Dog Model Research Articles

Comparison of Acute and Protracted Gamma Irradiation Effects During Perinatal Development in Beagle Dogs.

Ionizing radiation exposure during perinatal development can produce various biological effects on the developing offspring. These effects are dependent on a number of factors, including total dose, dose rate and the developmental processes occurring at the time of irradiation. The present study conducted an analysis of historical radiobiological archived data involving 60Co-gamma irradiation of beagle dogs at specific periods of prenatal or postnatal development. The original studies were performed at two sites where animals were exposed to a single, acute dose of 0.2 or 1.0 Gy at six different stages of perinatal development or with protracted exposures ranging from 0.004 to 0.35 Gy per day, over multiple days of gestation. A number of outcomes were investigated after perinatal irradiation including changes in sex ratio, survival probability, disease incidence and growth of animals, based on collected size and weight measurements of animals and different tissues. Protracted irradiations with doses up to 0.35 Gy per day did not significantly affect survival in animals when irradiated prenatally, although significant increases in the incidence of neoplasms and diseases related to the cardiovascular and urogenital system were observed at the time of death. Dogs irradiated at a dose rate of 0.10 Gy per day, with the irradiations continuing after birth and resulting in the accumulation of large total doses, were observed to have chronic radiation syndrome symptoms based on pathologies related to the hematopoietic system. Acute irradiation with 0.2 and 1.0 Gy resulted in changes of different body or tissue sizes measured in animals terminally, with changes detected after irradiation at all tested prenatal and postnatal time points, with the exception of irradiation at 365 days after birth. The present analysis provides new information regarding the biological effects of ionizing radiation during perinatal development in offspring in the unique mammalian study model of the beagle dog.

Efficacy of Spray Cryotherapy on Airway Secretions in Canine Models of Chronic Bronchitis and Mechanism Insights.

Introduction Bronchoscopic spray cryotherapy (SCT) is a novel treatment showing promise for chronic bronchitis (CB), characterized by excessive mucus secretion and productive cough. A large animal model for preclinical research of SCT is lacking, and its treatment's efficacy and mechanisms for CB are not well understood. Methods Eight Labradors were exposed to 200 ppm SO2 for 6 months to develop a CB model. Evaluations included pulmonary resistance, bronchoalveolar lavage fluid (BALF), CT images, and pathology. After model validation, six dogs received SCT and were observed for short-term (7 days) and long-term (30 days) outcomes. Metrics included pulmonary resistance, bronchoscopy findings, and BALF analysis for inflammatory factors, acetylcholine, and mucins. Bronchial tissue was assessed via HE staining, electron microscopy, and IHC staining. BEAS-2B cells were used to study MUC5AC expression in response to LPS and acetylcholine. Results SO2 exposure led to persistent cough, increased pulmonary resistance, goblet cell hyperplasia, and inflammation. Mucin, MUC5AC, and MUC5B levels in BALF increased over time, which validated the CB model. SCT treatment reduced mucus and pulmonary resistance, improved bronchial structure, and decreased goblet cells. SCT significantly reduced BALF mucin, MUC5AC, MUC5B, acetylcholine, IL-6, INF-γ, TNF-α, and IL-10, and bronchial MUC5AC and CHRM3. In the LPS treatment BEAS-2B cells, MUC5AC expression increased when acetylcholine pretreatment concentration increased. Conclusion The SO2 inhalation protocol effectively establishes a CB model in dogs. SCT effectively treats CB by reducing mucin levels and may lower MUC5AC expression by decreasing acetylcholine and CHRM3.

Clinical Evaluation of The Use of PRP as A Treatment for Achilles Tendon Defects in Dog Model

Clinical Evaluation of The Use of PRP as A Treatment for Achilles Tendon Defects in Dog Model

Decreases in hemoglobin and hematocrit may signal degree of hemorrhagic shock: retrospective evaluation in a dog model.

