Translational Medical Research Commons^™

An Observational Study Of The Effect Of Concomitant Levetiracetam On Apixaban Concentrations In A Hospital Cohort, Chazmyn Riley, Kevin Lam, Cristina Micale, Lynda Thomson, Douglas F. Stickle, Walter K. Kraft

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Despite the lack of evidence of a mechanism-based drug interaction, some professional organizations have advised caution coadministering apixaban and levetiracetam. Eligible patients taking apixaban with or without levetiracetam for any indication for at least 72 h were screened from the electronic medical records. Plasma samples from 77 patients were retrieved from salvaged clinical blood collections. Apixaban minimum and maximum concentrations (Cmin and Cmax) were compared using descriptive statistics in R. While the median Cmin and Cmax appear to be marginally elevated, there were no apparent differences relative to apixaban alone. These findings suggest no apparent interaction of levetiracetam and support …

E3 Ligase Rnf145 Regulates Airway Smooth Muscle Cell Proliferation Via The Pp2a-P70s6k Signaling Axis, Vijaya Kumar Gangipangi, Erin O. Curley, Deepak A. Deshpande, Pawan Sharma

Center for Translational Medicine Faculty Papers

Airway smooth muscle (ASM) is a key determinant of airway caliber and a major contributor to structural remodeling in obstructive lung diseases, including asthma and COPD. ASM proliferation is regulated by transcriptional and post-transcriptional mechanisms, including ubiquitin-dependent protein turnover mediated by E3 ubiquitin ligases. Here, we investigated the role of the RING-type E3 ligase RNF145 in mitogenic signaling and ASM cell proliferation. Human ASM cells were transfected with RNF145 shRNA or treated with the E3 ligase inhibitor SMER3, followed by stimulation with fetal bovine serum (FBS) or platelet-derived growth factor (PDGF). RNF145 knockdown or SMER3 treatment dose-dependently inhibited mitogen-induced ASM …

Targeting The Prmt5/Nur77 Methylation Axis Enhances Endometrial Decidualization Capacity And Female Fertility In Preclinical Models, Zhiwen Cao, Xinyu Cai, Jie Mei, Na Kong, Yang Liu, Xiaoyue Shen, Min Wu, Xin Zhen, Jianxin Sun, Rong Li, Ruiwei Jiang, Haixiang Sun, Guijun Yan

Center for Translational Medicine Faculty Papers

Defective endometrial decidualization is one major cause of female infertility, yet the underlying mechanisms remain elusive. Here, we identified that protein arginine methyltransferase 5 (PRMT5), which was upregulated during decidualization and by progesterone stimulation, was markedly downregulated in the endometria of patients with recurrent implantation failure (RIF), along with a global reduction of symmetric dimethylarginine (SDMA). Uterine stroma-specific ablation of Prmt5 in mice severely impaired decidualization, leading to infertility. A multiomics analysis in human endometrial stromal cells (EnSCs) revealed that PRMT5 promoted decidualization primarily by catalyzing SDMA at arginine 346 (R346) of the orphan nuclear receptor Nur77, which directs its …

Slc Transporter-Mediated Functional Imaging In Cancer Diagnosis, Lumeng Zhang, Jun He

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Functional imaging has become an important approach for evaluating tumor physiology in vivo beyond morphologic assessment. Radiotracers used for cancer imaging are designed to mimic endogenous substrates or substrate analogues, and their accumulation can depend on membrane transport, intracellular metabolism, and clearance from normal tissues. Specifically, SLC transporters contribute to tracer uptake and signal formation, linking transporter activity with measurable imaging signals in cancer. While [18F]FDG PET/CT remains the most widely used example of transporter-associated metabolic imaging, SLC transporter-mediated imaging strategies have been developed to assess amino acid transport, sodium-dependent glucose uptake, redox metabolism, lactate exchange, nucleoside metabolism, choline metabolism, …

Decorin Promotes Nascent Proteoglycan Retention In Cartilage Matrix By Strengthening Collagen Ii-Aggrecan Integration, Thomas Li, Gabriela Canziani, Yuchen Liu, Neil Patel, Biao Han, Mingyue Fan, Annie Porter, Bryan Kwok, Chao Wang, Qing Li, David E. Birk, Renato V. Iozzo, Irwin M. Chaiken, X. Lucas Lu, Robert L. Mauck, Lin Han

