Medical Sciences Commons^™

Calcineurin/Nfat Inhibitors Maintain Cognition In A Preclinical Prevention Study In An Aging Canine Model Of Alzheimer Disease, Lorena Sordo, Margo F. Ubele, Kathy Boaz, Jennifer L. Mefford, Erin Dehnart Jones, Katie L. Mccarty, Hollie Y. Van Rooyen, Jeffrey R. Smiley, Stasia A. Bembenek Bailey, Jessica A. Perpich, Beverly Meacham, David K. Powell, Frederick Bresch, Jacob W. Crump, Michael J. Phelan, Jessica A. Noche, Craig E. Stark, László G. Puskás, Christopher M. Norris, Elizabeth Head

Pharmacology and Nutritional Sciences Faculty Publications

Brain signaling of calcineurin (CN) and nuclear factor of activated T-cells (NFAT) transcription factor increases in Alzheimer disease (AD) and is associated with synaptic loss, neurodegeneration, neuroinflammation, amyloid-β (Aβ) production, and cognitive decline. CN/NFAT inhibitors ameliorate these neuropathologies in mouse models of AD. Further, chronic use of tacrolimus in transplant patients reduces risk of AD. Beagles naturally develop Aβ plaques and cognitive dysfunction. We evaluated the impact of FDA-approved CN inhibitor, tacrolimus, and experimental NFAT inhibitor, Q134R, on cognitive outcomes during a three-year prevention study in 37 middle-aged beagles. While beagles treated with CN/NFAT inhibitors showed differences in the pattern …

A 40-Week Phase 2b Randomized, Multicenter, Double-Blind, Placebo-Controlled Study Evaluating The Safety And Efficacy Of Memantine In Amyotrophic Lateral Sclerosis, Salman Bhai, Todd Levine, Dan Moore, Robert Bowser, Andrew J. Heim, Maureen Walsh, Aziz Shibani, Zachary Simmons, James Grogan, Namita A. Goyal, Raghav Govindarajan, Yessar Hussain, Tania Papsdorf, Tiffany Schwasinger-Schmidt, Nick Olney, Kim Goslin, Michael Pulley, Edward J. Kasarskis, Michael Weiss, Susan W. Katz, Suzan Moser, Duaa Jabari, Omar Jawdat, Jeffrey Statland, Mazen M. Dimachkie, Richard Barohn, Neuromuscular Study Group And Western Als Consortium Memantine Als Study Group

Neurology Faculty Publications

Introduction: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies.

Aims: This study investigated memantine's impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease.

Methods: A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20 mg twice daily) or placebo in a 2:1 ratio …

Extracellular Vesicles Released By All Patients Contain Hne-Adducted Proteins: Implications Of Collateral Damage, Jenni Ho, Suriyan Sukati, Tamara Taylor, Sherry Carter, Brittany Fuller, Amy Marmo, Caryn Sorge, John A. D'Orazio, D. Allan Butterfield, Subbarao Bondada, Heidi Weiss, Daret K. St. Clair, Luksana Chaiswing

Markey Cancer Center Faculty Publications

Off-target neuronal injury is a serious side-effect observed in cancer survivors. It has previously been shown that pediatric acute lymphoblastic leukemia (ALL) survivors have a decline in neurocognition compared to healthy age-matched counterparts. Elevated oxidative stress has been documented to be a mediator in off- target tissue damage in cancer survivors. Early detection of oxidative stress markers may provide an opportunity to prevent off-target tissue damage. Extracellular vesicles (EVs) have surfaced as a potential diagnostic tool due to molecular cargo they contain. We investigated the potential for EVs to be a sensitive indicator of oxidative stress and off-target tissue damage …

Nf-Κb-Mediated Oxidative Stress Drives Cigarette Smoke-Induced Emt In Human Bronchial Cells, Sarah M. Alqithami

