participant (€125.82 for each of the 501 intervention participants), the QALYs gained (11.98 post-12-W intervention, or 5.3% health improvement per participant) and estimated QALYs ratio costs of €3723 represents a cost-effective improvement when compared to known QALY guidelines. Conclusions The analysis shows that the cost per QALY achieved by MOM is significantly less than the existing benchmarks of £20 000 and €45 000 in the UK and Ireland respectively, demonstrating MOM to be cost-effective

Assessing women's preferences towards tests that may reveal uncertain results from prenatal genomic testing: Development of attributes for a discrete choice experiment, using a mixed-methods design

Prenatal DNA tests, such as chromosomal microarray analysis or exome sequencing, increase the likelihood of receiving a diagnosis when fetal structural anomalies are identified. However, some parents will receive uncertain results such as variants of uncertain significance and secondary findings. We aimed to develop a set of attributes and associated levels for a discrete-choice experiment (DCE) that will examine parents' preferences for tests that may reveal uncertain test results. A two phase mixed-methods approach was used to develop attributes for the DCE. In Phase 1, a “long list” of candidate attributes were identified via two approaches: 1) a systematic review of the literature around parental experiences of uncertainty following prenatal testing; 2) 16 semi-structured interviews with parents who had experienced uncertainty during pregnancy and 25 health professionals who return uncertain prenatal results. In Phase 2, a quantitative scoring exercise with parents prioritised the candidate attributes. Clinically appropriate levels for each attribute were then developed. A final set of five attributes and levels were identified: likelihood of getting a result, reporting of variants of uncertain significance, reporting of secondary findings, time taken to receive results, and who tells you about your result. These attributes will be used in an international DCE study to investigate preferences and differences across countries. This research will inform best practice for professionals supporting parents to manage uncertainty in the prenatal setting

Dealing with uncertain results from chromosomal microarray and exome sequencing in the prenatal setting: an international cross-sectional study with healthcare professionals.

OBJECTIVES: To conduct qualitative interviews with healthcare providers working in different countries to understand their experiences of dealing with uncertain results from prenatal chromosome microarray analysis (CMA) and exome sequencing (ES). METHODS: Semi-structured interviews with 31 healthcare providers who report or return prenatal CMA and/or ES results (clinicians, genetic counsellors and clinical scientists) in six countries with differing healthcare systems; Australia (4), Denmark (5), Netherlands (6), Singapore (4), Sweden (6) and United Kingdom (6). The topic guide explored the main sources of uncertainty and their management. RESULTS: There was variation in reporting practices both between and across countries for variants of uncertain significance (VUS), however, there was broad agreement on reporting practices for incidental findings. There was also variation in who decides what results are reported (clinical scientists or clinicians). Technical limitations and lack of knowledge (to classify variants and of prenatal phenotypes) were significant challenges, as were turnaround times and lack of guidelines. CONCLUSION: Health professionals around the globe are dealing with similar sources of uncertainty, but managing them in different ways, Continued dialogue with international colleagues on ways of managing uncertain results is important to compare and contrast the benefits and limitations of the different approaches. This article is protected by copyright. All rights reserved