Digital Commons Network^™

Dimeric P53 Mutant Elicits Unique Tumor-Suppressive Activities Through An Altered Metabolic Program, Jovanka Gencel-Augusto, Xiaoping Su, Yuan Qi, Elizabeth M Whitley, Vinod Pant, Shunbin Xiong, Vrutant Shah, Jerome Lin, Encarnacion Perez, Marta L Fiorotto, Iqbal Mahmud, Abhinav K Jain, Philip L Lorenzi, Nicholas E Navin, Ellen R Richie, Guillermina Lozano

Faculty, Staff and Student Publications

Cancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li-Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence …

Dual Myristic Acid And Trans-Activator Of Transcription Conjugation Of Pkc Beta Ii Peptide Inhibitor Augments Cellular Delivery To Counteract Myocardial Ischemia/Reperfusion Injury, James Ramsarran, Logan Clair, Taurai Augustin, Zinya Talukder, Emily Andrews, Tameka Dean, Qian Chen, Robert J. Barsotti, Lindon H. Young

Research Day

INTRODUCTION: Dual conjugation of PKC Beta II peptide inhibitor (PKCβII-) with myristic acid (myr) and trans-activator of transcription (Tat) (Myr-Tat-CC-SLNPEWNET [myr-Tat-PKCβII-]) has been shown to enhance intracellular delivery and attenuate myocardial ischemia/reperfusion (I/R) injury in an ex-vivo rat model. Previously, myr-Tat-PKCβII- demonstrated significant cardioprotective effects from 100nM to the 1pM concentration.

OBJECTIVES: The lowest concentration at which myr-Tat-PKCβII- is still cardioprotective has yet to be determined; this study investigates the 100fM concentration.

METHODS: Isolated rat hearts from anesthetized male SD rats (275g to 300g) underwent global I(30-min)/R(50-min). Cardiac function was recorded via a pressure transducer. Treatments were infused during the …

The Effects Of Mitoquinone Pretreatment On Doxorubicin-Induced Acute Cardiac Dysfunction, Kimberly Dawes, Juliet Melnik, Meagan Lyons, Jonathan Amora, Lindon H. Young, Robert J. Barsotti, Qian Chen

Research Day

Introduction:

Doxorubicin (DOX) is a widely used anti-cancer drug notorious for its irreversible cardiac toxicity. Currently, Dexrazoxane is the only FDA-approved treatment for this toxicity. However, Dexrazoxane still bears some serious adverse events, and developing new strategies to mitigate DOX-induced heart damage is critical. Our lab has shown that pretreatment of the H9c2 myoblast cells with mitoquinone (MitoQ), a mitochondrial-targeted antioxidant, and significantly improved cells’ resiliency to DOX. This study aimed to determine if MitoQ pretreatment can preserve cardiac function against DOX-induced damage in isolated rat hearts.

Objectives:

The effects of DOX and MitoQ on cardiac function were evaluated in …

Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy In Melanoma, Gabriele Romano, Francesca Paradiso, Peng Li, Pooja Shukla, Lindsay N Barger, Olivia El Naggar, John P Miller, Roger J Liang, Timothy L Helms, Alexander J Lazar, Jennifer A Wargo, Francesca Taraballi, James C Costello, Lawrence N Kwong

Faculty, Staff and Student Publications

Patients with BRAF-mutant melanoma show substantial responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically "cold" after MRD establishment. Computational analysis identified candidate T-cell recruiting chemokines as …

Meditation-Type Exercise For The Management Of Chemotherapy Related Cognitive Impairment In Breast Cancer Patients, Christine Cain

