Digital Commons Network^™

Probing The Metabolic Phenotype Of Breast Cancer Cells By Multiple Tracer Stable Isotope Resolved Metabolomics, Andrew N. Lane, Julie Tan, Yali Wang, Jun Yan, Richard M. Higashi, Teresa W. -M. Fan

Center for Environmental and Systems Biochemistry Faculty Publications

Breast cancers vary by their origin and specific set of genetic lesions, which gives rise to distinct phenotypes and differential response to targeted and untargeted chemotherapies. To explore the functional differences of different breast cell types, we performed Stable Isotope Resolved Metabolomics (SIRM) studies of one primary breast (HMEC) and three breast cancer cells (MCF-7, MDAMB-231, and ZR75-1) having distinct genotypes and growth characteristics, using ¹³C₆-glucose, ¹³C-1+2-glucose, ¹³C₅,¹⁵N₂-Gln, ¹³C₃-glycerol, and ¹³C₈-octanoate as tracers. These tracers were designed to probe the central energy producing …

Efficacy And Safety Of Abatacept, A T-Cell Modulator, In A Randomised, Double-Blind, Placebo-Controlled, Phase Iii Study In Psoriatic Arthritis., Philip Mease, Alice B Gottlieb, Désirée Van Der Heijde, Oliver Fitzgerald, Alyssa Johnsen, Marleen Nys, Subhashis Banerjee, Dafna D Gladman

Articles, Abstracts, and Reports

OBJECTIVES: To assess the efficacy and safety of abatacept, a selective T-cell costimulation modulator, in a phase III study in psoriatic arthritis (PsA).

METHODS: This study randomised patients (1:1) with active PsA (~60% with prior exposure to a tumour necrosis factor inhibitor) to blinded weekly subcutaneous abatacept 125 mg (n=213) or placebo (n=211) for 24 weeks, followed by open-label subcutaneous abatacept. Patients without ≥20% improvement in joint counts at week 16 were switched to open-label abatacept. The primary end point was the proportion of patients with ≥20% improvement in the American College of Rheumatology (ACR20) criteria at week 24.

RESULTS: …

Characterization Of Health Care Utilization In Patients Receiving Implantable Cardioverter-Defibrillator Therapies: An Analysis Of The Managed Ventricular Pacing Trial., John Rickard, David J. Whellan, Lou Sherfesee, Brett J. Peterson, Tara Nahey, Anthony S. Tang, Kenneth A. Ellenbogen, Alan Cheng

Division of Cardiology Faculty Papers

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are effective in terminating lethal arrhythmias, but little is known about the degree of health care utilization (HCU) after ICD therapies.

OBJECTIVE: Using data from the managed ventricular pacing trial, we sought to identify the incidence and types of HCU in ICD patients after receiving ICD therapy (shocks or antitachycardia pacing [ATP]).

METHODS: We analyzed HCU events (ventricular tachyarrhythmia [VTA]-related, heart failure-related, ICD implant procedure-related, ICD system-related, or other) and their association with ICD therapies (shocked ventricular tachycardia episode, ATP-terminated ventricular tachycardia episode, and inappropriately shocked episode).

RESULTS: A total of 1879 HCUs occurred in 695 …

Adverse Events In Veterans Affairs Inpatient Psychiatric Units: Staff Perspectives On Contributing And Protective Factors., Gala True, Rosemary Frasso, Sara W. Cullen, Richard C. Hermann, Steven C. Marcus

College of Population Health Faculty Papers

OBJECTIVES: This study sought to identify risk factors and protective factors in hospital-based mental health settings in the Veterans Health Administration (VHA), with the goal of informing interventions to improve care of persons with serious mental illness.

METHODS: Twenty key informants from a stratified sample of 7 VHA inpatient psychiatric units were interviewed to gain their insights on causes of patient safety events and the factors that constrain or facilitate patient safety efforts.

RESULTS: Respondents identified threats to patient safety at the system-, provider-, and patient-levels. Protective factors that, when in place, made patient safety events less likely to occur …

