A Comparative View on Molecular Alterations and Potential Therapeutic Strategies for Canine Oral Melanoma

Canine oral melanoma (COM) is a highly aggressive tumour associated with poor prognosis due to metastasis and resistance to conventional anti-cancer therapies. As with human mucosal melanoma, the mutational landscape is predominated by copy number aberrations and chromosomal structural variants, but differences in study cohorts and/or tumour heterogeneity can lead to discordant results regarding the nature of specific genes affected. This review discusses somatic molecular alterations in COM that result from single nucleotide variations, copy number changes, chromosomal rearrangements, and/or dysregulation of small non-coding RNAs. A cross-species comparison highlights notable recurrent aberrations, and functionally grouping dysregulated proteins reveals unifying biological pathways that may be critical for oncogenesis and metastasis. Finally, potential therapeutic strategies are considered to target these pathways in canine patients, and the benefits of collaboration between science, medical, and veterinary communities are emphasised.

The Effects of Sex Hormones on Food Intake, Body Weight, and Fat Composition: A Cross-Species Analysis

Reproductive hormones affect the physiology of eating, body weight, and fat composition differently among the sexes and across multiple species. While the reproductive influences on feeding are known, these studies have been previously limited to just one species in both studies and literature reviews. In addition, discrepancies have also been found across different species. For instance, female mice tend to experience no changes in food consumption whether estradiol is present or not, while female rats experience a decrease in food consumption with the presence of estradiol. The lack of cross-species comparison in these findings leads to a limited understanding of the overall effects of feeding and body composition. Not only are studies limited to one species, but studies are also limited to one sex. Not comparing results to the opposite sex prevents the consideration and realization of the discrepancies in the effects of hormones among the sexes. For example, men with higher levels of testosterone were correlated with healthy Body Mass Index (BMI) levels while women with higher levels of testosterone tend to weigh more than women with normal levels of testosterone. This literature review focuses on inter-species and sex differences of the effects of reproductive hormones on feeding, body weight, and fat composition.

Pharmacokinetics and Disposition of Contezolid in Humans—Resolution of a Disproportionate Human Metabolite for Clinical Development

Contezolid (MRX-I), a novel oxazolidinone antibiotic, was recently approved for the treatment of serious Gram-positive infections. The pharmacokinetics and disposition of [ 14 C]contezolid were investigated in a single-dose human mass balance study. Cross-species comparison of plasma exposure for contezolid and metabolites was performed, and the safety of the disproportionate metabolite in human was evaluated with additional nonclinical studies. After an oral administration of 99.1 μCi/602 mg dose of [ 14 C]contezolid, approximately 91.5% of the radioactivity was recovered in 0–168 h postdose, mainly in urine and followed by feces. The principal metabolic pathway of contezolid in human comprised an oxidative ring opening of 2,3-dihydropyridin-4-one fragment into polar metabolites MRX445-1 and MRX459, with recovery of approximately 48% and 15% of the dose, respectively, in urine and feces. Contezolid, MRX445-1, and MRX459 accounted for 68.0%, 19.5%, and 4.84% of the plasma exposure of the total radioactivity, respectively. Metabolites MRX445-1 and MRX459 were observed in disproportionately higher amounts in human plasma as compared to that rat or dog, the rodent and nonrodent species used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies, wherein the primary metabolite, MRX445-1, was further characterized. The no observed adverse effect level (NOAEL) of MRX445-1 was determined as 360 mg/kg/day in 14-day repeat-dose test in pregnant and non-pregnant SD rats. Furthermore, MRX445-1 exhibited no antibacterial activity in vitro. Thus, MRX445-1 is not expected to exert clinically relevant pharmacology and toxicity.

Murine allele and transgene symbols: ensuring unique, concise, and informative nomenclature

In addition to naturally occurring sequence variation and spontaneous mutations, a wide array of technologies exist for modifying the mouse genome. Standardized nomenclature, including allele, transgene, and other mutation nomenclature, as well as persistent unique identifiers (PUID) are critical for effective scientific communication, comparison of results, and integration of data into knowledgebases such as Mouse Genome Informatics (MGI), Alliance for Genome Resources, and International Mouse Strain Resource (IMSR). As well as being the authoritative source for mouse gene, allele, and strain nomenclature, MGI integrates published and unpublished genomic, phenotypic, and expression data while linking to other online resources for a complete view of the mouse as a valuable model organism. The International Committee on Standardized Genetic Nomenclature for Mice has developed allele nomenclature rules and guidelines that take into account the number of genes impacted, the method of allele generation, and the nature of the sequence alteration. To capture details that cannot be included in allele symbols, MGI has further developed allele to gene relationships using sequence ontology (SO) definitions for mutations that provide links between alleles and the genes affected. MGI is also using (HGVS) variant nomenclature for variants associated with alleles that will enhance searching for mutations and will improve cross-species comparison. With the ability to assign unique and informative symbols as well as to link alleles with more than one gene, allele and transgene nomenclature rules and guidelines provide an unambiguous way to represent alterations in the mouse genome and facilitate data integration among multiple resources such the Alliance of Genome Resources and International Mouse Strain Resource.