Theses and Dissertations--Toxicology and Cancer Biology

Cigarette smoke contains over 7,000 chemicals, many being carcinogens and proinflammatory agents contributing to chronic respiratory diseases like COPD and lung cancer. This study investigated responses of human bronchial epithelial cells (HBECs) to cigarette smoke condensate (CSC), focusing on oxidative stress and NF-κB signaling. Three HBEC lines were exposed to non-cytotoxic CSC doses for 48 hours, inducing morphological changes consistent with epithelial-to-mesenchymal transition (EMT). RNA sequencing revealed transcriptomic shifts in all cell lines, particularly affecting genes related to oxidative stress, inflammation, hypoxia, and metabolism. Enrichment analyses confirmed activation of NRF2 antioxidant, NF-κB and IL-17 inflammatory, and hypoxiainducible factor pathways, indicating …

Elucidating The Adverse Effects Of Chronic Pfos Exposure On Gastrointestinal Pathology And Colorectal Cancer, Jerika Durham

Theses and Dissertations--Toxicology and Cancer Biology

Commonly referred to as "forever chemicals," per- and polyfluoroalkyl substances (PFAS) have been linked to a number of detrimental health effects, including an elevated risk of cancer. One "long-chain" subtype of PFAS, perfluorooctanesulfonic acid (PFOS), has a long elimination half-life and a significant propensity for bioaccumulation. Because PFOS is commonly found in drinking water, the gastrointestinal system absorbs it at a high rate. Recent studies demonstrate that PFAS exposures promote intestinal inflammation and gut barrier dysfunction. However, how a long-term PFOS exposure affects colorectal cancer (CRC) progression is not known. Therefore, the purpose of this research is to understand how …

Investigating Plk1 In Pulmonary Fibrosis, Tempany Arbogast

Theses and Dissertations--Toxicology and Cancer Biology

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease, with a median survival of only 2–3 years following diagnosis. In the United States, the disease contributes to more than 40,000 deaths annually, underscoring its severe clinical burden. Alveolar type II (AT2) lung epithelial cells serve as progenitors that maintain alveolar integrity by replenishing epithelial populations and producing surfactants, while fibroblasts and myofibroblasts regulate the extracellular matrix and structural support. In pulmonary fibrosis (PF) injury to AT2 cells promotes cytokine and growth factor release, driving inflammation, fibroblast proliferation, myofibroblast accumulation, and excessive extracellular matrix deposition. Aberrant AT2 cell …

Weighted Family History Density Of Substance Use: Influence On Participant Substance Use Onset, Escalation, And Duration, Carleigh A. Litteral

Theses and Dissertations--Psychology

Substance use disorders impose a staggering toll on the United States (U.S.), straining healthcare systems, destabilizing communities, and profoundly impacting both individuals and families. Approximately one in six Americans aged 12 and older had a past-year substance use disorder in 2022 (Key Substance Use, 2022), and nearly one-third of adults experience a substance use disorder in their lifetime (Wu, 2010), contributing to an economic burden exceeding $400 billion annually (National Drug Threat Assessment, 2011). Family history of substance use disorders is a key predictor of vulnerability, with individuals who have affected relatives being 2–8 times more …

Apoa2 Increases Cholesterol Efflux Capacity To Plasma Hdl By Displacing The C-Terminus Of Resident Apoa1, Snigdha Sarkar, Jamie Morris, Youngki You, Hannah Sexmith, Scott E. Street, Stephanie M. Thibert, Isaac K. Attah, Chelsea M. Hutchinson Bunch, Irina V. Novikova, James E. Evans, Amy S. Shah, Scott M. Gordon, Jere P. Segrest, Karin E. Bornfeldt, Tomas Vaisar, Jay W. Heinecke, W. Sean Davidson, John T. Melchior

Saha Cardiovascular Research Center Faculty Publications

Abstract The ability of high-density lipoprotein (HDL) to promote cellular cholesterol efflux is a more robust predictor of cardiovascular disease protection than HDL-cholesterol levels in plasma. Previously, we found that lipidated HDL containing both apolipoprotein A-I (APOA1) and A-II (APOA2) promotes cholesterol efflux via the ATP-binding cassette transporter (ABCA1). In the current study, we directly added purified, lipid-free APOA2 to human plasma and found a dose-dependent increase in whole plasma cholesterol efflux capacity. APOA2 likewise increased the cholesterol efflux capacity of isolated HDL with the maximum effect occurring when equal masses of APOA1 and APOA2 coexisted on the particles. Follow-up …