Rare Coding Variants In Plcg2, Abi3, And Trem2 Implicate Microglial-Mediated Innate Immunity In Alzheimer's Disease., Rebecca Sims, Sven J Van Der Lee, Adam C Naj, Céline Bellenguez, Nandini Badarinarayan, Johanna Jakobsdottir, Brian W Kunkle, Anne Boland, Rachel Raybould, Joshua C Bis, Eden R Martin, Benjamin Grenier-Boley, Stefanie Heilmann-Heimbach, Vincent Chouraki, Amanda B Kuzma, Kristel Sleegers, Maria Vronskaya, Agustin Ruiz, Robert R Graham, Robert Olaso, Per Hoffmann, Megan L Grove, Badri N Vardarajan, Mikko Hiltunen, Markus M Nöthen, Charles C White, Kara L Hamilton-Nelson, Jacques Epelbaum, Wolfgang Maier, Seung-Hoan Choi, Gary W Beecham, Cécile Dulary, Stefan Herms, Albert V Smith, Cory C Funk, Céline Derbois, Andreas J Forstner, Shahzad Ahmad, Hongdong Li, Delphine Bacq, Denise Harold, Claudia L Satizabal, Otto Valladares, Alessio Squassina, Rhodri Thomas, Jennifer A Brody, Liming Qu, Pascual Sánchez-Juan, Taniesha Morgan, Frank J Wolters, Yi Zhao, Florentino Sanchez Garcia, Nicola Denning, Myriam Fornage, John Malamon, Maria Candida Deniz Naranjo, Elisa Majounie, Thomas H Mosley, Beth Dombroski, David Wallon, Michelle K Lupton, Josée Dupuis, Patrice Whitehead, Laura Fratiglioni, Christopher Medway, Xueqiu Jian, Shubhabrata Mukherjee, Lina Keller, Kristelle Brown, Honghuang Lin, Laura B Cantwell, Francesco Panza, Bernadette Mcguinness, Sonia Moreno-Grau, Jeremy D Burgess, Vincenzo Solfrizzi, Petra Proitsi, Hieab H Adams, Mariet Allen, Davide Seripa, Pau Pastor, L Adrienne Cupples, Nathan D Price, Didier Hannequin, Ana Frank-García, Daniel Levy, Paramita Chakrabarty, Paolo Caffarra, Ina Giegling, Alexa S Beiser, Vilmantas Giedraitis, Harald Hampel, Melissa E Garcia, Xue Wang, Lars Lannfelt, Patrizia Mecocci, Gudny Eiriksdottir, Paul K Crane, Florence Pasquier, Virginia Boccardi, Isabel Henández, Robert C Barber, Martin Scherer, Lluis Tarraga, Perrie M Adams, Markus Leber, Yuning Chen, Marilyn S Albert, Steffi Riedel-Heller, Valur Emilsson, Duane Beekly, Anne Braae, Reinhold Schmidt, Deborah Blacker, Carlo Masullo, Helena Schmidt, Rachelle S Doody, Gianfranco Spalletta, W T Longstreth, Thomas J Fairchild, Paola Bossù, Oscar L Lopez, Matthew P Frosch, Eleonora Sacchinelli, Bernardino Ghetti, Qiong Yang, Ryan M Huebinger, Frank Jessen, Shuo Li, M Ilyas Kamboh, John Morris, Oscar Sotolongo-Grau, Mindy J Katz, Chris Corcoran, Melanie Dunstan, Amy Braddel, Charlene Thomas, Alun Meggy, Rachel Marshall, Amy Gerrish, Jade Chapman, Miquel Aguilar, Sarah Taylor, Matt Hill, Mònica Díez Fairén, Angela Hodges, Bruno Vellas, Hilkka Soininen, Iwona Kloszewska, Makrina Daniilidou, James Uphill, Yogen Patel, Joseph T Hughes, Jenny Lord, James Turton, Annette M Hartmann, Roberta Cecchetti, Chiara Fenoglio, Maria Serpente, Marina Arcaro, Carlo Caltagirone, Maria Donata Orfei, Antonio Ciaramella, Sabrina Pichler, Manuel Mayhaus, Wei Gu, Alberto Lleó, Juan Fortea, Rafael Blesa, Imelda S Barber, Keeley Brookes, Chiara Cupidi, Raffaele Giovanni Maletta, David Carrell, Sandro Sorbi, Susanne Moebus, Maria Urbano, Alberto Pilotto, Johannes Kornhuber, Paolo Bosco, Stephen Todd, David Craig, Janet Johnston, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Nick C Fox, John Hardy, Roger L Albin, Liana G Apostolova, Steven E Arnold, Sanjay Asthana, Craig S Atwood, Clinton T Baldwin, Lisa L Barnes, Sandra Barral, Thomas G Beach, James T Becker, Eileen H Bigio, Thomas D Bird, Bradley F Boeve, James D Bowen, Adam Boxer, James R Burke, Jeffrey M Burns, Joseph D Buxbaum, Nigel J Cairns, Chuanhai Cao, Chris S Carlson, Cynthia M Carlsson, Regina M Carney, Minerva M Carrasquillo, Steven L Carroll, Carolina Ceballos Diaz, Helena C Chui, David G Clark, David H Cribbs, Elizabeth A Crocco, Charles Decarli, Malcolm Dick, Ranjan Duara, Denis A Evans, Kelley M Faber, Kenneth B Fallon, David W Fardo, Martin R