Data were extracted from preexisting published studies and evaluated retrospectively to compare lactate and base deficit values at baseline and posthemorrhage with changes in corresponding hemoglobin (Hb) and Hct measurements to assess any association of such changes with severity of hemorrhage over time. To understand the goal, the objective of this study was to demonstrate statistical changes in laboratory values as described above. Previous prospectively designed experiments on 120 mixed-breed dogs were conducted. Various parameters, including Hb and Hct, lactate concentration, and base deficit, were extracted from the previously mentioned experiments. To validate this retrospective study, subset data on heart rate and arterial pressure were compared. In a subset analysis, 60 experiments were extracted to compare baseline mean arterial pressure to posthemorrhagic values to prove the validity of this model. Published studies were evaluated retrospectively to compare lactate and base deficit values at baseline and posthemorrhage. Arterial pressure is lowest posthemorrhage, increases, then stabilizes. Baseline Hb averaged 15.1 g/dL and Hct 43.4%, and posthemorrhage values averaged 12.1 g/dL (Hb) and 35.3% (Hct). Significant differences were observed for both Hb (3.0 g/dL difference; P < .001) and Hct (8.3% difference; P < .001) posthemorrhage. Lactate significantly increased (2.1; P < .001), and base deficit significantly decreased (5.2; P < .001). The data collected retrospectively validated the model for significant hypotension. It was then possible to evaluate whether Hb and Hct may accurately predict the degree of hemorrhage. In this model, both Hb and Hct decreased posthemorrhage significantly, although the actual change in Hb and Hct posthemorrhage was modest. Lactate concentration increased, and base deficit decreased. The data suggest that Hb, Hct, lactate, and base deficit should be studied to see if they may have a potential role in guiding resuscitation decisions.

Comparison of accuracy of brain biopsy simulation between 3-dimensional-printed guides and neuronavigation in skull-brain tumor models of dogs and cats.

This study aimed to compare the accuracy of brain biopsies in skull-brain tumor models (SBTMs) of dogs and cats using 2 techniques: 3-D-printed brain biopsy guides (3D-BBGs) and electromagnetic (EM) neuronavigation. Based on the CT data from 12 dogs and 3 cats, a total of 30 SBTMs were created using 3-D-printing technology, with 2 models per data set. Thirty brain biopsies were performed: 15 using 3D-BBGs and 15 using EM neuronavigation. The accuracy of the brain biopsies was assessed by comparing the prebiopsy and postbiopsy models using computer-aided design software. The median needle placement error for all biopsies was 1.75 mm (range: 0.82 to 3.16 mm), with 1.79 mm (range: 0.94 to 2.94 mm) for the 3D-BBG group and 1.68 mm (range: 0.82 to 3.16 mm) for the EM neuronavigation group. There was no significant difference in accuracy between the 2 methods. In the EM neuronavigation group, the needle placement error correlated significantly with the total needle length, but no such correlation was observed in the 3D-BBG group. Both methods successfully retrieved samples from brain tumor models. There was no significant difference in the accuracy of brain biopsies performed using 3D-BBGs and EM neuronavigation. This suggests that the choice of method depends on veterinarian preference, available hospital resources, and patient-specific considerations. This study demonstrates that both 3D-BBG and EM neuronavigation are viable options for performing brain biopsies in veterinary practice, potentially improving the diagnosis and treatment of brain tumors in small animals.

Finite element analysis shows minimal stability difference between individualized mini-hemilaminectomy-corpectomy and partial lateral corpectomy in a dog model.

Use finite element analysis to evaluate the biomechanical effects of spinal decompression procedures in healthy Beagle dogs, comparing individualized mini-hemilaminectomy-corpectomy (iMHC), mini-hemilaminectomy, partial lateral corpectomy (PLC), and hemilaminectomy. A finite element model of the L1-L2 functional spinal unit was generated using CT data. For each decompression model, loads were applied in 0.2-Nm steps (maximum, 2.0 Nm) in 6 directions: flexion, extension, right and left lateral bending, and right and left axial rotation. The L1 spinous process tip displacement angle was quantified numerically. Among the 4 techniques, mini-hemilaminectomy exhibited the smallest displacement angles across all directions. Hemilaminectomy exhibited the largest displacement angles in extension, flexion, right rotation, and left rotation across all techniques. Left and right lateral bending displacement angles were marginally larger for iMHC than for hemilaminectomy at 0.4 Nm; however, at 2.0 Nm, displacement angles were similar. Mini-hemilaminectomy minimizes functional spinal unit instability to the greatest extent. Hemilaminectomy is more unstable than iMHC and PLC in flexion, extension, and rotation. Mini-hemilaminectomy-corpectomy and PLC are more unstable than hemilaminectomy in lateral bending, with iMHC being slightly more unstable than PLC or nearly equal. Mini-hemilaminectomy minimizes instability to the greatest extent in cases of ventrolateral spinal compression. In cases of ventral spinal compression, iMHC may be preferable to PLC for providing equivalent stability without impeding spinal cord visualization, but both techniques can cause instability depending on loading direction, so careful attention to postoperative instability is necessary when excessive vertebral body resection is involved.

