ATLA 39.2, May 2011

//ATLA 39.2, May 2011

News & Views

ATLA Staff Writer

Human Taste Cells in Culture
A Novel In Vitro Cell Culture Method for the Characterisation of Antiproliferative Agents
Single Cell Transcriptomics for the Identification of Potential Drug Targets
Closure of Databases
Sun Exposure Might Affect Drug Metabolism
BUAV Call to Ban Wild Monkey Trade
Study on the Suitability of FCS as a Supplement
Robotic Screening System to Test 10,000 Chemicals
Barbary Macaques Spontaneously Recognise Group Members in Photographs
‘Wearable’ PET Scanner for Rats
BUAV Report on Non-Animal Tests for Cosmetics
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2017-01-09T06:38:18+00:00 Tags: |

IIVS News & Views

ATLA Staff Writer

An In Vitro Model to Assess the Performance of Topical Antioxidants
IIVS Launches New Website Design
ECVAM’s Scientific Advisory Committee (ESAC)
Posters Available from the Society of Toxicology (SOT) Annual Meeting
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2017-01-09T06:38:18+00:00 Tags: |

CAAT News & Views

ATLA Staff Writer

CAAT to Make Three Awards
A Recent EBT Workshop
Altweb Project Team Meeting and Three Rs Organisations Meeting at the 8th World Congress on Alternatives and Animal Use in the Life Sciences
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2017-01-09T06:38:18+00:00 Tags: |

Alternatives for Lung Research: Stuck Between a Rat and a Hard Place

Kelly A. BéruBé

The respiratory system acts as a portal into the human body for airborne materials, which may gain access via the administration of medicines or inadvertently during inhalation of ambient air (e.g. air pollution). The burden of lung disease has been continuously increasing, to the point where it now represents a major cause of human morbidity and mortality worldwide. In the UK, more people die from respiratory disease than from coronary heart disease or non-respiratory cancer. For this reason alone, gaining an understanding of mechanisms of human lung biology, especially in injury and repair events, is now a principal focus within the field of respiratory medicine. Animal models are routinely used to investigate such events in the lung, but they do not truly reproduce the responses that occur in humans. Scientists committed to the more robust Three Rs principles of animal experimentation (Reduction, Refinement and Replacement) have been developing viable alternatives, derived from human medical waste tissues from patient donors, to generate in vitro models that resemble the in vivo human lung environment. In the specific case of inhalation toxicology, human-oriented models are especially warranted, given the new REACH regulations for the handling of chemicals, the rising air pollution problems and the availability of pharmaceutically valuable drugs. Advances in tissue- engineering have made it feasible and cost-effective to construct human tissue equivalents of the respiratory epithelia. The conducting airways of the lower respiratory system are a critical zone to recapitulate for use in inhalation toxicology. Three-dimensional (3- D) tissue designs which make use of primary cells, provide more in vivo-like responses, based on the targeted interactions of multiple cell types supported on artificial scaffolds. These scaffolds emulate the native extracellular matrix, in which cells differentiate into a functional pulmonary tissue. When 3-D cell cultures are employed for testing aerosolised chemicals, drugs and xenobiotics, responses are captured that mirror the events in the in situ human lung and provide human endpoint data.
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The Use of a Chemistry-based Profiler for Covalent DNA Binding in the Development of Chemical Categories for Read-across for Genotoxicity

Steven J. Enoch, Mark T.D. Cronin and Claire M. Ellison

An important molecular initiating event for genotoxicity is the ability of a compound to bind covalently with DNA. However, not all compounds that can undergo covalent binding mechanisms will result in genotoxicity. One approach to solving this problem, when in silico prediction techniques are being used, is to develop tools that allow chemicals to be grouped into categories based on their ability to bind covalently to DNA. For this analysis to take place, compounds need to be placed within categories where the trend in toxicity can be explained by simple descriptors, such as hydrophobicity. However, this can occur only when the compounds within a category are structurally and mechanistically similar. Chemistrybased profilers have the ability to screen compounds and highlight those with similar structures to a target compound, and are thus likely to act via a similar mechanism of action. Here, examples are reported to highlight how structure-based profilers can be used to form categories and hence fill data gaps. The importance of developing a well-defined and robust category is discussed in terms of both mechanisms of action and structural similarity.
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Toward Preclinical Predictive Drug Testing for Metabolism and Hepatotoxicity by Using In Vitro Models Derived from Human Embryonic Stem Cells and Human Cell Lines — A Report on the Vitrocellomics EU-project

