Medical Specialties Commons^™

In Utero And Post-Natal Opioid Exposure Followed By Mild Traumatic Brain Injury Contributes To Cortical Neuroinflammation, Mitochondrial Dysfunction, And Behavioral Deficits In Juvenile Rats, Austin M. Gowen, Jina Yi, Kelly L. Stauch, Luke Miles, Sanjay Srinivasan, Katherine Odegaard, Gurudutt Pendyala, Sowmya V. Yelamanchili

Journal Articles: Anesthesiology

Maternal opioid use poses a significant health concern not just to the expectant mother but also to the fetus. Notably, increasing numbers of children born suffering from neonatal opioid withdrawal syndrome (NOWS) further compounds the crisis. While epidemiological research has shown the heightened risk factors associated with NOWS, little research has investigated what molecular mechanisms underly the vulnerabilities these children carry throughout development and into later life. To understand the implications of in utero and post-natal opioid exposure on the developing brain, we sought to assess the response to one of the most common pediatric injuries: minor traumatic brain injury …

Factors Associated With Prevalent Mycobacterium Tuberculosis Infection And Disease Among Adolescents And Adults Exposed To Rifampin-Resistant Tuberculosis In The Household, Soyeon Kim, Anneke C. Hesseling, Xingye Wu, Michael D. Hughes, N. Sarita Shah, Sanjay Gaikwad, Nishi Kumarasamy, Erika Mitchell, Mey Leon, Pedro Gonzales, Sharlaa Badal-Faesen, Madeleine Lourens, Sandy Nerette, Justin Shenje, Petra De Koker, Supalert Nedsuwan, Lerato Mohapi, Unoda A. Chakalisa, Rosie Mngqbisa, Rodrigo Otávio Da Silva Escada, Samuel Ouma, Barbara Heckman, Linda Naini, Amita Gupta, Susan Swindells, Gavin Churchyard, Actg A5300/Impaact 2003 Phoenix Feasibility Study Team

Journal Articles: Infectious Diseases

BACKGROUND: Understanding factors associated with prevalent Mycobacterium tuberculosis infection and prevalent TB disease in household contacts of patients with drug-resistant tuberculosis (TB) may be useful for TB program staff conducting contact investigations.

METHODS: Using data from a cross-sectional study that enrolled index participants with rifampin-resistant pulmonary TB and their household contacts (HHCs), we evaluated HHCs age ≥15 years for factors associated with two outcomes: Mycobacterium tuberculosis infection and TB disease. Among HHCs who were not already diagnosed with current active TB disease by the TB program, Mycobacterium tuberculosis infection was determined by interferon-gamma release assay (IGRA). TB disease was adjudicated …

Something Smells Fishy: How Lipid Mediators Impact The Maternal-Fetal Interface And Neonatal Development, Maranda Thompson, Arzu Ulu, Maheswari Mukherjee, Ana G. Yuil-Valdes, Melissa K. Thoene, Matthew Van Ormer, Rebecca Slotkowski, Teri Mauch, Ann Anderson-Berry, Corrine K. Hanson, Tara M. Nordgren, Sathish Kumar Natarajan

Journal Articles: Pediatrics

Normal pregnancy relies on inflammation for implantation, placentation, and parturition, but uncontrolled inflammation can lead to poor maternal and infant outcomes. Maternal diet is one modifiable factor that can impact inflammation. Omega-3 and -6 fatty acids obtained through the diet are metabolized into bioactive compounds that effect inflammation. Recent evidence has shown that the downstream products of omega-3 and -6 fatty acids may influence physiology during pregnancy. In this review, the current knowledge relating to omega-3 and omega-6 metabolites during pregnancy will be summarized.

