Radioimmunotherapy Targeting IGF2R on Canine-Patient-Derived Osteosarcoma Tumors in Mice and Radiation Dosimetry in Canine and Pediatric Models

Background: Osteosarcoma (OS) has an overall patient survival rate of ~70% with no significant improvements in the last two decades, and novel effective treatments are needed. OS in companion dogs is phenotypically close to human OS, which makes a comparative oncology approach to developing new treatments for OS very attractive. We have recently created a novel human antibody, IF3 to IGF2R, which binds to this receptor on both human and canine OS tumors. Here, we evaluated the efficacy and safety of radioimmunotherapy with 177Lu-labeled IF3 of mice bearing canine-patient-derived tumors and performed canine and human dosimetry calculations. Methods: Biodistribution and microSPECT/CT imaging with 111In-IF3 was performed in mice bearing canine OS Gracie tumors, and canine and human dosimetry calculations were performed based on these results. RIT of Gracie-tumor-bearing mice was completed with 177Lu-IF3. Results: Biodistribution and imaging showed a high uptake of 111In-IF3 in the tumor and spleen. Dosimetry identified the tumor, spleen and pancreas as the organs with the highest uptake. RIT was very effective in abrogating tumor growth in mice with some spleen-associated toxicity. Conclusions: These results demonstrate that RIT with 177Lu-IF3 targeting IGF2R on experimental canine OS tumors effectively decreases tumor growth. However, because of the limitations of murine models, careful evaluation of the possible toxicity of this treatment should be performed via nuclear imaging and image-based dosimetry in healthy dogs before clinical trials in companion dogs with OS can be attempted.

Extended-Spectrum Beta-Lactamase-Producing and Carbapenem-Resistant Enterobacterales in Companion and Animal-Assisted Interventions Dogs

Animal-assisted interventions (AAIs) are being implemented in many countries for the beneficial effects they have on humans. Patients involved in AAI are often individuals at greater risk of acquiring infections, and these activities involve close contact between humans and animals, as is the case with humans living with a pet. The spread of multidrug-resistant Enterobacterales is a serious problem for human health; an integrated One Health strategy is imperative to combat this threat. Companion dogs can be a reservoir of multidrug-resistant pathogens, and animal-to-human transmission could occur during AAI sessions. The aim of this review was to collect the available data on the carriage of extended-spectrum beta-lactamase-producing and carbapenem-resistant Enterobacterales in companion dogs and in an AAI context. Several papers have generally addressed the issue of microbial transmission during AAIs. Studies on the intestinal carriage of extended-spectrum beta-lactamase and/or carbapenem-resistant Enterobacterales have mainly been conducted in companion animals while few data are available on the carriage in dogs participating in AAI sessions. This review aims to draw attention to the antibiotic resistance problem in a One Health context and to the importance of extending infection control measures to this human–animal interface, to keep the balance of benefits/risks for AAIs shifted towards the benefits of these activities.

Prevalence of extended-spectrum β-lactamase-producing Escherichia coli in companion dogs in animal clinics, Surabaya, Indonesia

Background and Aim: The practice of keeping animals as pets is becoming increasingly common. The upsurge of extended-spectrum β-lactamase (ESBL)-producing organisms of animal origin is a health threat globally. This study aimed to identify the presence of extended-spectrum β-lactamase-producing Escherichia coli in companion dogs in animal clinics in Surabaya, Indonesia. Materials and Methods: A total of 85 rectal swab samples were collected from companion dogs at five animal clinics in different regions of Surabaya, Indonesia. The presence of E. coli was identified from the samples using standard methods, followed by antibiotic sensitivity testing. The resistant isolates were examined for the presence of ESBL using the double-disk synergy test method. The phenotypically identified ESBL-producing E. coli was further confirmed with an automated system using Vitek-2. Results: The rectal swab samples (n=85) tested were 100% positive for E. coli isolates. Eight (9.41%) out of the 85 E. coli obtained from rectal swabs were extended-spectrum β-lactamase producers. All eight ESBL-producing E. coli were identified by automated Vitek-2 confirmatory tests. Conclusion: This study provides insight into the prevalence of ESBL-producing organisms isolated from companion dogs in Indonesia. This work indicates the need for the general public to be more aware of the role of companion animals in disseminating pathogenic organisms, since they serve as potential reservoirs in the spread of antibiotic resistance affecting human health.

