Cell transformation assays for prediction of carcinogenic potential: State of the science and future research needs

Copyright @ 2011 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Cell transformation assays (CTAs) have long been proposed as in vitro methods for the identification of potential chemical carcinogens. Despite showing good correlation with rodent bioassay data, concerns over the subjective nature of using morphological criteria for identifying transformed cells and a lack of understanding of the mechanistic basis of the assays has limited their acceptance for regulatory purposes. However, recent drivers to find alternative carcinogenicity assessment methodologies, such as the Seventh Amendment to the EU Cosmetics Directive, have fuelled renewed interest in CTAs. Research is currently ongoing to improve the objectivity of the assays, reveal the underlying molecular changes leading to transformation and explore the use of novel cell types. The UK NC3Rs held an international workshop in November 2010 to review the current state of the art in this field and provide directions for future research. This paper outlines the key points highlighted at this meeting

Decisional responsibility for mechanical ventilation and weaning: an international survey

Abstract Introduction Optimal management of mechanical ventilation and weaning requires dynamic and collaborative decision making to minimize complications and avoid delays in the transition to extubation. In the absence of collaboration, ventilation decision making may be fragmented, inconsistent, and delayed. Our objective was to describe the professional group with responsibility for key ventilation and weaning decisions and to examine organizational characteristics associated with nurse involvement. Methods A multi-center, cross-sectional, self-administered survey was sent to nurse managers of adult intensive care units (ICUs) in Denmark, Germany, Greece, Italy, Norway, Switzerland, Netherlands and United Kingdom (UK). We summarized data as proportions (95% confidence intervals (CIs)) and calculated odds ratios (OR) to examine ICU organizational variables associated with collaborative decision making. Results Response rates ranged from 39% (UK) to 92% (Switzerland), providing surveys from 586 ICUs. Interprofessional collaboration (nurses and physicians) was the most common approach to initial selection of ventilator settings (63% (95% CI 59 to 66)), determination of extubation readiness (71% (67 to 75)), weaning method (73% (69 to 76)), recognition of weaning failure (84% (81 to 87)) and weaning readiness (85% (82 to 87)), and titration of ventilator settings (88% (86 to 91)). A nurse-to-patient ratio other than 1:1 was associated with decreased interprofessional collaboration during titration of ventilator settings (OR 0.2, 95% CI 0.1 to 0.6), weaning method (0.4 (0.2 to 0.9)), determination of extubation readiness (0.5 (0.2 to 0.9)) and weaning failure (0.4 (0.1 to 1.0)). Use of a weaning protocol was associated with increased collaborative decision making for determining weaning (1.8 (1.0 to 3.3)) and extubation readiness (1.9 (1.2 to 3.0)), and weaning method (1.8 (1.1 to 3.0). Country of ICU location influenced the profile of responsibility for all decisions. Automated weaning modes were used in 55% of ICUs. Conclusions Collaborative decision making for ventilation and weaning was employed in most ICUs in all countries although this was influenced by nurse-to-patient ratio, presence of a protocol, and varied across countries. Potential clinical implications of a lack of collaboration include delayed adaptation of ventilation to changing physiological parameters, and delayed recognition of weaning and extubation readiness resulting in unnecessary prolongation of ventilation

The extraordinary evolutionary history of the reticuloendotheliosis viruses

The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruses isolated from birds. These viruses exhibit several highly unusual characteristics that have not so far been adequately explained, including their extremely close relationship to mammalian retroviruses, and their presence as endogenous sequences within the genomes of certain large DNA viruses. We present evidence for an iatrogenic origin of REVs that accounts for these phenomena. Firstly, we identify endogenous retroviral fossils in mammalian genomes that share a unique recombinant structure with REVs—unequivocally demonstrating that REVs derive directly from mammalian retroviruses. Secondly, through sequencing of archived REV isolates, we confirm that contaminated Plasmodium lophurae stocks have been the source of multiple REV outbreaks in experimentally infected birds. Finally, we show that both phylogenetic and historical evidence support a scenario wherein REVs originated as mammalian retroviruses that were accidentally introduced into avian hosts in the late 1930s, during experimental studies of P. lophurae, and subsequently integrated into the fowlpox virus (FWPV) and gallid herpesvirus type 2 (GHV-2) genomes, generating recombinant DNA viruses that now circulate in wild birds and poultry. Our findings provide a novel perspective on the origin and evolution of REV, and indicate that horizontal gene transfer between virus families can expand the impact of iatrogenic transmission events

Reduced Complexity MIMO Channel Estimation and Equalization using a Polynomial-Predictor Based Vector GLMS Algorithm

A reduced complexity multiple-input multiple-output (MIMO) channel estimator known as the polynomial-predictor-based vector generalized least mean squares (VGLMS) estimator is developed. It is a simplification of a previously developed polynomial-predictor-based vector generalized recursive least squares (VGRLS) estimator, achieved by replacing the online recursive computation of the ‘intermediate’ matrix by an offline pre-computed matrix. Similar to the VGRLS estimator, it is able to operate in Rayleigh or Rician fading environments without reconfiguration of the state transition matrix to accommodate the non-random mean components. It is seen to offer a trade-off between reduced complexity channel estimation and good system performance

Asymmetric triplex metallohelices with high and selective activity against cancer cells

Small cationic amphiphilic α-helical peptides are emerging as agents for the treatment of cancer and infection, but they are costly and display unfavourable pharmacokinetics. Helical coordination complexes may offer a three-dimensional scaffold for the synthesis of mimetic architectures. However, the high symmetry and modest functionality of current systems offer little scope to tailor the structure to interact with specific biomolecular targets, or to create libraries for phenotypic screens. Here, we report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices. Their anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host-defence peptides and ​p53. The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 ​p53++, causing dramatic changes in the cell cycle without DNA damage. They have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468) and, most remarkably, they show no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli. At a glanc

Microbial neuraminidase induces a moderate and transient myelin vacuolation independent of complement system activation

Aims: Some central nervous system pathogens express neuraminidase (NA) on their surfaces. In the rat brain, a single intracerebroventricular (ICV) injection of NA induces myelin vacuolation in axonal tracts. Here, we explore the nature, the time course, and the role of the complement system in this damage. Methods: The spatiotemporal analysis of myelin vacuolation was performed by optical and electron microscopy. Myelin basic protein-positive area and oligodendrocyte transcription factor (Olig2)-positive cells were quantified in the damaged bundles. Neuronal death in the affected axonal tracts was assessed by Fluoro-Jade B and anti-caspase-3 staining. To evaluate the role of the complement, membrane attack complex (MAC) deposition on damaged bundles was analyzed using anti-C5b9. Rats ICV injected with the anaphylatoxin C5a were studied for myelin damage. In addition, NA-induced vacuolation was studied in rats with different degrees of complement inhibition: normal rats treated with anti-C5-blocking antibody and C6-deficient rats. Results: The stria medullaris, the optic chiasm, and the fimbria were the most consistently damaged axonal tracts. Vacuolation peaked 7 days after NA injection and reverted by day 15. Olig2+ cell number in the damaged tracts was unaltered, and neurodegeneration associated with myelin alterations was not detected. MAC was absent on damaged axonal tracts, as revealed by C5b9 immunostaining. Rats ICV injected with the anaphylatoxin C5a displayed no myelin injury. When the complement system was experimentally or constitutively inhibited, NA-induced myelin vacuolation was similar to that observed in normal rats. Conclusion: Microbial NA induces a moderate and transient myelin vacuolation that is not caused either by neuroinflammation or complement system activation