Ventricular Tachycardia In A Pediatric Patient With High-Risk Thrombotic Thrombocytopenia Purpura, Taylor J. Kratochvil, Jeffrey A. Robinson

Journal Articles: Pediatrics

An 8-year-old previously healthy male was diagnosed with thrombotic thrombocytopenic purpura (TTP) and increased serum cardiac troponin I. Telemetry recorded non-sustained ventricular tachycardia, without ST-segment changes or other abnormalities on serial electrocardiogram. This case illustrates that cardiac monitoring by telemetry should be considered in high-risk TTP with elevated cardiac troponin.

Retinol And Pro-Vitamin A Carotenoid Nutritional Status During Pregnancy Is Associated With Newborn Hearing Screen Results, Rebecca Slotkowski, Matthew Van Ormer, Anum Akbar, Olivia Paetz, Taija Hahka, Maranda Thompson, Alyssa Freeman, Alexandra Hergenrader, Sarah Sweeney, Zeljka Korade, Thiago Genaro-Mattos, Corrine K. Hanson, Ann Anderson-Berry, Melissa K. Thoene

Journal Articles: Pediatrics

The prenatal period is critical for auditory development; thus, prenatal influences on auditory development may significantly impact long-term hearing ability. While previous studies identified a protective effect of carotenoids on adult hearing, the impact of these nutrients on hearing outcomes in neonates is not well understood. The purpose of this study is to investigate the relationship between maternal and umbilical cord plasma retinol and carotenoid concentrations and abnormal newborn hearing screen (NHS) results. Mother-infant dyads (n = 546) were enrolled at delivery. Plasma samples were analyzed using HPLC and LC-MS/MS. NHS results were obtained from medical records. Statistical analysis …

Plasma Retinol Concentrations And Dietary Intakes Of Mother-Infant Sets In Singleton Versus Twin Pregnancy, Anum Akbar, Sarah Duvall, Matthew Van Ormer, Rebecca Slotkowski, Taija Hahka, Thiago Genaro-Mattos, Zeljka Korade, Corrine K. Hanson, Ann Anderson-Berry, Melissa K. Thoene

Journal Articles: Pediatrics

Vitamin A (retinol) is essential for normal fetal development, but the recommendation for maternal dietary intake (Retinol Activity Equivalent, RAE) does not differ for singleton vs. twin pregnancy, despite the limited evaluation of retinol status. Therefore, this study aimed to evaluate plasma retinol concentrations and deficiency status in mother-infant sets from singleton vs. twin pregnancies as well as maternal RAE intake. A total of 21 mother-infant sets were included (14 singleton, 7 twin). The HPLC and LC-MS/HS evaluated the plasma retinol concentration, and data were analyzed using the Mann-Whitney U test. Plasma retinol was significantly lower in twin vs. singleton …

Evaluation Of Vitamin E Isoforms In Placental Tissue And Their Relationship With Maternal Dietary Intake And Plasma Concentrations In Mother-Infant Dyads, Ishani Jhamb, Alyssa Freeman, Michelle R. Lotfi, Matthew Van Ormer, Corrine K. Hanson, Ann Anderson-Berry, Melissa K. Thoene

Journal Articles: Pediatrics

α-tocopherol is a vitamin E isoform with potent antioxidant activity, while the γ-tocopherol isoform of vitamin E exerts more pro-inflammatory effects. In maternal-fetal environments, increased plasma α-tocopherol concentrations are associated with positive birth outcomes, while higher γ-tocopherol concentrations are linked with negative pregnancy outcomes. However, little is known about tocopherol concentrations in placental tissue and their role in modulating placental oxidative stress, a process that is implicated in many complications of pregnancy. The objectives of this research are to evaluate the concentrations of α- and γ-tocopherol in placental tissue and assess relationships with maternal and umbilical cord plasma concentrations. A …

The Relationship Between Nutrition, Gut Dysbiosis, And Pediatric Sickle Cell Pain Outcomes: A Pilot Study, Chinenye R. Dike, Corrine K. Hanson, Dele Davies, Stephen Obaro, Fang Yu, James L. Harper, Helen Grace, Jeffrey Lebensburger, Chittalsinh M. Raulji, Jihyun Ma, Peter Mannon

Journal Articles: Pediatrics

BACKGROUND: Nutritional deficiencies are prevalent in sickle cell disease (SCD) and may be associated with worse pain outcomes. Gut dysbiosis has been reported in patients with SCD and may contribute to both nutritional deficiencies and pain.

