Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results.

Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884 .

Investigation of the cardiac effects of exercise testing on apparently healthy Boxer dogs.

BACKGROUND: Holter electrocardiographic monitoring is a cornerstone of diagnostic testing for arrhythmogenic cardiomyopathy (ACM) in Boxer dogs, but physical activity during monitoring is not controlled. In humans, exercise testing (ExT) can identify latent tachyarrhythmias associated with cardiomyopathy, and exercise increases serum cardiac troponin-I concentrations ([hs-cTnI]). These effects have not yet been investigated in Boxer dogs. HYPOTHESIS/OBJECTIVES: Subjecting Boxer dogs to brief, moderate-intensity ExT can identify changes in Holter recordings and [hs-cTnI] compared to baseline results. ANIMALS: Thirty overtly healthy, client-owned Boxer dogs. METHODS: Prospective interventional study. Dogs underwent baseline diagnostic testing including 24-hour Holter monitoring and [hs-cTnI], followed by brief ExT (accompanied, brisk stair-climbing and -descending for <5 minutes). RESULTS: Eleven dogs (37%) had >100 premature ventricular complexes (PVCs)/24 hours at baseline (3), ExT (3), or both (5). After ExT, these dogs had more PVCs/24 hours and greater increases in [hs-cTnI] compared to those with ≤100 PVCs/24 hours. Dogs with the striatin mutation had more PVCs/24 hours and a greater increase in [hs-cTnI] after ExT than did dogs without the striatin mutation. CONCLUSIONS AND CLINICAL IMPORTANCE: Exercise testing may improve the binary classification of Boxer dogs with or without ACM by increasing the number of PVCs and [hs-cTnI] in affected dogs to a greater degree than in unaffected dogs. This effect also is associated with presence or absence of the striatin mutation. Exercise should be a controlled variable when screening Boxer dogs for ACM.

Taurine deficiency and dilated cardiomyopathy in golden retrievers fed commercial diets.

INTRODUCTION: Golden retrievers are over-represented in cases of taurine-deficient dilated cardiomyopathy and recently a surge in cases has prompted further investigation. OBJECTIVE: To describe the clinical, dietary, and echocardiographic features in golden retrievers diagnosed with taurine deficiency and dilated cardiomyopathy, and to determine specific dietary associations. A second aim was to determine the whole blood taurine concentrations in a representative sample of healthy golden retrievers. ANIMALS: Twenty-four client-owned golden retrievers with documented taurine deficiency and dilated cardiomyopathy and 52 healthy client-owned golden retrievers. METHODS: In this multicenter prospective observational study, baseline and follow-up echocardiographic data, complete diet and medical histories, and whole blood, plasma, or serum taurine concentrations were obtained. Baseline and follow-up echocardiographic data were compared. Associations were evaluated between specific diets and taurine deficiency or congestive heart failure. The prevalence of low whole blood taurine concentrations in the healthy golden retrievers was calculated. RESULTS: Twenty-three of 24 dogs diagnosed with taurine deficiency and dilated cardiomyopathy were fed diets that were either grain-free, legume-rich, or a combination of these factors. None of these diets were feeding trial tested using Association of American Feed Control Officials (AAFCO) procedures. Twenty-three of 24 dogs had significant improvement in their echocardiographic parameters and normalization of taurine concentrations following diet change and taurine supplementation. Nine of 11 dogs diagnosed with congestive heart failure (CHF) had resolution of their congestion at follow-up with five no longer requiring diuretic therapy and four tolerating diuretic dose reduction by >50%. CONCLUSIONS: Certain diets and diet characteristics were associated with the development of taurine deficiency. Taurine deficiency and dilated cardiomyopathy in golden retrievers is likely multifactorial, including a combination of dietary, metabolic, and genetic factors.

Correction: Taurine deficiency and dilated cardiomyopathy in golden retrievers fed commercial diets.

[This corrects the article DOI: 10.1371/journal.pone.0209112.].

Ectopic thyroid carcinoma causing right ventricular outflow tract obstruction in a dog.

A 9-year-old Bouvier des Flandres was presented with coughing, lethargy, chylous pleural effusion, and a heart murmur. An echocardiogram revealed the presence of an intracardiac mass causing right ventricular outflow tract obstruction. The mass was successfully removed surgically, using total inflow occlusion. Histopathology and immunohistochemistry identified the tumor as an ectopic thyroid carcinoma. The dog was euthanized 11 months after diagnosis at the request of the owner because of nonresolving chylothorax.