Evaluation of a six-minute walk test in the DE50-MD canine model of Duchenne muscular dystrophy and its effect on blood-borne biomarkers

Background Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by mutations in the dystrophin gene resulting in cycles of muscle degeneration, inflammation and regeneration. The 6-minute walk test (6MWT) is a key functional outcome measure for DMD patient clinical trials and has been adapted for use in animal models of the disease. The DE50-MD dog model of DMD closely reflects the DMD patient phenotype prior to loss of ambulation. For pre-clinical trials using this model, functional outcome measures must be established. Methods This longitudinal study compared distance walked in a 6MWT by DE50-MD and WT control dogs and assessed the utility of the 6MWT as a functional biomarker. Dogs underwent two 6MWTs conducted approximately 48-hours apart, at 3, 6, 9, 12, 15 and 18 months of age. In addition, we evaluated the stability of selected blood-borne biomarkers in 12-month old DE50-MD and WT dogs 0, 3, 6, 24 and 48 hours following a 6MWT. Results DE50-MD dogs exhibited significantly shorter 6-minute walk distance (6MWD) than WT dogs at all timepoints (P&lt;0.05), with no difference in 6MWD between the first and second 6MWT. C-C motif chemokine ligand 2 (CCL2), myomesin-3 (MYOM3) and myostatin (MSTN) were biomarkers of the DE50-MD phenotype that remained unchanged in DE50-MD dogs following the 6MWT, while creatine kinase (CK) activity significantly increased 3-hours following the test in DE50-MD dogs but remained unchanged in WT dogs. Conclusions The 6MWT effectively discriminates DE50-MD from WT dogs aged 3-18 months and a single 6MWT is sufficient for future studies. Serum MYOM3, CCL2 and MSTN are good biomarkers of the DE50-MD phenotype that are unaffected by this relatively low level exertion.

Bioavailability improvement by atomic layer coating: Fenofibrate a case study

Biopharmaceutical Classification Systems (BCS) class II drugs show poor solubility and high permeability in the body. Fenofibrate (FF) is a classic example of a BCS class II drug, used to treat high cholesterol and triglyceride (fat-like substances) levels in the blood. Atomic layer coating (ALC) is a surface engineering technology adapted from the semiconductor industry, where metal oxides are coated one atomic layer at a time over the active pharmaceutical ingredients (API) particles. ALC coating was proven to improve the processability, alter the hydrophilicity, improve the stability, and fine-tune the release of drugs. Herein, we report the intervention of ALC coating in enhancing the bioavailability of a poorly water-soluble drug (fenofibrate) in the animal model. The physical properties of uncoated fenofibrate were compared with those of zinc oxide-coated and silicon oxide-coated fenofibrate. Following the application of the coatings, the structural integrity (both chemical stability and solid-state stability) of the active pharmaceutical ingredient (API) remained uncompromised, as corroborated by 1H NMR and powder X-ray diffraction analyses. Notably, zinc oxide-coated fenofibrate exhibited favorable flow characteristics, whereas no discernible enhancement in flow behavior was observed for silicon oxide-coated fenofibrate. The results from contact angle measurements suggest that the silicon oxide-coated fenofibrate exhibits superior wetting behavior, as indicated by a contact angle nearing 0°. The application of ALC demonstrates an enhanced dissolution rate when compared to the uncoated active pharmaceutical ingredient (API) while leaving its equilibrium solubility unaffected. Coating the API with silicon oxide improves particle hydrophilicity and wetting properties, whereas zinc oxide coating aids in particle de-agglomeration, thereby enhancing their interaction with an aqueous medium. In vivo bioavailability studies conducted on rodents and larger animal (dog) models indicate a substantial increase in bioavailability (approximately 2 times) for the silicon oxide-coated API in comparison to the uncoated API, as determined by the area under the curve (AUC). Furthermore, the Cmax values for the silicon oxide-coated API also demonstrate a significant increase (approximately 3 times) over the uncoated API. Notably, an oral subacute toxicity study of ALC silicon-coated fenofibrate revealed no toxic effects attributable to the coating. This study underscores the potential of ALC in augmenting the bioavailability of BCS(II) drugs.

