Polymyositis in Kooiker dogs is associated with a 39 kb deletion upstream of the canine IL21/IL2 locus.

Recently we characterized polymyositis in the Dutch Kooiker dog. The familial occurrence of the disease were suggestive of an inherited cause. Here we report the results of our molecular genetic investigation.

Development and validation of animal variant classification guidelines to objectively evaluate genetic variant pathogenicity in domestic animals.

Assessing the pathogenicity of a disease-associated genetic variant in animals accurately is vital, both on a population and individual scale. At the population level, breeding decisions based on invalid DNA tests can lead to the incorrect inclusion or exclusion of animals and compromise the long-term health of a population, and at the level of the individual animal, lead to incorrect treatment and even life-ending decisions. Criteria to determine pathogenicity are not standardized, i.

Artificial Intelligence Advancements in Cardiomyopathies: Implications for Diagnosis and Management of Arrhythmogenic Cardiomyopathy.

Purpose Of Review: This review aims to explore the emerging potential of artificial intelligence (AI) in refining risk prediction, clinical diagnosis, and treatment stratification for cardiomyopathies, with a specific emphasis on arrhythmogenic cardiomyopathy (ACM).

Recent Findings: Recent developments highlight the capacity of AI to construct sophisticated models that accurately distinguish affected from non-affected cardiomyopathy patients. These AI-driven approaches not only offer precision in risk prediction and diagnostics but also enable early identification of individuals at high risk of developing cardiomyopathy, even before symptoms occur.

Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3 in the Netherlands.

Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in the cardiac myosin binding protein-C (cMyBP-C) encoding gene MYBPC3. In the Netherlands, approximately 25% of patients carry the MYBPC3 founder mutation. Most patients are heterozygous (MYBPC3) and have highly variable phenotypic expression, whereas homozygous (MYBPC3) patients have severe HCM at a young age.

Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human.

Background: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis.

Methods: We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM.

Whole transcriptome analysis of canine pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising from the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia, respectively. Local invasion, concurrent disorders, and metastases prevent surgical removal, which is the most effective treatment to date. Given the current lack of effective medical treatment, there is a need for novel therapeutic strategies.

Targeting lipid metabolism as a new therapeutic strategy for inherited cardiomyopathies.

Inherited cardiomyopathies caused by pathological genetic variants include multiple subtypes of heart disease. Advances in next-generation sequencing (NGS) techniques have allowed for the identification of numerous genetic variants as pathological variants. However, the disease penetrance varies among mutated genes.

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing.

Emerging advances in the field of in vitro toxicity testing attempt to meet the need for reliable human-based safety assessment in drug development. Intrahepatic cholangiocyte organoids (ICOs) are described as a donor-derived in vitro model for disease modelling and regenerative medicine. Here, we explored the potential of hepatocyte-like ICOs (HL-ICOs) in in vitro toxicity testing by exploring the expression and activity of genes involved in drug metabolism, a key determinant in drug-induced toxicity, and the exposure of HL-ICOs to well-known hepatotoxicants.

Transcriptome sequencing reveals two subtypes of cortisol-secreting adrenocortical tumours in dogs and identifies CYP26B1 as a potential new therapeutic target.

Cushing's syndrome (CS) is a serious endocrine disorder that is relatively common in dogs, but rare in humans. In ~15%-20% of cases, CS is caused by a cortisol-secreting adrenocortical tumour (csACT). To identify differentially expressed genes that can improve prognostic predictions after surgery and represent novel treatment targets, we performed RNA sequencing on csACTs (n = 48) and normal adrenal cortices (NACs; n = 10) of dogs.

Investigation of Genetic Modifiers of Copper Toxicosis in Labrador Retrievers.

Copper toxicosis is a complex genetic disorder in Labrador retrievers characterized by hepatic copper accumulation eventually leading to liver cirrhosis. The variation of hepatic copper levels in Labrador retrievers has been partly explained by mutations in c.980C>T and c.

Large Animal Models in Regenerative Medicine and Tissue Engineering: To Do or Not to Do.

Rapid developments in Regenerative Medicine and Tissue Engineering has witnessed an increasing drive toward clinical translation of breakthrough technologies. However, the progression of promising preclinical data to achieve successful clinical market authorisation remains a bottleneck. One hurdle for progress to the clinic is the transition from small animal research to advanced preclinical studies in large animals to test safety and efficacy of products.

A Chemically Defined Hydrogel for Human Liver Organoid Culture.

End-stage liver diseases are an increasing health burden, and liver transplantations are currently the only curative treatment option. Due to a lack of donor livers, alternative treatments are urgently needed. Human liver organoids are very promising for regenerative medicine; however, organoids are currently cultured in Matrigel, which is extracted from the extracellular matrix of the Engelbreth-Holm-Swarm mouse sarcoma.

