| 1. |
- Adamson, L, et al.
(författare)
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Insulin and IGF-1 mediated inhibition of apoptosis in CHO cells grown in suspension in a protein-free medium
- 2007
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Ingår i: Alternatives to laboratory animals : ATLA. - : SAGE Publications. - 0261-1929 .- 2632-3559. ; 35:3, s. 349-352
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Tidskriftsartikel (refereegranskat)abstract
- When Chinese hamster ovary (CHO) cells were grown in suspension and deprived of serum, 40% of them became apoptotic after 72 hours, as determined by flow cytometry analysis of TUNEL-labelled cells. Cell viability, assessed by erythrocin B staining, decreased correspondingly. An increase in the total fraction of cells expressing interleukin converting enzyme (ICE; caspase 1), B-cell lymphoma 2 protein (Bcl-2,) and Bcl-2 associated x protein (Bax) was shown by antibody probing and subsequent flow cytometry. The p53 tumour suppressor gene product level remained low within the cell population. Insulin-like growth factor-1 (IGF-1) inhibited cell death in a concentration-dependent manner, and at 20ng/ml, cell viability was maintained close to 100% and no apoptotic cells were detected. Also, insulin was shown to inhibit cell death — at 1.0μg/ml, cell viability was 95%, whereas 10% of the cells stained for apoptosis. At the highest concentrations of IGF-1 and insulin, the expression of ICE, Bcl-2 and Bax was fully suppressed, whereas the p53 product level increased, despite still being detectable in a minority of cells. Under these conditions, IGF-1 may increase p53 expression to restrain abnormal cell proliferation. It is concluded that special attention should be paid to exposure and culture conditions that induce acquired susceptibility to a toxic insult, during the development and validation of cell-based assays.
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| 2. |
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| 3. |
- Andersson, Martin, et al.
(författare)
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In Silico Prediction of Eye Irritation Using Hansen Solubility Parameters and Predicted pKa Values
- 2023
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Ingår i: ATLA (Alternatives to Laboratory Animals). - : SAGE Publications Inc.. - 0261-1929. ; 51:3, s. 204-
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Tidskriftsartikel (refereegranskat)abstract
- An in silico method has been developed that permits the binary differentiation between pure liquids causing serious eye damage or eye irritation, and pure liquids with no need for such classification, according to the UN GHS system. The method is based on the finding that the Hansen Solubility Parameters (HSP) of a liquid are collectively important predictors for eye irritation. Thus, by applying a two-tier approach in which in silico predicted pKa values (firstly) and a trained model based solely on in silico-predicted HSP data (secondly) were used, we have developed, and validated, a fully in silico approach for predicting the outcome of a Draize test (in terms of UN GHS Cat. 1/Cat. 2A/Cat. 2B or UN GHS No Cat.) with high validation set performance (sensitivity = 0.846, specificity = 0.818, balanced accuracy = 0.832) using SMILES only. The method is applicable to pure non-ionic liquids with molecular weight below 500 g/mol, fewer than six hydrogen bond donors (e.g. nitrogen–hydrogen or oxygen–hydrogen bonds) and fewer than eleven hydrogen bond acceptors (e.g. nitrogen or oxygen atoms). Due to its fully in silico characteristics, this method can be applied to pure liquids that are still at the desktop design stage and not yet in production.
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| 4. |
- Baumans, V
(författare)
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Methods for evaluation of laboratory animal well-being
- 2004
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Ingår i: Alternatives to laboratory animals : ATLA. - : SAGE Publications. - 0261-1929 .- 2632-3559. ; 3232 Suppl 1A, s. 161-162
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Tidskriftsartikel (refereegranskat)abstract
- Well-being is a relative concept, referring to the state of an animal in relation to its ability to cope with its environment. This ability to cope is what we usually try to measure when evaluating the animal's well-being. Good welfare is, in general, considered to be related to a broad behavioural repertoire, which requires a considerable knowledge of the animal's species-specific behaviour and their basic biology. Ideally, well-being should be measured in a positive way, such as measuring pleasure by anticipatory behaviour. However, parameters have more often been designed for detecting failures to cope, leading to stress and/or discomfort. Parameters used in the assessment of discomfort are behavioural parameters, such as stereotypies, reduction in grooming, changes in activity; physiological parameters, such as body weight, abnormal posture, respiratory signs, heart rate, hormone levels; and post-mortem signs, as retrospective parameters, such as stomach ulcers, adrenal cortex size, fatty deposits. The usefulness of these parameters is discussed.
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| 8. |
- Brandmaier, Stefan, et al.
(författare)
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The QSPR-THESAURUS : The Online Platform of the CADASTER Project
- 2014
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Ingår i: ATLA (Alternatives to Laboratory Animals). - : SAGE Publications. - 0261-1929. ; 42:1, s. 13-24
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the CADASTER project (CAse Studies on the Development and Application of in Silico Techniques for Environmental Hazard and Risk Assessment) was to exemplify REACH-related hazard assessments for four classes of chemical compound, namely, polybrominated diphenylethers, per and polyfluorinated compounds, (benzo)triazoles, and musks and fragrances. The QSPR-THESAURUS website (http: / /qspr-thesaurus.eu) was established as the project's online platform to upload, store, apply, and also create, models within the project. We overview the main features of the website, such as model upload, experimental design and hazard assessment to support risk assessment, and integration with other web tools, all of which are essential parts of the QSPR-THESAURUS.
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| 10. |
- Burt, Tal, et al.
(författare)
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Phase 0, Including Microdosing Approaches : Applying the Three Rs and Increasing the Efficiency of Human Drug Development
- 2018
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Ingår i: ATLA (Alternatives to Laboratory Animals). - : FRAME. - 0261-1929. ; 46:6, s. 335-346
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Tidskriftsartikel (refereegranskat)abstract
- Phase 0 approaches, including microdosing, involve the use of sub-therapeutic exposures to the tested drugs, thus enabling safer, more-relevant, quicker and cheaper first-in-human (FIH) testing. These approaches also have considerable potential to limit the use of animals in human drug development. Recent years have witnessed progress in applications, methodology, operations, and drug development culture. Advances in applications saw an expansion in therapeutic areas, developmental scenarios and scientific objectives, in, for example, protein drug development and paediatric drug development. In the operational area, the increased sensitivity of Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS), expansion of the utility of Positron Emission Tomography (PET) imaging, and the introduction of Cavity Ring-Down Spectroscopy (CRDS), have led to the increased accessibility and utility of Phase 0 approaches, while reducing costs and exposure to radioactivity. PET has extended the application of microdosing, from its use as a predominant tool to record pharmacokinetics, to a method for recording target expression and target engagement, as well as cellular and tissue responses. Advances in methodology include adaptive Phase 0/Phase 1 designs, cassette and cocktail microdosing, and Intra-Target Microdosing (ITM), as well as novel modelling opportunities and simulations. Importantly, these methodologies increase the predictive power of extrapolation from microdose to therapeutic level exposures. However, possibly the most challenging domain in which progress has been made, is the culture of drug development. One of the main potential values of Phase 0 approaches is the opportunity to terminate development early, thus not only applying the principle of 'kill-early-kill-cheap' to enhance the efficiency of drug development, but also obviating the need for the full package of animal testing required for therapeutic level Phase 1 studies. Finally, we list developmental scenarios that utilised Phase 0 approaches in novel drug development.
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