Untargeted Lipidomics Reveals Novel Hdl Metabotypes And Lipid-Clinical Correlates, Peer W. F. Karmaus, Scott M. Gordon, Marcus Y. Chen, Alison A. Motsinger-Reif, Rodney W. Snyder, Timothy R. Fennell, Suramya Waidyanatha, Reshan A. Fernando, Alan T. Remaley, Michael B. Fessler

Saha Cardiovascular Research Center Faculty Publications

Plasma high-density lipoprotein (HDL), originally studied for its role in lipid transport, is now appreciated to have wide-ranging biological functions that become defective during disease. While >200 lipids have collectively been detected in HDL, published HDL lipidomic analyses in different diseases have commonly been targeted to prespecified subsets of lipids. Here, we report the results of untargeted lipidomic analysis of HDL isolated from 101 subjects referred for computed tomographic coronary imaging for whom multiple additional clinical and lipoprotein metadata were measured. Unsupervised clustering of the total HDL lipidome revealed that the subjects fell into one of two discrete groups, herein …

Tissue Plasminogen Activator Associated Pulmonary Hemorrhage In Patient With Acta2-Associated Arteriopathy, Travis G. Hughes, Mark A. Wurth, Mary Burchett Sheppard

Saha Cardiovascular Research Center Faculty Publications

Pulmonary hemorrhage after administration of tissue plasminogen activator (tPA) is a rare complication. We present a 15- year-old boy with a heterozygous pathogenic variant in ACTA2 who presented with right brachial artery aneurysm thrombosis treated initially with tPA, resulting in pulmonary hemorrhage. We hypothesize that the underlying pulmonary abnormalities caused by the pathogenic ACTA2 variant may be a risk factor for pulmonary hemorrhage after tPA administration. (J Vasc Surg Cases Innov Tech 2024;10:101558.)

Knockdown Of Ketohexokinase Versus Inhibition Of Its Kinase Activity Exert Divergent Effects On Fructose Metabolism, Se-Hyung Park, Taghreed Fadhul, Lindsey R. Conroy, Harrison A. Clarke, Ramon Sun, Kristina Wallenius, Jeremie Boucher, Gavin O'Mahony, Alessandro Boianelli, Marie Persson, Sunhee Jung, Cholsoon Jang, Analia S. Loria, Genesee J. Martinez, Zachary A. Kipp, Evelyn A. Bates, Terry D. Hinds Jr., Senad Divanovic, Samir Softic

Markey Cancer Center Faculty Publications

Excessive fructose intake is a risk factor for the development of obesity and its complications. Targeting ketohexokinase (KHK), the first enzyme of fructose metabolism, has been investigated for the management of metabolic dysfunction–associated steatotic liver disease (MASLD). We compared the effects of systemic, small molecule inhibitor of KHK enzymatic activity with hepatocyte-specific, N-acetylgalactosamine siRNA–mediated knockdown of KHK in mice on an HFD. We measured KHK enzymatic activity, extensively quantified glycogen accumulation, performed RNA-Seq analysis, and enumerated hepatic metabolites using mass spectrometry. Both KHK siRNA and KHK inhibitor led to an improvement in liver steatosis; however, via substantially different mechanisms, KHK …

The Absence Of Cxcl10 Activity Does Not Affect The Capability Of Cd8+ T Cells To Migrate And Eliminate The Tissue Cysts Of Toxoplasma Gondii From The Brains Of Chronically Infected Mice, Rajesh Mani, Yasuhiro Suzuki

Markey Cancer Center Faculty Publications

Toxoplasma gondii forms tissue cysts in neurons and astrocytes in the brain to establish chronic infection, and astrocytes express the CXCL10 chemokine in chronically infected mice. Since chemokines mediate the migration of T cells to attack their targets, and since CXCL10 plays key roles in T cell-mediated control of the proliferation of tachyzoites (the acute stage form) of T. gondii during the acute stage of infection, we examined whether CXCL10 is involved in recruiting anti-cyst CD8+ cytotoxic T cells to eliminate the cysts in their brains. We employed adoptive transfer of CD8+ immune T cells to infected, T cell-deficient SCID …