Long-Term Survival of Transplanted Autologous Canine Liver Organoids in a -Deficient Dog Model of Metabolic Liver Disease.

The shortage of liver organ donors is increasing and the need for viable alternatives is urgent. Liver cell (hepatocyte) transplantation may be a less invasive treatment compared with liver transplantation. Unfortunately, hepatocytes cannot be expanded in vitro, and allogenic cell transplantation requires long-term immunosuppression.

Large-Scale Production of LGR5-Positive Bipotential Human Liver Stem Cells.

Background And Aims: The gap between patients on transplant waiting lists and available donor organs is steadily increasing. Human organoids derived from leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5)-positive adult stem cells represent an exciting new cell source for liver regeneration; however, culturing large numbers of organoids with current protocols is tedious and the level of hepatic differentiation is limited.

Approach And Results: Here, we established a method for the expansion of large quantities of human liver organoids in spinner flasks.

Characterization of Endothelial and Smooth Muscle Cells From Different Canine Vessels.

Vasculature performs a critical function in tissue homeostasis, supply of oxygen and nutrients, and the removal of metabolic waste products. Vascular problems are implicated in a large variety of pathologies and accurate models resembling native vasculature are of great importance. Unfortunately, existing models do not sufficiently reflect their counterpart.

Pulmonary veno-occlusive disease as a cause of severe pulmonary hypertension in a dog.

Background: Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary arterial hypertension (PAH) in humans and can be classified in idiopathic, heritable, drug and radiation-induced, and associated with connective tissue disease or human immunodeficiency virus infection. Recently, biallelic mutations of the EIF2AK4 gene have been discovered as a cause for an autosomal recessive form of PVOD in humans. In dogs, PAH is poorly characterized and is generally considered to be idiopathic or secondary to (for example) congenital left-to right cardiovascular shunts or heartworm disease.

Genome-wide based model predicting recovery from portosystemic shunting after liver shunt attenuation in dogs.

Background: In dogs with congenital portosystemic shunt (CPSS), recovery after surgical CPSS attenuation is difficult to predict.

Objectives: Our aim was to build a model with plasma albumin concentration and mRNA expression levels of hepatic gene products as predictors of recovery from portosystemic shunting after surgery.

Animals: Seventy-three client-owned dogs referred for surgical attenuation of CPSS.

Intestinal Organoids-Current and Future Applications.

Recent technical advances in the stem cell field have enabled the in vitro generation of complex structures resembling whole organs termed organoids. Most of these approaches employ culture systems that allow stem cell-derived or tissue progenitor cells to self-organize into three-dimensional (3D)-structures. Since organoids can be grown from different species (human, mouse, cat, dog), organs (intestine, kidney, brain, liver), and from patient-derived induced pluripotent stem cells, they create significant prospects for modelling development and diseases, for toxicology and drug discovery studies, and in the field of regenerative medicine.

Aberrant hepatic lipid storage and metabolism in canine portosystemic shunts.

Non-alcoholic fatty liver disease (NAFLD) is a poorly understood multifactorial pandemic disorder. One of the hallmarks of NAFLD, hepatic steatosis, is a common feature in canine congenital portosystemic shunts. The aim of this study was to gain detailed insight into the pathogenesis of steatosis in this large animal model.

Gene expression patterns in the progression of canine copper-associated chronic hepatitis.

Copper is an essential trace element, but can become toxic when present in abundance. The severe effects of copper-metabolism imbalance are illustrated by the inherited disorders Wilson disease and Menkes disease. The Labrador retriever dog breed is a novel non-rodent model for copper-storage disorders carrying mutations in genes known to be involved in copper transport.

Isolation and Culture of Primary Endothelial Cells from Canine Arteries and Veins.

Cardiovascular disease is studied in both human and veterinary medicine. Endothelial cells have been used extensively as an in vitro model to study vasculogenesis, (tumor) angiogenesis, and atherosclerosis. The current standard for in vitro research on human endothelial cells (ECs) is the use of Human Umbilical Vein Endothelial Cells (HUVECs) and Human Umbilical Artery Endothelial Cells (HUAECs).

Dwarfism with joint laxity in Friesian horses is associated with a splice site mutation in B4GALT7.

Background: Inbreeding and population bottlenecks in the ancestry of Friesian horses has led to health issues such as dwarfism. The limbs of dwarfs are short and the ribs are protruding inwards at the costochondral junction, while the head and back appear normal. A striking feature of the condition is the flexor tendon laxity that leads to hyperextension of the fetlock joints.