Evidence-Based Practice Project Reports

Chemotherapy-related cognitive impairment (CRCI), or “chemobrain”, is one of the most troublesome side effects of chemotherapy (Dijkshoorn et al., 2020). Ongoing CRCI may negatively affect relationships, confidence, sleep, fatigue, anxiety, and the ability to return to work activities leading to a decreased quality of life (Johns et al., 2016; Gokal et al., 2018). The purpose of this evidence-based practice (EBP) project was to assess the efficiency of a meditation-type exercise intervention, chair yoga, on decreasing perceived cognitive impairment (PCI) in breast cancer patients. The PICOT question for this project was: In breast cancer patients with chemotherapy related cognitive impairment (P), …

Cancer Stem Cell Assay-Guided Chemotherapy Improves Survival Of Patients With Recurrent Glioblastoma In A Randomized Trial, Tulika Ranjan, Soma Sengupta, Michael J. Glantz, Richard M. Green, Alexander Yu, Dawit Aregawi, Rekha Chaudhary, Ricky Chen, Mario Zuccarello, Christine Lu-Emerson, Hugh D. Moulding, Neil Belman, Jon Glass, Aaron Mammoser, Mark Anderson, Jagan Valluri, Nicholas Marko, Jason Schroeder, Steven Jubelirer, Frances Chow, Pier Paolo Claudio, Anthony M. Alberico, Seth T. Lirette, Krista L. Denning, Candace M. Howard

Department of Neurosurgery Faculty Papers

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors.

In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = …

A Geospatial Approach To Identify Patterns Of Antibiotic Susceptibility At A Neighborhood Level In Wisconsin, United States, Laurel Legenza, Kyle Mcnair, Song Gao, James P Lacy, Brooke J Olson, Thomas R Fritsche, Lucas T Schulz, Samantha Lamuro, Frances Spray-Larson, Tahmeena Siddiqui, Warren E Rose

Faculty, Staff and Student Publications

The global threat of antimicrobial resistance (AMR) varies regionally. This study explores whether geospatial analysis and data visualization methods detect both clinically and statistically significant variations in antibiotic susceptibility rates at a neighborhood level. This observational multicenter geospatial study collected 10 years of patient-level antibiotic susceptibility data and patient addresses from three regionally distinct Wisconsin health systems (UW Health, Fort HealthCare, Marshfield Clinic Health System [MCHS]). We included the initial Escherichia coli isolate per patient per year per sample source with a patient address in Wisconsin (N = 100,176). Isolates from U.S. Census Block Groups with less than 30 isolates …

Rerupture Outcome Of Conservative Versus Open Repair Versus Minimally Invasive Repair Of Acute Achilles Tendon Ruptures: A Systematic Review And Meta-Analysis, Haidong Deng, Xin Cheng, Yi Yang, Fang Fang, Jialing He, Yixin Tian, Tiangui Li, Yangchun Xiao, Yuning Feng, Peng Wang, Weelic Chong, Yang Hai, Yu Zhang

Department of Medicine Faculty Papers

OBJECTIVE: To compare the rerupture rate after conservative treatment, open repair, and minimally invasive surgery management of acute Achilles tendon ruptures.

DESIGN: Systematic review and network meta-analysis.

DATA SOURCES: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to August 2022.

METHODS: Randomised controlled trials involving different treatments for Achilles tendon rupture were included. The primary outcome was rerupture. Bayesian network meta-analysis with random effects was used to assess pooled relative risks (RRs) and 95% confidence intervals. We evaluated the heterogeneity and publication bias.

RESULTS: Thirteen trials with 1465 patients were included. In direct comparison, …

Adiposity-Associated Atrial Fibrillation: Molecular Determinants, Mechanisms, And Clinical Significance, Monika Gawałko, Arnela Saljic, Na Li, Issam Abu-Taha, Thomas Jespersen, Dominik Linz, Stanley Nattel, Jordi Heijman, Anke Fender, Dobromir Dobrev

