Congratulations to Erin Taylor who successfully defended her Ph.D. dissertation entitled “Immune Modulation Response to Checkpoint Inhibition in Metastatic Melanoma” on December 1st. Erin was a student in the laboratory of Dr. Alan Tackett.
November publications
Toxicol Lett.
Drug Metab Dispos.
Identifying RNA Helicase Inhibitors Using Duplex Unwinding Assays.
Methods Mol Biol.
Urbaniak A, Piña-Oviedo S, Yuan Y, Huczyński A, Chambers TC.
European Journal of Pharmacology
Congratulations Dr. Koss!
Congratulations to Brian Koss who successfully defended his Ph.D. dissertation entitled “Epigenetic control of Cdkn2a.Arf protects tumor-infiltrating lymphocytes from exhaustion” on November 18th. Brian was a student in the laboratory of Dr. Alan Tackett and is now a post-doctoral fellow in the Center for Translational Pediatric Research as part of the Proteomics Technology Development Shared Resource under the direction of Dr. Rick Edmondson. A summary of his research is below.
T cell exhaustion in cancer is linked to poor clinical outcomes and evidence suggests T cell metabolic changes precede functional exhaustion. Direct competition between tumor-infiltrating lymphocytes (TILs) and cancer cells for metabolic resources often renders T cells dysfunctional. Here, we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TILs. Environmental stress produces epigenome remodeling events within tumor-infiltrating lymphocytes resulting from loss of the histone methyltransferase EZH2. Using a multi-omics approach, we have defined an ARF-mediated, p53-independent mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth. Our data suggest manipulation of T cell EZH2 within the context of cellular therapies may yield lymphocytes which are able to withstand harsh tumor metabolic environments and collateral pharmacologic insults.
Grad School Informational Webinar
Thinking about graduate school in the biomedical sciences?
Join us on Thursday November 9, 2020 for a free online event where our current students will share their experiences in the UAMS Graduate Program in Interdisciplinary Sciences (GPIBS) Biochemistry Track.
Programmatic details & the application process will also be discussed.
Mary “Allie” Schleiff Student Highlight
Allie is a GPIBS Ph.D. student in the Biochemistry and Molecular Biology track. She is a fourth year student in the laboratory of Dr. Grover Paul Miller.
She graduated from Henderson State University in 2017 with an Honors Bachelor of Science degree in Biochemistry and a minor in Biology, and she received a regulatory sciences certification from the UAMS Department of Environmental and Occupational Health in Spring 2020.
Research Interest Statement
My research focuses on a subset of structurally similar non-steroidal anti-inflammatory drugs (NSAIDs) known as diphenylamine NSAIDs. Diphenylamine NSAIDs are taken more than 15 million times each year in the United States, but roughly 15% of all people administered diphenylamine NSAIDs have a clinically observable case of hepatotoxicity from the compounds. Previous studies identified that diphenylamine hepatotoxicity is dependent upon metabolic bioactivation and varied depending upon minor structural modifications to the diphenylamine structural scaffold, but little work exists to identify the specific mechanisms by which diphenylamines cause hepatotoxicity. I used computational tools to identify potential diphenylamine metabolic bioactivations in seven marketed or withdrawn diphenylamine drugs and experimentally validate these computational results. Thus far, I have discovered that diphenylamine NSAIDs are preferentially bioactivated into quinone-species metabolites in variable amounts and by a variety of cytochrome P450 enzymes dependent upon minor structural modifications to the diphenylamine scaffold. I hope that results from this work can help direct future development of diphenylamine-containing drugs in the future and help identify and stratify patients at-risk following diphenylamine NSAID dosage to promote more personalized patient care.
Something Notable About Time as a Graduate Student
I am so grateful that I was trained as a fresh graduate student by Dr. Dusty Barnette. I was always dropping things, breaking things, and having the same information repeated to me over and over again and Dusty never batted an eye, scolded me, or made me feel like a burden. Specifically, I’m appreciative to him for always getting the tall things off the high shelves for me!
Career Goals
My dream job would be in a contract research organization conducting preclinical and clinical studies for pharmaceutical clients. Once I obtain my PhD, I intend to take a post-doctoral position through the Center for Drug Evaluation and Research (CDER) to enhance my regulatory experience and make myself more marketable!
