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MSTPublications: November 2021

Posted by on Tuesday, November 30, 2021 in New Publications .


Leptin Augments Antitumor Immunity in Obesity by Repolarizing Tumor-Associated Macrophages.

Dudzinski SO, Bader JE, Beckermann KE, Young KL, Hongo R, Madden MZ, Abraham A, Reinfeld BE, Ye X, MacIver NJ, Giorgio TD, Rathmell JC.

J Immunol. 2021 Nov 12:ji2001152. doi: 10.4049/jimmunol.2001152. Online ahead of print.

Although obesity can promote cancer, it may also increase immunotherapy efficacy in what has been termed the obesity-immunotherapy paradox. Mechanisms of this effect are unclear, although obesity alters key inflammatory cytokines and can promote an inflammatory state that may modify tumor-infiltrating lymphocytes and tumor-associated macrophage populations. To identify mechanisms by which obesity affects antitumor immunity, we examined changes in cell populations and the role of the proinflammatory adipokine leptin in immunotherapy. Single-cell RNAseq demonstrated that obesity decreased tumor-infiltrating lymphocyte frequencies, and flow cytometry confirmed altered macrophage phenotypes with lower expression of inducible NO synthase and MHC class II in tumors of obese animals. When treated with anti-programmed cell death protein 1 (PD-1) Abs, however, obese mice had a greater absolute decrease in tumor burden than lean mice and a repolarization of the macrophages to inflammatory M1-like phenotypes. Mechanistically, leptin is a proinflammatory adipokine that is induced in obesity and may mediate enhanced antitumor immunity in obesity. To directly test the effect of leptin on tumor growth and antitumor immunity, we treated lean mice with leptin and observed tumors over time. Treatment with leptin, acute or chronic, was sufficient to enhance antitumor efficacy similar to anti-PD-1 checkpoint therapy. Further, leptin and anti-PD-1 cotreatment may enhance antitumor effects consistent with an increase in M1-like tumor-associated macrophage frequency compared with non-leptin-treated mice. These data demonstrate that obesity has dual effects in cancer through promotion of tumor growth while simultaneously enhancing antitumor immunity through leptin-mediated macrophage reprogramming.


Axonal Injury Partially Mediates Associations Between Increased Left Ventricular Mass Index and White Matter Damage.

Moore EE, Khan OA, Shashikumar N, Pechman KR, Liu D, Bell SP, Nair S, Terry JG, Gifford KA, Anderson AW, Landman BA, Blennow K, Zetterberg H, Hohman TJ, Carr JJ, Jefferson AL.

Stroke. 2021 Oct 27:STROKEAHA121034349. doi: 10.1161/STROKEAHA.121.034349. Online ahead of print.

Background and purpose: Left ventricular (LV) mass index is a marker of subclinical LV remodeling that relates to white matter damage in aging, but molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of microglial activation (sTREM2 [soluble triggering receptor expressed on myeloid cells 2]), axonal injury (NFL [neurofilament light]), neurodegeneration (total-tau), and amyloid-β, and whether these biomarkers partially accounted for associations between increased LV mass index and white matter damage. We hypothesized higher LV mass index would relate to greater CSF biomarker levels, and these pathologies would partially mediate associations with cerebral white matter microstructure.

Methods: Vanderbilt Memory and Aging Project participants who underwent cardiac magnetic resonance, lumbar puncture, and diffusion tensor imaging (n=142, 72±6 years, 37% mild cognitive impairment [MCI], 32% APOE-ε4 positive, LV mass index 51.4±8.1 g/m2, NFL 1070±588 pg/mL) were included. Linear regressions and voxel-wise analyses related LV mass index to each biomarker and diffusion tensor imaging metrics, respectively. Follow-up models assessed interactions with MCI and APOE4. In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated white matter associations.

Results: Among all participants, LV mass index was unrelated to CSF biomarkers (P>0.33). LV mass index interacted with MCI (P=0.01), such that higher LV mass index related to increased NFL among MCI participants. Associations were also present among APOE-ε4 carriers (P=0.02). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter damage.

