The translational value of calcium pyrophosphate deposition disease experimental mouse models.

The deposition of calcium pyrophosphate (CPP) crystals in joint tissues causes acute and chronic arthritis that commonly affect the adult and elderly population. Experimental calcium pyrophosphate deposition disease (CPPD) models are divided into genetically modified models and crystal-induced inflammation models. The former do not reproduce phenotypes overlapping with the human disease, while in the latter, the direct injection of crystals into the ankles, dorsal air pouch or peritoneum constitutes a useful and reliable methodology that resembles the CPP induced-inflammatory condition in humans. The translational importance of the induced model is also strengthened by the fact that the key molecular and cellular mediators involved in inflammation are shared between humans and laboratory rodents. Although, in vivo models are indispensable tools for studying the pathogenesis of the CPPD and testing new therapies, their development is still at an early stage and major efforts are needed to address this issue. Here, we analyze the strenghts and limitations of each currently available CPPD in vivo model, and critically discuss their translational value.

How can we achieve more accurate reporting of average dog lifespan?

Despite major advances in our understanding of dogs as a biological system (including genetics/epigenetics, physiology, cognition, and behavior), the veterinary field lacks consensus around a critical piece of information: namely, the average lifespan/life expectancy of a domestic dog. This deficiency is due in part to unavailable and/or inconsistent collection of dog mortality data. In an effort to review historical and current reports of dog lifespan to determine whether the domestic dog's lifespan has changed over time, we found that incongruous data were prohibitive to conducting a formal meta-analysis of dog lifespan reports. However, in examining several different kinds of dog aging and mortality studies covering a span of about 40 years (1981 to 2023), it seems apparent that the median lifespan of domesticated dogs has not recently decreased, as has been reported in the popular press, but rather has increased steadily over that time frame. Still, assessing the validity of these numbers is a challenge, as methodology, cohort, and covariates (such as weight, breed, etc) vary from study to study. We therefore recommend the adoption of a comprehensive, standardized method for reporting and recording dog mortality so that a more accurate understanding of dogs' average lifespan can be obtained in the future.

Maximizing translational value in models of compulsive behavior: A commentary on Pickenhan et al. (2024).

In this issue of Cognitive, Affective, and Behavioral Neuroscience, Pickenhan et al. (2024) discuss the need for translational studies to understand features underlying obsessive-compulsive disorder (OCD). They highlight the translational value of the observing-response task (ORT) for modeling functional and maladaptive checking behaviors, a common symptom of OCD.

The potential role of omentin-1 in obesity-related metabolic dysfunction-associated steatotic liver disease: evidence from translational studies.

BACKGROUND: Obesity, characterized by visceral adipose tissue (VAT) expansion, is closely associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Recent research has highlighted the crucial role of the adipose tissue-liver axis in the development of MASLD. In this study, we investigated the potential role of omentin-1, a novel adipokine expressed by VAT, in obesity-related MASLD pathogenesis. METHODS: Through in silico analysis of differentially expressed genes in VAT from obese patients with and without MASH, we identified omentin-1 as a significant candidate. To validate our findings, we measured omentin-1 levels in VAT and plasma of lean controls and obese patients with biopsy-proven MASLD. Additionally, we assessed omentin-1 expression in the VAT of diet-induced mice MASLD model. In vitro and ex vivo studies were conducted to investigate the effects of omentin-1 on MASLD-related mechanisms, including steatosis, inflammation, endoplasmic reticulum (ER) stress, and oxidative stress. We also analyzed the impact of D-glucose and insulin on VAT omentin-1 levels ex vivo. RESULTS: Compared to the lean group, the obese groups exhibited significantly lower VAT and plasma levels of omentin-1. Interestingly, within the obese groups, omentin-1 is further decreased in MASH groups, independent of fibrosis. Likewise, VAT of mice fed with high-fat diet, showing histological signs of MASH showed decreased omentin-1 levels as compared to their control diet counterpart. In vitro experiments on fat-laden human hepatocytes revealed that omentin-1 did not affect steatosis but significantly reduced TNF-α levels, ER stress, and oxidative stress. Similar results were obtained using ex vivo VAT explants from obese patients upon omentin-1 supplementation. Furthermore, omentin-1 decreased the mRNA expression of NF-κB and mitogen-activated protein kinases (ERK and JNK). Ex vivo VAT explants showed that D-glucose and insulin significantly reduced omentin-1 mRNA expression and protein levels. CONCLUSIONS: Collectively, our findings suggest that reduced omentin-1 levels contribute to the development of MASLD. Omentin-1 supplementation likely exerts its beneficial effects through the inhibition of the NF-κB and MAPK signaling pathways, and it may additionally play a role in the regulation of glucose and insulin metabolism. Further research is warranted to explore omentin-1 as a potential therapeutic target and/or biomarker for MASLD.