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cartilage extracellular matrix (ECM), a hydrated collagen II-aggrecan composite, undergoes dynamic turnover during both normal homeostasis and disease-associated remodeling. This study elucidates a crucial role for decorin in promoting the retention and stability of nascent aggrecan within this matrix. By applying bio-orthogonal click-labeling, we demonstrate that loss of decorin accelerates the release of nascent aggrecan under both physiological and inflammatory conditions, without affecting its preferential localization to the pericellular matrix. Conversely, supplementation with exogenous decorin mitigates inflammation-induced loss of nascent aggrecan, supporting its potential as a therapeutic target. At the molecular level, decorin exhibits strong binding affinity for aggrecan, and …

Clonal Reshaping And Clinical Outcomes After Rechallenge In Ici-Associated Myocarditis: Integrated Single-Cell And Tcr Repertoire Analysis, Jian Zhang, Xiaozhen He, Yerui Zhang, Xianling Qian, Yu Song, Shilong Zhang, Zheng Li, Zhiming Wang, Bo Lu, Qingqing Cai, Leilei Cheng, Yan Wang

Center for Translational Medicine Faculty Papers

BACKGROUND: Immune checkpoint inhibitor-associated myocarditis (ICIAM) poses significant challenges for cancer immunotherapy, particularly regarding the safety and efficacy of immune checkpoint blockade (ICB) rechallenge.

METHODS: The present study analyzed 23 cases of ICIAM by integrating longitudinal clinical data with single-cell RNA sequencing and T-cell receptor profiling of peripheral blood mononuclear cells (PBMCs) obtained from three representative patients before and after ICB rechallenge. The single-cell cohort comprised two patients who experienced recurrent irAEs upon rechallenge and one patient who did not develop recurrent irAEs.

RESULTS: Among 12 patients (52%) who experienced recurrent irAEs upon rechallenge, myocarditis recurrence occurred in 8 cases, …

Acidic Extracellular Ph-Induced Pth Secretion In Male Mouse Parathyroids Is Ogr1-Dependent, Yanmei Yang, Mengcun Chen, Mingshu Cui, Elisabeth Lashbrooks, Bin Wang

Center for Translational Medicine Faculty Papers

The role of extracellular acidity in regulating PTH secretion in cultured mouse parathyroid glands (PTGs) has not been studied to date, largely because of the technical difficulty of isolating mouse PTGs. We hypothesized that acidic extracellular pH directly stimulates PTH secretion through activation of a proton-sensing receptor, specifically ovarian cancer G protein-coupled receptor 1 (OGR1, also known as GPR68). To test this, we developed a method to reliably identify and isolate PTGs from male mice by administering 5-aminolevulinic acid, which induced selective fluorescence in these glands. Using this model, we demonstrate that acidic extracellular pH significantly stimulates PTH secretion in …

Acidic Extracellular Ph-Induced Pth Secretion In Male Mouse Parathyroids Is Ogr1-Dependent, Yanmei Yang, Mengcun Chen, Mingshu Cui, Elisabeth Lashbrooks, Bin Wang

Center for Translational Medicine Faculty Papers

The role of extracellular acidity in regulating PTH secretion in cultured mouse parathyroid glands (PTGs) has not been studied to date, largely because of the technical difficulty of isolating mouse PTGs. We hypothesized that acidic extracellular pH directly stimulates PTH secretion through activation of a proton-sensing receptor, specifically ovarian cancer G protein-coupled receptor 1 (OGR1, also known as GPR68). To test this, we developed a method to reliably identify and isolate PTGs from male mice by administering 5-aminolevulinic acid, which induced selective fluorescence in these glands. Using this model, we demonstrate that acidic extracellular pH significantly stimulates PTH secretion in …

Mitochondrial Ca2+ Uniporter (Mcu) Variants Form Plasma-Membrane Channels, Iuliia Polina, Jyotsna Mishra, Michael Cypress, Maria Landherr, Nedyalka Valkov, Isabel Chaput, Bridget Nieto, Brian Rhee, Ameneh Ahrari, Nathan Demichaelis, Kye-Im Jeon, Ulrike Mende, Peng Zhang, Bong Sook Jhun, Jin O-Uchi