Targeting Biological Aging: A New Paradigm for 21st Century Medicine

Biological age is the greatest risk factor for nearly every major cause of death and disability, including COVID-19. Yet, traditional biomedical research and clinical approaches have focused on waiting until people are sick and treating individual diseases one at a time. Attempts to “cure” age-related diseases have proven unsuccessful, and the impact of “disease-first” approaches continue to be incremental. Recent advances in understanding them mechanisms linking biological aging to disease, or geroscience, have identified interventions that directly target the molecular hallmarks of aging. Unlike disease-specific approaches, such interventions have the potential to prevent multiple diseases of aging simultaneously, thereby greatly enhancing healthspan and lifespan for most individuals. Here I will provide an overview of translational geroscience, which I believe will become the paradigm for the practice of medicine in the 21st century. I will also discuss recent work with one such intervention, the drug rapamycin, and our efforts to eventually delay or reverse biological aging in companion dogs and people.

The Link Between Environment, Age, and Health in a Large Cohort of Companion Dogs from the Dog Aging Project

Exposure to social environmental adversity strongly predicts health and survival in many species such as non-human primates, wild mammals, and humans. However, little is known about how the health and mortality effects of these social determinants vary across the lifespan. Using the companion dog, which serves as a powerful comparative model for human health and aging due to our shared biology and environment, we examined which components of the social environment impact health, and how the effects vary with age, in dogs. We first drew on detailed survey data from owners of 27,547 dogs from the Dog Aging Project and identified six factors that together explained 35% of the variation in dog’s social environment. These factors all predicted measures of health, disease, and mobility, when controlling for dog age and weight. Factors capturing measures of financial and household adversity were linked to poorer companion dog health, while factors associated with the social companions, like dogs and adults, were linked to better health. Interestingly, some of these effects differed across a dog’s lifespan: for instance, the effect of neighborhood disadvantage on disease instances was strongest in older dogs. Together, our findings point to similar links between adversity and health in companion dogs, and set up future work on the molecular and biological changes associated with environmental variation in order to identify ways to mitigate or even reverse the negative environmental effects.

Age-Related Changes in Posture Steadiness in the Companion Dog

Aging is associated with changes in the sensory-motor system that could lead to dynamic instability. In fact, postural control deficits have been proposed as an early indicator of frailty. Measurements of the displacement of the center of pressure (COP) using pressure mat data are useful tools to determine postural steadiness. Companion dogs represent a powerful model to study aging in people because they share our environment and experience similar age-related diseases. To date, the effect of aging on postural control in dogs has not yet been evaluated. The aim of this study was to determine the correlation between age and the displacement of the COP in dogs during quiet standing. Due to the diversity of life expectancy in dogs according to their body size, age was normalized as a fraction of the predicted life expectancy. Dogs older than 75% of their life expectancy (n=18) were asked to stand on a pressure mat for 8 seconds per trial during at least five trials. Only the frames where the dogs were standing still and facing forward were analyzed. Age as a fraction of life expectancy was significantly correlated (p<0.05) with the Medio-lateral Range, Root-Mean-Square Distance, 95% Confidence Ellipse, and Total Sway Area of the COP. These results show that, as in humans, aging in dogs is associated with postural control deficits and therefore reinforce the dog as a suitable model for translational studies of aging and postural steadiness.

An Analytic Method for Improving the Reliability of Models Based on a Histogram for Prediction of Companion Dogs’ Behaviors

Dogs and cats tend to show their conditions and desires through their behaviors. In companion animal behavior recognition, behavior data obtained by attaching a wearable device or sensor to a dog’s body are mostly used. However, differences occur in the output values of the sensor when the dog moves violently. A tightly coupled RGB time tensor network (TRT-Net) is proposed that minimizes the loss of spatiotemporal information by reflecting the three components (x-, y-, and z-axes) of the skeleton sequences in the corresponding three channels (red, green, and blue) for the behavioral classification of dogs. This paper introduces the YouTube-C7B dataset consisting of dog behaviors in various environments. Based on a method that visualizes the Conv-layer filters in analyzable feature maps, we add reliability to the results derived by the model. We can identify the joint parts, i.e., those represented as rows of input images showing behaviors, learned by the proposed model mainly for making decisions. Finally, the performance of the proposed method is compared to those of the LSTM, GRU, and RNN models. The experimental results demonstrate that the proposed TRT-Net method classifies dog behaviors more effectively, with improved accuracy and F1 scores of 7.9% and 7.3% over conventional models.