👤 E Vasseur

Hypochondroplasia is a rare genetic form of skeletal dysplasia, caused by gain-of-function pathogenic variants in the FGF receptor 3 (FGFR3). It is characterized by disproportionate short stature and has a wide spectrum of clinical features. Currently, there are no precision therapeutic options approved for hypochondroplasia. Infigratinib is an orally bioavailable FGFR1-3 selective tyrosine kinase inhibitor in development for achondroplasia and hypochondroplasia. Infigratinib acts directly at the source of the pathophysiological cause of both conditions by inhibiting the phosphorylation of FGFR3 and attenuating both main downstream signaling pathways that are involved in the conditions. Results from a phase 2 study support the concept that infigratinib has a potential to improve bone growth in achondroplasia. We report results of a step-wise evaluation of the therapeutic relevance of infigratinib for hypochondroplasia: in silico assessment of infigratinib with hypochondroplasia associated FGFR3 variants suggest strong interaction; in vitro, infigratinib showed potent inhibitory effect; in a mouse model of hypochondroplasia (Fgfr3N534K/+), infigratinib resulted in significant improvement in skeletal growth. These data in addition to the clinical results from the phase 2 study conducted in children with achondroplasia provide support for the development of infigratinib in the treatment of hypochondroplasia. Show less

Selecting and raising dairy animals that are more likely to reach their potential is a strategy to increase milk production efficiency and overall profitability. However, indicators are necessary for the early identification of animals that are less likely to perform well, allowing for their early culling and ensuring that resources are allocated to those with the highest potential. The objective of this study was to analyze the association between early-life animal health and performance with longevity, production, and profitability. After data cleaning, the following early-life measures (i.e., predictors) were available for 363 female calves born between June 2014 and November 2015 in eight dairy herds from New Brunswick, Canada (average: 45 calves/farm; SD: 26.1 calves/farm; median: 42 calves/farm; range: 15-95 calves/farm): birth weight, weaning weight, weaning age, weaning average daily gain (weaning ADG), immunoglobulin G (IgG) serum concentration, the occurrence of navel infection, diarrhea, and pneumonia, and if animals received antibiotic treatment between birth and weaning. Their subsequent length of life (LL), length of productive life (LPL), lifetime cumulative energy-corrected milk (ECM), and lifetime cumulative milk value (i.e., response variables) were provided by the Canadian dairy herd improvement agency. Bayesian Additive Regression Tree models were trained for each response variable using 5-fold cross-validation. Models were evaluated using the RMSE and R Show less