Cross-species comparison of human and rodent primary reward consumption under budget constraints

We live in a world of limited resources. Optimal use of resources is therefore of great importance for survival. Previous studies have shown that rodents optimize their allocation of a limited number of operant responses (akin to a finite budget) to trade for food rewards. Here, we propose a novel human cost-benefit decision paradigm translated from an economic choice task initially developed for rodents, to examine human consumption of primary rewards in a budget-constrained consumption scenario. In the first study, heterosexual male participants made effortful presses to obtain the opportunity to watch erotic pictures (task 1: picture task) or drink milk rewards (task 2: milk task) with a limited budget (i.e. finite total amount of presses). Participants adapted their choice allocation when the price (i.e. number of presses required to produce a reward) and the budget changed. We compared our participants' choice pattern to that of rodent consumers performing a matched economic decision task. Our cross-species comparison suggests that humans responded to price and budget changes in a similar way as rat consumers when purchasing milk rewards. However, this was not the case when purchasing the opportunity to watch picture rewards: compared to the milk task and to the rodent task, participants made more internally inconsistent choices in the picture task that failed to comply to the requirements of rational choice theory, despite otherwise identical task structure. We found non-linear changes in arousal state as a function of choice selection of rewards that might potentially underlie the increased choice inconsistency in the picture task. In two control experiments, we replicated our main findings. Our study shows that humans and rodents comply surprisingly well to the predictions of rational choice theory, but that deviations from the rational ideal can be elicited depending on the reward type.

Sucrose Metabolism and Transport in Grapevines, with Emphasis on Berries and Leaves and Insights Gained from a Cross-Species Comparison

In grapevines, as in other plants, sucrose and its constituents glucose and fructose are fundamentally important and carry out a multitude of roles. The aims of this review are three-fold. First, to provide a summary of the metabolism and transport of sucrose in grapevines, together with new insights and interpretations. Second, to stress the importance of considering the compartmentation of metabolism. Third, to outline the key role of acid invertase in osmoregulation associated with sucrose metabolism and transport in plants.

Cross-species comparison of the oncogenomic landscape of canine and feline hemangiosarcoma shows novel parallels with human angiosarcoma

Angiosarcoma (AS) is a highly aggressive tumor of blood and lymphatic vessels in humans that carries a poor prognosis. The rarity of AS, together with its heterogeneous nature, and locations (skin, breast, visceral organs and deep soft tissues), makes understanding the pathogenesis of AS challenging. Dogs and cats spontaneously develop hemangiosarcoma (HSA), an aggressive tumor that shares many histopathological and clinical similarities to AS. To investigate the genetic suitability of spontaneously occurring HSA as a model for AS, we sequenced ∼1,000 cancer genes in 41 cases of HSA and matched germline tissue; 15 canine visceral HSAs, 13 canine skin HSAs and 13 feline skin HSAs. Analysis of visceral HSAs from dogs presenting with concurrent splenic and cardiac neoplasms showed that the tumors were not independent primaries, consistent with the highly metastatic nature of HSA. Comparison of canine and feline HSA to human AS revealed that several driver genes were recurrently mutated in both species, such as TP53, PIK3CA, ATRX, GRIN2A and LRP1B. In the germlines, by focusing specifically on canine and feline orthologs of human AS risk genes, we identified several candidate pathogenic variants. Similar to AS, a UV mutational signature was found in a subset of canine cutaneous HSAs. Furthermore, both AS and canine HSA show differing mutational profiles between tissue sites. Our characterization of canine and feline HSA demonstrate many important parallels to AS and provides hope that future studies on these cancers will benefit patients of all three species.

Obesity-instructed TREM2high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution

Mouse models are a tool for studying the mechanisms underlying complex diseases; however, differences between species pose a significant challenge for translating findings to patients. Here, we used single-cell transcriptomics and orthogonal validation approaches to provide cross-species taxonomies, identifying shared broad cell classes and unique granular cellular states, between mouse and human kidney. We generated cell atlases of the diabetic and obese kidney using two different mouse models, a high-fat diet (HFD) model and a genetic model (BTBR ob/ob), at multiple time points along disease progression. Importantly, we identified a previously unrecognized, expanding Trem2high macrophage population in kidneys of HFD mice that matched human TREM2high macrophages in obese patients. Taken together, our cross-species comparison highlights shared immune and metabolic cell-state changes.