Biology subjects

Olson, A. K.

Publications and source records attributed to Olson, A. K..

3 recordsLinked to original sources

bioRxiv2025

Detection of Cardiac O-GlcNAcylation via Subcellular Fractionation and Dual Antibody Analysis in Pressure Overload Cardiac Hypertrophy

Protein O-GlcNAcylation is a dynamic post-translational modification with emerging roles in cardiac pathophysiology. The availability of differenct pan-specific antibodies to assess global O-GlcNAc levels, and variability in Western blot results has hindered cross-study reproducibility and interpretation. In this study, we applied optimized immunoblotting protocols using both CTD110.6 and RL2 O-GlcNAc antibodies, alongside subcellular fractionation, to investigate temporal and sex-specific changes in cardiac O-GlcNAcylation during pressure overload hypertrophy (POH) from transverse aortic constriction (TAC) during early (1-week POH, 1wTAC) and chonic (6-weeks POH, 6wTAC) POH in mice. Global O-GlcNAc levels were elevated in early POH and returned to baseline in chronic POH, consistent across both antibodies and sexes. Subcellular fractionation revealed persistent O-GlcNAc elevations in cytoplasmic and membrane fractions in chronic POH for both sexes, which were not detected in unfractionated samples. Female mice exhibited significantly higher O-GlcNAc levels than males during POH, particularly at early POH, highlighting sex-specific regulation. OGT and OGA protein levels also varied by compartment and sex, suggesting differential enzymatic control. In conclusion, our findings underscore the importance of methodological rigor in O-GlcNAc detection and demonstrate that fractionation enhances sensitivity to subtle changes in cardiac O-GlcNAcylation. Our principal new findings are protein O-GlcNAcylation dysregulation continues from early POH (1wTAC) into chronic POH (6wTAC groups) along with showing differences in O-GlcNAc levels between males and females during POH. These results provide new insights into the temporal and sex-dependent dynamics of O-GlcNAc signaling in POH and support its potential as a therapeutic target in cardiovascular disease.

microbiology↗

bioRxiv2025

Determining preclinical safety of Aclarubicin in pediatric malignancies

BackgroundAnthracyclines are among the most effective chemotherapeutic agents used to treat pediatric malignancies. However, their clinical use is limited by dose-dependent toxicities, particularly cardiotoxicity and secondary malignancies. Aclarubicin (Acla) is an anthracycline derivative that induces chromatin damage while sparing DNA, offering potential therapeutic benefit with reduced longterm toxicity. MethodsWe evaluated the anti-tumor efficacy and safety profile of Acla in multiple in vitro pediatric cancer models and in vivo mouse models designed to mimic anthracycline re-treatment following prior doxorubicin (Doxo) exposure. Tumor growth, genotoxic stress, survival, and organ toxicity were assessed. ResultsAcla demonstrated robust anti-tumor activity comparable to Doxo across diverse pediatric in vitro models. Unlike Doxo, Acla treatment did not induce significant genotoxic stress. In vivo, mice receiving Acla after Doxo exposure showed no evidence of cumulative cardiotoxicity or end-organ damage. In contrast, a second course of Doxo led to significant toxic mortality, but was surprisingly not attributable to classic cardiac injury. ConclusionOur study highlights Acla as a promising anthracycline derivative for pediatric cancers, with potent anti-tumor efficacy and a superior safety profile, even following prior anthracycline exposure. These results support continued investigation of chromatin-damaging anthracyclines that can kill pediatric cancer cells without inducing genotoxic stress. In addition, our studies underscore the need to refine preclinical models to better understand both acute and chronic anthracycline toxicities in pediatric and adolescent populations.

cancer biology↗

bioRxiv2021

Brain capillary obstruction as a novel mechanism of anti-CD19 CAR T cell neurotoxicity

Immunotherapy for hematologic malignancies with CD19-directed CAR T cells is associated with neurotoxicity in about 40% of patients. Systemic cytokine release syndrome, endothelial activation, and disruption of endothelial integrity have all been associated with neurotoxicity, but it remains unclear how these mechanisms interact and how they lead to neurologic dysfunction. We developed a syngeneic mouse model which manifests systemic cytokine release and behavioral abnormalities within 3-5 days after infusion of high-dose murine CD19-CAR T cells. Histologic examination revealed widespread brain hemorrhages, diffuse extravascular IgG deposition, loss of capillary pericyte coverage and increased prevalence of string capillaries. In vivo two-photon imaging of blood flow revealed plugging of >10% of capillaries by leukocytes, associated with regions of localized hypoxia. These data reveal capillary obstruction and associated brain hypoxia and microvascular decline as a potential basis for neurotoxicity during CD19-CAR T cell treatment in humans, which may be amenable to therapeutic interventions.

neuroscience↗