Protein Carbonylation as a Biomarker of Oxidative Stress and a Therapeutic Target in Neonatal Brain Damage.

Oxidative stress (OS) constitutes a pivotal factor within the mechanisms underlying brain damage, for which the immature brain is particularly vulnerable. This vulnerability is caused by the abundance of immature oligodendrocytes in the immature brain, which are highly susceptible to OS-induced harm. Consequently, any injurious process involving OS within the immature brain can lead to long-term myelination impairment. Among the detrimental repercussions of OS, protein carbonylation stands out as a prominently deleterious consequence. Noteworthy elevation of protein carbonylation is observable across diverse models of neonatal brain injury, following both diffuse and focal hypoxic-ischemic insults, as well as intraventricular hemorrhage, in diverse animal species encompassing rodents and larger mammals, and at varying stages of brain development. In the immature brain, protein carbonylation manifests as a byproduct of reactive nitrogen species, bearing profound implications for cell injury, particularly in terms of inflammation amplification. Moreover, protein carbonylation appears as a therapeutic target for mitigating neonatal brain damage. The administration of a potent antioxidant, such as cannabidiol, yields substantial neuroprotective effects. These encompass the reduction in cerebral damage, restoration of neurobehavioral performance, and preservation of physiological myelination. Such effects are linked to the modulation of protein carbonylation. The assessment of protein carbonylation emerges as a reliable method for comprehending the intricate mechanisms underpinning damage and neuroprotection within neonatal brain injury.

Immp2l knockdown in male mice increases stimulus-driven instrumental behaviour but does not alter goal-directed learning or neuron density in cortico-striatal circuits in a model of Tourette syndrome and autism spectrum disorder.

Cortico-striatal neurocircuits mediate goal-directed and habitual actions which are necessary for adaptive behaviour. It has recently been proposed that some of the core symptoms of autism spectrum disorder (ASD) and Gilles de la Tourette syndrome (GTS), such as tics and other repetitive behaviours, may emerge because of imbalances in these neurocircuits. We have recently developed a model of ASD and GTS by knocking down Immp2l, a mitochondrial gene frequently associated with these disorders. The current study sought to determine whether Immp2l knockdown (KD) in male mice alters flexible, goal- or cue- driven behaviour using procedures specifically designed to examine response-outcome and stimulus-response associations, which underlie goal-directed and habitual behaviour, respectively. Whether Immp2l KD alters neuron density in cortico-striatal neurocircuits known to regulate these behaviours was also examined. Immp2l KD mice and wild type-like mice (WT) were trained on Pavlovian and instrumental learning procedures where auditory cues predicted food delivery and lever-press responses earned a food outcome. It was demonstrated that goal-directed learning was not changed for Immp2l KD mice compared to WT mice, as lever-press responses were sensitive to changes in the value of the food outcome, and to contingency reversal and degradation. There was also no difference in the capacity of KD mice to form habitual behaviours compared to WT mice following extending training of the instrumental action. However, Immp2l KD mice were more responsive to auditory stimuli paired with food as indicated by a non-specific increase in lever response rates during Pavlovian-to-instrumental transfer. Finally, there were no alterations to neuron density in striatum or any prefrontal cortex or limbic brain structures examined. Thus, the current study suggests that Immp2l is not necessary for learned maladaptive goal or stimulus driven behaviours in ASD or GTS, but that it may contribute to increased capacity for external stimuli to drive behaviour. Alterations to stimulus-driven behaviour could potentially influence the expression of tics and repetitive behaviours, suggesting that genetic alterations to Immp2l may contribute to these core symptoms in ASD and GTS. Given that this is the first application of this battery of instrumental learning procedures to a mouse model of ASD or GTS, it is an important initial step in determining the contribution of known risk-genes to goal-directed versus habitual behaviours, which should be more broadly applied to other rodent models of ASD and GTS in the future.