Potential new treatment for inferior vena cava injury using extracorporeal membrane oxygenation applying flow diversion effect

BackgroundRetrohepatic inferior vena cava (IVC) injuries remain among the most lethal and serious liver injuries. Gauze packing is currently the first choice for IVC injuries; however, laparotomy itself poses the risk of circulatory collapse. Thus, less invasive treatment strategies are needed.MethodsIn this study, we conducted an animal experiment to replicate and validate successful treatments for an actual case of retrohepatic IVC injury that we had encountered.ResultsA woman in her 80s presented to our hospital due to cardiac arrest caused by a pulmonary artery embolism. Venoarterial extracorporeal membrane oxygenation (ECMO) was introduced, and the patient was resuscitated. After resuscitation, contrast-enhanced CT revealed liver and retrohepatic IVC injuries, possibly caused by chest compressions. Liver injury was treated using transarterial embolization of the left hepatic artery. To treat the retrohepatic IVC injury, ECMO flow was increased to enhance the negative drainage pressure. The extravasation of the contrast medium had resolved in IVC angiography, and we opted for nonoperative management. The patient’s hemodynamic status gradually stabilized, and ECMO was withdrawn on day 6. We confirmed these findings in a dog model of retrohepatic IVC injury.ConclusionsOur findings from the patient and the animal model suggest that the flow diversion effect of ECMO can effectively manage active bleeding from the IVC by inserting a drainage cannula across the injured lesion. We think this procedure represents a novel treatment option for retrohepatic IVC injuries.

Comparative induction of benign prostate hyperplasia using testosterone propionate and estradiol benzoate in rabbit model

Benign prostatic hyperplasia (BPH) is a common non-cancerous enlargement of the prostate that usually occurs in aging men and some higher mammals. Many studies have been conducted to explore different treatment strategies for managing BPH. However, a suitable animal model for studying BPH is necessary. So far, only a few animal models, such as rat and dog models, have been used for this purpose. This study aimed to compare the assessment of the BPH model induced in rabbits through the administration of exogenous testosterone and estrogen post-bilateral orchidectomy. Fifteen (N=15) indigenous Nigerian rabbits were used for this experiment. The rabbits were orchiectomized and randomly divided into 3 groups: the testosterone, estrogen, and control groups. Seven days after bilateral orchidectomy, BPH was induced using exogenous subcutaneous administration of testosterone (15 mg kg-1), estrogen (0.75 mg kg-1), and normal saline (1 mL) for 4 weeks. After completion of the treatments, prostates were removed. The weight, volume, prostate index, and histologic scoring were determined. There were significant changes (p&lt;0.05) in prostate weight, volume, and index. Testosterone and estrogen-treated groups differed significantly from the control groups. There were no significant differences in all the parameters between the testosterone and the estrogen groups. Histological evaluation revealed hyperplasia of the epithelium of the prostate gland and increased stromal connective tissues with a corresponding increase in the number of glandular units with secretory-filled fluid within the lumens of the glands. The benign prostate hyperplasia rabbit model was developed successfully using exogenous treatment with testosterone propionate. Testosterone appeared to have significant roles in the development of prostate hyperplasia when compared to estrogen.

Analyze of Application of Artificial Intelligence in Robotic Guide Dogs

As society develops, people are paying more attention to disabilities. Visually impaired people as a group, are one of the largest populations of disabilities. Nowadays, scientists are finding approaches to give them more convenience. Robotic guide dogs, which aid the visually impaired to travel, becoming a standout topic in society. As an emerging technology in recent years, artificial intelligence (AI) gives technical support to the study of robotic guide dogs. By examining a number of current robotic guide dog models, this paper will demonstrate how AI can be used to improve robotic guide dogs in a number of ways. The research shows that AI plays an important role in the operation of the robotic guide dog. This research will also point out some directions for future studies.