The Impact Of Pdcd4, A Translation Inhibitor, On Drug Resistance, Qing Wang, Hsin-Sheng Yang

Markey Cancer Center Faculty Publications

Programmed cell death 4 (Pdcd4) is a tumor suppressor, which has been demonstrated to efficiently suppress tumorigenesis. Biochemically, Pdcd4 binds with translation initiation factor 4A and represses protein translation. Beyond its role in tumor suppression, growing evidence suggests that Pdcd4 enhances the chemosensitivity of several anticancer drugs. To date, numerous translational targets of Pdcd4 have been identified. These targets govern important signal transduction pathways, and their attenuation may improve chemosensitivity or overcome drug resistance. This review will discuss the signal transduction pathways regulated by Pdcd4 and the potential mechanisms through which Pdcd4 enhances chemosensitivity or counteracts drug resistance.

Planetary Health Learning Objectives: Foundational Knowledge For Global Health Education In An Era Of Climate Change, Kathryn H. Jacobsen, Caryl E. Waggett, Pamela Berenbaum, Brett R. Bayles, Gail L. Carlson, René English, Carlos A Faerron Guzmán, Meredith L. Gartin, Liz Grant, Thomas L. Henshaw, Lora L. Iannotti, Philip J. Landrigan, Nina Lansbury, Hao Li, Maureen Y. Lichtveld, Ketrell Mcwhorter, Jessica E. Rettig, Cecilia J. Sorensen, Eric J. Wetzel, Dawn Michele Whitehead, Peter J. Winch, Keith Martin

Earth and Environmental Sciences Faculty Publications

Planetary health is an emerging field that emphasises that humans depend on a healthy Earth for survival and, conversely, that the sustainability of Earth systems is dependent on human behaviours. In response to member demands for resources to support teaching and learning related to planetary health, the Consortium of Universities for Global Health (CUGH) convened a working group to develop a set of planetary health learning objectives (PHLOs) that would complement the existing ten CUGH global health learning objectives. The eight PHLOs feature Earth system changes, planetary boundaries, and climate change science; ecological systems and One Health; human health outcomes; …

Enhancement Of High-Density Lipoprotein-Associated Protease Inhibitor Activity Prevents Atherosclerosis Progression, Maura Mobilia, Alexander A. Karakashian, Khaga R. Neupane, Olivia Hage, Callie Whitus, Abigail Carter, Clairity Voy, Lance A. Johnson, Gregory A. Graf, Scott M. Gordon

Saha Cardiovascular Research Center Faculty Publications

Background and aims: Inflammatory cells within atherosclerotic lesions secrete proteolytic enzymes that contribute to lesion progression and destabilization, increasing the risk for an acute cardiovascular event. Elastase is a serine protease, secreted by macrophages and neutrophils, that may contribute to the development of unstable plaque. We previously reported interaction of endogenous protease-inhibitor proteins with high- density lipoprotein (HDL), including alpha-1-antitrypsin, an inhibitor of elastase. These findings support a potential role for HDL as a modulator of protease activity. In this study, we test the hypothesis that enhancement of HDL-associated elastase inhibitor activity is protective against atherosclerotic lesion progression.

Methods: We …

Nsd3::Nutm1 Fusion Sarcoma Mimicking Malignant Peripheral Nerve Sheath Tumor With Prolonged Survival, Jing Di, Ali M. Alhaidary, Chi Wang, Jinge Liu, Sainan Wei, Joseph Valentino, Therese J. Bocklage

Markey Cancer Center Faculty Publications

Nuclear Protein in Testis (NUT)-rearranged tumors comprise predominantly NUT car- cinoma but also include certain lymphomas, leukemias, skin appendage tumors, and sarcomas. Although histologically diverse, all are genetically identified by oncogenic rearrangement in the NUTM1 gene. Many fusion partners occur, and NSD3 is NUT carcinoma’s third most common partner. Herein, we present a case of a 26-year-old man with an NSD3::NUTM1 fusion sarcoma. The patient presented at the age of 13 months with a scalp nodule. Over the next 24 years, he experienced five local recurrences and ultimately expired of a rapidly progressive recurrence. His treatment included surgical resections, radiation, …

Adhesion G Protein-Coupled Receptor Latrophilin 1 (Adgrl1): A Novel Regulator Of Glucose And Energy Homeostasis., Kavaljit H Chhabra

Pharmacology and Nutritional Sciences Faculty Publications

No abstract provided.