Farlow, Steven Ferris, Tatiana M Foroud, Douglas R Galasko, Marla Gearing, Daniel H Geschwind, John R Gilbert, Neill R Graff-Radford, Robert C Green, John H Growdon, Ronald L Hamilton, Lindy E Harrell, Lawrence S Honig, Matthew J Huentelman, Christine M Hulette, Bradley T Hyman, Gail P Jarvik, Erin Abner, Lee-Way Jin, Gyungah Jun, Anna Karydas, Jeffrey A Kaye, Ronald Kim, Neil W Kowall, Joel H Kramer, Frank M Laferla, James J Lah, James B Leverenz, Allan I Levey, Ge Li, Andrew P Lieberman, Kathryn L Lunetta, Constantine G Lyketsos, Daniel C Marson, Frank Martiniuk, Deborah C Mash, Eliezer Masliah, Wayne C Mccormick, Susan M Mccurry, Andrew N Mcdavid, Ann C Mckee, Marsel Mesulam, Bruce L Miller, Carol A Miller, Joshua W Miller, John C Morris, Jill R Murrell, Amanda J Myers, Sid O'Bryant, John M Olichney, Vernon S Pankratz, Joseph E Parisi, Henry L Paulson, William Perry, Elaine Peskind, Aimee Pierce, Wayne W Poon, Huntington Potter, Joseph F Quinn, Ashok Raj, Murray Raskind, Barry Reisberg, Christiane Reitz, John M Ringman, Erik D Roberson, Ekaterina Rogaeva, Howard J Rosen, Roger N Rosenberg, Mark A Sager, Andrew J Saykin, Julie A Schneider, Lon S Schneider, William W Seeley, Amanda G Smith, Joshua A Sonnen, Salvatore Spina, Robert A Stern, Russell H Swerdlow, Rudolph E Tanzi, Tricia A Thornton-Wells, John Q Trojanowski, Juan C Troncoso, Vivianna M Van Deerlin, Linda J Van Eldik, Harry V Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A Welsh-Bohmer, Kirk C Wilhelmsen, Jennifer Williamson, Thomas S Wingo, Randall L Woltjer, Clinton B Wright, Chang-En Yu, Lei Yu, Fabienne Garzia, Feroze Golamaully, Gislain Septier, Sebastien Engelborghs, Rik Vandenberghe, Peter P De Deyn, Carmen Muñoz Fernadez, Yoland Aladro Benito, Hakan Thonberg, Charlotte Forsell, Lena Lilius, Anne Kinhult-Stählbom, Lena Kilander, Rosemarie Brundin, Letizia Concari, Seppo Helisalmi, Anne Maria Koivisto, Annakaisa Haapasalo, Vincent Dermecourt, Nathalie Fievet, Olivier Hanon, Carole Dufouil, Alexis Brice, Karen Ritchie, Bruno Dubois, Jayanadra J Himali, C Dirk Keene, Joann Tschanz, Annette L Fitzpatrick, Walter A Kukull, Maria Norton, Thor Aspelund, Eric B Larson, Ron Munger, Jerome I Rotter, Richard B Lipton, María J Bullido, Albert Hofman, Thomas J Montine, Eliecer Coto, Eric Boerwinkle, Ronald C Petersen, Victoria Alvarez, Fernando Rivadeneira, Eric M Reiman, Maura Gallo, Christopher J O'Donnell, Joan S Reisch, Amalia Cecilia Bruni, Donald R Royall, Martin Dichgans, Mary Sano, Daniela Galimberti, Peter St George-Hyslop, Elio Scarpini, Debby W Tsuang, Michelangelo Mancuso, Ubaldo Bonuccelli, Ashley R Winslow, Antonio Daniele, Chuang-Kuo Wu, Oliver Peters, Benedetta Nacmias, Matthias Riemenschneider, Reinhard Heun, Carol Brayne, David C Rubinsztein, Jose Bras, Rita Guerreiro, Ammar Al-Chalabi, Christopher E Shaw, John Collinge, David Mann, Magda Tsolaki, Jordi Clarimón, Rebecca Sussams, Simon Lovestone, Michael C O'Donovan, Michael J Owen, Timothy W Behrens, Simon Mead, Alison M Goate, Andre G Uitterlinden, Clive Holmes, Carlos Cruchaga, Martin Ingelsson, David A Bennett, John Powell, Todd E Golde, Caroline Graff, Philip L De Jager, Kevin Morgan, Nilufer Ertekin-Taner, Onofre Combarros, Bruce M Psaty, Peter Passmore, Steven G Younkin, Claudine Berr, Vilmundur Gudnason, Dan Rujescu, Dennis W Dickson, Jean-François Dartigues, Anita L Destefano, Sara Ortega-Cubero, Hakon Hakonarson, Dominique Campion, Merce Boada, John Keoni Kauwe, Lindsay A Farrer, Christine Van Broeckhoven, M Arfan Ikram, Lesley Jones, Jonathan L Haines, Christophe Tzourio, Lenore J Launer, Valentina Escott-Price, Richard Mayeux, Jean-François Deleuze, Najaf Amin, Peter A Holmans, Margaret A Pericak-Vance, Philippe Amouyel, Cornelia M Van Duijn, Alfredo Ramirez, Li-San Wang, Jean-Charles Lambert, Sudha Seshadri, Julie Williams, Gerard D Schellenberg