OBJECTIVES: We tested the association of nutrition, fat-soluble vitamin (FSV) deficiency, and gut microbiome composition on clinical outcomes in SCD. Second, we measured the association between diet and exocrine pancreatic function on FSV levels.

METHODS: Using case control design, we enrolled children with SCD (n = 24) and matched healthy controls (HC; n = 17, age, sex, race/ethnicity). Descriptive statistics summarized demographic and clinical …

Verification Of Proton Range Predictions In Proton Treatment Planning Using X-Ray Ct Or Proton Ct Imaging, Nicholas S. Yee

Graduate Research Theses & Dissertations

The objective of this paper is to compare the range errors for two treatment plans; one using x-ray CT and the other using proton CT for calculating dose distributions in an animal tissue phantom. We shot 150 MeV proton beam through a meat phantom to a film stack to measure the exponential drop of dose at the Bragg peak until zero dose remained. Plotting the depth dose curves and performing gamma analyses are two ways to quantify the proton range errors when comparing them to depth dose curves from film measurements in the phantom. The depth dose curves give us …

Energy Cost Of Walking In Diabetic Partial-Foot Amputees As Related To Amputation Level, Nicholas Obias, Javier La Fontaine, Javier Cavazos, Luis Venegas, Hafizur Rahman

School of Podiatric Medicine - Student Research

This review will explore how the energy cost of walking changes with different levels of partial-foot amputation in diabetic patients. Patient populations with advanced stages of diabetes and associated complications have a high incidence of distal lower extremity amputation. Diabetes associated conditions and altered foot function in post-amputation patients affect gait biomechanics and energy expenditure in gait. We will review studies utilizing advanced biomechanical tools to quantify and compare energy expenditure (defined as cardiac function and oxygen consumption) in established post-operative partial-foot amputees at various levels (post-operative day >90*) to controls. Dr. Rahman and his team aim to provide further …

Premature Senescence And Cardiovascular Disease Following Cancer Treatments: Mechanistic Insights, Ashita Jain, Diego Casanova, Alejandra Valdivia Padilla, Angelica Paniagua Bojorges, Sivareddy Kotla, Kyung Ae Ko, Venkata S K Samanthapudi, Khanh Chau, Minh T H Nguyen, Jake Wen, Selina L Hernandez Gonzalez, Shaefali P Rodgers, Elizabeth A Olmsted-Davis, Dale J Hamilton, Cielito Reyes-Gibby, Sai-Ching J Yeung, John P Cooke, Joerg Herrmann, Eduardo N Chini, Xiaolei Xu, Syed Wamique Yusuf, Momoko Yoshimoto, Philip L Lorenzi, Brain Hobbs, Sunil Krishnan, Efstratios Koutroumpakis, Nicolas L Palaskas, Guangyu Wang, Anita Deswal, Steven H Lin, Jun-Ichi Abe, Nhat-Tu Le

Faculty, Staff and Student Publications

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality, especially among the aging population. The "response-to-injury" model proposed by Dr. Russell Ross in 1999 emphasizes inflammation as a critical factor in atherosclerosis development, with atherosclerotic plaques forming due to endothelial cell (EC) injury, followed by myeloid cell adhesion and invasion into the blood vessel walls. Recent evidence indicates that cancer and its treatments can lead to long-term complications, including CVD. Cellular senescence, a hallmark of aging, is implicated in CVD pathogenesis, particularly in cancer survivors. However, the precise mechanisms linking premature senescence to CVD in cancer survivors remain …

Uncovering The Role Of Fat-Infiltrated Axillary Lymph Nodes In Obesity-Related Diseases With Statistical And Machine Learning Analyses, Qingyuan Song