Patient-derived preclinical models to develop immunotherapies.

Cancer immunotherapy has revolutionized the treatment of some malignancies. Yet, many tumors do not unfortunately respond to immune-based therapies. Deeper insights into the biology of the immune response to cancer are required to identify novel therapeutic targets and advance immuno-oncology. To do so, we need to study cancer in patient-derived models that can faithfully recapitulate and capture the complexity and heterogeneity of the tumor immune ecosystem. Platforms facilitating the analysis of the human tumor immune microenvironment of individual patients are crucial. Patient-derived models are fundamental not only to better understand the biology of the cancer immune system but also to discern the mechanism of action of therapeutic compounds and perform preclinical studies toward improving the success of subsequent clinical testing. In this viewpoint, I present a brief review of patient-derived models for cancer immunotherapy.

Effects of Transient Administration of the NMDA Receptor Antagonist MK-801 in Drosophila melanogaster Activity, Sleep, and Negative Geotaxis.

MK-801, also called dizocilpine, is an N-methyl-D-aspartate (NMDA) receptor antagonist widely used in animal research to model schizophrenia-like phenotypes. Although its effects in rodents are well characterised, little is known about the outcomes of this drug in other organisms. In this study, we characterise the effects of MK-801 on the locomotion, sleep, and negative geotaxis of the fruit fly Drosophila melanogaster. We observed that acute (24 h) and chronic (7 days) administration of MK-801 enhanced negative geotaxis activity in the forced climbing assay for all tested concentrations (0.15 mM, 0.3 mM, and 0.6 mM). Moreover, acute administration, but not chronic, increased the flies' locomotion in a dose-dependent matter. Finally, average sleep duration was not affected by any concentration or administration protocol. Our results indicate that acute MK-801 could be used to model hyperactivity phenotypes in Drosophila melanogaster. Overall, this study provides further evidence that the NMDA receptor system is functionally conserved in flies, suggesting the usefulness of this model to investigate several phenotypes as a complement and replacement of the rodent models within drug discovery.

Spontaneous Behavioural Recovery Following Stroke Relates to the Integrity of Parietal and Temporal Regions.

Stroke is a devastating disease that results in neurological deficits and represents a leading cause of death and disability worldwide. Following a stroke, there is a degree of spontaneous recovery of function, the neural basis of which is of great interest among clinicians in their efforts to reduce disability following stroke and enhance rehabilitation. Conventionally, work on spontaneous recovery has tended to focus on the neural reorganization of motor cortical regions, with comparably little attention being paid to changes in non-motor regions and how these relate to recovery. Here we show, using structural neuroimaging in a macaque stroke model (N = 31) and by exploiting individual differences in spontaneous behavioural recovery, that the preservation of regions in the parietal and temporal cortices predict animal recovery. To characterize recovery, we performed a clustering analysis using Non-Human Primate Stroke Scale (NHPSS) scores and identified a good versus poor recovery group. By comparing the preservation of brain volumes in the two groups, we found that brain areas in integrity of brain areas in parietal, temporal and somatosensory cortex were associated with better recovery. In addition, a decoding approach performed across all subjects revealed that the preservation of specific brain regions in the parietal, somatosensory and medial frontal cortex predicted recovery. Together, these findings highlight the importance of parietal and temporal regions in spontaneous behavioural recovery.

Goats as Valuable Animal Model to Test the Targeted Glutamate Supplementation upon Antral Follicle Number, Ovulation Rate, and LH-Pulsatility.