Conclusions: Subclinical cardiovascular remodeling, measured as an increase in LV mass index, is associated with neuroaxonal degeneration among individuals with MCI and APOE-ɛ4. Neuroaxonal degeneration partially reflects associations between higher LV mass index and white matter damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or microglia, may be more relevant in pathways between structural cardiovascular remodeling and white matter damage.


β-Glucan Induces Distinct and Protective Innate Immune Memory in Differentiated Macrophages.

Stothers CL, Burelbach KR, Owen AM, Patil NK, McBride MA, Bohannon JK, Luan L, Hernandez A, Patil TK, Williams DL, Sherwood ER.

J Immunol. 2021 Nov 5:ji2100107. doi: 10.4049/jimmunol.2100107. Online ahead of print.

Bacterial infections are a common and deadly threat to vulnerable patients. Alternative strategies to fight infection are needed. β-Glucan, an immunomodulator derived from the fungal cell wall, provokes resistance to infection by inducing trained immunity, a phenomenon that persists for weeks to months. Given the durability of trained immunity, it is unclear which leukocyte populations sustain this effect. Macrophages have a life span that surpasses the duration of trained immunity. Thus, we sought to define the contribution of differentiated macrophages to trained immunity. Our results show that β-glucan protects mice from Pseudomonas aeruginosa infection by augmenting recruitment of innate leukocytes to the site of infection and facilitating local clearance of bacteria, an effect that persists for more than 7 d. Adoptive transfer of macrophages, trained using β-glucan, into naive mice conferred a comparable level of protection. Trained mouse bone marrow-derived macrophages assumed an antimicrobial phenotype characterized by enhanced phagocytosis and reactive oxygen species production in parallel with sustained enhancements in glycolytic and oxidative metabolism, increased mitochondrial mass, and membrane potential. β-Glucan induced broad transcriptomic changes in macrophages consistent with early activation of the inflammatory response, followed by sustained alterations in transcripts associated with metabolism, cellular differentiation, and antimicrobial function. Trained macrophages constitutively secreted CCL chemokines and robustly produced proinflammatory cytokines and chemokines in response to LPS challenge. Induction of the trained phenotype was independent of the classic β-glucan receptors Dectin-1 and TLR-2. These findings provide evidence that β-glucan induces enhanced protection from infection by driving trained immunity in macrophages.


MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function.

Sugiura A, Andrejeva G, Voss K, Heintzman DR, Xu X, Madden MZ, Ye X, Beier KL, Chowdhury NU, Wolf MM, Young AC, Greenwood DL, Sewell AE, Shahi SK, Freedman SN, Cameron AM, Foerch P, Bourne T, Garcia-Canaveras JC, Karijolich J, Newcomb DC, Mangalam AK, Rabinowitz JD, Rathmell JC.

Immunity. 2021 Nov 3:S1074-7613(21)00448-9. doi: 10.1016/j.immuni.2021.10.011. Online ahead of print.

Antigenic stimulation promotes T cell metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) regulates de novo purine synthesis and signaling in activated T cells to promote proliferation and inflammatory cytokine production. In pathogenic T helper-17 (Th17) cells, MTHFD2 prevented aberrant upregulation of the transcription factor FoxP3 along with inappropriate gain of suppressive capacity. MTHFD2 deficiency also promoted regulatory T (Treg) cell differentiation. Mechanistically, MTHFD2 inhibition led to depletion of purine pools, accumulation of purine biosynthetic intermediates, and decreased nutrient sensor mTORC1 signaling. MTHFD2 was also critical to regulate DNA and histone methylation in Th17 cells. Importantly, MTHFD2 deficiency reduced disease severity in multiple in vivo inflammatory disease models. MTHFD2 is thus a metabolic checkpoint to integrate purine metabolism with pathogenic effector cell signaling and is a potential therapeutic target within 1C metabolism pathways.


DDIWAS: High-throughput electronic health record-based screening of drug-drug interactions.

Wu P, Nelson SD, Zhao J, Stone CA Jr, Feng Q, Chen Q, Larson EA, Li B, Cox NJ, Stein CM, Phillips EJ, Roden DM, Denny JC, Wei WQ.