Dartmouth College Ph.D Dissertations

The link between obesity and pathogenesis is a complex and multifaceted area of research that is yet to be fully understood. Ample evidence exists to demonstrate the direct relationship between excessive internal fat and various health conditions such as cancer, and metabolic and cardiovascular diseases. The infiltration of ectopic fat into axillary lymph nodes, observable on breast cancer screening images, has been shown to be correlated with body mass index (BMI) in women undergoing screening. This study aimed to explore the relationship between fat-infiltrated axillary lymph nodes (FIN) and obesity-related diseases, with the goal of evaluating the clinical value of …

Pediatric In-Hospital Cardiac Arrests: We Have More To Learn About Patient Demographics And Outcomes, Nathan Lavoy, John Cowden, Jenna Miller, Asdis Finnsdottir Wagner, Shekinah Hensley, Stephen Pfeiffer

Presentations

Introduction: Prior pediatric studies show an association between patient demographics and mortality after in-hospital cardiac arrests (IHCA). To our knowledge, this has not been assessed in pediatric intensive care units (PICU). This study aims to evaluate the impact of demographics and code characteristics on outcomes after IHCA in a quaternary referral PICU. Methods: A single center retrospective review of PICU IHCA events from 2010-2021 was performed. Patient demographics included age, gender, race/ethnicity, and language. Primary diagnosis was defined as cardiac or non-cardiac. The use of ECMO, CRRT, or defibrillation were included as code characteristics. The primary outcome was survival to …

Protein S In Coagulation And Inflammation, Martha Mega Silvia Sim

Theses and Dissertations--Molecular and Cellular Biochemistry

Protein S (PS) is a key regulator, which links inflammation and coagulation and performs multiple proposed functions in both processes. PS exists in the blood as a free soluble form (~40%), bound to complement component 4b-binding protein/ C4BP (~60%), and packaged in platelet α-granules (~2.5%). Subendothelial tissue factor (TF), upon exposure to blood, initiates coagulation, a proteolytic cascade which results in the activation of thrombin, the enzyme responsible for formation of a fibrin clot. PS is a critical anticoagulant that inhibits multiple steps of this process. Only the free fraction of PS has full anticoagulant properties, as C4BP blocks this …

Metabolic Reprogramming Driven By Ezh2 Inhibition Depends On Cell–Matrix Interactions, Teresa W-M Fan, Jahid M. M. Islam, Richard M. Higashi, Penghui Lin, Christine F. Brainson, Andrew N. Lane

Markey Cancer Center Faculty Publications

EZH2 (Enhancer of Zeste Homolog 2), a subunit of Poly- comb Repressive Complex 2 (PRC2), catalyzes the trimethyla- tion of histone H3 at lysine 27 (H3K27me3), which represses expression of genes. It also has PRC2-independent functions, including transcriptional coactivation of oncogenes, and is frequently overexpressed in lung cancers. Clinically, EZH2 in- hibition can be achieved with the FDA-approved drug EPZ- 6438 (tazemetostat). To realize the full potential of EZH2 blockade, it is critical to understand how cell-cell/cell-matrix interactions present in 3D tissue and cell culture systems in- fluences this blockade in terms of growth-related metabolic functions. Here, we show that …

A Monoadduct Generating Ru(Ii) Complex Induces Ribosome Biogenesis Stress And Is A Molecular Mimic Of Phenanthriplatin, Richard Joseph Mitchell, Sarah M. Kriger, Alexander D. Fenton, Dmytro Havrylyuk, Ankit Pandeya, Yang Sun, Tami Smith, Jason E. Derouchey, David K. Heidary, Edith C. Glazer