The potential effect of intravenous administration of glutamate on the ovarian activity and the LH secretion pattern, considering the anestrous yearling goat as an animal model, were assessed. In late April, yearling goats (n = 20) were randomly assigned to either (1) Glutamate supplemented (GLUT; n = 10, Live Weight (LW) = 29.6 ± 1.02 kg, Body Condition (BCS) = 3.4 ± 0.2 units; i.v. supplemented with 7 mg GLUT kg−1 LW) or (2) Non-supplemented (CONT; n = 10; LW = 29.2 ± 1.07 kg, BCS = 3.5 ± 0.2 units; i.v. saline). The oats were estrus-synchronized; blood sampling (6 h × 15 min) was carried out for LH quantification. Response variables included pulsatility (PULSE), time to first pulse (TTFP), amplitude (AMPL), nadir (NAD), and area under the curve (AUC) of LH. Ovaries were ultra-sonographically scanned to assess ovulation rate (OR), number of antral follicles (AF), and total ovarian activity (TOA = OR + AF). LH-PULSE was quantified with the Munro algorithm; significant treatment x time interactions were evaluated across time. The variables LW and BCS did not differ (p > 0.05) between the experimental groups. Nevertheless, OR (1.77 vs. 0.87 ± 0.20 units), TOA (4.11 vs. 1.87 ± 0.47 units) and LH-PULSE (5.0 vs. 2.2 pulses 6 h-1) favored (p < 0.05) to the GLUT group. Our results reveal that targeted glutamate supplementation, the main central nervous system neurotransmitter, arose as an interesting strategy to enhance the hypothalamic−hypophyseal−ovarian response considering the anestrous-yearling goat as an animal model, with thought-provoking while promising translational applications.

Evaluating Translational Methods for Personalized Medicine-A Scoping Review.

The introduction of personalized medicine, through the increasing multi-omics characterization of disease, brings new challenges to disease modeling. The scope of this review was a broad evaluation of the relevance, validity, and predictive value of the current preclinical methodologies applied in stratified medicine approaches. Two case models were chosen: oncology and brain disorders. We conducted a scoping review, following the Joanna Briggs Institute guidelines, and searched PubMed, EMBASE, and relevant databases for reports describing preclinical models applied in personalized medicine approaches. A total of 1292 and 1516 records were identified from the oncology and brain disorders search, respectively. Quantitative and qualitative synthesis was performed on a final total of 63 oncology and 94 brain disorder studies. The complexity of personalized approaches highlights the need for more sophisticated biological systems to assess the integrated mechanisms of response. Despite the progress in developing innovative and complex preclinical model systems, the currently available methods need to be further developed and validated before their potential in personalized medicine endeavors can be realized. More importantly, we identified underlying gaps in preclinical research relating to the relevance of experimental models, quality assessment practices, reporting, regulation, and a gap between preclinical and clinical research. To achieve a broad implementation of predictive translational models in personalized medicine, these fundamental deficits must be addressed.

Myxofibrosarcoma landscape: diagnostic pitfalls, clinical management and future perspectives.

Myxofibrosarcoma (MFS) is a common entity of adult soft tissue sarcomas (STS) characterized by a predilection of the extremities and a high local recurrence rate. Originally classified as a myxoid variant of malignant fibrous histiocytoma, this musculoskeletal tumor has been recognized since 2002 as a distinct histotype showing a spectrum of malignant fibroblastic lesions with myxoid stroma, pleomorphism and curvilinear vessels. Currently, the molecular pathogenesis of MFS is still poorly understood and its genomic profile exhibits a complex karyotype with a number of aberrations including amplifications, deletions and loss of function. The diagnosis is challenging due to the unavailability of specific immunohistochemical markers and is based on the analysis of cytomorphologic features. The mainstay of treatment for localized disease is represented by surgical resection, with (neo)-adjuvant radio- and chemotherapy. In the metastatic setting, chemotherapy represents the backbone of treatments, however its role is still controversial and the outcome is very poor. Recent advent of genomic profiling, targeted therapies and larger enrollment of patients in translational and clinical studies, have improved the understanding of biological behavior and clinical outcome of such a disease. This review will provide an overview of current diagnostic pitfalls and clinical management of MFS. Finally, a look at future directions will be discussed.

Porcine Models of the Intestinal Microbiota: The Translational Key to Understanding How Gut Commensals Contribute to Gastrointestinal Disease.