Articles, Abstracts, and Reports

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10

The Rna-Binding Protein Hur Contributes To Neuroinflammation By Promoting C-C Chemokine Receptor 6 (Ccr6) Expression On Th17 Cells., Jing Chen, Jennifer L. Martindale, Carole Cramer, Myriam Gorospe, Ulus Atasoy, Paul D. Drew, Shiguang Yu

Department of Neurology Faculty Papers

In both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), the C-C chemokine receptor 6 (CCR6) is critical for pathogenic T helper 17 (Th17) cell migration to the central nervous system (CNS). Whereas many cytokines and their receptors are potently regulated via post-transcriptional mechanisms in response to various stimuli, how CCR6 expression is post-transcriptionally regulated in Th17 cells is unknown. Here, using RNA-binding protein HuR conditional knock-out (KO) and wild-type (WT) mice, we present evidence that HuR post-transcriptionally regulates CCR6 expression by binding to and stabilizing Ccr6 mRNA and by promoting CCR6 translation. We also found that HuR down-regulates several microRNA …

Sources Of Medical Student Stress, Krishna Subhash Vyas, Terry D. Stratton, Neelkamal S. Soares

Behavioral Science Faculty Publications

Background: Key elements in the clinical practice of prevention, health and wellness are best cultivated in medical professionals during undergraduate medical training. This study explores students' self-assessed stress relative to gender, academic expectations, and level of medical training to guide development of targeted wellness interventions. Methods: In early 2012, undergraduate (M1-M4) students in four Southeastern U.S. allopathic medical schools were surveyed about health-related attitudes and behaviors. Results: A total of 575 students returned completed questionnaires. Students in the preclinical years (M1-M2), especially females, reported significantly higher stress levels. Academic expectations and satisfaction were also significantly implicated. Discussion: These findings highlight …

N-Acetylcysteine Reduces Cocaine-Cue Attentional Bias And Differentially Alters Cocaine Self-Administration Based On Dosing Order, B. Levi Bolin, Joseph L. Alcorn Iii, Joshua A. Lile, Craig R. Rush, Abner O. Rayapati, Lon R. Hays, William W. Stoops

Behavioral Science Faculty Publications

Background—Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans.

Methods—The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400 mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60 mg). Fourteen individuals …

Healthcare Contact And Treatment Uptake Following Hepatitis C Virus Screening And Counseling Among Rural Appalachian People Who Use Drugs, Dustin B. Stephens, April M. Young, Jennifer R. Havens

Behavioral Science Faculty Publications

Background—Hepatitis C virus (HCV) remains a major contributor to morbidity and mortality worldwide. Since 2009, Kentucky has led the United States in cases of acute HCV, driven largely by injection drug use in rural areas. Improved treatment regimens hold promise of mitigating the impact and transmission of HCV, but numerous barriers obstruct people who inject drugs (PWID) from receiving care, particularly in medically underserved settings.

Methods—503 rural people who use drugs were recruited using respondent-driven sampling and received HCV screening and post-test counseling. Presence of HCV antibodies was assessed using enzyme immunoassay of dried blood samples. Sociodemographic and …

Multimodality Therapy Improves Survival In Intramedullary Spinal Cord Metastasis Of Lung Primary, Hayder Saeed, Reema Patel, Jigisha Thakkar, Lames Hamoodi, Li Chen, John L. Villano

Internal Medicine Faculty Publications

Background: Most metastatic spinal cord lesions are located either in the intradural, extramedullary, or in the epidural compartments. Intramedullary spinal cord metastasis (ISCM) is a rare central nervous system spread of cancer. The aim of this report was to evaluate ISCM in the published literature.