Development and validation of 3D printed epidural nerve block simulation model in dogs

Development and validation of 3D printed epidural nerve block simulation model in dogs

Scientific substantiation of the maximum permissible concentration of the pharmaceutical substance osimertinib mesylate in the air of the working area

Introduction. Osimertinib, a 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor, is currently the only drug registered for the treatment of metastatic non-small cell lung cancer in patients with a positive T790M mutation status. The production of osimertinib mesylate is planned on the territory of the Russian Federation, which necessitates research to substantiate the hygienic standard for the aerosol content of the substance in the air of the working area. Conducting research to substantiate the maximum permissible concentration of a substance requires significant material and time resources, while using the results of preclinical and clinical studies, mathematical modeling of processes, and risk assessment methodology allows for a comprehensive assessment of the substance, while significantly reducing the time and cost of work. The study aims to scientifically substantiate the maximum permissible concentration of the pharmaceutical substance osimertinib mesylate in the air of the working area using data from toxicological studies and mathematical modeling of the effects of the substance on humans in industrial conditions. Materials and methods. The materials used were domestic and international databases, reports, research protocols, scientific articles and monographs containing information on the physico-chemical and toxic properties, pharmacotherapeutic activity of osimertinib. Results. The specialists have conducted hygienic regulation of osimertinib, taking into account data on its toxicity, danger, pharmacotherapeutic activity, side effects, long-term consequences, pharmacokinetic studies and modeling. To substantiate the value of the maximum permissible concentration, the authors used the reference points: an inactive NOEL level of 1 mg/­kg/­day for general toxic effect, established in a 92-day experiment on rats with intragastric administration; the lowest observed level of adverse effects of LOAEL is 0.5 mg/kg/day for general toxic effect, established in a 180-day experiment on dogs with intragastric administration; the level that does not cause adverse effects of NOAEL is 10 mg/kg/day for general toxic effect, established in a 180-day experiment on mice with intragastric administration. Safe concentrations of osimertinib in the air of the work area were evaluated using reference points, including the pharmacological effect and the minimum daily therapeutic dose; toxicokinetic modeling of concentrations of a substance in the human body under production conditions and the level of minimal risk. Limitation. The study is limited to the review of open literature sources describing the toxicological/toxicokinetic characteristics of osimertinib mesylate. Conclusion. The most stringent indicators of safe exposure levels, established on the basis of pharmacological effect and toxicokinetic modeling in dogs, allowed us to recommend 0.005 mg/m3, aerosol, hazard class 1 as the maximum permissible concentration in the air of the working area for osimertinib mesylate. Ethics. This study did not require the conclusion of the Ethics Committee.

Development of a novel intramuscular liposomal injection for advanced meloxicam delivery: Preparation, characterization, in vivo pharmacokinetics, pharmacodynamics, and pain assessment in an orthopedic pain model

Pain produces several physiological, and degenerative complications. This study aimed to formulate meloxicam (MLX) in liposomes to increase solubility and deliver MLX in a controlled manner to overcome its poor aqueous solubility and relatively short t1/2 problems. Liposomes were prepared by thin film hydration followed by ultrasonication. Tests for characterizing formulations included particle size, span, entrapment efficiency, drug loading, stability, differential scanning calorimetry (DSC), Fourier transformation infrared (FT-IR) spectroscopy, morphology, in vitro release, release kinetics mathematical modeling, and an in vivo pain model in dogs undergoing orthopedic surgeries, followed by in vivo pharmacokinetics, pharmacodynamics, and pain assessment studies in comparison to the reference standard, Mobitil®. Liposomal MLX had a particle size of around 100 nm, 82 % entrapment efficiency, and 4.62 % drug loading. Stability studies, DSC, and FT-IR spectroscopy indicated that liposomes were highly stable. The formulation showed an improved in vitro controlled release pattern and an enhanced in vivo pharmacokinetic behavior as manifested by higher t1/2 and AUC0–24 and lower Cl/F in comparison to Mobitil®. The pharmacodynamics study and pain scales demonstrated liposomal MLX managed postoperative pain better than Mobitil®. In conclusion, the incorporation of MLX in liposomes increased its solubility and stability, as well as its pain management properties.

Long-term inflammatory outcome after placement of a novel two-piece dental implant in a dog model experimental peri-implantitis.