Challenges Of Spatially Resolved Metabolism In Cancer Research, Andrew N. Lane, Richard M. Higashi, Teresa W-M Fan

Markey Cancer Center Faculty Publications

Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing the basis for flux analysis. As the diversity of stable isotope-enriched compounds is very high, and with newer approaches to multiplexing, the coverage of metabolism is now very extensive. However, as the complexity of the model increases, including more kinds of interacting cell types and interorgan communication, the analytical complexity also increases. Further, as studies move further …

14-3-3Ζ Suppresses Rankl Signaling By Destabilizing Traf6, R. Ayyasamy, S. Fan, P. Czernik, B. Lecka-Czernik, Somsubhra Chattopadhyay, R. Chakravarti

Markey Cancer Center Faculty Publications

Macrophages are essential regulators of inflammation and bone loss. Receptor activator of nuclear factor-κβ ligand (RANKL), a pro-inflammatory cytokine, is responsible for macrophage differentiation to osteoclasts and bone loss. We recently showed that 14-3-3ζ-knockout (Ywhaz^KO) rats exhibit increased bone loss in the inflammatory arthritis model. 14-3-3ζ is a cytosolic adaptor protein that actively participates in many signaling transductions. However, the role of 14-3-3ζ in RANKL signaling or bone remodeling is unknown. We investigated how 14-3-3ζ affects osteoclast activity by evaluating its role in RANKL signaling. We utilized 14-3-3ζ-deficient primary bone marrow–derived macrophages obtained from wildtype and Ywhaz^{KO …}

Single-Cell Analysis Identifies Plk1 As A Driver Of Immunosuppressive Tumor Microenvironment In Luad, Yifan Kong, Chaohao Li, Jinpeng Liu, Sai Wu

Markey Cancer Center Faculty Publications

PLK1 (Polo-like kinase 1) plays a critical role in the progression of lung adenocarcinoma (LUAD). Recent studies have unveiled that targeting PLK1 improves the efficacy of immuno- therapy, highlighting its important role in the regulation of tumor immunity. Nevertheless, our understanding of the intricate interplay between PLK1 and the tumor microenvironment (TME) remains incomplete. Here, using genetically engineered mouse model and single- cell RNA-seq analysis, we report that PLK1 promotes an immunosuppressive TME in LUAD, characterized with enhanced M2 polarization of tumor associated macrophages (TAM) and dampened antigen presentation process. Mechanistically, elevated PLK1 coin- cides with increased secretion of CXCL2 …

Travel-Time Disparities In Access To Proton Beam Therapy For Cancer Treatment, Todd Burus, Alexander D. Vanhelene, Michael K. Rooney, Krystle A. Lang Kuhs, W. Jay Christian, Christopher Mcnair, Sanjay Mishra, Arnold C. Paulino, Grace L. Smith, Steven J. Frank, Jeremy L. Warner

Markey Cancer Center Faculty Publications

IMPORTANCE Proton beam therapy is an emerging radiotherapy treatment for patients with cancer that may produce similar outcomes as traditional photon-based therapy for many cancers while delivering lower amounts of toxic radiation to surrounding tissue. Geographic proximity to a proton facility is a critical component of ensuring equitable access both for indicated diagnoses and ongoing clinical trials.

OBJECTIVE To characterize the distribution of proton facilities in the US, quantify drive-time access for the population, and investigate the likelihood of long commutes for certain population subgroups.

