Deconstructing tumor heterogeneity: the stromal perspective.

Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive versus suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Frailty, inflammation and the elderly

Frailty is a term used as a marker of vulnerability, identifying individuals with a diminished capacity to respond to external stressors. Those who are frail are at increased risk of death, institutionalisation and worsening disability. While the associations of frailty with increasing chronological age, female gender, functional dependence and chronic disease are now well described, the aetiology of frailty remains less clearly understood. The growing body of evidence linking inflammation and frailty in older people, an association that seems consistent across different frailty definitions, is therefore of great interest to research gerontologists. However, further studies are needed to establish the exact nature of this relationship. Inflammation may be primarily causal, a compensatory response to viral antigens or subclinical disease or an epi-phenomenon, merely a marker of another key pathophysiological process such as excessive oxidative stress. Furthermore, it has recently been recognised that frailty is most strongly associated with a combination of immunological and physiological impairments rather than a single biomarker. This supports the conceptualisation of ageing as the progressive accumulation of damage to a complex system resulting in aggregate loss of system redundancy. The frail older person is analogous to a complex system without redundancy: capacity to respond to external stressors is reduced. A critical mass of abnormalities across different systems may therefore be a more important determinant of frailty than any individual pathway

Electronic Medical Records: TAM, UTAUT, and Culture

Many policymakers, industry experts, and medical practitioners contend that the U.S. health care system—in both the public and private sectors—is in crisis. Among the numerous policy issues associated with the provision of US healthcare is the call for increased adoption and use of health care information technology (HIT) to address structural inefficiencies and care quality issues [11, p. 33]. This paper reports the first steps in a multi-phased research effort into Electronic Medical Records system adoption. The first two phases of our research applies the Unified Theory of Acceptance and Use of Technology as a lens to interpret the responses of physicians completing their Residency in Family Medicine and the third phase examines the role of organizational culture as a critical variable for effective strategy implementation in the same setting. © 2009, IGI Global. All rights reserved

Plasma esterases and inflammation in ageing and frailty

Objectives Esterases are enzymes of drug metabolism known to be reduced in frail older people and during acute illness. The mechanism for this is unknown. The aim of this study was to examine esterase activity and inflammation in ageing and frailty.Methods Thirty frail patients (mean age 84.9 years) dependent on continuing inpatient care, 40 patients of intermediate frailty attending Day Hospital (84.2 years), 40 fit older controls (82.7 years) and 30 young controls (23.3 years) were studied. Frailty indicators, plasma esterase activities and markers of inflammation were measured.Results With increasing patient frailty, C-reactive protein (CRP), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) increased significantly and esterase activity, with the exception of aspirin esterase, fell significantly (p < 0.005). There were significant negative correlations between log-transformed IL-6 and acetylcholinesterase (r=-0.354, p < 0.01), butyrylcholinesterase (r=-0.392, p < 0.01) and benzoyl-cholinesterase activity (r=-0.241, p < 0.05) and significant negative correlations between TNF-alpha and acetylcholinesterase (r=-0.223, p < 0.01), butyrylcholinesterase (r=-0.279, p < 0.01) and benzoylcholinesterase activity (r=-0.253, p < 0.01). Aspirin esterase activity did not correlate with IL-6 or TNF- alpha.Conclusion Frailty was associated with higher inflammatory markers and lower esterase activity. There was a weak but significant negative correlation between both IL-6 and TNF-alpha and the activity of three of four esterases. The negative correlation between esterase activity and inflammatory markers may have a causal basis, comparable to the inflammatory suppression of cytochrome P-450 enzymes

Nutrition, inflammation, and leptin levels in aging and frailty

OBJECTIVES: To examine nutritional indices and levels of leptin and inflammatory markers across age and frailty.DESIGN: Observational study.SETTING: Continuing care wards and a day hospital in Cardiff, South Wales, United Kingdom.PARTICIPANTS: Thirty dependent patients (mean age 84.9) needing continuing inpatient care, 40 patients with falls attending a day hospital (mean age 84.2), 40 independent controls (mean age 82.7), and 30 young controls (mean age 23.3).MEASUREMENTS: Functional status, including the five frailty indicators proposed by Fried et al., anthropometry, and serum markers of nutrition and inflammation.RESULTS: The continuing care patients were frail, all having three to five frailty indicators. Day hospital patients were of intermediate frailty (mean Fried score 2.97), and the independent group was fittest (0.83). Body mass index, triceps skinfold thickness (TSF), and mid-arm muscle area were lowest in continuing care patients. With increasing patient frailty, albumin levels fell significantly (