Evaluate the inflammatory outcome of a two-piece novel titanium dental implant (test article) vs. a one- piece titanium dental implant (control article) inducing experimental peri-implantitis in a dog model. A novel, two-piece pre-assembled implant with a 0.2-thickness sleeve in its coronal 4.2mm part was developed (Test article). Ligature-induced experimental periimplantitis model was applied, followed by decontamination and bone grafting in seven dogs. Four groups were assessed according to decontamination and resurfacing protocol: E1 (Experimental 1): test article- sleeve removed, mechanical and chemical decontamination, new rough surface non-threaded sleeve was inserted; E2 (Experimental 2): test article- sleeve removed, mechanical and chemical decontamination, test article remained denuded presenting a turned non-threaded surface; C1 (Control 1): sleeve remained, mechanical and chemical decontamination in test article, original rough surface, non-threaded sleeve; C2 (Control 2): control article cleaning, mechanical and chemical decontamination of original rough surface, threaded implant. Buccolingual and mesiodistal sections were prepared for each site. Resin qualitative and semi-quantitative histopathologic inflammatory parameters were analyzed. Group C1 showed statistically significant highest signs of residual long-term inflammation, followed by groups E1, and C2. Group E2 displayed the lowest local inflammation. Mesio/Distal aspects displayed increased long-term inflammatory infiltrate albeit not statistically significant. Within the limits of the present study, it may be concluded that - (1) The decontamination procedure is more effective in a commercial one-piece vs. a two-piece dental implant. (2) Mechanical and chemical decontamination outcome is insufficient. Resurfacing improves the decontamination outcome. (3) Decontamination of the turned surface is superior to the rough surface. When choosing the most appropriate dental implant for individuals with a high risk for peri-implant disease, a one-piece dental implant with a turned crestal surface is preferable. Once occurring, the control of peri-implant disease inflammation may be more successful. Decontamination is usually not enough. Resurfacing is highly recommended if possible.

The Properties of the Transient Outward, Inward Rectifier and Acetylcholine-Sensitive Potassium Currents in Atrial Myocytes from Dogs in Sinus Rhythm and Experimentally Induced Atrial Fibrillation Dog Models.

Atrial fibrillation (AF) is the most common chronic/recurrent arrhythmia, which significantly impairs quality of life and increases cardiovascular morbidity and mortality. Therefore, the aim of the present study was to investigate the properties of three repolarizing potassium currents which were shown to contribute to AF-induced electrical remodeling, i.e., the transient outward (Ito), inward rectifier (IK1) and acetylcholine-sensitive (IK,ACh) potassium currents in isolated atrial myocytes obtained from dogs either with sinus rhythm (SR) or following chronic atrial tachypacing (400/min)-induced AF. Atrial remodeling and AF were induced by chronic (4-6 weeks of) right atrial tachypacing (400/min) in dogs. Transmembrane ionic currents were measured by applying the whole-cell patch-clamp technique at 37 °C. The Ito current was slightly downregulated in AF cells when compared with that recorded in SR cells. This downregulation was also associated with slowed inactivation kinetics. The IK1 current was found to be larger in AF cells; however, this upregulation was not statistically significant in the voltage range corresponding with atrial action potential (-80 mV to 0 mV). IK,ACh was activated by the cholinergic agonist carbachol (CCh; 2 µM). In SR, CCh activated a large current either in inward or outward directions. The selective IK,ACh inhibitor tertiapin (10 nM) blocked the outward CCh-induced current by 61%. In atrial cardiomyocytes isolated from dogs with AF, the presence of a constitutively active IK,ACh was observed, blocked by 59% with 10 nM tertiapin. However, in "AF atrial myocytes", CCh activated an additional, significant ligand-dependent and tertiapin-sensitive IK,ACh current. In our dog AF model, Ito unlike in humans was downregulated only in a slight manner. Due to its slow inactivation kinetics, it seems that Ito may play a more significant role in atrial repolarization than in ventricular working muscle myocytes. The presence of the constitutively active IK,ACh in atrial myocytes from AF dogs shows that electrical remodeling truly developed in this model. The IK,ACh current (both ligand-dependent and constitutively active) seems to play a significant role in canine atrial electrical remodeling and may be a promising atrial selective drug target for suppressing AF.

Toxicity Profile of eBAT, a Bispecific Ligand-Targeted Toxin Directed to EGFR and uPAR, in Mice and a Clinical Dog Model.