Markey Cancer Center Faculty Publications

Ruthenium complexes are often investigated as potential replacements for platinum-based chemotherapeutics in hopes of identifying systems with improved tolerability in vivo and reduced susceptibility to cellular resistance mechanisms. Inspired by phenanthriplatin, a non-traditional platinum agent that contains only one labile ligand, monofunctional ruthenium polypyridyl agents have been developed, but until now, few demonstrated promising anticancer activity. Here we introduce a potent new scaffold, based on [Ru(tpy)(dip)Cl]Cl (tpy = 2,20:60,200-terpyridine and dip = 4,7-diphenyl-1,10-phenanthroline) in pursuit of effective Ru(II )-based monofunctional agents. Notably, the extension of the terpyridine at the 40 position with an aromatic ring resulted in a molecule that …

Assessment Of Opioid-Induced Immunomodulation In Experimental And Clinical Sepsis, Brittany Dawn Bissell, Jamie L. Sturgill, Maria E. C. Bruno, Erick D. Lewis, Marlene E. Starr

Markey Cancer Center Faculty Publications

CONTEXT: Opioids remain a standard supportive therapy in patients admitted to the ICU with sepsis. However, as preclinical models indicate an association between opioid exposure and immunosuppression, the use of this class of drugs warrants investigation. The objective of this study was to investigate whether opioid exposure causes immunosuppression in patients with sepsis, and to use a murine sepsis model to determine the effects of opioid exposure on secondary infection.

HYPOTHESIS: We hypothesized opioid exposure would be associated with immunosuppression in patients with sepsis and secondary infection in a murine sepsis model.

METHODS AND MODELS: This was a two-phase preclinical …

Bilirubin Levels Are Negatively Correlated With Adiposity In Obese Men And Women, And Its Catabolized Product, Urobilin, Is Positively Associated With Insulin Resistance, Zachary A. Kipp, Mei Xu, Evelyn A. Bates, Wang-Hsin Lee, Philip A. Kern, Terry D. Hinds Jr.

Markey Cancer Center Faculty Publications

Bilirubin levels in obese humans and rodents have been shown to be lower than in their lean counterparts. Some studies have proposed that the glucuronyl UGT1A1 enzyme that clears bilirubin from the blood increases in the liver with obesity. UGT1A1 clearance of bilirubin allows more conjugated bilirubin to enter the intestine, where it is catabolized into urobilin, which can be then absorbed via the hepatic portal vein. We hypothesized that when bilirubin levels are decreased, the urobilin increases in the plasma of obese humans, as compared to lean humans. To test this, we measured plasma levels of bilirubin and urobilin, …

Computational Investigation Of A Series Of Small Molecules As Potential Compounds For Lysyl Hydroxylase-2 (Lh2) Inhibition, Yazdan Maghsoud, Erik Antonio Vázquez-Montelongo, Xudong Yang, Chengwen Liu, Zhifeng Jing, Juhoon Lee, Matthew Harger, Ally K. Smith, Miguel Espinoza, Hou-Fu Guo, Jonathan M. Kurie, Kevin N. Dalby, Pengyu Ren, G. Andrés Cisneros

Markey Cancer Center Faculty Publications

The catalytic function of lysyl hydroxylase-2 (LH2), a member of the Fe(II)/αKG-dependent oxygenase superfamily, is to catalyze the hydroxylation of lysine to hydroxylysine in collagen, resulting in stable hydroxylysine aldehyde-derived collagen cross- links (HLCCs). Reports show that high amounts of LH2 lead to the accumulation of HLCCs, causing fibrosis and specific types of cancer metastasis. Some members of the Fe(II)/αKG-dependent family have also been reported to have intramolecular O2 tunnels, which aid in transporting one of the required cosubstrates into the active site. While LH2 can be a promising target to combat these diseases, efficacious inhibitors are still lacking. We …

Dysregulated Polycomb Repressive Complex 2 Contributes To Chronic Obstructive Pulmonary Disease By Rewiring Stem Cell Fate, Aria Byrd, Xufeng Qu, Alexsandr Lukyanchuk, Jinpeng Liu, Fan Chen, Kassandra J. Naughton, Tanner Ducote, Xiulong Song, Hannah Bowman, Yanming Zhao, Abigail R Edgin, Chi Wang, Jinze Liu, Christine Fillmore Brainson