Center for Translational Medicine Faculty Papers

MCU, originally known as CCDC109A, is widely recognized as the gene responsible for encoding a pore-forming subunit of a Ca2+-selective channel, mitochondrial Ca2+ uniporter complex (mtCUC). While MCU expression is typically highly mitochondrial-specific, we report here a protein variant derived from the MCU gene, termed MCU-S, which lacks the mitochondria-targeting sequence (MTS) and forms a Ca2+-permeable channel outside of mitochondria. The mRNA of MCU-S was ubiquitously expressed in all cell types/tissues tested, with particularly high expression in human platelets. MCU-S protein formed Ca2+ channels at the plasma membrane, which exhibited similar channel properties to those observed in mtCUC. MCU-S channels …

Imbalance In Wnt: Retinoic Acid Signaling Dysregulates Hox Gene Expression: Implications For Cancer Stem Cell Heterogeneity And Crc Patient Survival, Brian Osmond, Chi Zhang, Pascal K. Kataboh, Caroline O. B. Facey, Lynn M. Opdenaker, Bruce M. Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

How HOX transcription factors play a role in the stem cell (SC) origin of cancer is unclear. Our goal is to determine how dysregulation of HOX gene expression promotes colorectal cancer (CRC) development through aberrant SC regulatory mechanisms. We investigated retinoic acid (RA) and WNT signaling because they regulate HOX expression and both pathways are dysregulated in cancer. Previously, we reported WNT and RA pathways are functionally linked, and in CRC, APC mutation generates a WNT:RA imbalance leading to incomplete differentiation and SC overpopulation. We hypothesize that aberrant WNT- and RA-signaling dysregulates HOX expression that contributes to the SC origin …

Type-1 Ryanodine Receptor Plays An Important Role In Cardiac Hypertrophy And Heart Failure By Increasing Type-2 Ryanodine Receptor-Mediated Calcium Release, Yong-Xiao Wang, Ed Wilson Santos, Sarahann Mistretta, Yuexing Yuan, Harold A. Singer, Shey-Shing Sheu, Yun-Min Zheng

Center for Translational Medicine Faculty Papers

Type-1 ryanodine receptor (RyR1) is essential for skeletal muscle contraction. This Ca²⁺ release channel is expressed in cardiac myocytes; however, its function remains elusive. Cardiac-specific RyR1 overexpression (OE) mice were generated under the cardiac-specific Myh6 promoter. Cardiac hypertrophy (CH), cardiac functions, and mechanistic changes in RyR1 OE and control (wildtype, WT) mice were assessed using hematoxylin and eosin staining, echocardiography, electrocardiogram, quantitative RT-PCR, Western blotting, [³H]-ryanodine binding assay, confocal microscope, ROS dye Amplex Red and 2′,7′-dichlorofluorescein diacetate. RyR1 OE mice had increased whole heart, left ventricular weight, and left ventricular wall thickness, but decreased cardiac output and …

Feeding The Future: Prenatal Dietary Effects On Offspring Neurodevelopment, Emma Whatley

Senior Honors Theses

This study examined the effects of prenatal Western (WD) and Mediterranean (MD) diets on offspring metabolic, cognitive, and neurobiological outcomes in a preclinical mouse model. Working and long-term memory performance, dendritic morphology, and gene expression were assessed using behavioural tests (CAL, YMRM, WM) and Golgi-Cox analyses. Behavioural effects were minimal, with female MD offspring showing improved memory performance under standard conditions. Metabolic findings showed effects on body weight and blood glucose. Dendritic morphology was largely unchanged; however, subtle, sex-specific differences were observed. Differential gene expression between MD and WD suggests a role for future environmental stressors. Prenatal diet affects molecular …

Improving Functional Electrical Stimulation Prescription For Persons With Multiple Sclerosis: A Case Series, Kurt Jackson

Thomas C. Hunt Building a Research Community Day

Purpose: Despite a growing body of evidence supporting the use of functional electrical stimulation (FES) in persons with MS (PwMS), prescription remains a highly individualized process with no well-established guidelines for assessing the immediate or long-term effects to ensure maximum benefit.  The purpose of this case series was to assess the feasibility and benefits of using wearable sensors and video analysis to provide immediate feedback on gait performance, when using lower leg and thigh stimulation individually or in combination, to improve FES prescription.