Faculty, Staff and Students Publications

Obesity is an important contributing factor to the pathophysiology of atrial fibrillation (AF) and its complications by causing systemic changes, such as altered haemodynamic, increased sympathetic tone, and low-grade chronic inflammatory state. In addition, adipose tissue is a metabolically active organ that comprises various types of fat deposits with discrete composition and localization that show distinct functions. Fatty tissue differentially affects the evolution of AF, with highly secretory active visceral fat surrounding the heart generally having a more potent influence than the rather inert subcutaneous fat. A variety of proinflammatory, profibrotic, and vasoconstrictive mediators are secreted by adipose tissue, particularly …

Very-Long-Chain Fatty Acids Induce Glial-Derived Sphingosine-1-Phosphate Synthesis, Secretion, And Neuroinflammation, Hyung-Lok Chung, Qi Ye, Ye-Jin Park, Zhongyuan Zuo, Jung-Wan Mok, Oguz Kanca, Sudhir Gopal Tattikota, Shenzhao Lu, Nobert Perrimon, Hyun Kyoung Lee, Hugo J Bellen

Faculty, Staff and Students Publications

VLCFAs (very-long-chain fatty acids) are the most abundant fatty acids in myelin. Hence, during demyelination or aging, glia are exposed to higher levels of VLCFA than normal. We report that glia convert these VLCFA into sphingosine-1-phosphate (S1P) via a glial-specific S1P pathway. Excess S1P causes neuroinflammation, NF-κB activation, and macrophage infiltration into the CNS. Suppressing the function of S1P in fly glia or neurons, or administration of Fingolimod, an S1P receptor antagonist, strongly attenuates the phenotypes caused by excess VLCFAs. In contrast, elevating the VLCFA levels in glia and immune cells exacerbates these phenotypes. Elevated VLCFA and S1P are also …

Assessing The Impact Of Ebola Virus Inoculum Size On Likelihood Of Infection, Joseph Lukowski

Capstone Experience: Master of Public Health

Background: Indirect transmission of Ebola virus disease (EVD) is not uncommon but is poorly understood. Improving the understanding of the potential risk of EVD transmission from fomites should result in new or updated prevention or control measures for suspected or confirmed EVD cases or outbreaks.

Objective: This study aims to compile and understand pertinent data from peer-reviewed literature, establish the dose-response relationship between inoculum doses introduced to mucous membranes, and finally estimate the risk of EVD transmission from fomites.

Methods: A literature search was conducted through PubMed to obtain relevant data. This study employed this data to perform Poisson regression …

Meta-Analysis Of The Association Between Atrial Fibrillation, Hypertension, Sleep-Disordered Breathing, And Wake-Up Stroke, Jin Zhou, Jing Xu, Aijuan Cheng, Yimiti Kadier, Xiaoli Liang, Maimaitijiang Mutailipu, Shan Sun

The Texas Heart Institute Journal

BACKGROUND: The occurrence of atrial fibrillation, circadian fluctuation in blood pressure, and oxygen desaturation at night is likely associated with the pathophysiology of wake-up stroke. Whether patients who experience wake-up strokes are candidates for thrombolysis treatment is a serious dilemma. The aim is to investigate the association between risk factors and wake-up stroke and to determine variations that are associated with the pathophysiology of wake-up stroke.

METHODS: Five major electronic databases were searched using a fitted search strategy to identify relevant studies. Odds ratios with 95% CIs were used to calculate estimates, and the Quality Assessment for Diagnostic Accuracy Studies-2 …

Emerging Tick-Borne Diseases In Northeast Tennessee, Jacob Schultz

Electronic Theses and Dissertations

Tick populations have been immigrating into northeast Tennessee from east Tennessee, Kentucky, Virginia, and North Carolina. Counties in states bordering northeast Tennessee harbor tick species associated with human illness. Human diseases transmitted by ticks include ehrlichiosis, spotted fever rickettsial group diseases, tularemia, anaplasmosis, babesiosis, Lyme disease, alpha-gal syndrome, Heartland virus, Powassan virus, and southern tick-associated rash illness (STARI). These diseases cause morbidity and mortality in human populations and may pose a high risk to individuals, wildlife, and livestock. The Cherokee National Forest covering the east Tennessee border provides a permissible environment for ticks to immigrate and thrive. Residents of northeast …

