Prevention in the age of personal responsibility: epigenetic risk-predictive screening for female cancers as a case study

Epigenetic markers could potentially be used for risk assessment in risk-stratified population-based cancer screening programmes. Whereas current screening programmes generally aim to detect existing cancer, epigenetic markers could be used to provide risk estimates for not-yet-existing cancers. Epigenetic risk-predictive tests may thus allow for new opportunities for risk assessment for developing cancer in the future. Since epigenetic changes are presumed to be modifiable, preventive measures, such as lifestyle modification, could be used to reduce the risk of cancer. Moreover, epigenetic markers might be used to monitor the response to risk-reducing interventions. In this article, we address ethical concerns related to personal responsibility raised by epigenetic risk-predictive tests in cancer population screening. Will individuals increasingly be held responsible for their health, that is, will they be held accountable for bad health outcomes? Will they be blamed or subject to moral sanctions? We will illustrate these ethical concerns by means of a Europe-wide research programme that develops an epigenetic risk-predictive test for female cancers. Subsequently, we investigate when we can hold someone responsible for her actions. We argue that the standard conception of personal responsibility does not provide an appropriate framework to address these concerns. A different, prospective account of responsibility meets part of our concerns, that is, concerns about inequality of opportunities, but does not meet all our concerns about personal responsibility. We argue that even if someone is responsible on grounds of a negative and/or prospective account of responsibility, there may be moral and practical reasons to abstain from moral sanctions

Continuous flow mechanochemistry: reactive extrusion as an enabling technology in organic synthesis

Rapid and wide-ranging developments have established mechanochemistry as a powerful avenue in sustainable organic synthesis. This is primarily due to unique opportunities which have been offered in solvent-free - or highly solvent-minimised - reaction systems. Nevertheless, despite elegant advances in ball-milling technology, limitations in scale-up still remain. This tutorial review covers the first reports into the translation from "batch-mode" ball-milling to "flow-mode" reactive extrusion, using twin-screw extrusion

Therapeutic trial of silicone in peptic ulcer

In a controlled double-blind trial of the therapeutic effectiveness of silicone in patients with duodenal ulcer, the silicone tested was shown to be slightly less effective than placebo medication. The relatively good early response of chronically recurring ulcer disease appeared to be due to the emotional impact of “a new treatment of ulcers.”Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44434/1/10620_2005_Article_BF02232021.pd

Reconstructing mass profiles of simulated galaxy clusters by combining Sunyaev-Zeldovich and X-ray images

We present a method to recover mass profiles of galaxy clusters by combining data on thermal Sunyaev-Zeldovich (tSZ) and X-ray imaging, thereby avoiding to use any information on X-ray spectroscopy. This method, which represents a development of the geometrical deprojection technique presented in Ameglio et al. (2007), implements the solution of the hydrostatic equilibrium equation. In order to quantify the efficiency of our mass reconstructions, we apply our technique to a set of hydrodynamical simulations of galaxy clusters. We propose two versions of our method of mass reconstruction. Method 1 is completely model-independent, while Method 2 assumes instead the analytic mass profile proposed by Navarro et al. (1997) (NFW). We find that the main source of bias in recovering the mass profiles is due to deviations from hydrostatic equilibrium, which cause an underestimate of the mass of about 10 per cent at r_500 and up to 20 per cent at the virial radius. Method 1 provides a reconstructed mass which is biased low by about 10 per cent, with a 20 per cent scatter, with respect to the true mass profiles. Method 2 proves to be more stable, reducing the scatter to 10 per cent, but with a larger bias of 20 per cent, mainly induced by the deviations from equilibrium in the outskirts. To better understand the results of Method 2, we check how well it allows to recover the relation between mass and concentration parameter. When analyzing the 3D mass profiles we find that including in the fit the inner 5 per cent of the virial radius biases high the halo concentration. Also, at a fixed mass, hotter clusters tend to have larger concentration. Our procedure recovers the concentration parameter essentially unbiased but with a scatter of about 50 per cent.Comment: 13 pages, 11 figures, submitted to MNRA

Silicones in experimental peptic ulceration

In the search for a silicone as uniformly successful as the one used earlier, in preventing and treating experimental peptic ulceration in animals, 30 different silicones were used in pylorus-ligated rats, Mann-Williamson dogs and histamine ulcerated dogs. None were found to be uniformly effective and the initial encouraging results reported by us could not be reproduced with subsequent silicone preparations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44435/1/10620_2005_Article_BF02232022.pd

Characterization of multi-layered tissue engineered human alveolar bone and gingival mucosa