Carl-Fredrik Mandenius, Tommy B. Andersson, Paula M. Alves, Christine Batzl-Hartmann, Petter Björquist, Manuel J.T. Carrondo, Christophe Chesne, Sandra Coecke, Josefina Edsbagge, J. Magnus Fredriksson, Jörg C. Gerlach, Elmar Heinzle, Magnus Ingelman- Sundberg, Inger Johansson, Barbara Küppers-Munther, Ursula Müller-Vieira, Fozia Noor and Katrin Zeilinger

Drug-induced liver injury is a common reason for drug attrition in late clinical phases, and even for post-launch withdrawals. As a consequence, there is a broad consensus in the pharmaceutical industry, and within regulatory authorities, that a significant improvement of the current in vitro test methodologies for accurate assessment and prediction of such adverse effects is needed. For this purpose, appropriate in vivo-like hepatic in vitro models are necessary, in addition to novel sources of human hepatocytes. In this report, we describe recent and ongoing research toward the use of human embryonic stem cell (hESC)-derived hepatic cells, in conjunction with new and improved test methods, for evaluating drug metabolism and hepatotoxicity. Recent progress on the directed differentiation of human embryonic stem cells to the functional hepatic phenotype is reported, as well as the development and adaptation of bioreactors and toxicity assay technologies for the testing of hepatic cells. The aim of achieving a testing platform for metabolism and hepatotoxicity assessment, based on hESC-derived hepatic cells, has advanced markedly in the last 2–3 years. However, great challenges still remain, before such new test systems could be routinely used by the industry. In particular, we give an overview of results from the Vitrocellomics project (EU Framework 6) and discuss these in relation to the current state-of-the-art and the remaining difficulties, with suggestions on how to proceed before such in vitro systems can be implemented in industrialdiscovery and development settings and in regulatory acceptance.
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Evaluation of Anti-inflammatory and Atrophogenic Effects of Glucocorticoids on Reconstructed Human Skina

Günther Weindl, Francesca Castello and Monika Schäfer-Korting

Topical glucocorticoids (GCs) are extensively used in the treatment of inflammatory skin diseases. However, their long-term use is often accompanied by severe and eventually irreversible adverse effects, with atrophy being the most important limitation. Currently, most non-clinical studies involve animal testing, so the results are not always representative of the situation in humans. The aim of this project was to establish an in vitro test protocol for the evaluation of the anti-inflammatory and atrophic potential of topically applied GCs in reconstructed human skin. Initial studies with fibroblasts and keratinocytes confirmed the anti-inflammatory and atrophogenic effects of GCs, as evidenced by decreased cytokine production and collagen mRNA expression. In non-pretreated reconstructed human skin (EpiDermFT™), the topical application of GCs for seven days strongly reduced the secretion of interleukin (IL)-6. GC-induced skin atrophy, known to appear only after prolonged treatment, was not detected by the analysis of epidermal thickness and collagen mRNA expression. However, reproducible epidermal inflammation was established for the first time in reconstructed human skin. Topical treatment with tumour necrosis factor (TNF) increased IL-6 release and strongly reduced epidermal thickness accompanied by severe parakeratosis. GC treatment of reconstructed human skin reduced IL-6 levels and completely resolved parakeratosis, leading to the normalisation of epidermal thickness. These induced inflammatory conditions mimic more closely the clinical situations in which GCs are used, and therefore appear to be more suitable for future investigations for the establishment of a human-based in vitro test protocol for evaluating wanted and unwanted GC effects.
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