EGFR-targeted therapies are efficacious, but toxicity is common and can be severe. Urokinase type plasminogen activator receptor (uPAR)-targeted drugs are only emerging, so neither their efficacy nor toxicity is fully established. Recombinant eBAT was created by combining cytokines EGF and uPA on the same single-chain molecule with truncated Pseudomonas toxin. Its purpose was to simultaneously target tumors and their vasculature in the tumor microenvironment. In prior studies on mice and dogs, the drug proved efficacious. Here, we report the safety of eBAT in normal wildtype, uPAR knockout, and immunoreplete and immunodeficient tumor-bearing mice, as well as in dogs with spontaneous sarcoma that more closely mirror human cancer onset. In immunocompetent mice, tumor-bearing mice, uPAR knockout mice, and mice receiving species-optimized eBAT, toxicities were mild and self-limiting. Likewise, in dogs with life-threatening sarcoma given dosages found to be biologically active, eBAT was well tolerated. In mice receiving higher doses, eBAT was associated with dose-dependent evidence of liver injury, including portal biliary hyperplasia, oval cell proliferation, lymphoplasmacytic inflammation, periportal hepatocellular microvesicular change, hemorrhage, necrosis, and apoptosis. The results support continuing the clinical development of eBAT as a therapeutic agent for individuals with sarcoma and other cancers.

Bringing the Genomic Revolution to Comparative Oncology: Human and Dog Cancers.

Dogs are humanity's oldest friend, the first species we domesticated 20,000-40,000years ago. In this unequaled collaboration, dogs have inadvertently but serendipitously been molded into a potent human cancer model. Unlike many common model species, dogs are raised in the same environment as humans and present with spontaneous tumors with human-like comorbidities, immunocompetency, and heterogeneity. In breast, bladder, blood, and several pediatric cancers, in-depth profiling of dog and human tumors has established the benefits of the dog model. In addition to this clinical and molecular similarity, veterinary studies indicate that domestic dogs have relatively high tumor incidence rates. As a result, there are a plethora of data for analysis, the statistical power of which is bolstered by substantial breed-specific variability. As such, dog tumors provide a unique opportunity to interrogate the molecular factors underpinning cancer and facilitate the modeling of new therapeutic targets. This review discusses the emerging field of comparative oncology, how it complements human and rodent cancer studies, and where challenges remain, given the rapid proliferation of genomic resources. Increasingly, it appears that human's best friend is becoming an irreplaceable component of oncology research.

Genomic analyses identify 15 susceptibility loci and reveal HDAC2, SOX2-OT, and IGF2BP2 in a naturally-occurring canine model of gastric cancer.

Gastric cancer (GC) is the fifth most common human cancer worldwide, but the genetic etiology is largely unknown. We performed a Bayesian genome-wide association study and selection analyses in a naturally-occurring canine model of GC, the Belgian Tervuren and Sheepdog breeds, to elucidate underlying genetic risk factors. We identified 15 loci with over 90% predictive accuracy for the GC phenotype. Variant filtering revealed germline putative regulatory variants for the EPAS1 (HIF2A) and PTEN genes and a coding variant in CD101. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop GC. Across-breed analyses uncovered protective haplotypes under selection in Malinois at SOX2-OT and IGF2BP2. Among Tervuren and Sheepdogs, HDAC2 putative regulatory variants were present at comparatively high frequency and were associated with GC. Here, we describe a complex genetic architecture governing GC in a dog model, including genes such as PDZRN3, that have not been associated with human GC.

Nerve Regeneration Potential of Antioxidant-Modified Black Phosphorus Quantum Dots in Peripheral Nerve Injury.

Peripheral nerve injury is a major societal concern. Black phosphorus (BP) has inherent advantages over cell-based therapies in regenerative medicine. However, controlling spontaneous degradation and size-dependent cytotoxicity remains challenging and poses difficulties for clinical translation. In this study, we constructed zero-dimensional BP quantum dots (QDs) modified with antioxidant β-carotene and comprehensively investigated them in Schwann cells (SCs) to elucidate their potential for peripheral nerve repair. In vitro experiments demonstrated that BPQD@β-carotene has an inappreciable toxicity and good biocompatibility, favoring neural regrowth, angiogenesis, and inflammatory regulation of SCs. Furthermore, the PI3K/Akt and Ras/ERK1/2 signaling pathways were activated in SCs at the genetic, protein, and metabolite levels. The BPQD@β-carotene-embedded GelMA/PEGDA scaffold enhanced functional recovery by promoting axon remyelination and regeneration and facilitating intraneural angiogenesis in peripheral nerve injury models of rats and beagle dogs. These results contribute to advancing knowledge of BP nanomaterials in tissue regeneration and show significant potential for application in translational medicine.