scholarly journals Development of a Web-Based Toolbox to Support Quantitative In-Vitro-to-In-Vivo Extrapolations (QIVIVE) within Nonanimal Testing Strategies

2020 ◽  
Author(s):  
Ans Punt ◽  
Nicole Pinckaers ◽  
Ad Peijnenburg ◽  
Jochem Louisse
Keyword(s):  
Web Based ◽  
Testing Strategies

scholarly journals A fast and reliable method for monitoring genomic instability in the model organism Caenorhabditis elegans

2021 ◽  
Author(s):  
Merle Marie Nicolai ◽  
Barbara Witt ◽  
Andrea Hartwig ◽  
Tanja Schwerdtle ◽  
Julia Bornhorst
Keyword(s):  
Caenorhabditis Elegans ◽  
Animal Experiments ◽  
Model Organism ◽  
Animal Testing ◽  
C Elegans ◽  
Testing Strategies ◽  
Genotoxic Agents ◽  
Genotoxicity Testing

AbstractThe identification of genotoxic agents and their potential for genotoxic alterations in an organism is crucial for risk assessment and approval procedures of the chemical and pharmaceutical industry. Classically, testing strategies for DNA or chromosomal damage focus on in vitro and in vivo (mainly rodent) investigations. In cell culture systems, the alkaline unwinding (AU) assay is one of the well-established methods for detecting the percentage of double-stranded DNA (dsDNA). By establishing a reliable lysis protocol, and further optimization of the AU assay for the model organism Caenorhabditis elegans (C. elegans), we provided a new tool for genotoxicity testing in the niche between in vitro and rodent experiments. The method is intended to complement existing testing strategies by a multicellular organism, which allows higher predictability of genotoxic potential compared to in vitro cell line or bacterial investigations, before utilizing in vivo (rodent) investigations. This also allows working within the 3R concept (reduction, refinement, and replacement of animal experiments), by reducing and possibly replacing animal testing. Validation with known genotoxic agents (bleomycin (BLM) and tert-butyl hydroperoxide (tBOOH)) proved the method to be meaningful, reproducible, and feasible for high-throughput genotoxicity testing, and especially preliminary screening.

scholarly journals Predicting the In Vivo Performance of Cardiovascular Biomaterials: Current Approaches In Vitro Evaluation of Blood-Biomaterial Interactions

2021 ◽  
Vol 22 (21) ◽  
pp. 11390
Author(s):  
Anne Strohbach ◽  
Raila Busch
Keyword(s):  
Complement Activation ◽  
Clinical Success ◽  
In Vitro Models ◽  
The Body ◽  
Coagulation Cascade ◽  
Biological Processes ◽  
Testing Strategies ◽  
Cardiovascular Implants

The therapeutic efficacy of a cardiovascular device after implantation is highly dependent on the host-initiated complement and coagulation cascade. Both can eventually trigger thrombosis and inflammation. Therefore, understanding these initial responses of the body is of great importance for newly developed biomaterials. Subtle modulation of the associated biological processes could optimize clinical outcomes. However, our failure to produce truly blood compatible materials may reflect our inability to properly understand the mechanisms of thrombosis and inflammation associated with biomaterials. In vitro models mimicking these processes provide valuable insights into the mechanisms of biomaterial-induced complement activation and coagulation. Here, we review (i) the influence of biomaterials on complement and coagulation cascades, (ii) the significance of complement-coagulation interactions for the clinical success of cardiovascular implants, (iii) the modulation of complement activation by surface modifications, and (iv) in vitro testing strategies.

scholarly journals The Current Understanding of Autophagy in Nanomaterial Toxicity and Its Implementation in Safety Assessment-Related Alternative Testing Strategies

2020 ◽  
Vol 21 (7) ◽  
pp. 2387 ◽  
Author(s):  
Rong-Jane Chen ◽  
Yu-Ying Chen ◽  
Mei-Yi Liao ◽  
Yu-Hsuan Lee ◽  
Zi-Yu Chen ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Health And Safety ◽  
Adverse Outcomes ◽  
Testing Strategy ◽  
C Elegans ◽  
Testing Strategies ◽  
Alternative Testing ◽  
Alternative Testing Strategies