Methods: A literature review of PubMed from 1960 to 2016 was undertaken for the publications having demographic, clinical, histological, and outcome data.

Results: A total of 59 relevant papers were identified, showing 128 cases of intramedullary metastasis from lung cancer. The incidence of lung cancer as the primary malignancy with intramedullary metastasis was 56%. The …

A Longitudinal Study Of The Reciprocal Relationship Between Ever Smoking And Urgency In Early Adolescence, Jessica L. Burris, Elizabeth N. Riley, Gabriella E. Puleo, Gregory T. Smith

Psychology Faculty Publications

Background—Among early adolescents in the United States (U.S.), the prevalence of cigarette smoking is at its lowest level in recent decades. Nonetheless, given the risks of smoking in early development, it remains critically important to study both risk factors for smoking and risks from smoking. This longitudinal study with U.S. early adolescents examines smoking initiation and tests a model of reciprocal prediction between ever smoking and the personality trait of urgency (i.e., mood-based impulsivity), a trait that increases risk for multiple forms of dysfunction.

Methods—Participants (n=1906; 90% 10–11 years old, 50% female, 39% racial minorities at …

Cross-Lagged Relations Between Motives And Substance Use: Can Use Strengthen Your Motivation Over Time?, Christine A. Lee, Karen J Derefinko, Heather A. Davis, Richard S. Milich, Donald R. Lynam

Psychology Faculty Publications

Motives for substance use have garnered considerable attention due to the strong predictive utility of this construct, both in terms of use and problems associated with use. The current study examined the cross-lagged relations between alcohol use and motives, and marijuana use and motives over three yearly assessment periods in a large sample (N = 526, 48% male) of college students. The relations between substance use and motives were assessed at each time point, allowing for the examination of these inter-relations over time. Results indicated different trends based on the type of substance. For alcohol use, cross-lagged trends were …

Thiamine Deficiency And Neurodegeneration: The Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, And Autophagy, Dexiang Liu, Zunji Ke, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Thiamine (vitamin B1) is an essential nutrient and indispensable for normal growth and development of the organism due to its multilateral participation in key biochemical and physiological processes. Humans must obtain thiamine from their diet since it is synthesized only in bacteria, fungi, and plants. Thiamine deficiency (TD) can result from inadequate intake, increased requirement, excessive deletion, and chronic alcohol consumption. TD affects multiple organ systems, including the cardiovascular, muscular, gastrointestinal, and central and peripheral nervous systems. In the brain, TD causes a cascade of events including mild impairment of oxidative metabolism, neuroinflammation, and neurodegeneration, which are commonly observed in …

Tailoring A Nicu-Based Tobacco Treatment Program For Mothers Who Are Dependent On Opioids, Amanda Fallin-Bennett, Kristin Ashford

Nursing Faculty Publications

Objective—To collect formative information to design a tailored tobacco treatment intervention for women with newborns treated or evaluated for neonatal abstinence syndrome and to explore current tobacco use behaviors and facilitators and barriers to smoking cessation.

Design—Qualitative descriptive study.

Setting—An academic medical center in the southern United States.

Participants—Mothers of newborns who were treated or evaluated for neonatal abstinence syndrome at birth within the preceding three months. Women were recruited who were older than 18 and reported opioid dependence and smoking during pregnancy.

Methods—Participants took part in semi-structured individual interviews that lasted approximately one hour. …

Incidence, Risks, And Types Of Infections In Pediatric Long-Term Care Facilities, Lisa Saiman, Philip Maykowski, Meghan Murray, Bevin Cohen, Natalie Neu, Gordon R. Hutcheon, Elaine Larson

NYMC Faculty Publications

Importance: The population of infants, children, and adolescents cared for at pediatric long-term care facilities is increasing in complexity and size and thus consumes substantial health care resources. Infections are a significant cause of morbidity and mortality in this population, but few recent data describe their incidence and effects.

Objectives: To describe the types of infections diagnosed in residents of pediatric long-term care facilities, calculate infection rates, and identify risk factors for respiratory tract infections (RTIs).