In the United States, gastrointestinal disorders account for in excess of $130 billion in healthcare expenditures and 22 million hospitalizations annually. Many of these disorders, including necrotizing enterocolitis of infants, obesity, diarrhea, and inflammatory bowel disease, are associated with disturbances in the gastrointestinal microbial composition and metabolic activity. To further elucidate the pathogenesis of these disease syndromes as well as uncover novel therapies and preventative measures, gastrointestinal researchers should consider the pig as a powerful, translational model of the gastrointestinal microbiota. This is because pigs and humans share striking similarities in their intestinal microbiota as well as gastrointestinal anatomy and physiology. The introduction of gnotobiotic pigs, particularly human-microbial associated pigs, has already amplified our understanding of many gastrointestinal diseases that have detrimental effects on human health worldwide. Continued utilization of these models will undoubtedly inform translational advancements in future gastrointestinal research and potential therapeutics.

Genetic testing of dogs predicts problem behaviors in clinical and nonclinical samples.

BACKGROUND: Very little is known about the etiology of personality and psychiatric disorders. Because the core neurobiology of many such traits is evolutionarily conserved, dogs present a powerful model. We previously reported genome scans of breed averages of ten traits related to fear, anxiety, aggression and social behavior in multiple cohorts of pedigree dogs. As a second phase of that discovery, here we tested the ability of markers at 13 of those loci to predict canine behavior in a community sample of 397 pedigree and mixed-breed dogs with individual-level genotype and phenotype data. RESULTS: We found support for all markers and loci. By including 122 dogs with veterinary behavioral diagnoses in our cohort, we were able to identify eight loci associated with those diagnoses. Logistic regression models showed subsets of those loci could predict behavioral diagnoses. We corroborated our previous findings that small body size is associated with many problem behaviors and large body size is associated with increased trainability. Children in the home were associated with anxiety traits; illness and other animals in the home with coprophagia; working-dog status with increased energy and separation-related problems; and competitive dogs with increased aggression directed at familiar dogs, but reduced fear directed at humans and unfamiliar dogs. Compared to other dogs, Pit Bull-type dogs were not defined by a set of our markers and were not more aggressive; but they were strongly associated with pulling on the leash. Using severity-threshold models, Pit Bull-type dogs showed reduced risk of owner-directed aggression (75th quantile) and increased risk of dog-directed fear (95th quantile). CONCLUSIONS: Our association analysis in a community sample of pedigree and mixed-breed dogs supports the interbreed mapping. The modeling shows some markers are predictive of behavioral diagnoses. Our findings have broad utility, including for clinical and breeding purposes, but we caution that thorough understanding is necessary for their interpretation and use.

Using zebrafish (Danio rerio) models to understand the critical role of social interactions in mental health and wellbeing.

Social behavior represents a beneficial interaction between conspecifics that is critical for maintaining health and wellbeing. Dysfunctional or poor social interaction are associated with increased risk of physical (e.g., vascular) and psychiatric disorders (e.g., anxiety, depression, and substance abuse). Although the impact of negative and positive social interactions is well-studied, their underlying mechanisms remain poorly understood. Zebrafish have well-characterized social behavior phenotypes, high genetic homology with humans, relative experimental simplicity and the potential for high-throughput screens. Here, we discuss the use of zebrafish as a candidate model organism for studying the fundamental mechanisms underlying social interactions, as well as potential impacts of social isolation on human health and wellbeing. Overall, the growing utility of zebrafish models may improve our understanding of how the presence and absence of social interactions can differentially modulate various molecular and physiological biomarkers, as well as a wide range of other behaviors.

Convergent cross-species pro-cognitive effects of RGH-235, a new potent and selective histamine H3 receptor antagonist/inverse agonist.

The histamine H3 receptor is a favourable target for the treatment of cognitive deficits. Here we report the in vitro and in vivo profile of RGH-235, a new potent, selective, and orally active H3 receptor antagonist/inverse agonist developed by Gedeon Richter Plc. Radioligand binding and functional assays were used for in vitro profiling. Procognitive efficacy was investigated in rodent cognitive tests, in models of attention deficit hyperactive disorder (ADHD) and in cognitive tests of high translational value (rat touch screen visual discrimination test, primate fixed-foreperiod visual reaction time task). Results were supported by pharmacokinetic studies, neurotransmitter release, sleep EEG and dipsogenia. RGH-235 displayed high affinity to H3 receptors (Ki = 3.0-9.2 nM, depending on species), without affinity to H1, H2 or H4 receptors and >100 other targets. RGH-235 was an inverse agonist ([35S] GTPγS binding) and antagonist (pERK1/2 ELISA), showing favourable kinetics, inhibition of the imetit-induced dipsogenia and moderate effects on sleep-wake EEG. RGH-235 stimulated neurotransmitter release both in vitro and in vivo. RGH-235 was active in spontaneously hypertensive rats (SHR), generally considered as a model of ADHD, and revealed a robust pro-cognitive profile both in rodent and primate tests (in 0.3-1 mg/kg) and in models of high translational value (e.g. in a rodent touch screen test and in non-human primates). The multiple and convergent procognitive effects of RGH-235 support the view that beneficial cognitive effects can be linked to antagonism/inverse agonism of H3 receptors.

