Back to the lab, back to basic research: autophagy, ERK and Akt pathways are among some of the key topics of this week.

The teams of Sakuma et al. and Vincente et al. studied these pathways in vitro and were able to give us great insights in the role of these pathways in cancer.

Preclinical veterinary research lives from this:

Bold ideas

Empirical data

In vitro work

I am curious to see if any pharma will pick up these ideas and which new projects will be started because of these insights

Enjoy this week’s edition!

In Vitro

Effects of blocking cancer-related pathways in canine tumor cells

In this study, Sakuma et al. from the Universität Tokio , Japan, investigated whether blocking two pathways—ERK and Akt, which are known to be active in CHS—could slow down CHS cell growth. The researchers tested drugs that specifically inhibit each pathway and observed their effects on CHS cell lines, both individually and in combination. The study found that ERK and Akt inhibitors successfully blocked their respective pathways in the cancer cells. However, while blocking the ERK pathway reduced cell growth, inhibiting the Akt pathway alone didn’t consistently prevent cell proliferation. They also tested two other drugs, dasatinib and trametinib, which target Akt and ERK pathways, respectively. Results showed that these drugs slowed down cell growth to varying degrees across different CHS cell lines. Interestingly, combining the drugs had a stronger effect in only some of the cell lines. This suggests that further research is needed to understand why certain CHS cells respond differently to these treatments.

Sakuma, H., Tomiyasu, H., Tani, A., Goto-Koshino, Y., Tani, H., Ohno, K., Tsujimoto, H., Bonkobara, M., & Okuda, M. (2024). Antitumor effects of inhibitors of ERK and Akt pathways in canine histiocytic sarcoma cell lines. The Veterinary Journal, 106264. https://doi.org/10.1016/j.tvjl.2024.106264

Cell recycling markers in dog skin tumors: A microscopic study

This study by Vicente et al. from the University of Bologna (Alma Mater Studiorum – Università di Bologna) , Italy, examined the role of autophagy in canine mast cell tumors (MCTs) by analyzing the expression of two key proteins, Beclin-1 and LC3B, which are involved in the autophagy process. Autophagy, a cellular process that helps remove damaged components, is believed to impact cancer cell survival and tumor progression. Using immunohistochemical and immuno-ultrastructural techniques, the researchers studied the levels of Beclin-1 and LC3B in MCT samples. Their findings revealed varying levels of these proteins, suggesting differences in autophagic activity among tumors. This variation could help explain why some mast cell tumors are more aggressive or respond differently to treatment. In summary, this research highlights the potential role of autophagy in MCT progression and suggests that Beclin-1 and LC3B expression might be useful markers for understanding tumor behavior and possibly guiding treatment decisions in canine MCTs.

Vicente, G. P., Della Salda, L., & Strefezzi, R. F. (2024). Beclin-1 and LC3B expression in canine mast cell tumours: an immuno-ultrastructural and immunohistochemical study of autophagy. Veterinary Quarterly, 44(1), 1–15. https://doi.org/10.1080/01652176.2024.2419585

Diagnostics & Biomarkers

Urine protein signals kidney damage in cats

This study by Chen et al. from the The Hebrew University of Jerusalem , Israel,explored the potential of urinary Cystatin B as an indicator of acute kidney injury (AKI) in cats. AKI is challenging to detect early in cats, making timely diagnosis crucial. Cystatin B, a protein found in urine, was evaluated for its reliability as a marker for AKI. The researchers measured Cystatin B levels in cats with and without AKI to determine if elevated levels correlated with kidney injury. Their findings suggest that urinary Cystatin B could serve as an early and specific marker for AKI in cats, potentially helping veterinarians diagnose and manage kidney issues sooner. This promising marker could improve outcomes for cats by enabling faster intervention.

Chen, H., Avital, Y., Peterson, S., Ouyang, Z., Yerramilli, M., Aroch, I., & Segev, G. (2024). Urinary Cystatin B as a marker of acute kidney injury in cats. The Veterinary Journal, 106262. https://doi.org/10.1016/j.tvjl.2024.106262

Heart and kidney hormone levels in healthy small dogs

This study by Galizzi et al. from the Università degli Studi di Milano , Italy, aimed to establish reference ranges for two potential biomarkers—N-terminal pro-B-type natriuretic peptide (NT-proBNP) and urinary aldosterone-to-creatinine ratio (UAldo: C)—specifically in healthy Chihuahuas, as these markers differ across breeds. Forty-three healthy Chihuahuas were tested. The median NT-proBNP was 347 pmol/L, and the median UAldo: C was 2.59 µg/g. Most Chihuahuas (91%) fell below the general threshold for NT-proBNP (900 pmol/L), suggesting that NT-proBNP might have breed-specific cut-offs. The UAldo: C values were generally higher than in other breeds, supporting the idea that Chihuahuas may have distinct renin-angiotensin-aldosterone system activity. No significant differences were found between males and females for either marker. In summary, these findings provide breed-specific reference intervals for NT-proBNP and UAldo: C in Chihuahuas, which could improve heart disease screening and management for this breed.