Subjects: 3 adults with multiple sclerosis (MS) with varying levels of gait dysfunction.

Methods: During …

E3 Ubiquitin Ligases And Asthma Relief, Ajay P. Nayak

Department of Medicine Faculty Papers

No abstract provided.

Hiv Infection, Neurotoxicity, Inflammation, Premature Aging, And Therapeutic Challenges To Plwh: An Overview, Mudit Tyagi, Ulhas P. Naik, Kratika Tyagi, Madhulika Sharma, Gagan Kaushal, Alok Bhushan, Michael Bukrinsky, Priya Tyagi

Department of Medicine Faculty Papers

HIV infection remains a major global health challenge due to its complex pathogenesis and lifelong persistence in people living with HIV (PLWH). A central barrier to eradication is the virus's ability to establish long-lived latent reservoirs in different tissues, including the central nervous system (CNS), where it evades immune clearance and antiretroviral therapy (ART). These reservoirs, seeded early during infection, fuel viral rebound if ART is interrupted, requiring lifelong treatment. In the CNS, HIV persists despite systemic viral suppression because of limited ART penetration across the blood-brain barrier (BBB), and infection of long-lived cells such as microglia and perivascular macrophages. …

Editorial: Unveiling The Next Generation Of Cancer Immunity & Immunotherapy, Mohanraj Sadasivam, Nethaji Muniraj, Chellappagounder Thangavel

Center for Translational Medicine Faculty Papers

[This corrects the article DOI: 10.3389/fimmu.2025.1769324.].

Oncofetal Reprogramming: A New Frontier In Cancer Therapy Resistance, Anh Nguyen, Molly Lausten, Bruce M. Boman

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Oncofetal reprogramming has recently emerged as a critical concept in translational cancer research, particularly for its role in driving therapeutic resistance across a variety of malignancies. This biological process refers to a pattern of gene expression that is restricted to embryogenesis, but becomes expressed again in a subpopulation of cancer cells. These genes are typically suppressed after embryogenesis, and their aberrant re-expression in tumors endows cancer cells with stem-like properties and enhanced adaptability. The goal of this review is the following: (i) comprehensively examine the multifaceted nature of oncofetal reprogramming; (ii) elucidate its underlying molecular mechanisms, including its regulators and …

Editorial: Advancing Musculoskeletal Health: Bridging Basic And Clinical Research On Biomechanical Properties Of Joints, Ligaments, Tendons, And Associated Structures, Xin Jin, Snehal S. Shetye, Mengcun Chen

Center for Translational Medicine Faculty Papers

No abstract provided.

Synergistic Anti-Tumor Activity Of Ciclopirox Olamine And Metformin In Triple-Negative Breast Cancer, Yakun Wu, Hui Lyu, Congcong Tan, Margaret E. Larsen, Shou Ching Tang, Shile Huang, Bolin Liu

School of Graduate Studies Faculty Publications

No abstract provided.

Microglial Expression Of Serotonin Receptors Reveals Parallel Regulation Of 5-Ht2b And Bdnf In The Rat Hippocampus, Andrei Turkin, Maria Sidorova, Ekaterina Kurilova, Natalia Alenina, Oksana Tuchina, Friederike Klempin

School of Graduate Studies Faculty Publications

Growing evidence suggests that psychiatric disorders are characterized by a prolonged inflammatory state, which may influence the efficacy of compounds targeting serotonin. Serotonin is a key signaling molecule in neuroplasticity of the adult hippocampus and involved in antidepressant action. Recent in vitro studies indicate the neurotransmitter may also facilitate the response to inflammation and potentially modulate microglial function towards neuroprotection. Using Tph2−/− rats depleted of brain serotonin, we examined microglial expression of various serotonin receptors (5-HTRs) in vivo in both the hippocampus and prefrontal cortex and assessed mRNA levels of cytokines and brain-derived neurotrophic factor (BDNF). We observed age-dependent and …