Experiment or Technique You Would Most Like to Do
Nuclear magnetic resonance is a major technique used frequently in regulatory science and in the pharmaceutical industry, but my only exposure to it was for a week or so as an undergraduate in my Analytical Chemistry course. I was overwhelmed and scared of it then and I still am, though I want to change that!
Fun Fact
Cleaning is legitimately one of my favorite hobbies, so most laboratories stress me out a bit – ha. If I wasn’t working in science, I would want to be a professional home organizer.
Publications
- Schleiff, M., Payakachat, S., Schleiff, B., Pinson, A., Flynn, N., Province, D., Boysen, G., Swamidass, S. J., Miller, G. P. “Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics.”
- Publication – Accepted, Drug Metabolism and Disposition.
- Barnette, D., Schleiff, M., Datta, A., Flynn, N., Swamidass, S. J., Miller, G. P. “Meloxicam Methyl Group Determines Enzyme Specificity for Thiazole Bioactivation Compared to Sudoxicam.”
- Publication – Accepted, Toxicology Letters.
- Pinson, A., Pouncey, D., Schleiff, M., Fantegrossi, W., Prather, P., Radominska-Pandya, A., Boysen, G., Miller, G. P. “Significance of Competing Metabolic Pathways for Synthetic Cannabinoid 5F-APINACA as Revealed through Novel Reaction Kinetics.”
- Publication – Published, Molecules. DOI: 3390/molecules25204820
- Schleiff, M., Russell, L., Gonzalez, E., Bart, A., Broccatelli, F., Humphreys, G., Scott, E., Segall, M., Prasad, B., Hartman, J., Lauschke, V., Nwabufo, C., Takahashi, R., Durmus, S., Nichols, C., Martin, I., and Taub, M., Sodhi, J. “Advances in the Study of Drug Metabolism – Symposium Report of the 12th Meeting of the International Society for the Study of Xenobiotics (ISSX).”
- Publication – May 2020, Drug Metabolism Reviews. DOI: 1080/03602532.2020.1765793
Grants
I am partially supported by a training grant through the Pharmacology, Toxicology, and Experimental Therapeutics Department in the UAMS Graduate School entitled, “Systems Pharmacology and Toxicology” (T32GM106999).
Awards
- 2020 Third Place Bhuvan Award for Excellence in Biochemistry Graduate Research – University of Arkansas for Medical Sciences Student Research Day
- 2020 Top 30 Finalist with Honorarium – Sternfels Prize in Drug Safety Discoveries
- 2020 Pfizer Society of Toxicology National Conference Student Travel Award – Society of Toxicology Computational Toxicology Specialty Section
- 2019 First Place Oral Presentation – University of Arkansas for Medical Sciences Graduate Student Association Research Symposium
- 2019 South Central Chapter Society of Toxicology Regional Conference Travel Award
- Graduate Student Achievement Award for Selection to the Drug Metabolism Reviews Editorial Board – University of Arkansas for Medical Sciences Fall Research Award Ceremony
- Graduate Student Achievement Award for Selection to the International Society for the Study of Xenobiotics New Investigator Group – University of Arkansas for Medical Sciences Fall Research Award Ceremony
- 2019 Outstanding Graduate Student Poster Presentation – Drug Discovery and Development Colloquium
- 2019 Invited Speaker with Honorarium – Drug Metabolism and Pharmacokinetics Symposium hosted by Genentech
- 2018 MC-Bios Computational Biology Conference Travel Award – Midsouth Computational Biology and Bioinformatics Society
Alicja Urbaniak appointed to JBMT editorial board
Congratulations to Dr. Alicja Urbaniak who has been appointed to the Editorial Advisory Board of the Journal of Biochemical and Molecular Toxicology (JBMT).
Five UAMS Researchers Receive Seed Funding for New Projects
Five UAMS scientists were awarded $15,000 each to fund research projects in the coming year, thanks to an endowment created by generous donors nearly four decades ago.
The Medical Research Endowment Fund was one of the first major fundraising campaigns of the UAMS Board of Advisors. Established in 1982 to stimulate and support research programs of UAMS faculty, the fund has received financial contributions from individuals, corporations and foundations. It’s a way for donors to make an immediate impact in valuable research at the ground level.
The awards are a vital bridge between the researchers’ initial ideas and major discoveries. By providing seed funding for research, individual researchers or teams can collect preliminary data and form hypotheses before seeking major research grants.