J Am Med Inform Assoc. 2021 Jul 14;28(7):1421-1430. doi: 10.1093/jamia/ocab019.

Objective: We developed and evaluated Drug-Drug Interaction Wide Association Study (DDIWAS). This novel method detects potential drug-drug interactions (DDIs) by leveraging data from the electronic health record (EHR) allergy list.

Materials and methods: To identify potential DDIs, DDIWAS scans for drug pairs that are frequently documented together on the allergy list. Using deidentified medical records, we tested 616 drugs for potential DDIs with simvastatin (a common lipid-lowering drug) and amlodipine (a common blood-pressure lowering drug). We evaluated the performance to rediscover known DDIs using existing knowledge bases and domain expert review. To validate potential novel DDIs, we manually reviewed patient charts and searched the literature.

Results: DDIWAS replicated 34 known DDIs. The positive predictive value to detect known DDIs was 0.85 and 0.86 for simvastatin and amlodipine, respectively. DDIWAS also discovered potential novel interactions between simvastatin-hydrochlorothiazide, amlodipine-omeprazole, and amlodipine-valacyclovir. A software package to conduct DDIWAS is publicly available.

Conclusions: In this proof-of-concept study, we demonstrate the value of incorporating information mined from existing allergy lists to detect DDIs in a real-world clinical setting. Since allergy lists are routinely collected in EHRs, DDIWAS has the potential to detect and validate DDI signals across institutions.


Multi-Site Optical Monitoring of Spinal Cord Ischemia during Spine Distraction.

Busch DR, Lin W, Cai C, Cutrone A, Tatka J, Kovarovic BJ, Yodh AG, Floyd TF, Barsi J.

J Neurotrauma. 2020 Sep 15;37(18):2014-2022. doi: 10.1089/neu.2020.7012. Epub 2020 Jul 20.


Elevated Aortic Pulse Wave Velocity Relates to Longitudinal Gray and White Matter Changes.

Bown CW, Khan OA, Moore EE, Liu D, Pechman KR, Cambronero FE, Terry JG, Nair S, Davis LT, Gifford KA, Landman BA, Hohman TJ, Carr JJ, Jefferson AL.

Arterioscler Thromb Vasc Biol. 2021 Oct 28:ATVBAHA121316477. doi: 10.1161/ATVBAHA.121.316477. Online ahead of print.


Lower cerebral oxygen utilization is associated with Alzheimer’s disease-related neurodegeneration and poorer cognitive performance among apolipoprotein E ε4 carriers.

Robb WH, Khan OA, Ahmed HA, Li J, Moore EE, Cambronero FE, Pechman KR, Liu D, Gifford KA, Landman BA, Donahue MJ, Hohman TJ, Jefferson AL.

J Cereb Blood Flow Metab. 2021 Nov 7:271678X211056393. doi: 10.1177/0271678X211056393. Online ahead of print.


Primary care visits and ambulatory care sensitive diabetes hospitalizations among adult Alabama Medicaid beneficiaries.

Bronstein JM, Huang L, Shelley JP, Levitan EB, Presley CA, Agne AA, Mondesir FL, Riggs KR, Pisu M, Cherrington AL.

Prim Care Diabetes. 2021 Nov 9:S1751-9918(21)00190-X. doi: 10.1016/j.pcd.2021.10.005. Online ahead of print.


Sex and gender in asthma.

Chowdhury NU, Guntur VP, Newcomb DC, Wechsler ME.

Eur Respir Rev. 2021 Nov 17;30(162):210067. doi: 10.1183/16000617.0067-2021. Print 2021 Dec 31.


Identification and Remediation of Environmental Exposures in Patients With Interstitial Lung Disease: Evidence Review and Practical Considerations.

Copeland CR, Collins BF, Salisbury ML.

Chest. 2021 Jul;160(1):219-230. doi: 10.1016/j.chest.2021.02.021. Epub 2021 Feb 18.


Network dysfunction in pre and postsurgical epilepsy: connectomics as a tool and not a destination.

Johnson GW, Doss DJ, Englot DJ.

Curr Opin Neurol. 2021 Nov 18. doi: 10.1097/WCO.0000000000001008. Online ahead of print.