Protocol For Nucleo-Cytoplasmic Fractionation Of Mammalian Cells To Study Protein Translocation Via Immunoblotting, Adhikarimayum Lakhikumar Sharma, Eddy Zhu, Rithika Padyala, Kavya Parikh, Mudit Tyagi

Center for Translational Medicine Faculty Papers

Studying protein translocation is essential for understanding protein function and regulatory mechanisms, including the activity of transcription factors. Here, we present a protocol for isolating high-quality cytoplasmic and nuclear protein fractions from mammalian cells. We describe steps for separating cytoplasmic proteins, washing nuclei, and extracting nuclear proteins. We then detail procedures for quantifying proteins and analyzing their distribution by immunoblotting within a single immunoblot. This protocol is applicable to both suspension and adherent cell types. For complete details on the use and execution of this protocol, please refer to Sharma et al.

Long Covid Incidence Across Sars-Cov-2 Lineages And Identification Of Conserved Spike Targets For Multivalent Vaccines, Grace J. Kim, Md Ashad Alam, Judy S. Crabtree, Rebecca Rose, Susanna L. Lamers, San Chu, Ronald Horswell, Daniel Fort, Lucio Miele

School of Graduate Studies Faculty Publications

Background: Long COVID remains poorly characterized at the genomic level. The primary aim of this study was to examine the relationship between viral sequences and the incidence of Long COVID at a tertiary care center in Louisiana between April 2020 and December 2022. A secondary aim was analysis of the Spike protein to identify conserved regions for multivalent vaccine targets. Method: To estimate Long COVID incidence across variants, we linked 4,789 SARS-CoV-2 sequences to 3,090 de-identified patient electronic health record information. The base population was defined as any patient with an International Classification of Diseases-10-Clinical Modification COVID-19 diagnosis code (U07.1) …

The Need To Incorporate Polysubstance Use In Neuropsychopharmacology Research: Biological Lessons And New Opportunities, Max E. Joffe, Susan M. Ferguson, Nick W. Gilpin, Melissa A. Herman, Lori A. Knackstedt, Patrick A. Randall, Abigail G. Schindler, Mary M. Torregrossa, Jennifer A. Rinker

School of Medicine Faculty Publications

Critical evaluation and refinement of animal models is essential for neuroscientists to understand complex physiological and pathological processes related to psychiatric diseases. In general, preclinical studies modeling drug dependence and problematic substance use have been limited to the administration of a single substance; however, there is a growing appreciation that this approach has failed to capture the complexities of humans and has stifled translational efforts. Polysubstance use represents the overwhelmingly common patterns of alcohol and drug use in humans. For example, epidemiological studies generally determine that between 70–95 % of individuals with alcohol use disorder use tobacco daily, and upwards …

Are E-Cigarettes A Safer Alternative? Revisiting The Cardiovascular Cost Of Nicotine Delivery, Jason D. Gardner

School of Graduate Studies Faculty Publications

No abstract provided.

Low Magnetic Fields Stimulate Cardiac Mitochondrial Bioenergetics With A Bell-Shaped Response: Possibly Via A Radical Pair Mechanism, Gisela Beutner, Huoy-Jen Yuh, Ilan Goldenberg, Douglas C. Wallace, George A. Porter, Arthur J. Moss, Shey-Shing Sheu

Center for Translational Medicine Faculty Papers

Low magnetic fields (LMFs) of less than 1 × 10 3 Tesla (T) affect numerous biological processes, including plant growth and bird migration. At a cellular level, LMFs influence intracellular Ca2+ concentrations and generation of mitochondrial reactive oxygen species (mROS). However, the mechanisms that account for these effects are controversial. Here, by applying a static LMF, ranging from ~2.7 × 10 4 to ~1.9 × 10 3 T, to mitochondria isolated from adult rat hearts, a bell-shaped increase in State 3 respiration (S3R) was observed, up to 40 %. A similar LMF-induced increase in S3R was also observed in mitochondria …

Dietary Fiber Modulates Gut Microbiota And Lipid Metabolism Ameliorating Alzheimer's Pathology In 5xfad Mice, Yuhai Zhao, Christopher M. Taylor, Walter J. Lukiw, Nicolas G. Bazan