Design, Setting, and Participants: This prospective cohort study, which was part of a larger trial called Keep It Clean for Kids, was conducted from …

Effects Of Intensive Bp Control In Ckd, Alfred K. Cheung, Mahboob Rahman, David M. Reboussin, Timothy E. Craven, Tom Greene, Paul L. Kimmel, William C. Cushman, Amret T. Hawfield, Karen C. Johnson, Cora E. Lewis, Suzanne Oparil, Michael V. Rocco, Kaycee M. Sink, Paul K. Whelton, Jackson T. Wright, Jan Basile, Srinivasan Beddhu, Udayan Bhatt, Tara I. Chang, Glenn M. Chertow, Michel Chonchol, Barry I. Freedman, William Haley, Joachim H. Ix, Lois A. Katz, Anthony A. Killeen, Vasilios Papademetriou, Ana C. Ricardo, Karen Servilla, Barry Wall, Dawn Wolfgram, Jerry Yee

Nephrology Articles

The appropriate target for BP in patients with CKD and hypertension remains uncertain. We report prespecified subgroup analyses of outcomes in participants with baseline CKD in the Systolic Blood Pressure Intervention Trial. We randomly assigned participants to a systolic BP target of(intensive group;

Extended-Spectrum Antiprotozoal Bumped Kinase Inhibitors: A Review, Wesley C. Van Voorhis, J. Stone Doggett, Marilyn Parsons, Matthew A. Hulverson, Ryan Choi, Samuel L. M. Arnold, Michael W. Riggs, Andrew Hemphill, Daniel K. Howe, Robert H. Mealey, Audrey O. T. Lau, Ethan A. Merritt, Dustin J. Maly, Erkang Fan, Kayode K. Ojo

Veterinary Science Faculty Publications

Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites’ survival and proliferation. In this review, we review efficacy against the kinase target, the parasite growth in vitro, and in animal infection models, as well …

Peer Review Certifies Quality And Innovation In Clinical Pharmacology & Therapeutics., Scott A. Waldman, Andre M. Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Clinical Pharmacology & Therapeutics (CPT) is an established voice of the discipline, a trusted source of new knowledge showcasing discovery, translation, and application of novel therapeutic paradigms to advance the management of patients and populations. Identifying, evaluating, prioritizing, and disseminating the best science along the discovery-development-regulatory-utilization continuum are responsibilities shared through peer review. To enhance the uniformity of this essential component of quality assurance and innovation, and maximize the value of the journal and its contents to authors, reviewers, and the readership, we review key concepts concerning peer review as it specifically relates to CPT.

Ibrutinib Unmasks Critical Role Of Bruton Tyrosine Kinase In Primary Cns Lymphoma., Christian Grommes, Alessandro Pastore, Nicolaos Palaskas, Sarah S. Tang, Carl Campos, Derrek Schartz, Paolo Codega, Donna Nichol, Owen Clark, Wan-Ying Hsieh, Dan Rohle, Marc Rosenblum, Agnes Viale, Viviane S. Tabar, Cameron W. Brennan, Igor T. Gavrilovic, Thomas J. Kaley, Craig P. Nolan, Antonio Omuro, Elena Pentsova, Alissa A. Thomas, Elina Tsyvkin, Ariela Noy, M. Lia Palomba, Paul Hamlin, Craig S. Sauter, Craig H. Moskowitz, Julia Wolfe, Ahmet Dogan, Minhee Won, Jon Glass, Scott Peak, Enrico C. Lallana, Vaios Hatzoglou, Anne S. Reiner, Philip H. Gutin, Jason T. Huse, Katherine S. Panageas, Thomas G. Graeber, Nikolaus Schultz, Lisa M. Deangelis, Ingo K. Mellinghoff

Department of Neurology Faculty Papers

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated …

Hyperfiltration-Associated Biomechanical Forces In Glomerular Injury And Response: Potential Role For Eicosanoids., Mukut Sharma, Ram Sharma, Ellen T. Mccarthy, Virginia J. Savin, Tarak Srivastava

Manuscripts, Articles, Book Chapters and Other Papers

Hyperfiltration is a well-known risk factor in progressive loss of renal function in chronic kidney disease (CKD) secondary to various diseases. A reduced number of functional nephrons due to congenital or acquired cause(s) results in hyperfiltration in the remnant kidney. Hyperfiltration-associated increase in biomechanical forces, namely pressure-induced tensile stress and fluid flow-induced shear stress (FFSS) determine cellular injury and response. We believe the current treatment of CKD yields limited success because it largely attenuates pressure-induced tensile stress changes but not the effect of FFSS on podocytes. Studies on glomerular podocytes, tubular epithelial cells and bone osteocytes provide evidence for a …

Pathway Of Protection: Ethnic Identity, Self-Esteem, And Substance Use Among Multiracial Youth, Sycarah Fisher, Tamika C. B. Zapolski, Chelsea Sheehan, Jessica Barnes-Najor

