Bag, A. | Search bioRxiv

bioRxiv2025

Enhanced Temporal-Resolution CEST Imaging method for reliable mapping of muscle OXPHOS

PurposeTo develop and validate a novel chemical exchange saturation transfer (CEST) MRI method to map skeletal muscle OXPHOS (Oxidative Phosphorylation CEST or OXCEST). Theory and MethodsOur proposed OXCEST method acquires creatine (Cr)-weighted CEST maps by applying RF saturation (B1) at only two frequency offsets: +1.8 ppm (targeting the Cr amine resonance) and -1.8 ppm (to calculate MTRasym at 1.8 ppm). The pre-exercise MTRasym is modeled as a second-order polynomial function (f) of B0. Next, the post-exercise alteration in MTRasym is hypothesized to be affected by both an exercise-induced increase in Cr and changes in B0 inhomogeneity. By inputting post-exercise B0 values into f, the change in MTRasym due to B0 variation alone was estimated. Thus, the Cr-related post-exercise MTRasym could be isolated and quantified. OXCEST and 31P-MRS were performed in seven subjects across two sessions to compare the OXCEST-derived Cr recovery time constant (TCr) with the ground-truth phosphocreatine recovery time constant (TPCr). ResultsA second-order polynomial function f could reliably describe the relationship between pre-exercise MTRasym and B0 (R2=0.87{+/-}0.07 in the lateral gastrocnemius (LG); R2=0.98{+/-}0.01 in the medial gastrocnemius (MG); R2=0.96{+/-}0.03 in the soleus). The mean pre-exercise MTRasym was approximately 6-7% for all muscle groups. Following exercise, MTRasym increased by 11.4{+/-}4.5% in LG and 8{+/-}2.4% in MG, and showed mono-exponential recovery (R2>0.97). The combined TCr of LG and MG was found to be significantly correlated with TPCr (R{superscript 2}=0.83, p=0.005). ConclusionOXCEST enables reliable assessment of post-exercise Cr recovery and demonstrated strong agreement with 31P-MRS.

bioengineering↗

bioRxiv2021

The immunomodulatory properties of the HDAC6 inhibitor ACY241 supports robust anti-tumor response in NSCLC when coupled with the chemotherapy drug Oxaliplatin

BackgroundDurable treatments that benefit a wide pool of patients remain elusive for Non-small cell lung cancer (NSCLC). The success of immunotherapy in a subset of NSCLC patients highlights the potential contribution of immune response to anti-tumor immunity while underscoring a need for broadly applicable therapeutic strategies. HDAC inhibitors are a promising class of drugs whose immunomodulatory properties are now being appreciated. In the present study, we evaluated the effects of the HDAC6 inhibitor, ACY241 on lung tumor immune compartment with the goal of understanding the scope of its immunomodulatory properties and its therapeutic potential in combination with Oxaliplatin. MethodsLung adenocarcinoma-bearing mice were treated with ACY241 or vehicle after which the proportions and phenotype of tumor-associated T cells and macrophages were evaluated by comprehensive flow cytometric analysis. Bulk RNA-sequencing was also conducted on both cellular subsets to interrogate the transcriptomic changes associated with ACY241 treatment relative to vehicle controls. In vivo drug efficacy study was performed by administration of ACY241 and/or Oxaliplatin and assessing tumor growth and survival of tumor-bearing mice. Ex vivo functional studies was performed to assess tumor-associated T cell effector function as it correlates with measured outcomes. ResultsWe demonstrate that ACY241 promotes increased presence of T and NK cells in the lung tumors of treated mice. The tumor-associated T cells under ACY241 treatment displayed enhanced activation, proliferation, and effector profile. In addition, tumor-associated macrophages exhibited increased expression of MHC and co-stimulatory molecules while expression of inhibitory ligands were reduced. RNA-sequencing of both tumor-associated T cells and macrophages revealed significant genomic changes in both subsets that is consistent with ACY241-mediated enhancement of immune priming. These broad immunomodulatory properties of ACY241 were associated with significantly enhanced tumor-associated T cell effector functionality, robust anti-tumor response, and significantly prolonged survival of NSCLC-bearing mice when combined with the chemotherapy drug Oxaliplatin. ConclusionCollectively, our studies highlight the broad immunomodulatory effect of ACY241 as a promising HDAC6 inhibitor which coupled with Oxaliplatin promotes robust therapeutic outcomes in a pre-clinical model of NSCLC, providing compelling rationale for the clinical testing of this novel combinatorial regimen in NSCLC.

immunology↗