The Influence Of Vitamin D Levels On Dental Caries: A Retrospective Study Of The United States Population, Canon C Cornelius, Stephen Warner, Joel Thomas, David Rodriguez-Quintana

Faculty, Staff and Student Publications

Introduction

Periprosthetic femur fractures (PPFF) are increasing in incidence and management of such injuries requires a specialized skill set combined with detailed knowledge of component design. To assist with planning, computed tomography (CT) can be used pre-operatively to give a surgeon more information. No study to date has shown the utility of obtaining preoperative CT. The goal of this study is to show that CT is a useful diagnostic adjunct and report any differences in how subspecialties such as orthopedic traumatologists and arthroplasty surgeons use it.

Methods

Seventeen PPFF cases met our inclusion criteria. They were shown to six faculty, …

Combination Therapy With Trastuzumab And Niraparib: Quantifying Early Proliferative Alterations In Her2+ Breast Cancer Models, Ameer Mansur, Patrick N. Song, Yun Lu, Andrew C. Burns, Luke Sligh, Eddy S. Yang, Anna G. Sorace

Markey Cancer Center Faculty Publications

HER2–targeted treatments have improved survival rates in HER2+ breast cancer patients, yet poor responsiveness remains a major clinical obstacle. Recently, HER2+ breast cancer cells, both resistant and responsive to HER2–targeted therapies, have demonstrated sensitivity to poly–(ADP– ribose) polymerase (PARP) inhibition, independent of DNA repair deficiencies. This study seeks to describe biological factors that precede cell viability changes in response to the combination of trastuzumab and PARP inhibition. Treatment response was evaluated in HER2+ and HER2– breast cancer cells. Further, we evaluated the utility of 3′–Deoxy–3′–[18F]–fluorothymidine positron emission tomography ([18F]FLT–PET) imaging for early response assessment in a HER2+ patient derived xenograft …

Impact Of Lyophilization On Porcine Hemoglobin Properties., Mustafa Almosawi

College of Arts & Sciences Senior Theses

Blood transfusion is the single most often performed lifesaving procedure in hospitals worldwide. Unfortunately, packed red blood cells (RBCs) used for transfusion can only be stored for 42 days at 4 °C before being discarded due to irreversible damage that occurs during storage. Any reduction in available RBCs for an extended period can lead to blood shortages. To increase the shelf-life of RBCs, we investigated freeze-drying (lyophilizing) in the presence of the non-toxic sugar trehalose as a method for long-term preservation. However, the oxidative stress of the lyophilization and storage processes can compromise the functionality of these cells, and the …

Phenotype Characterization Of Genetic Murine Mouse Models Of Developmental Dysplasia Of The Hip (Ddh), Stephanie Mrowczynski, Kevin Baker, Michael Newton

Posters

Developmental dysplasia of the hip (DDH) is a congenital hip alteration that changes the “ball in socket” movement of the leg inside the pelvis. Genome-wide association studies have identified CX3CR1 polymorphisms associated with increased risk of Developmental Dysplasia of the Hip. Mouse models of CX3CR1 knock-out (KO) mice show unilateral, bony discrepancies between the femur head and acetabulum in comparison to wild-type (WT) mice, as well as gait impairment similar to that of humans with osteoarthritis (which develops in DDH patients later in life). The primary goal of this project is to assess joint congruity in a CX3CR1 KO model …

N-Terminal Egfp-Tagging Of Rabbit Apolipoprotein A-I Decreases Expression And Impairs Cholesterol-Efflux Activity, Bradley K Wacker, Lianxiang Bi, Li Liu, Mary G Sorci-Thomas, Philip Ng, Donna J Palmer, Chongren Tang, David A Dichek

Faculty, Staff and Students Publications

No abstract provided.