Advances in tissue engineering have permitted assembly of multi-layered composite tissue constructs for potential applications in the treatment of combined hard and soft tissue defects and as an alternative in vitro test model to animal experimental systems. The aim of this study was to develop and characterize a novel three-dimensional combined human alveolar bone and gingival mucosal model based on primary cells isolated from the oral tissues. Bone component of the model was engineered by seeding primary human alveolar osteoblasts (HAOBs) into a hydroxyapatite/tricalcium phosphate (HA/TCP) scaffold and culturing in a spinner bioreactor. The engineered bone was then laminated, using an adhesive tissue sealant, with tissue engineered gingival mucosa consisting of air/liquid interface-cultured normal human gingival keratinocytes on oral fibroblast-populated collagen gel scaffold. Histological characterization revealed a structure consisting of established epithelial, connective tissue, and bone layers closely comparable to normal oral tissue architecture. The mucosal component demonstrated a mature epithelium undergoing terminal differentiation similar to that characteristic of native buccal mucosa, as confirmed using cytokeratin 13 (CK13) and cytokeratin 14 (CK14) immunohistochemistry. Ultrastructural analysis confirmed the presence of desmosomes and hemi-desmosomes in the epithelial layer, a continuous basement membrane and newly synthesized collagen in the connective tissue layer. Quantitative PCR (qPCR) assessment of osteogenesis-related gene expression showed a higher expression of genes encoded Collagen I (COL1) and Osteonectin (ON) compared with Osteocalcin (OC), Osteopontin (OPN), and Alkaline phosphatase (ALP). ELISA quantification of COL1, ON, and OC confirmed a pattern of secretion which paralleled the model’s gene expression profile. We demonstrate here that replicating the anatomical setting between oral mucosa and the underlying alveolar bone is feasible and the developed model showed characteristics similar to those of normal tissue counterparts. This tri-layered model therefore offers great scope as an advanced, and anatomically-representative tissue-engineered alternative to animal models

Superhumps in Cataclysmic Binaries. XXV. q_crit, epsilon(q), and Mass-Radius

We report on successes and failures in searching for positive superhumps in cataclysmic variables, and show the superhumping fraction as a function of orbital period. Basically, all short-period systems do, all long-period systems don't, and a 50% success rate is found at P_orb=3.1+-0.2 hr. We can use this to measure the critical mass ratio for the creation of superhumps. With a mass-radius relation appropriate for cataclysmic variables, and an assumed mean white-dwarf mass of 0.75 M_sol, we find a mass ratio q_crit=0.35+-0.02. We also report superhump studies of several stars of independently known mass ratio: OU Virginis, XZ Eridani, UU Aquarii, and KV UMa (= XTE J1118+480). The latter two are of special interest, because they represent the most extreme mass ratios for which accurate superhump measurements have been made. We use these to improve the epsilon(q) calibration, by which we can infer the elusive q from the easy-to-measure epsilon (the fractional period excess of P_superhump over P_orb). This relation allows mass and radius estimates for the secondary star in any CV showing superhumps. The consequent mass-radius law shows an apparent discontinuity in radius near 0.2 M_sol, as predicted by the disrupted magnetic braking model for the 2.1-2.7 hour period gap. This is effectively the "empirical main sequence" for CV secondaries.Comment: PDF, 45 pages, 9 tables, 12 figures; accepted, in press, to appear November 2005, PASP; more info at http://cba.phys.columbia.edu

The role of endogenous versus exogenous sources in the exposome of putative genotoxins and consequences for risk assessment

The “totality” of the human exposure is conceived to encompass life-associated endogenous and exogenous aggregate exposures. Process-related contaminants (PRCs) are not only formed in foods by heat processing, but also occur endogenously in the organism as physiological components of energy metabolism, potentially also generated by the human microbiome. To arrive at a comprehensive risk assessment, it is necessary to understand the contribution of in vivo background occurrence as compared to the ingestion from exogenous sources. Hence, this review provides an overview of the knowledge on the contribution of endogenous exposure to the overall exposure to putative genotoxic food contaminants, namely ethanol, acetaldehyde, formaldehyde, acrylamide, acrolein, α,β-unsaturated alkenals, glycation compounds, N-nitroso compounds, ethylene oxide, furans, 2- and 3-MCPD, and glycidyl esters. The evidence discussed herein allows to conclude that endogenous formation of some contaminants appears to contribute substantially to the exposome. This is of critical importance for risk assessment in the cases where endogenous exposure is suspected to outweigh the exogenous one (e.g. formaldehyde and acrolein)