DESIGN, SETTING, AND PARTICIPANTS This population-based cross-sectional study analyzed travel times to proton facilities in …

Protein Oxidation In Aging And Alzheimer’S Disease Brain, Rukhsana Sultana, D. Allan Butterfield

Markey Cancer Center Faculty Publications

Proteins are essential molecules that play crucial roles in maintaining cellular homeostasis and carrying out biological functions such as catalyzing biochemical reactions, structural proteins, immune response, etc. However, proteins also are highly susceptible to damage by reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this review, we summarize the role of protein oxidation in normal aging and Alzheimer’s disease (AD). The major emphasis of this review article is on the carbonylation and nitration of proteins in AD and mild cognitive impairment (MCI). The oxidatively modified proteins showed a strong correlation with the reported changes in brain structure, carbohydrate …

Chromosomal 3q Amplicon Encodes Essential Regulators Of Secretory Vesicles That Drive Secretory Addiction In Cancer, Xiaochao Tan, Shike Wang, Guan-Yu Xiao, Chao Wu, Xin Liu, Biyao Zhou, Yu Jiang, Dzifa Y. Duose, Yuanxin Xi, Jing Wang, Kunika Gupta, Apar Pataer, Jack A. Roth, Michael P. Kim, Fengju Chen, Chad J. Creighton, William K. Russell, Jonathan M. Kurie

Markey Cancer Center Faculty Publications

Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identified a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase secretory pathway Ca2+ transporting 1 (ATP2C1). We show that GOLIM4 recruited ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate Ca2+ -dependent cargo loading, Golgi membrane bending, and vesicle scission. GOLIM4 depletion disrupted the protein complex, resulting in a secretory blockade that inhibited the progression of 3q-amplified malignancies. In addition to its role …

Shared Genomic Segments Analysis Identifies Mhc Class I And Class Iii Molecules As Genetic Risk Factors For Juvenile Idiopathic Arthritis, Cecile N. Avery, Nicole D. Russell, Cody J. Steely, Aimee O. Hersh, John F. Bohnsack, Sampath Prahalad, Lynn B. Jorde

Markey Cancer Center Faculty Publications

Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease encompassing several clinically defined subtypes of varying severity. The etiology of JIA remains largely unknown, but genome-wide association studies (GWASs) have identified up to 22 genes associated with JIA susceptibility, including a well-established association with HLA-DRB1. Continued investigation of heritable risk factors has been hindered by disease heterogeneity and low disease prevalence. In this study, we utilized shared genomic segments (SGS) analysis on whole-genome sequencing of 40 cases from 12 multi-generational pedigrees significantly enriched for JIA. Subsets of cases are connected by a common ancestor in large extended pedigrees, increasing the …

Antisense Oligonucleotide Targeting Hepatic Serum Amyloid A Limits The Progression Of Angiotensin Ii-Induced Abdominal Aortic Aneurysm Formation, Preetha Shridas, Ailing Ji, Andrea C. Trumbauer, Victoria P. Noffsinger, Luke W. Meredith, Frederick C. De Beer, Adam E. Mullick, Nancy R. Webb, Dennis G. Karounos, Lisa R. Tannock

Saha Cardiovascular Research Center Faculty Publications

Background and aims: Obesity increases the risk for abdominal aortic aneurysms (AAA) in humans and enhances angiotensin II (AngII)-induced AAA formation in C57BL/6 mice. We reported that deficiency of Serum Amyloid A (SAA) significantly reduces AngII-induced inflammation and AAA in both hyperlipidemic apoE-deficient and obese C57BL/6 mice. The aim of this study is to investigate whether SAA plays a role in the progression of early AAA in obese C57BL/6 mice.

Methods: Male C57BL/6J mice were fed a high-fat diet (60% kcal as fat) throughout the study. After 4 months of diet, the mice were infused with AngII until the end …

Relative Adrenal Insufficiency Is A Risk Factor For Pediatric Sepsis: A Proof-Of-Concept Study, Dan Hao, Ling Guo, Qian Wang, Misa Ito, Bin Huang, Chieko Mineo, Philip W. Shaul, Xiang-An Li