Galizzi, A., Dossi, G., Pocar, P. et al. Plasma N-terminal pro-B-type natriuretic peptide and urinary aldosterone-to-creatinine ratio in healthy Chihuahuas. BMC Vet Res 20, 501 (2024). https://doi.org/10.1186/s12917-024-04344-w

Effects of sildenafil on kidney health in cats with worsening chronic kidney disease

This study by Maden et al. from the University of Ankara, Türkyie, explored the effects of sildenafil on mitochondrial health and kidney damage in cats with acute on chronic kidney disease (ACKD). Sildenafil is known for activating the cGMP/NO pathway, which could support kidney function and reduce damage in cases of kidney disease. Thirty-three cats were involved, divided into healthy (non-azotemic) and ACKD groups. Both groups received sildenafil for 30 days. Researchers measured various kidney-related biomarkers in their blood and urine over this period. Results showed that sildenafil raised cGMP levels in healthy cats but had limited impact in the ACKD cats. Some markers of kidney function (such as NO) increased in the ACKD cats, indicating some benefit in glomerular filtration. However, the drug did not significantly reduce kidney damage or fibrosis linked to the TGF-β/SMAD pathway. In summary, sildenafil showed mild support for kidney function but did not effectively prevent damage or fibrosis in cats with ACKD.

Maden, M., Ider, M., Or, M.E. et al. The clinical efficacy of cGMP-specific sildenafil on mitochondrial biogenesis induction and renal damage in cats with acute on chronic kidney disease. BMC Vet Res 20, 499 (2024). https://doi.org/10.1186/s12917-024-04345-9

Clinical

Analyzing breathing patterns to measure breathing problems in flat-faced dogs

This study, by Dimopoulou et al. from the Swedish University of Agricultural Sciences (SLU) , Sweden, explored using respiratory signal analysis to assess BOAS severity in dogs. A total of 117 dogs, both brachycephalic (flat- faced) and non-brachycephalic, were included. Researchers recorded respiratory sounds with an electronic stethoscope before and after a 3-minute exercise test. Dogs were then assigned a BOAS severity grade (0–3) using a validated grading system. Through sound analysis, the team identified seven sound variables and used statistical techniques to link these variables to BOAS severity. They found that as BOAS severity increased, sound intensity and the presence of lower frequencies (170–260 Hz) also increased. One sound variable, “Peak 1,” was particularly effective in identifying BOAS-positive dogs before exercise, while “Valley 1” was most accurate after exercise. These findings suggest that respiratory signal analysis could help veterinarians assess BOAS severity more effectively, aiding in treatment decisions and assisting breeders in selecting healthier dogs.

Dimopoulou, M., Peterson, H., Stensöta, O., Karlsteen, M., Ljungvall, N., Rydén, J., Skiöldebrand, E. (2024). Use of respiratory signal analysis to assess severity of Brachycephalic Obstructive Airway Syndrome (BOAS) in dogs. The Veterinary Journal, 106261. https://doi.org/10.1016/j.tvjl.2024.106261

Preventive antibiotics for dogs receiving cancer treatment

This study by Meredith Gumash ash et al. from the University of Tennessee, USA, investigated whether using preventive antibiotics could help reduce febrile neutropenia (a dangerous drop in white blood cells and onset of fever) in dogs with tumors being treated with lomustine, a chemotherapy drug. Febrile neutropenia is a common risk in dogs undergoing chemotherapy, as it can lead to serious infections. The researchers tested if giving antibiotics before neutropenia occurred would lower the chances of dogs developing this condition. Results showed that prophylactic (preventive) antibiotic use reduced febrile neutropenia cases, suggesting it may be a beneficial strategy for dogs undergoing lomustine chemotherapy. This approach could improve safety and outcomes for dogs in cancer treatment by helping to prevent infection-related complications.

Gumash, M., Martin, O.A., Lindley, S.E.S. and Zhu, X. (2024), Prophylactic Antimicrobials for Prevention of Febrile Neutropenia in Tumour-Bearing Dogs Treated With Lomustine. Vet Comp Oncol. https://doi.org/10.1111/vco.13022

New chewable medicine treats skin mites in dogs

This study by Becskei et al. from Zoetis, Belgium, evaluated the effectiveness of a chewable tablet containing sarolaner, moxidectin, and pyrantel for treating generalized demodicosis (a skin mite infection) in dogs. Generalized demodicosis can cause severe skin issues, and finding effective treatment options is important for affected dogs. In the study, dogs with demodicosis were given the chewable tablet, and researchers monitored the reduction in mites and improvement in skin health. The results showed that the tablet was effective in reducing mite numbers and improving skin condition, making it a promising treatment option for managing generalized demodicosis in dogs. This convenient chewable tablet could help simplify treatment for both dogs and owners.

Becskei C, Liebenberg J, Fernandes T, Borowski S, D’Hanis L, Mahabir SP. Efficacy of a chewable tablet containing sarolaner, moxidectin and pyrantel for the treatment of generalised demodicosis in dogs. Vet Dermatol. 2024; 00: 1–9. https://doi.org/10.1111/vde.13305