Animal blood in translational research: How to adjust animal blood viscosity to the human standard.
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ABSTRACT:
SUBMITTER: Ecker P
PROVIDER: S-EPMC8157792 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder caused by mutations in the dystrophin gene. Affecting approximately 1 in 3,600-9337 boys, DMD patients exhibit progressive muscle degeneration leading to fatality as a result of heart or respiratory failure. Despite the severity and prevalence of the disease, there is no cure available. While murine models have been successfully used in illustrating the mechanisms of DMD, their utility in DMD research is limited due to their mild disease phenotypes such as lack of severe skeletal muscle and cardiac symptoms. To address the discrepancy between the severity of disease displayed by murine models and human DMD patients, dystrophin-deficient dog models with a splice site mutation in intron 6 were established. Examples of these are Golden Retriever muscular dystrophy and beagle-based Canine X-linked muscular dystrophy. These large animal models are widely employed in therapeutic DMD research due to their close resemblance to the severity of human patient symptoms. Recently, genetically tailored porcine models of DMD with deleted exon 52 were developed by our group and others, and can potentially act as a new large animal model. While therapeutic outcomes derived from these large animal models can be more reliably extrapolated to DMD patients, a comprehensive understanding of these models is still needed. This paper will discuss recent progress and future directions of DMD studies with large animal models such as canine and porcine models.
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Project description:BackgroundThe methodological quality of animal studies is an important factor hampering the translation of results from animal studies to a clinical setting. Systematic reviews of animal studies may provide a suitable method to assess and thereby improve their methodological quality.ObjectivesThe aims of this study were: 1) to evaluate the risk of bias assessment in animal-based systematic reviews, and 2) to study the internal validity of the primary animal studies included in these systematic reviews.Data sourcesWe systematically searched Pubmed and Embase for SRs of preclinical animal studies published between 2005 and 2012.ResultsA total of 91 systematic reviews met our inclusion criteria. The risk of bias was assessed in 48 (52.7%) of these 91 systematic reviews. Thirty-three (36.3%) SRs provided sufficient information to evaluate the internal validity of the included studies. Of the evaluated primary studies, 24.6% was randomized, 14.6% reported blinding of the investigator/caretaker, 23.9% blinded the outcome assessment, and 23.1% reported drop-outs.ConclusionsTo improve the translation of animal data to clinical practice, systematic reviews of animal studies are worthwhile, but the internal validity of primary animal studies needs to be improved. Furthermore, risk of bias should be assessed by systematic reviews of animal studies to provide insight into the reliability of the available evidence.
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Project description:Fibromyalgia is a refractory disease characterized by chronic intractable pain and psychological suffering, the cause of which has not yet been elucidated due to its complex pathology. Activation of immune cells in the brain called microglia has attracted attention as a potential underlying pathological mechanism in chronic pain. Until recently, however, technological and ethical considerations have limited the ability to conduct research using human microglia. To overcome this limitation, we have recently developed a technique to create human-induced microglia-like (iMG) cells from human peripheral blood monocytes. In this study, we created the iMG cells from 14 patients with fibromyalgia and 10 healthy individuals, and compared the activation of iMG cells between two groups at the cellular level. The expression of tumor necrosis factor (TNF)-? at mRNA and protein levels significantly increased in ATP-stimulated iMG cells from patients with fibromyalgia compared to cells from healthy individuals. Interestingly, there was a moderate correlation between ATP-induced upregulation of TNF-? expression and clinical parameters of subjective pain and other mental manifestations of fibromyalgia. These findings suggest that microglia in patients with fibromyalgia are hypersensitive to ATP. TNF-? from microglia may be a key factor underlying the complex pathology of fibromyalgia.
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Project description:To gain regulatory approval for the clinical use of knee biologics and devices in humans, translational large-animal studies are typically required. Animal models that permit second-look arthroscopy are valuable because they allow for longitudinal assessment of the treated tissue without needing to sacrifice the animal. The minipig is an ideal preclinical animal model for the investigation of therapies for the knee, in part because arthroscopy can be performed in its stifle (knee) joint with the use of standard surgical equipment used in humans. The purpose of this Technical Note is to describe a reproducible technique for diagnostic arthroscopy of the minipig stifle (knee) joint.
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Project description:The mouse is the main model organism used to study the functions of human genes because most biological processes in the mouse are highly conserved in humans. Recent reports that compared identical transcriptomic datasets of human inflammatory diseases with datasets from mouse models using traditional gene-to-gene comparison techniques resulted in contradictory conclusions regarding the relevance of animal models for translational research. To reduce susceptibility to biased interpretation, all genes of interest for the biological question under investigation should be considered. Thus, standardized approaches for systematic data analysis are needed. We analyzed the same datasets using gene set enrichment analysis focusing on pathways assigned to inflammatory processes in either humans or mice. The analyses revealed a moderate overlap between all human and mouse datasets, with average positive and negative predictive values of 48 and 57% significant correlations. Subgroups of the septic mouse models (i.e., Staphylococcus aureus injection) correlated very well with most human studies. These findings support the applicability of targeted strategies to identify the optimal animal model and protocol to improve the success of translational research.
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Project description:The Sydney Heart Bank (SHB) is one of the largest human heart tissue banks in existence. Its mission is to provide high-quality human heart tissue for research into the molecular basis of human heart failure by working collaboratively with experts in this field. We argue that, by comparing tissues from failing human hearts with age-matched non-failing healthy donor hearts, the results will be more relevant than research using animal models, particularly if their physiology is very different from humans. Tissue from heart surgery must generally be used soon after collection or it significantly deteriorates. Freezing is an option but it raises concerns that freezing causes substantial damage at the cellular and molecular level. The SHB contains failing samples from heart transplant patients and others who provided informed consent for the use of their tissue for research. All samples are cryopreserved in liquid nitrogen within 40 min of their removal from the patient, and in less than 5-10 min in the case of coronary arteries and left ventricle samples. To date, the SHB has collected tissue from about 450 failing hearts (>15,000 samples) from patients with a wide range of etiologies as well as increasing numbers of cardiomyectomy samples from patients with hypertrophic cardiomyopathy. The Bank also has hearts from over 120 healthy organ donors whose hearts, for a variety of reasons (mainly tissue-type incompatibility with waiting heart transplant recipients), could not be used for transplantation. Donor hearts were collected by the St Vincent's Hospital Heart and Lung transplantation team from local hospitals or within a 4-h jet flight from Sydney. They were flushed with chilled cardioplegic solution and transported to Sydney where they were quickly cryopreserved in small samples. Failing and/or donor samples have been used by more than 60 research teams around the world, and have resulted in more than 100 research papers. The tissues most commonly requested are from donor left ventricles, but right ventricles, atria, interventricular system, and coronary arteries vessels have also been reported. All tissues are stored for long-term use in liquid N or vapor (170-180 °C), and are shipped under nitrogen vapor to avoid degradation of sensitive molecules such as RNAs and giant proteins. We present evidence that the availability of these human heart samples has contributed to a reduction in the use of animal models of human heart failure.
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