Investigating Gene-Diet Interactions Impacting The Association Between Macronutrient Intake And Glycemic Traits, Kenneth E Westerman, Maura E Walker, Sheila M Gaynor, Jennifer Wessel, Daniel Dicorpo, Jiantao Ma, Alvaro Alonso, Stella Aslibekyan, Abigail S Baldridge, Alain G Bertoni, Mary L Biggs, Jennifer A Brody, Yii-Der Ida Chen, Joseé Dupuis, Mark O Goodarzi, Xiuqing Guo, Natalie R Hasbani, Adam Heath, Bertha Hidalgo, Marguerite R Irvin, W Craig Johnson, Rita R Kalyani, Leslie Lange, Rozenn N Lemaitre, Ching-Ti Liu, Simin Liu, Jee-Young Moon, Rami Nassir, James S Pankow, Mary Pettinger, Laura M Raffield, Laura J Rasmussen-Torvik, Elizabeth Selvin, Mackenzie K Senn, Aladdin H Shadyab, Albert V Smith, Nicholas L Smith, Lyn Steffen, Sameera Talegakwar, Kent D Taylor, Paul S De Vries, James G Wilson, Alexis C Wood, Lisa R Yanek, Jie Yao, Yinan Zheng, Eric Boerwinkle, Alanna C Morrison, Miriam Fornage, Tracy P Russell, Bruce M Psaty, Daniel Levy, Nancy L Heard-Costa, Vasan S Ramachandran, Rasika A Mathias, Donna K Arnett, Robert Kaplan, Kari E North, Adolfo Correa, April Carson, Jerome I Rotter, Stephen S Rich, Joann E Manson, Alexander P Reiner, Charles Kooperberg, Jose C Florez, James B Meigs, Jordi Merino, Deirdre K Tobias, Han Chen, Alisa K Manning

Faculty, Staff and Student Publications

Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate …

Closed Mitral Valvotomy: Celebrating 100 Years Of Surgical History, Uberto Bortolotti, Igor Vendramin, Aldo Domenico Milano, Ugolino Livi

The Texas Heart Institute Journal

The year 2023 marks the 100th anniversary of the first successful valvotomy for mitral valve stenosis by Elliott C. Cutler in 1923. Closed-chest mitral valve commissurotomy developed further before being replaced by an open procedure after the advent of the heart-lung machine. Currently, because of the almost complete disappearance of rheumatic disease in the Western World, mitral commissurotomies are infrequently performed in those countries, although the procedure-either closed or open-is still performed in developing countries and select patients. This review retraces the 100-year journey from a historic operation to the current era-a milestone in the treatment of patients with mitral …

Spatial Metabolomics Reveals Glycogen As An Actionable Target For Pulmonary Fibrosis, Lindsey R. Conroy, Harrison A. Clarke, Derek B. Allison, Samuel Santos Valenca, Qi Sun, Tara R. Hawkinson, Lyndsay E. A. Young, Juanita E. Ferreira, Autumn V. Hammonds, Jaclyn B. Dunne, Robert J. Mcdonald, Kimberly J. Absher, Brittany Dong, Ronald C. Bruntz, Kia H. Markussen, Jelena A. Juras, Warren J. Alilain, Jinze Liu, Matthew S. Gentry, Peggi M. Angel, Christopher M. Waters, Ramon C. Sun

Saha Cardiovascular Research Center Faculty Publications

Matrix assisted laser desorption/ionization imaging has greatly improved our understanding of spatial biology, however a robust bioinformatic pipeline for data analysis is lacking. Here, we demonstrate the application of high- dimensionality reduction/spatial clustering and histopathological annotation of matrix assisted laser desorption/ionization imaging datasets to assess tissue metabolic heterogeneity in human lung diseases. Using metabolic features identified from this pipeline, we hypothesize that metabolic channeling between glycogen and N-linked glycans is a critical metabolic process favoring pulmonary fibrosis progression. To test our hypothesis, we induced pulmonary fibrosis in two different mouse models with lysosomal glycogen utilization deficiency. Both mouse models displayed …