School of Graduate Studies Faculty Publications

The gut-brain axis plays a critical role in maintaining neuronal integrity and influencing the progression of Alzheimer's disease (AD). Here, we investigated how commonly consumed dietary fibers modulate gut microbiota, lipid metabolism, and AD pathology in 5xFAD mice. Male mice were fed either fiber-free (FF) or fiber-plus (FP; 1% cellulose, 2% pectin, 2% inulin) diets for five months, followed by integrated analyses of gut microbiota (16 S rRNA sequencing), fecal lipid metabolites (LC-MS/MS), and neuropathological and behavioral outcomes. FP diets markedly altered microbial composition, characterized by increases in Muribaculaceae, Ileibacterium, and Lachnospiraceae NK4A136 group and reductions in Faecalibaculum and Coriobacteriaceae …

Diurnal Behavioral Outcomes And Bbb Integrity In Adult Male Shr And Wky Rats, Pallavi Shrivastava, Oluchukwu D. Biose, Riya Dahal, Abdallah Jwayyed, Rukayat A. Raji, Huijing Xia, Eric Lazartigues, Ifechukwude J. Biose

School of Graduate Studies Faculty Publications

Day and night neurobehavioral tests were performed for Spontaneously Hypertensive rats (SHR) and Wistar Kyoto rats (WKY) to establish an optimal testing window. Also, blood–brain barrier (BBB) integrity in brain areas related to cognition was measured to determine strain-specific differences. Six months old male SHR and WKY were randomly divided into day (i.e., 9–11 a.m.) and nighttime (i.e., 7–9 p.m.) testing regimen. Neurobehavioral tests included: Y-maze spontaneous alternation, open field, novel object recognition (NOR), and tail suspension test (TST). BBB integrity was measured in the cortex, hippocampus and striatum. WKY showed higher recognition memory at night compared to SHR and …

Hypertensive Remodelling: When Bigger Body Means Bigger Problems, Eric Lazartigues

School of Medicine Faculty Publications

No abstract provided.

Estrogen And Obesity Synergistically Suppress Protein S Via Hif1Α, Enhancing Thrombosis Potential, Mohammad A. Mohammad, Narender Kumar, Sonali Ghosh, Ashley L. Paysse, Claudia Leonardi, Vijaya Pilli, Ma Lorena Duhaylungsod, Eric Lazartigues, Diana Polania-Villanueva, Sadaf Nouman, Logan A. Barrios, Rima Chattopadhyay, Rafika Yasmin, Alaina Guilbeau, Manoj Kumar, Tina H. Nguyen, Jovanny Zabaleta, Li Li, Luis Del Valle M.D., Mallory T. Barbier, Samarpan Majumder, Laurent O. Mosnier, Samarpan Majumder

School of Graduate Studies Faculty Publications

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality, with risk heightened in premenopausal women with obesity or use estrogen-based oral contraceptives. When both risk factors are present, the thrombosis risk increases substantially. Protein S (PS), an essential anticoagulant cofactor, is downregulated by both estrogen and obesity, but the molecular basis for this suppression remains poorly defined. We investigated the effect of estrogen and obesity on PS expression using plasma samples from 157 women stratified by BMI and contraceptive use, alongside 40 mice categorized as lean or obese with or without estrogen pellet treatment. The levels of PS …

Cardiac Sr-Mitochondria Contacts-Impact On Cardiac Physiology And Mitochondrial Fitness, Celia Fernandez-Sanz, Shey-Shing Sheu, Sergio De La Fuente

Center for Translational Medicine Faculty Papers

In adult cardiomyocytes, within the Mitochondrial Associated Membranes (MAMs), the sarcoplasmic reticulum (SR) and mitochondria juxtapose each other, forming a unique and highly repetitive functional structure throughout the cells. These SR-mitochondria contact sites have emerged as critical structures that regulate various physiological processes, including lipid exchange, calcium (Ca²⁺) communication, control of excitation-contraction bioenergetics coupling, and reactive oxygen species (ROS) production. Over the years, several scientific studies have reported the accumulation of diverse proteins within these SR-mitochondria close contacts. Some proteins strategically accumulate in these areas to enhance their function, such as the mitochondrial Ca²⁺ uniporter, while others …