Educational, School, and Counseling Psychology Faculty Publications

Fifty percent of adolescents have tried an illicit drug and 70% have tried alcohol by the end of high school, with even higher rates among multiracial youth. Ethnic identity is a protective factor against substance use for minority groups. However, little is known about the mechanisms that facilitate its protective effects, and even less is known about this relationship for multiracial youth. The purpose of the present study was to examine the protective effect of ethnic identity on substance use and to determine whether this relationship operated indirectly through self-esteem, a strong predictor of substance use for among adolescent populations. …

Intracranial Eeg Fluctuates Over Months After Implanting Electrodes In Human Brain., Hoameng Ung, Steven N. Baldassano, Hank Bink, Abba M. Krieger, Shawniqua Williams, Flavia Vitale, Chengyuan Wu, Dean Freestone, Ewan Nurse, Kent Leyde, Kathryn A. Davis, Mark Cook, Brian Litt

Department of Neurosurgery Faculty Papers

OBJECTIVE: Implanting subdural and penetrating electrodes in the brain causes acute trauma and inflammation that affect intracranial electroencephalographic (iEEG) recordings. This behavior and its potential impact on clinical decision-making and algorithms for implanted devices have not been assessed in detail. In this study we aim to characterize the temporal and spatial variability of continuous, prolonged human iEEG recordings.

APPROACH: Intracranial electroencephalography from 15 patients with drug-refractory epilepsy, each implanted with 16 subdural electrodes and continuously monitored for an average of 18 months, was included in this study. Time and spectral domain features were computed each day for each channel for …

Redefining The Endophenotype Concept To Accommodate Transdiagnostic Vulnerabilities And Etiological Complexity, Theodore P. Beauchaine, John N. Constantino

Open Access Publications

In psychopathology research, endophenotypes are a subset of biomarkers that indicate genetic vulnerability independent of clinical state. To date, an explicit expectation is that endophenotypes be specific to single disorders. We evaluate this expectation considering recent advances in psychiatric genetics, recognition that transdiagnostic vulnerability traits are often more useful than clinical diagnoses in psychiatric genetics, and appreciation for etiological complexity across genetic, neural, hormonal and environmental levels of analysis. We suggest that the disorder-specificity requirement of endophenotypes be relaxed, that neural functions are preferable to behaviors as starting points in searches for endophenotypes, and that future research should focus on …

The Role Of Efferent Reduction Of Cochlear Compression In The Detection Of Tones In Noise, Shaum Bhagat, Anusha Yellamsetty

Faculty Publications

Stimulation of medial olivocochlear (MOC) efferent neurons reduces basilar membrane (BM) sensitivity and increases the slope of BM input-output (I/O) functions in animal models. Decreased compression of I/O functions associated with activation of MOC efferent neurons may assist in extending the neural response to the tone above that of noise, leading to an improvement in masked thresholds. To evaluate this hypothesis, the distortion-product otoacoustic emission (DPOAE) I/O function, a proxy measure of BM compression, was examined in conditions with presentation of contralateral noise. DPOAE I/O functions were measured at f2 frequencies of 1000 and 2000 Hz in 16 normal-hearing adults. …

Other Tobacco Product Use Among Sexual Minority Young Adult Bar Patrons, Amanda Fallin-Bennett, Nadra E. Lisha, Pamela M. Ling

Nursing Faculty Publications

Introduction—Lesbian, gay, and bisexual (LGB) individuals smoke at rates 1.5–2 times higher than the general population, but less is known about LGB consumption of other tobacco products (OTPs) and gender differences. OTP use among young adult LGB bar patrons and the relationship among past quit attempts, intention to quit, and binge drinking with OTP use was examined.

Methods—A cross-sectional survey of young adults (aged 18–26) in bars/nightclubs in seven U.S. cities between 2012 and 2014 (N=8,010; 1,101 LGB participants) was analyzed in 2016. Logistic regressions examined current use of five OTPs (cigarillos, electronic cigarettes, hookah, chewing tobacco, and …

Advertising Exposure And Use Of E-Cigarettes Among Female Current And Former Tobacco Users Of Childbearing Age, Kristin Ashford, Emily Rayens, Amanda T. Wiggins, Mary Kay Rayens, Amanda Fallin-Bennett, Molly Malany Sayre

Nursing Faculty Publications

Objective: The study examined the relationship between exposure to e‐cigarette advertising and e‐cigarette use by pregnancy status, including use of flavored e‐cigarette products, among women of childbearing age.

Design: A cross‐sectional, correlational design was used.

