👤 Emily Durham

Many pediatric cancer survivors experience chemotherapy-induced cognitive impairment (CICI), which negatively impacts their quality of life. However, while some patients develop CICI, others do not, suggesting that genetic variants may contribute to the development of CICI. The Apolipoprotein E (ApoE) E4 allele has been identified as a risk variant for CICI among pediatric cancer survivors. However, the mechanisms by which ApoE4 contributes to the development of CICI remain unknown. Using a commonly used chemotherapeutic agent known to induce CICI, doxorubicin, we treated five-week-old rats homozygous for either the human ApoE3 or ApoE4 allele with doxorubicin (2 mg/kg/week for 4 weeks) or saline. Behavioral assessments revealed that ApoE4 rats were more susceptible to doxorubicin-induced impairments in visual and spatial memory compared to ApoE3 rats. Pathophysiological analyses showed a significant reduction in hippocampal neurogenesis of ApoE4 doxorubicin-treated rats relative to the other groups. Serum levels of GFAP were significantly increased in ApoE4 doxorubicin-treated rats. These findings suggest that the ApoE genotype influences vulnerability to CICI and highlight a potential mechanistic link through impaired neurogenesis, laying the groundwork for genotype-specific therapeutic strategies. Show less

Branched chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a recently described inherited neurometabolic disorder of branched chain amino acid (BCAA) metabolism implying increased BCAA catabolism. It has been hypothesized that a severe reduction in systemic BCAA levels underlies the disease pathophysiology, and that BCAA supplementation may ameliorate disease phenotypes. To test this hypothesis, we characterized a recent mouse model of BCKDK deficiency and evaluated the efficacy of enteral BCAA supplementation in this model. Surprisingly, BCAA supplementation exacerbated neurodevelopmental deficits and did not correct biochemical abnormalities despite increasing systemic BCAA levels. These data suggest that aberrant flux through the BCAA catabolic pathway, not just BCAA insufficiency, may contribute to disease pathology. In support of this conclusion, genetic re-regulation of BCAA catabolism, through Show less

Branched chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a recently described inherited neurometabolic disorder of branched chain amino acid (BCAA) metabolism implying increased BCAA catabolism. It has been hypothesized that a severe reduction in systemic BCAA levels underlies the disease pathophysiology, and that BCAA supplementation may ameliorate disease phenotypes. To test this hypothesis, we characterized a recent mouse model of BCKDK deficiency and evaluated the efficacy of enteral BCAA supplementation in this model. Surprisingly, BCAA supplementation exacerbated neurodevelopmental deficits and did not correct biochemical abnormalities despite increasing systemic BCAA levels. These data suggest that aberrant flux through the BCAA catabolic pathway, not just BCAA insufficiency, may contribute to disease pathology. In support of this conclusion, genetic re-regulation of BCAA catabolism, through Show less

The melanocortin-4 receptor (MC4R) antagonistic peptide TCMCB07 was developed for the treatment of cachexia. The objectives of this study were to examine pharmacokinetics and safety of TCMCB07 administered subcutaneously to healthy dogs. Dogs were treated with high- (2.25 mg kg Show less