Markey Cancer Center Faculty Publications

Glucocorticoid (GC) therapy had been strongly recommended for pediatric sepsis (grade 1A). However, the recommendation was changed to grade 2C in 2020 due to weak evidence. About 32.8% of patients with pediatric septic develop relative adrenal insufficiency (RAI). But whether GC therapy should be determined by RAI status is controversial. This study utilized 21-day- old SF1CreSRBIfl/fl mice as the first pediatric RAI mouse model to assess the pathogenesis of RAI and evaluate GC therapy. RAI mice exhibited a substantially higher mortality rate in cecal ligation and puncture and cecal slurry–induced sepsis. These mice featured persistent inflammatory responses and were effectively …

The Nonvesicular Sterol Transporter Aster-C Plays A Minor Role In Whole Body Cholesterol Balance, Ranjan Banerjee, Rachel C. Hohe, Shijie Cao, Bryan M. Jung, Anthony J. Horak, Iyappan Ramachandiran, William J. Massey, Venkateshwari Varadharajan, Natalie I. Zajczenko, Amy C. Burrows, Sumita Dutta, Maryam Goudarzi, Kala Mahen, Abigail Carter, Robert N. Helsley, Scott M. Gordon, Richard E. Morton, Christopher Strauch, Belinda Willard, Camelia Baleanu Gogonea, Valentin Gogonea, Matteo Pedrelli, Paolo Parini, J. Mark Brown

Markey Cancer Center Faculty Publications

Introduction: The Aster-C protein (encoded by the Gramd1c gene) is an endoplasmic reticulum (ER) resident protein that has been reported to transport cholesterol from the plasma membrane to the ER. Although there is a clear role for the closely-related Aster-B protein in cholesterol transport and downstream esterification in the adrenal gland, the specific role for Aster-C in cholesterol homeostasis is not well understood. Here, we have examined whole body cholesterol balance in mice globally lacking Aster-C under low or high dietary cholesterol conditions.

Method: Age-matched Gramd1c^+/+ and Gramd1c^−/− mice were fed either low (0.02%, wt/wt) or high (0.2%, …

A Dynamic Model Of Inorganic Arsenic-Induced Carcinogenesis Reveals An Epigenetic Mechanism For Epithelial–Mesenchymal Plasticity, Matthew Rea, Greg Kimmerer, Shania Mittendorf, Xiaopeng Xiong, Megan Green, Darrell Chandler, Wesley Saintilnord, Jessica S. Blackburn, Tianyan Gao, Yvonne N. Fondufe-Mittendorf

Markey Cancer Center Faculty Publications

Inorganic arsenic (iAs) causes cancer by initiating dynamic transitions between epithelial and mesenchymal cell phenotypes. These transitions transform normal cells into cancerous cells, and cancerous cells into metastatic cells. Most in vitro models assume that transitions between states are binary and complete, and do not consider the possibility that intermediate, stable cellular states might exist. In this paper, we describe a new, two-hit in vitro model of iAs-induced carcinogenesis that extends to 28 weeks of iAs exposure. Through week 17, the model faithfully recapitulates known and expected phenotypic, genetic, and epigenetic characteristics of iAs-induced carcinogenesis. By 28 weeks, however, exposed …

Abdominal Aortic Aneurysms And Platelets: Infiltration, Inflammation, And Elastin Disintegration, Bowen Li, Hong S. Lu, Alan Daugherty

Saha Cardiovascular Research Center Faculty Publications

No abstract provided.

Staphylococcus Aureus Oleate Hydratase Produces Ligands That Activate Host Ppara, Christopher D. Radka, Matthew W. Frank, Tyler S. Simmons, Cydney N. Johnson, Jason W. Rosch, Charles O. Rock

Markey Cancer Center Faculty Publications

Commensal gut bacteria use oleate hydratase to release a spectrum of hydroxylated fatty acids using host-derived unsaturated fatty acids. These compounds are thought to attenuate the immune response, but the underlying signaling mechanism(s) remain to be established. The pathogen Staphylococcus aureus also expresses an oleate hydratase and 10- hydroxyoctadecanoic acid (h18:0) is the most abundant oleate hydratase metabolite found at Staphylococcal skin infection sites. Here, we show h18:0 stimulates the transcription of a set of lipid metabolism genes associated with the activation of peroxisome proliferator activated receptor (PPAR) in the RAW 264.7 macrophage cell line and mouse primary bone marrow-derived …