Psychometric Evaluation Of The Computerized Battery For Neuropsychological Evaluation Of Children (Benci) Among School Aged Children In The Context Of Hiv In An Urban Kenyan Setting, Rachel Maina, He Jia, Amina Abubakar, Miguel Perez-Garcia, Manasi Kumar, Jelte M. Wicherts

Brain and Mind Institute

Introduction Culturally validated neurocognitive measures for children in Low‐ and Middle‐Income Countries are important in the timely and correct identification of neurocognitive impairments. Such measures can inform develop‐ ment of interventions for children exposed to additional vulnerabilities like HIV infection. The Battery for Neuropsy‐ chological Evaluation of Children (BENCI) is an openly available, computerized neuropsychological battery specifically developed to evaluate neurocognitive impairment. This study adapted the BENCI and evaluated its reliability and validity in Kenya.

Methodology The BENCI was adapted using translation and back‐translation from Spanish to English. The psy‐ chometric properties were evaluated in a case–control study of 328 …

Sexual Dimorphism Of Glomerular Capillary Morphology In Rats, Zackarias Coker

Undergraduate Honors Theses

Chronic kidney disease (CKD) progresses faster in males than females; however, the underlying mechanisms remain poorly understood. Sex differences in glomerular capillary morphology has been hypothesized to contribute, in part, to the increased susceptibility to hypertension-induced renal injury and CKD progression in males, but this has not been investigated. The goal of the present study was to assess glomerular capillary morphology in male vs. female rats with intact kidneys and after uninephrectomy (UNX). We hypothesized that glomerular capillary radii (R_CAP) and length (L_CAP) would be greater in male rats.

Male (n=4) and female (n=4) with intact …

Adjuncts And Additives To Regional Anesthesia, Kaisi Dye, Kelcie Brunnert

Doctor of Nursing Practice Projects

With regional anesthesia becoming increasingly popular, an emphasis has been placed on choosing appropriate adjunct medications to local anesthetics for prolonging peripheral nerve blocks- lengthening postoperative pain control and decreasing perioperative narcotic usage. This project aimed to increase provider knowledge of the proven efficacy of block and adjunct selection for breast, shoulder, and knee surgeries with intended results being prolonged block duration and increased patient satisfaction post-operatively. A focused lecture along with a Likert-scale questionnaire and quiz were administered to a small sample of anesthesia providers at a rural Illinois hospital. Half (55.6%) of the providers showed evidence of knowledge …

Opensim-Based Musculoskeletal Modeling: Foundation For Interactive Obstetric Simulator, Bahador Dodge

Electrical & Computer Engineering Theses & Dissertations

The use of mathematical and computational models to understand complex biological systems, such as the human birth process, is a rapidly growing field in medicine. These models can be used to optimize and personalize medical treatments for individual patients, enhance training, and aid in educational efforts. While recent advancements in healthcare, particularly in obstetrics, have improved care for mothers and babies, studies and government reports indicate a rising rate of maternal mortality in the United States.

Despite this rising trend, there is a lack of detailed studies concerning the use of modeling and simulation to develop an interactive obstetrics simulator …

Development And Characterization Of Nanobodies That Specifically Target The Oncogenic Phosphatase Of Regenerating Liver-3 (Prl-3) And Impact Its Interaction With A Known Binding Partner, Cnnm3, Caroline N. Smith, Kyle Kihn, Zachary A. Williamson, K. Martin Chow, Louis B. Hersh, Konstantin V. Korotkov, Daniel Deredge, Jessica S. Blackburn