Markey Cancer Center Faculty Publications

Aberrant lung cell differentiation is a hallmark of many lung diseases including chronic obstructive pulmonary disease (COPD). The EZH2-containing Polycomb Repressive Complex 2 (PRC2) regulates embryonic lung stem cell fate, but its role in adult lung is obscure. Histological analysis of patient tissues revealed that loss of PRC2 activity was correlated with aberrant bronchiolar cell differentiation in COPD lung. Histological and single-cell RNA-sequencing analyses showed that loss of EZH2 in mouse lung organoids led to lowered self- renewal capability, increased squamous morphological development, and marked shifts in progenitor cell populations. Evaluation of in vivo models revealed that heterozygosity of Ezh2 …

Extracellular Vesicle Distribution And Localization In Skeletal Muscle At Rest And Following Disuse Atrophy, Ahmed Ismaeel, Douglas W. Van Pelt, Zachary Hettinger, Xu Fu, Christopher I. Richards, Timothy A. Butterfield, Jonathan J. Petrocelli, Ivan J. Vechetti Jr., Amy L. Confides, Micah J. Drummond, Esther E. Dupont-Versteegden

Markey Cancer Center Faculty Publications

Background Skeletal muscle (SkM) is a large, secretory organ that produces and releases myokines that can have autocrine, paracrine, and endocrine effects. Whether extracellular vesicles (EVs) also play a role in the SkM adaptive response and ability to communicate with other tissues is not well understood. The purpose of this study was to investigate EV biogenesis factors, marker expression, and localization across cell types in the skeletal muscle. We also aimed to investigate whether EV concentrations are altered by disuse atrophy.

Methods To identify the potential markers of SkM‑derived EVs, EVs were isolated from rat serum using density gradient ultracentrifugation, …

Glycolytic Regulation Of Intestinal Stem Cell Self-Renewal And Differentiation, Chang Li, Yuning Zhou, Ruozheng Wei, Dana L. Napier, Tomoko Sengoku, Michael Alstott, Jinpeng Liu, Chi Wang, Yekaterina Y. Zaytseva, Heidi L. Weiss, Qingding Wang, B. Mark Evers

Markey Cancer Center Faculty Publications

BACKGROUND AND AIMS: The intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. An imbalance in this highly regimented process within the intestinal crypts is associated with several intestinal pathologies. Although metabolic changes are known to play a pivotal role in cell proliferation and differentiation, how glycolysis contributes to intestinal epithelial homeostasis remains to be defined.

METHODS: Small intestines were harvested from mice with specific hexokinase 2 (HK2) deletion in the intestinal epithelium or LGR5þ stem cells. Glycolysis was measured using the Seahorse XFe96 analyzer. Expression of phospho-p38 mitogen- activated protein kinase, the transcription factor atonal homolog 1, …

Impact Of The Affordable Care Act On Providing Equitable Healthcare Access For Ibd In The Kentucky Appalachian Region, Jennifer T. Castle, Brittany Levy, Anthony A. Mangino, Hannah G. Mcdonald, Erin E. Mcatee, Jitesh A. Patel, B. Mark Evers, Avinash S. Bhakta

Markey Cancer Center Faculty Publications

BACKGROUND: Medicaid expansion improved insurance coverage for patients with chronic conditions and low income. The effect of Medicaid expansion on patients with IBD from high-poverty communities is unknown.

OBJECTIVE: This study aimed to evaluate the impact of Medicaid expansion in Kentucky on care for patients with IBD from the Eastern Kentucky Appalachian community, a historically impoverished area.

DESIGN: This study was a retrospective, descriptive, and ecological study.

SETTINGS: This study was conducted in Kentucky using the Hospital Inpatient Discharge and Outpatient Services Database.

