A novel MCT1 and MCT4 dual inhibitor reduces mitochondrial metabolism and inhibits tumour growth of feline oral squamous cell carcinoma

Monocarboxylate transporters (MCTs) support tumour growth by regulating the transport of metabolites in the tumour microenvironment. High MCT1 or MCT4 expression is correlated with poor outcomes in human patients with head and neck squamous cell carcinoma (HNSCC). Recently, drugs targeting these transporters have been developed and may prove to be an effective treatment strategy for HNSCC. Feline oral squamous cell carcinoma (OSCC) is an aggressive and treatment‐resistant malignancy resembling advanced or recurrent HNSCC. The goals of this study were to investigate the effects of a previously characterized dual MCT1 and MCT4 inhibitor, MD‐1, in OSCC as a novel treatment approach for feline oral cancer. We also sought to determine the potential of feline OSCC as a large animal model for the further development of MCT inhibitors to treat human HNSCC. In vitro, MD‐1 reduced the viability of feline OSCC and human HNSCC cell lines, altered glycolytic and mitochondrial metabolism and synergized with platinum‐based chemotherapies. While MD‐1 treatment increased lactate concentrations in an HNSCC cell line, the inhibitor failed to alter lactate levels in feline OSCC cells, suggesting an MCT‐independent activity. In vivo, MD‐1 significantly inhibited tumour growth in a subcutaneous xenograft model and prolonged overall survival in an orthotopic model of feline OSCC. Our results show that MD‐1 may be an effective therapy for the treatment of feline oral cancer. Our findings also support the further investigation of feline OSCC as a large animal model to inform the development of MCT inhibitors and future clinical studies in human HNSCC.     

Electromyographic activity of the longissimus dorsi muscles in horses during trotting on a treadmill

OBJECTIVE: To use electromyography (EMG) to measure physiologic activity of the longissimus dorsi muscles of horses during trotting on a treadmill. ANIMALS: 15 adult horses (5 to 20 years old that weighed 450 to 700 kg) that did not have clinical signs of back pain. PROCEDURE: Data were recorded for each horse during trotting on a treadmill at speeds of 2.6 to 4.4 m/s. Surface electromyography was recorded bilaterally from the longissimus dorsi muscles at the levels of T12, T16, and L3. RESULTS: In each motion cycle, 2 EMG maxima were found at the end of the diagonal stance phases. The EMG activity peaked slightly later at L3 than at T12 and T16. Maximum EMG amplitudes were highest at T12 and decreased caudally, with mean +/- SD values of 4.51 +/- 1.20 mV at T12, 3.00 +/- 0.83 mV at T16, and 1.78 +/- 0.67 mV at L3. Mean minimum EMG activity was 1.30 +/- 0.63 mV at T12, 0.83 +/- 0.35 mV at T16, and 0.80 +/- 0.39 mV at L3. The relative amplitudes (ie, [maximum - minimum]/maximum) were 67 +/- 11% at T12, 66 +/- 8% at T16, and 71 +/- 8% at L3. CONCLUSIONS AND CLINICAL RELEVANCE: Activity of the longissimus dorsi muscles is mainly responsible for stabilization of the vertebral column against dynamic forces. The difference between minimum and maximum activity may allow application of this method as a clinical tool. Data reported here can serve as reference values for comparison with values from clinically affected horses.     

Hair coat contamination with zoonotic helminth eggs of farm and pet dogs and foxes

Infections of dogs with Toxocara canis and Echinococcus multilocularis pose an infection-risk particularly for contact persons. We examined specimens of hair coat and faeces of 124 farm dogs, 118 household dogs, 49 kennel dogs, 15 puppies from two litters, and 46 red foxes. Microscopically identified eggs of Toxocara or taeniids were further investigated by species-specific PCRs. In farm dogs, eggs of E. multilocularis or T. canis were identified in each 2.4% of faecal samples, eggs of T. cati (gastrointestinal passage) in 7.3%, respectively. Household dogs excreted eggs of T. canis (0.8%) and of T. cati (2.5%). In kennel dogs, eggs of T. canis (4.1%), but not of T. cati were detectable. Coat samples contaminated with eggs of Toxocara spp. were found from farm dogs (5.6%), household dogs (1.7%) and kennel dogs (2.0%). Taeniid eggs were isolated from the coat samples from only two farm dogs (1.6%); a molecular species determination was not achieved. In six intrauterinely infected puppies, Toxocara-eggs were found in 17/38 samples taken within six weeks. No intact Toxocara eggs could be isolated from the coat of nine puppies from a second litter 13 days after deworming. Of the 46 red foxes investigated (dissection and faecal samples) 13 (28.3%) were infected with E. multilocularis and 20 (43.5%) with Toxocara. Eggs of taeniids and Toxocara were found in 13% (in three cases confirmed as E. multilocularis) and 21.7%, respectively, of the coat samples. None of the retrieved Toxocara eggs in the coat samples were embryonated. Thus, an infection of humans through the transmission of E. multilocularis eggs after direct contact with dogs or foxes is conceivable, whereas a corresponding infection risk by Toxocara eggs must be critically challenged.     

Comparison of cardiac output determined by arterial pulse pressure waveform analysis method (FloTrac/Vigileo) versus lithium dilution method in anesthetized dogs

Objective – To compare the determination of cardiac output (CO) via arterial pulse pressure waveform analysis (FloTrac/Vigileo) versus lithium dilution method. Design – Prospective study. Setting – University teaching hospital. Animals – Six adult dogs. Interventions – Dogs were instrumented for CO determinations using lithium dilution (LiDCO) and FloTrac/Vigileo methods. Direct blood pressure, heart rate, arterial blood gases, and end‐tidal isoflurane (ETIso) and CO₂ concentrations were measured throughout the study while CO was manipulated with different depth of anesthesia and rapid administration of isotonic crystalloids at 60 mL/kg/h. Measurements and Main Results – Baseline CO measurements were obtained at 1.3% ETIso and were lowered by 3% ETIso. Measurements were obtained in duplicate or triplicate with LiDCO and averaged for comparison with corresponding values measured continuously with the FloTrac/Vigileo method. For 30 comparisons between methods, a mean bias of ?100 mL/kg/min and 95% limits of agreement between ?311 and +112 mL/kg/min (212 mL/kg/min) was determined. The mean (mL/kg/min) of the differences of LiDCO?Vigileo=62.0402+?0.8383 × Vigileo, and the correlation coefficient (r) between the 2 methods 0.70 for all CO determinations. The repeatability coefficients for the individual LiDCO and FloTrac/Vigileo methods were 187 and 400 mL/kg/min, respectively. Mean LiDCO and FloTrac/Vigileo values from all measurements were 145 ± 68 mL/kg/min (range, 64–354) and 244 ± 144 mL/kg/min (range, 89–624), respectively. The overall mean relative error was 48 ± 14%. Conclusion – The FloTrac/Vigileo overestimated CO values compared with LiDCO and the relative error was high, which makes this method unreliable for use in dogs.