The grant awards provide seed funding for research that has the potential to develop into scientifically significant research projects. Grants support new areas of research for junior investigators and new lines of investigation for established faculty. Awards are made annually in early fall, with funds becoming available to each investigator in January. MRE funds provide for equipment, operating expenses and consultation costs for 12 months.
The grant awardees and their projects are:
- Alicia Byrd, Ph.D., assistant professor, Department of Biochemistry and Molecular Biology, College of Medicine; The Role of DNA Helicase B in Response to DNA Replication Stress
- Rupak Pathak, Ph.D., assistant professor, Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy; Improving Efficacy and Safety of Prostate Cancer Radiotherapy with Mevalonate Pathway Inhibitors
- Youssef Aachoui, Ph.D., assistant professor, Department of Microbiology and Immunology, College of Medicine; Host-Pathogen Interplay Between Shigella and the Inflammasome
- Behjatolah “BJ” Karbassi, Ph.D., assistant professor, Department of Pathology, College of Medicine; Defining Tumor-Associated Glycans on Breast Cancer Cells that are Ligands for Macrophage SR-A
- Merideth Addicott, Ph.D., assistant professor, Department of Psychology, College of Medicine; Validating Electronic Nicotine Delivery System (END) Self-Reports Using Biochemical and Topographical Measures
Because of the generosity of donors who continue to support UAMS’ pioneering research efforts and the Medical Research Support Endowment Fund, hundreds of investigators have received funding totaling more than $3.1 million since the awards’ inception in 1982. Their return on investment has been significant, generating tens of millions of dollars in extramural funding.
October Publications
NAR Cancer. 2020
Significance of Competing Metabolic Pathways for 5F-APINACA Based on Quantitative Kinetics.
Molecules. 2020
September publications
Taylor EM, Byrum SD, Edmondson JL, Wardell CP, Griffin BG, Shalin SC, Gokden M, Makhoul I, Tackett AJ, Rodriguez A.
Acta Neuropathol Commun.
DNA-PKcs Inhibition Extends Allogeneic Skin Graft Survival.
Transplantation.
Congratulations Dr. Barnette!
Congratulations to Dustyn Barnette who successfully defended his Ph.D. dissertation entitled “Determining Metabolic Pathways to Liver Toxicity for Multiple Drug Classes Through Integrated Computational and Experimental Techniques” on September 10th. Dustyn was a student in the laboratory of Dr. Grover Paul Miller and is now a post-doctoral fellow at the National Center for Toxicological Research under the direction of Dr. Qiang Shi. A summary of his work is below.
Idiosyncratic adverse drug reactions (IADRs) present a challenge for drugs during development and after marketing. Drug bioactivation by liver xenobiotic enzymes is a prominent mechanism behind IADRs, often resulting in drug-induced liver injury. Avoidance of structural alerts is the common practice used in drug design to minimize bioactivation, but the strategy is prone to false predictions. A deeper mechanistic knowledge of drug bioactivation mechanisms, though requiring more resource-intensive strategies, can lead to safer drug design and clinical use. Herein, I used a strategic combination of investigative methodologies to study and elucidate bioactivation and detoxification pathways of drugs on and off the market. Multiple deep-learning neural network models provided high-throughput and efficient predictions of drug metabolism and analysis of patient data. These were complemented with in vitro experiments using enzyme systems to conduct kinetics analysis and phenotyping for targeted study of metabolism for specific drugs. My application of these techniques focused on two types of drug bioactivation. First, a study of the antifungal terbinafine identified a multi-pathway and multi-step series of N-dealkylations leading to formation of a reactive aldehyde. The complex pathway was catalyzed by seven different P450s, possibly explaining the difficulty of predicting liver injury in patients. Second, a comparative study of thiazole epoxidation for the never-marketed sudoxicam and its safer marketed derivative meloxicam identified multiple mechanisms by which thiazole substituents can determine toxicity risks, affecting both bioactivation and detoxifications pathways. Varied enzyme specificity for the different pathways implied a major role for enzyme affinity in determining bioactivation outcomes. Overall, newly gained mechanistic knowledge for specific drug bioactivation was achieved by leveraging the strengths of two different investigational approaches, each of which informed and improved the other. These findings deepen our understanding of how structural alerts translate to risks of liver injury. Newly discovered promising targets for identifying toxicity predictive factors in patient data offer exciting opportunities for future studies of clinical outcomes for these and similar drugs.