PATIENTS: All encounters for IBD care for 2009–2020 for patients from the Eastern Kentucky Appalachian region were …

Long-Term Kidney Function Recovery And Mortality After Covid-19-Associated Acute Kidney Injury: An International Multi-Centre Observational Cohort Study, Byom W. L. Tan, Bryce W. Q. Tan, Kee Yuan Ngiam, The Consortium For Clinical Characterization Of Covid-19 By Ehr (4ce)

Markey Cancer Center Faculty Publications

Background While acute kidney injury (AKI) is a common complication in COVID-19, data on post-AKI kidney function recovery and the clinical factors associated with poor kidney function recovery is lacking.

Methods A retrospective multi-centre observational cohort study comprising 12,891 hospitalized patients aged 18 years or older with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction from 1 January 2020 to 10 September 2020, and with at least one serum creatinine value 1–365 days prior to admission. Mortality and serum creatinine values were obtained up to 10 September 2021.

Findings Advanced age (HR 2.77, 95%CI 2.53–3.04, p < 0.0001), severe COVID-19 (HR 2.91, 95%CI 2.03–4.17, p < 0.0001), severe AKI (KDIGO stage 3: HR 4.22, 95%CI 3.55–5.00, p < 0.0001), and ischemic heart disease (HR 1.26, 95%CI 1.14–1.39, p < 0.0001) were associated with worse mortality outcomes. AKI severity (KDIGO stage 3: HR 0.41, 95%CI 0.37–0.46, p < 0.0001) was associated with worse kidney function recovery, whereas remdesivir use (HR 1.34, 95%CI 1.17–1.54, p < 0.0001) was associated with better kidney function recovery. In a subset of patients without chronic kidney disease, advanced age (HR 1.38, 95%CI 1.20–1.58, p < 0.0001), male sex (HR 1.67, 95%CI 1.45–1.93, p < 0.0001), severe AKI (KDIGO stage 3: HR 11.68, 95%CI 9.80–13.91, p < 0.0001), and hypertension (HR 1.22, 95%CI 1.10–1.36, p = 0.0002) were associated with post-AKI kidney function impairment. Furthermore, patients with COVID-19-associated AKI had significant and persistent elevations of baseline serum creatinine 125% or more at 180 days (RR 1.49, 95%CI 1.32–1.67) and 365 days (RR 1.54, 95%CI 1.21–1.96) compared to COVID-19 patients with no AKI.

Interpretation COVID-19-associated …

Polycomb Deficiency Drives A Foxp2-High Aggressive State Targetable By Epigenetic Inhibitors, Fan Chen, Aria Byrd, Jinpeng Liu, Robert M. Flight, Tanner Ducote, Kassandra J. Naughton, Xiulong Song, Abigail R Edgin, Alexsandr Lukyanchuk, Danielle T. Dixon, Christian M. Gosser, Dave-Preston Esoe, Rani Jayswal, Stuart H. Orkin, Hunter N. B. Moseley, Chi Wang, Christine Fillmore Brainson

Markey Cancer Center Faculty Publications

Inhibitors of the Polycomb Repressive Complex 2 (PRC2) histone methyltransferase EZH2 are approved for certain cancers, but realizing their wider utility relies upon understanding PRC2 biology in each cancer system. Using a genetic model to delete Ezh2 in KRAS-driven lung adenocarcinomas, we observed that Ezh2 haplo-insufficient tumors were less lethal and lower grade than Ezh2 fully-insufficient tumors, which were poorly differentiated and metastatic. Using three-dimensional cultures and in vivo experiments, we determined that EZH2-deficient tumors were vulnerable to H3K27 demethylase or BET inhibitors. PRC2 loss/inhibition led to de-repression of FOXP2, a transcription factor that promotes migration and stemness, and FOXP2 …

Suppressing Hepatic Ugt1a1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways And Lipid Species And Improves Fatty Liver Disease, Evelyn A. Bates, Zachary A. Kipp, Genesee J. Martinez, Olufunto O. Badmus, Mangala M. Soundarapandian, Donald Foster, Mei Xu, Justin F. Creeden, Jennifer R. Greer, Andrew J. Morris, David E. Stec, Terry D. Hinds Jr.