Nanotechnology has rapidly promoted the development of a new generation of industrial and commercial products; however, it has also raised some concerns about human health and safety. To evaluate the toxicity of the great diversity of nanomaterials (NMs) in the traditional manner, a tremendous number of safety assessments and a very large number of animals would be required. For this reason, it is necessary to consider the use of alternative testing strategies or methods that reduce, refine, or replace (3Rs) the use of animals for assessing the toxicity of NMs. Autophagy is considered an early indicator of NM interactions with cells and has been recently recognized as an important form of cell death in nanoparticle-induced toxicity. Impairment of autophagy is related to the accelerated pathogenesis of diseases. By using mechanism-based high-throughput screening in vitro, we can predict the NMs that may lead to the generation of disease outcomes in vivo. Thus, a tiered testing strategy is suggested that includes a set of standardized assays in relevant human cell lines followed by critical validation studies carried out in animals or whole organism models such as C. elegans (Caenorhabditis elegans), zebrafish (Danio rerio), and Drosophila (Drosophila melanogaster)for improved screening of NM safety. A thorough understanding of the mechanisms by which NMs perturb biological systems, including autophagy induction, is critical for a more comprehensive elucidation of nanotoxicity. A more profound understanding of toxicity mechanisms will also facilitate the development of prevention and intervention policies against adverse outcomes induced by NMs. The development of a tiered testing strategy for NM hazard assessment not only promotes a more widespread adoption of non-rodent or 3R principles but also makes nanotoxicology testing more ethical, relevant, and cost- and time-efficient.

Current development of integrated web servers for preclinical safety and pharmacokinetics assessments in drug development

2020 ◽  
Author(s):  
Yi Hsiao ◽  
Bo-Han Su ◽  
Yufeng J Tseng
Keyword(s):  
Drug Development ◽  
In Vitro Tests ◽  
Web Servers ◽  
Web Based ◽  
Structural Modifications ◽  
Drug Candidates ◽  
Alternative Choice ◽  
Preclinical Safety

Abstract In drug development, preclinical safety and pharmacokinetics assessments of candidate drugs to ensure the safety profile are a must. While in vivo and in vitro tests are traditionally used, experimental determinations have disadvantages, as they are usually time-consuming and costly. In silico predictions of these preclinical endpoints have each been developed in the past decades. However, only a few web-based tools have integrated different models to provide a simple one-step platform to help researchers thoroughly evaluate potential drug candidates. To efficiently achieve this approach, a platform for preclinical evaluation must not only predict key ADMET (absorption, distribution, metabolism, excretion and toxicity) properties but also provide some guidance on structural modifications to improve the undesired properties. In this review, we organized and compared several existing integrated web servers that can be adopted in preclinical drug development projects to evaluate the subject of interest. We also introduced our new web server, Virtual Rat, as an alternative choice to profile the properties of drug candidates. In Virtual Rat, we provide not only predictions of important ADMET properties but also possible reasons as to why the model made those structural predictions. Multiple models were implemented into Virtual Rat, including models for predicting human ether-a-go-go-related gene (hERG) inhibition, cytochrome P450 (CYP) inhibition, mutagenicity (Ames test), blood–brain barrier penetration, cytotoxicity and Caco-2 permeability. Virtual Rat is free and has been made publicly available at https://virtualrat.cmdm.tw/.

Empirical comparison and analysis of web-based cell-penetrating peptide prediction tools

2019 ◽  
Vol 21 (2) ◽  
pp. 408-420 ◽  
Author(s):  
Ran Su ◽  
Jie Hu ◽  
Quan Zou ◽  
Balachandran Manavalan ◽  
Leyi Wei
Keyword(s):  
Prediction Models ◽  
Cell Penetrating Peptides ◽  
Web Based ◽  
Practical Applications ◽  
Prediction Tools ◽  
Cell Penetrating ◽  
Potential Applications ◽  
Peptide Prediction

Abstract Cell-penetrating peptides (CPPs) facilitate the delivery of therapeutically relevant molecules, including DNA, proteins and oligonucleotides, into cells both in vitro and in vivo. This unique ability explores the possibility of CPPs as therapeutic delivery and its potential applications in clinical therapy. Over the last few decades, a number of machine learning (ML)-based prediction tools have been developed, and some of them are freely available as web portals. However, the predictions produced by various tools are difficult to quantify and compare. In particular, there is no systematic comparison of the web-based prediction tools in performance, especially in practical applications. In this work, we provide a comprehensive review on the biological importance of CPPs, CPP database and existing ML-based methods for CPP prediction. To evaluate current prediction tools, we conducted a comparative study and analyzed a total of 12 models from 6 publicly available CPP prediction tools on 2 benchmark validation sets of CPPs and non-CPPs. Our benchmarking results demonstrated that a model from the KELM-CPPpred, namely KELM-hybrid-AAC, showed a significant improvement in overall performance, when compared to the other 11 prediction models. Moreover, through a length-dependency analysis, we find that existing prediction tools tend to more accurately predict CPPs and non-CPPs with the length of 20–25 residues long than peptides in other length ranges.