Patient-Derived Explants of Colorectal Cancer: Histopathological and Molecular Analysis of Long-Term Cultures.

Colorectal cancer (CRC) is one of the most common cancers worldwide. Although short-term cultures of tumour sections and xenotransplants have been used to determine drug efficacy, the results frequently fail to confer clinically useful information. Biomarker discovery has changed the paradigm for advanced CRC, though the presence of a biomarker does not necessarily translate into therapeutic success. To improve clinical outcomes, translational models predictive of drug response are needed. We describe a simple method for the fast establishment of CRC patient-derived explant (CRC-PDE) cultures from different carcinogenesis pathways, employing agitation-based platforms. A total of 26 CRC-PDE were established and a subset was evaluated for viability (n = 23), morphology and genetic key alterations (n = 21). CRC-PDE retained partial tumor glandular architecture and microenvironment features were partially lost over 4 weeks of culture. Key proteins (p53 and Mismatch repair) and oncogenic driver mutations of the original tumours were sustained throughout the culture. Drug challenge (n = 5) revealed differential drug response from distinct CRC-PDE cases. These findings suggest an adequate representation of the original tumour and highlight the importance of detailed model characterisation. The preservation of key aspects of the CRC microenvironment and genetics supports CRC-PDE potential applicability in pre- and co-clinical settings, as long as temporal dynamics are considered.

Translational Animal Models Provide Insight Into Mesenchymal Stromal Cell (MSC) Secretome Therapy.

The therapeutic potential of the mesenchymal stromal cell (MSC) secretome, consisting of all molecules secreted by MSCs, is intensively studied. MSCs can be readily isolated, expanded, and manipulated in culture, and few people argue with the ethics of their collection. Despite promising pre-clinical studies, most MSC secretome-based therapies have not been implemented in human medicine, in part because the complexity of bioactive factors secreted by MSCs is not completely understood. In addition, the MSC secretome is variable, influenced by individual donor, tissue source of origin, culture conditions, and passage. An increased understanding of the factors that make up the secretome and the ability to manipulate MSCs to consistently secrete factors of biologic importance will improve MSC therapy. To aid in this goal, we can draw from the wealth of information available on secreted factors from MSC isolated from veterinary species. These translational animal models will inspire efforts to move human MSC secretome therapy from bench to bedside.

Mouse avatars of human cancers: the temporality of translation in precision oncology.

Patient-derived xenografts (PDXs) are currently promoted as new translational models in precision oncology. PDXs are immunodeficient mice with human tumors that are used as surrogate models to represent specific types of cancer. By accounting for the genetic heterogeneity of cancer tumors, PDXs are hoped to provide more clinically relevant results in preclinical research. Further, in the function of so-called "mouse avatars", PDXs are hoped to allow for patient-specific drug testing in real-time (in parallel to treatment of the corresponding cancer patient). This paper examines the circulation of knowledge and bodily material across the species boundary of human and personalized mouse model, historically as well as in contemporary practices. PDXs raise interesting questions about the relation between animal model and human patient, and about the capacity of hybrid or interspecies models to close existing translational gaps. We highlight that the translational potential of PDXs not only depends on representational matching of model and target, but also on temporal alignment between model development and practical uses. Aside from the importance of ensuring temporal stability of human tumors in a murine body, the mouse avatar concept rests on the possibility of aligning the temporal horizons of the clinic and the lab. We examine strategies to address temporal challenges, including cryopreservation and biobanking, as well as attempts to speed up translation through modification and use of faster developing organisms. We discuss how featured model virtues change with precision oncology, and contend that temporality is a model feature that deserves more philosophical attention.