Markey Cancer Center Faculty Publications

Several population studies have observed lower serum bilirubin levels in patients with non-alcoholic fatty liver disease (NAFLD). Yet, treatments to target this metabolic phenotype have not been explored. Therefore, we designed an N-Acetylgalactosamine (GalNAc) labeled RNAi to target the enzyme that clears bilirubin from the blood, the UGT1A1 glucuronyl enzyme (GNUR). In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks to induce NAFLD and were treated subcutaneously with GNUR or sham (CTRL) once weekly for six weeks while continuing the HFD. The results show that GNUR treatments significantly raised plasma bilirubin levels and …

Impact Of The Appalachian Career Training In Oncology (Action) Program On Undergraduate Participants, Carol Hanley, Lauren Hudson, Chris Prichard, Nathan L. Vanderford

Markey Cancer Center Faculty Publications

Kentucky ranks first in the nation in cancer incidence and mortality. The Appalachian region of the state experiences the highest cancer disparities due to inequities in many social determinants of health. As a strategy for addressing cancer and education disparities in the region, the Appalachian Career Training in Oncology (ACTION) Program at the University of Kentucky Markey Cancer Center engaged 16 Appalachian-native undergraduate student participants annually in cancer-related activities. Students were recruited on an annual basis for the 2-year ACTION program. Entry, mid-point, and exit surveys were administered to participants. Classical test theory and exploratory factor analysis were used to …

A Qualitative Study Of Participant Perceptions Of A Cancer Research Education Program, Olivia Allran, Nathan L. Vanderford

Markey Cancer Center Faculty Publications

Kentucky ranks first in the nation in cancer incidence and mortality rates, with the greatest burden of disease being in the Appalachian region. The cancer disparities in the Appalachian region of the state are tied to high poverty rates, low education attainment, low health care access, and high rates of poor health behaviors, such as tobacco use. The University of Kentucky (UK) Markey Cancer Center (MCC) developed the Appalachian Career Training in Oncology (ACTION) program to address the cancer and education disparities in the region. ACTION is a two-year program that focuses on cancer education and training for high school …

The Link Between Intracellular Calcium Signaling And Exosomal Pd-L1 In Cancer Progression And Immunotherapy, Rakibul Alam, Mizanur Rahman, Zhiguo Li

Markey Cancer Center Faculty Publications

Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release exo- somes to reprogram the factors associated with the tumor microenvironment (TME) causing tu- mor metastasis and immune escape. Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1 (PD-L1) that binds with re- ceptor program death protein 1 (PD-1) and promote tumor progression by escaping immune response. Currently, some FDA-approved monoclonal antibodies are clinically used for cancer treatment by blocking PD-1/PD-L1 interaction. Despite notable treatment outcomes, some pa- tients show …

Xylazine Suppresses Fentanyl Consumption During Self-Administration And Induces A Unique Sex-Specific Withdrawal Syndrome That Is Not Altered By Naloxone In Rats, Shailesh N. Khatri, Safiyah M. Sadek, Percell T. Kendrick, Emma O. Bondy, Mei Hong, Sally Pauss, Dan Luo, Thomas E. Prisinzano, Kelly E. Dunn, Julie A. Marusich, Joshua S. Beckmann, Terry D. Hinds Jr., Cassandra D. Gipson

Markey Cancer Center Faculty Publications

Prescription and illicit opioid use are a public health crisis, with the landscape shifting to fentanyl use. Since fentanyl is 100-fold more potent than morphine, its use is associated with a higher risk of fatal overdose that can be remediated through naloxone (Narcan) administration. However, recent reports indicate that xylazine, an anesthetic, is increasingly detected in accidental fentanyl overdose deaths. Anecdotal reports suggest that xylazine may prolong the fentanyl “high,” alter the onset of fentanyl withdrawal, and increase resistance to naloxone-induced reversal of overdose. To date, no preclinical studies have evaluated the impacts of xylazine on fentanyl self-administration (SA; 2.5 …