Biology subjects

King, M. T.

Publications and source records attributed to King, M. T..

3 recordsLinked to original sources

bioRxiv2025

Immune Spatial Organization Predicts Metastasis Risk in Aggressive Localized Prostate Cancer

Risk stratification in localized prostate cancer (PCa) remains imprecise. Computational pathology has emerged as an attractive option for improving risk stratification, but current approaches either lack interpretability or focus solely on tumor morphology. Here, we identify, validate, and provide interpretability for an immune microenvironment-derived computational pathology biomarker for high-grade PCa. Using digitized hematoxylin and eosin-stained (H&E) slides from two independent cohorts of patients treated with radical prostatectomy (n=490), we found that spatial clustering of immune clusters, but not immune cell abundance, was independently associated with reduced risk of distant metastasis for high-grade disease but not low-grade. Joint analysis of H&E images and RNA sequencing (n=326) revealed that in high-grade disease, high-cluster samples were enriched in CD8+ T cells, activated memory CD4+ T cells, and Tregs, as well as clonal T cell populations, overall suggestive of an underlying T cell-mediated antitumor response. No such enrichment was found in low-grade tumors. These findings establish immune spatial architecture as a novel, interpretable computational pathology biomarker and provide insight into the immune landscape of high-grade PCa.

bioinformatics↗

bioRxiv2022

Ketone ester-enriched diet ameliorates motor and dopamine release deficits in MitoPark mice

BackgroundParkinsons disease is a progressive, neurodegenerative disease characterized by motor dysfunction and dopamine deficits. The MitoPark mouse recapitulates several facets of Parkinsons disease, including gradual development of motor deficits, which enables the study of potential therapeutic interventions. One therapeutic strategy involves decreasing the mitochondrial metabolic load by inducing ketosis and providing an alternative energy source for neurons, leading to decreased neuronal oxidative stress. ObjectiveWe assessed whether administration of a ketone ester-enriched diet would improve motor and dopamine release deficits in MitoPark mice. MethodsMotor function (rotarod and open field tests), dopamine release (fast-scan cyclic voltammetry), tissue dopamine levels (GC-MS), and dopamine neurons and axons (immunofluorescence) were assessed in MitoPark and control mice fed either the standard or ketone ester-enriched diets. ResultsWhen started on the ketone diet before motor dysfunction onset, MitoPark mice had preserved motor function relative to standard diet MitoPark mice. While the ketone ester enriched diet did not preserve dopamine neurons or striatal dopamine axons, dopamine release in ketone diet MitoPark mice was greater than standard diet MitoPark mice but less than control mice. In a follow up experiment, we began the ketone diet after motor dysfunction onset and observed a modest preservation of motor function in ketone diet MitoPark mice relative to standard diet MitoPark mice. ConclusionThe improvement in motor dysfunction indicates that a ketone ester enriched diet or ketone supplement may represent a promising adjunct treatment for Parkinsons disease.

neuroscience↗

bioRxiv2020

Ketogenic Diet Prevents Heart Failure from Defective Mitochondrial Pyruvate Metabolism

The myocardium is metabolically flexible and can use fatty acids, glucose, lactate/pyruvate, ketones, or amino acids to fuel mechanical work. However, impaired metabolic flexibility is associated with cardiac dysfunction in conditions including diabetes and heart failure. The mitochondrial pyruvate carrier (MPC) is required for pyruvate metabolism and is composed of a hetero-oligomer of two proteins known as MPC1 and MPC2. Interestingly, MPC1 and MPC2 expression is downregulated in failing human hearts and in a mouse model of heart failure. Mice with cardiac-specific deletion of MPC2 (CS-MPC2-/-) exhibited loss of both MPC2 and MPC1 proteins and reduced pyruvate-stimulated mitochondrial respiration. CS-MPC2-/- mice exhibited normal cardiac size and function at 6-weeks old, but progressively developed cardiac dilation and contractile dysfunction thereafter. Feeding CS-MPC2-/- mice a ketogenic diet (KD) completely prevented or reversed the cardiac remodeling and dysfunction. Other diets with higher fat content and enough carbohydrate to limit ketosis also improved heart failure in CS-MPC2-/- mice, but direct ketone body provisioning provided only minor improvements in cardiac remodeling. Finally, KD was also able to prevent further remodeling in an ischemic, pressure-overload mouse model of heart failure. In conclusion, loss of mitochondrial pyruvate utilization leads to dilated cardiomyopathy that can be corrected by a ketogenic diet.

physiology↗