TEST:

nCounter® Metabolic Pathways Panel

Consequently, we observed higher levels of uracil in tissue and CSF samples from patients with IDH wild-type gliomas. These data provide a framework to study the relationship between mutations, methylation, gene expression and metabolism in diffuse gliomas.

Elderly event-free FH patients displayed a different PBMC gene expression profile compared to FH patients with CHD. Differences in gene expression compared to healthy controls were more pronounced in the CHD group, indicating a less atherogenic gene expression profile in event-free individuals. Overall, identification of cardioprotective factors could lead to future therapeutic targets.

Overall, our results demonstrate HuR as a positive regulator of aerobic glycolysis in TNBCs and the ability of CMLD2 to inhibit HuR provides a rationale to consider it as a potential anticancer agent for TNBCs.

Our results showed significant differences in gene expression between IDH-mutant and IDH-wildtype diffuse gliomas, including higher levels of MAPT (Tau) in IDH-mutant tumors. We are in the process of incorporating the results of mass spectrometry and genome-wide methylation analysis in the context of gene expression data. We anticipate that this analysis will yield new insights into how the metabolic alterations in diffuse gliomas are influenced by epigenetic and gene expression changes.

To characterize signaling changes with FASN inhibition and identify any off-target signaling, we used a Nanostring metabolic pathways nCounter panel to perform differential expression analysis on cells treated with the FASN inhibitor, TVB-2640, vs. vehicle control across the four cell lines... In our study, we have shown that the combination of SN-38 and FASN inhibitors is synergistic in the TNBC brain-seeking cell lines, and that FASN inhibition alone causes on-target transcriptome-level changes and a decrease in spheroid invasion. Next, we plan on testing the brain-metastatic potential of these cell lines in the presence and absence of a FASN inhibitor using an organ-on-chip microfluidic device developed by our lab that mimics the blood-brain barrier, to identify if this strategy has a potential role in prevention of brain metastases. Further studies to refine the molecular basis of the mechanism of action of the combination are underway.

In accordance with this, the expression of glycolytic proteins LDHA, PFKP, and MCT1 was found to be reduced upon CMLD2 treatment. Consistent results were obtained on HuR knockdown by siRNA suggesting that HuR-mediated effects on TNBC progression might be in part through its modulation of aerobic glycolysis.ConclusionTo our knowledge, this is the first report that demonstrates HuR as a positive regulator of aerobic glycolysis in TNBCs and the ability of CMLD2 to inhibit HuR provides a rationale to consider it as a potential anticancer agent for TNBCs.

The universal loss of Complex I activity in ROs is independent of mtDNA mutations. Complex I loss in RO is associated with increased glutathione, which in turn may result in impaired mitophagy. We continue to develop models to interrogate key drivers in this process.

Specific key metabolic genes were differentially expressed in acral melanomas, likely contributing to the aggressive biological behavior. Validation of the findings on a larger cohort and correlation study of these findings with clinicopathologic data (Table 1) are underway.