Regulatory Genotoxicity Testing: A Critical Appraisal

1995 ◽  
Vol 23 (3) ◽  
pp. 352-379
Author(s):  
Robert D. Combes
Keyword(s):  
Data Interpretation ◽  
In Vitro Tests ◽  
Negative Results ◽  
Testing Strategies ◽  
Current Controversy ◽  
In Vivo Testing ◽  
Development And Validation ◽  
Genotoxicity Testing

This review considers current approaches to regulatory genotoxicity testing, focusing on how the use of animals can be further replaced, reduced and refined. The complementary roles of in vitro and in vivo testing, and the justification for using animals, are discussed in detail. Recommendations are made for improvements and further work, in the light of the considerable current controversy surrounding the composition and deployment of testing strategies, and the interpretation of the data generated, particularly for carcinogenicity prediction. The major problems are the oversensitivity of in vitro tests and the insensitivity of in vivo assays. On the basis of an analysis of some published databases, it is concluded that there is insufficient support for using in vivo genotoxicity assays for screening. Also, it is questionable whether the scientific benefits of using such assays always outweigh the costs to the animals involved. The considerable efforts being made to harmonise in vivo protocols and to develop improved methods for detecting genotoxicity are discussed. It is recommended that more emphasis be placed on characterising genotoxins in vitro, especially for mechanisms of activity, to optimise the benefits of any confirmatory animal tests.. Also, regulatory agencies are urged to require better-designed and more-scientifically sound protocols, in which animal numbers are minimised and data interpretation, particularly that of negative results, is facilitated. Lastly, in the development and validation of transgenic rodent systems, emphasis should be placed on developing protocols in which other acute toxicity and metabolism endpoints can be measured simultaneously with in vivo mutagenesis, while minimising animal numbers.

scholarly journals Characterization of an engineered live bacterial therapeutic for the treatment of phenylketonuria in a human gut-on-a-chip

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
M. Tyler Nelson ◽  
Mark R. Charbonneau ◽  
Heidi G. Coia ◽  
Mary J. Castillo ◽  
Corey Holt ◽  
...  
Keyword(s):  
Mechanistic Models ◽  
Human Gut ◽  
Primate Model ◽  
New Class ◽  
Testing Strategies ◽  
Dose Dependent ◽  
Engineered Strain

AbstractEngineered bacteria (synthetic biotics) represent a new class of therapeutics that leverage the tools of synthetic biology. Translational testing strategies are required to predict synthetic biotic function in the human body. Gut-on-a-chip microfluidics technology presents an opportunity to characterize strain function within a simulated human gastrointestinal tract. Here, we apply a human gut-chip model and a synthetic biotic designed for the treatment of phenylketonuria to demonstrate dose-dependent production of a strain-specific biomarker, to describe human tissue responses to the engineered strain, and to show reduced blood phenylalanine accumulation after administration of the engineered strain. Lastly, we show how in vitro gut-chip models can be used to construct mechanistic models of strain activity and recapitulate the behavior of the engineered strain in a non-human primate model. These data demonstrate that gut-chip models, together with mechanistic models, provide a framework to predict the function of candidate strains in vivo.

Induction and Differentiation of Dental Epithelium in Vivo and in Vitro

1982 ◽  
Vol 40 ◽  
pp. 142-145
Author(s):  
E. J. Kollar
Keyword(s):  
Connective Tissue ◽  
Oral Mucosa ◽  
Basal Lamina ◽  
Functional Derivatives ◽  
Specific Source ◽  
Dental Epithelium ◽  
Connective Tissue Stroma

The differentiation and maintenance of many specialized epithelial structures are dependent on the underlying connective tissue stroma and on an intact basal lamina. These requirements are especially stringent in the development and maintenance of the skin and oral mucosa. The keratinization patterns of thin or thick cornified layers as well as the appearance of specialized functional derivatives such as hair and teeth can be correlated with the specific source of stroma which supports these differentiated expressions.

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