Subjects: Female current or former tobacco users in Central and Eastern Kentucky, 18–45 years old (N = 194, 52% pregnant).

Measures: Demographics, pregnancy status, cigarette and e‐cigarette use, and exposure to e‐cigarette advertising.

Results: Younger age, white non‐Hispanic race, and greater exposure to e‐cigarette advertising were associated with a higher likelihood of ever using e‐cigarettes (p < .05 for each variable). Pregnancy was not associated with ever use (p = .11). Younger age was associated …

Amlexanox Enhances Premature Termination Codon Read-Through In Col7a1 And Expression Of Full Length Type Vii Collagen: Potential Therapy For Recessive Dystrophic Epidermolysis Bullosa., Velina S. Atanasova, Qiujie Jiang, Marco Prisco, Christina Gruber, Josefina Piñón Hofbauer, Mei Chen, Cristina Has, Leena Bruckner-Tuderman, John A. Mcgrath, Jouni Uitto, Andrew P. South

Department of Dermatology and Cutaneous Biology Faculty Papers

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare monogenic blistering disorder caused by the lack of functional type VII collagen, leading to skin fragility and subsequent trauma-induced separation of the epidermis from the underlying dermis. A total of 46% of patients with RDEB harbor at least one premature termination codon (PTC) mutation in COL7A1, and previous studies have shown that aminoglycosides are able to overcome RDEB PTC mutations by inducing "read-through" and incorporation of an amino acid at the PTC site. However, aminoglycoside toxicity will likely prevent widespread clinical application. Here the FDA-approved drug amlexanox was tested for its ability …

Increasing Use Of Allogeneic Hematopoietic Cell Transplantation In Patients Aged 70 Years And Older In The United States, Lori Muffly, Marcelo C. Pasquini, Michael Martens, Ruta Brazauskas, Xiaochun Zhu, Kehinde Adekola, Mahmoud Aljurf, Karen K. Ballen, Ashish Bajel, Frederic Baron, Minoo Battiwalla, Amer Beitinjaneh, Jean-Yves Cahn, Mathew Carabasi, Yi-Bin Chen, Saurabh Chhabra, Stefan Ciurea, Edward Copelan, Anita D'Souza, John Edwards, James Foran, Cesar O. Freytes, Henry C. Fung, Robert Peter Gale, Sergio Giralt, Shahrukh K. Hashmi, Gerhard C. Hildebrandt, Vincent Ho, Ann Jakubowski, Hillard Lazarus

Internal Medicine Faculty Publications

In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥ 70 years with hematologic malignancies across the United States. Adults ≥ 70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥ 70 years underwent HCT across 103 transplant centers. The number and proportion of allografts …

Pulmonary Tumor Embolism Secondary To Soft Tissue And Bone Sarcomas: A Case Report And Literature Review., Nicholas Latchana, Vincent C Daniel, Robert W Gould, Raphael E Pollock

Oncology Articles

BACKGROUND: Tumor embolisms (TE) are an underappreciated source of pulmonary embolisms in sarcoma. Most evidence in the literature is limited to case reports and none have described the presence of TE secondary to myxofibrosarcoma. We report the first case of myxofibrosarcoma TE and perform a review of the literature for TE secondary to bone and soft tissue sarcomas (STS).

CASE PRESENTATION: A 36-year-old female presented with debilitating pain of the right upper extremity secondary to a recurrent soft tissue sarcoma. She had distant metastasis to the lung. An MRI revealed a 25-cm shoulder mass involving the proximal arm muscles with …

Challenges And Considerations Related To Studying Dementia In Blacks/African Americans, Eseosa T. Ighodaro, Peter T. Nelson, Walter A. Kukull, Frederick A. Schmitt, Erin L. Abner, Allison M. Caban-Holt, Shoshana H. Bardach, Derrick C. Hord, Crystal M. Glover, Gregory A. Jicha, Linda J. Van Eldik, Alexander X. Byrd, Anita Fernander

Neuroscience Faculty Publications

Blacks/African Americans have been reported to be ~2–4 times more likely to develop clinical Alzheimer’s disease (AD) compared to Whites. Unfortunately, study design challenges (e.g., recruitment bias), racism, mistrust of healthcare providers and biomedical researchers, confounders related to socioeconomic status, and other sources of bias are often ignored when interpreting differences in human subjects categorized by race. Failure to account for these factors can lead to misinterpretation of results, reification of race as biology, discrimination, and missed or delayed diagnoses. Here we provide a selected historical background, discuss challenges, present opportunities, and suggest considerations for studying health outcomes among racial/ethnic …