Markey Cancer Center Faculty Publications

Phosphatase of Regenerating Liver-3 (PRL-3) is associated with cancer progression and metastasis. The mechanisms that drive PRL-3’s oncogenic functions are not well under- stood, partly due to a lack of research tools available to study this protein. We have begun to address these issues by developing alpaca-derived single domain antibodies, or nanobo- dies, targeting PRL-3 with a KD of 30–300 nM and no activity towards highly homologous family members PRL-1 and PRL-2. We found that longer and charged N-terminal tags on PRL-3, such as GFP and FLAG, changed PRL-3 localization compared to untagged protein, indicating that the nanobodies may provide …

Icam-1-Supar-Cd11b Axis Is A Novel Therapeutic Target For Metastatic Triple-Negative Breast Cancer, Dong Li, Hami Hemati, Younhee Park, Rokana Taftaf, Youbin Zhang, Jinpeng Liu, Massimo Cristofanilli, Xia Liu

Markey Cancer Center Faculty Publications

Accumulating evidence demonstrates that circulating tumor cell (CTC) clusters have higher metastatic ability than single CTCs and negatively correlate with cancer patient outcomes. Along with homotypic CTC clusters, heterotypic CTC clusters (such as neutrophil–CTC clusters), which have been identified in both cancer mouse models and cancer patients, lead to more efficient metastasis formation and worse patient outcomes. However, the mechanism by which neutrophils bind to CTCs remains elusive. In this study, we found that intercellular adhesion molecule-1 (ICAM-1) on triple- negative breast cancer (TNBC) cells and CD11b on neutrophils mediate tumor cell–neutrophil binding. Consequently, CD11b deficiency inhibited tumor cell–neutrophil binding …

Single Fraction And Hypofractionated Radiation Cause Cochlear Damage, Hearing Loss, And Reduced Viability Of Merlin-Deficient Schwann Cells, Christine T. Dinh, Si Chen, Aida Nourbakhsh, Kyle Padgett, Perry Johnson, Stefania Goncalves, Olena Bracho, Esperanza Bas, Jorge Bohorquez, Paula V. Monje, Cristina Fernandez-Valle, Nagy Elsayyad, Xuezhong Liu, Scott M. Welford, Fred Telischi

Markey Cancer Center Faculty Publications

Background: Vestibular schwannomas (VS) are benign intracranial tumors caused by loss of function of the merlin tumor suppressor. We tested three hypotheses related to radiation, hearing loss (HL), and VS cell survival: (1) radiation causes HL by injuring auditory hair cells (AHC), (2) fractionation reduces radiation-induced HL, and (3) single fraction and equivalent appropriately dosed multi-fractions are equally effective at controlling VS growth. We investigated the effects of single fraction and hypofractionated radiation on hearing thresholds in rats, cell death pathways in rat cochleae, and viability of human merlin-deficient Schwann cells (MD-SC). Methods: Adult rats received cochlear irradiation with single …

The Plod2/Succinate Axis Regulates The Epithelial–Mesenchymal Plasticity And Cancer Cell Stemness, Yuxin Tong, Yifei Qi, Gaofeng Xiong, Junyan Li, Timothy L. Scott, Jie Chen, Daheng He, Linzhang Li, Chi Wang, Andrew N. Lane, Ren Xu

Markey Cancer Center Faculty Publications

Aberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate …

Identification Of Molecular Markers Associated With Copd In Non-Smokers And Smokers: A Bioinformatics Analysis, Agede O. Ayodele, Isa M. Wasagu, Ademola E. Fawibe, Alakija K. Salami

The University of Louisville Journal of Respiratory Infections

Background

Even though the proportional burden of COPD among never-smokers is significant in both developing and developed nations, accounting for around 30% of all COPD in the community, there is little awareness of the prevalence of COPD in this population. Understanding the molecular processes that underlie COPD in nonsmokers is essential.

Methods

Dataset (GSE146560) was acquired from the Gene Expression Omnibus (GEO). The limma and clusterProfiler software tools were used to identify differentially expressed genes (DEGs) and conduct a functional enrichment analysis respectively.

Results

In all, 10,583 DEGs were found, of which 1,065 were up-regulated and 9,518 were down-regulated. The …