News

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 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.

Activation-induced cytidine deaminase localizes to G-quadruplex motifs at mutation hotspots in lymphoma.

Proteogenomic analysis of melanoma brain metastases from distinct anatomical sites identifies pathways of metastatic progression.

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.

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.

A shout-out to MD/PhD student L. Clai Morehead, a student in Isabelle Miousse’s and Alan Tackett’s labs, who has been selected to present a talk at the annual MD/PhD National Student Conference this week. Clai also received a Diversity Award to support her participation in the virtual conference. Her talk, “Caloric restriction mimetics as an adjuvant to immune checkpoint inhibitors for treatment of melanoma,” is one of only six in the conference’s general medicine category, and Clai is among just 24 MD/PhD students chosen to present at the conference. Clai’s talk tied for best student talk. We’re proud of you Clai!

A $1.9 million grant from the National Institute of General Medical Studies (NIGMS) will allow a scientist at the University of Arkansas for Medical Sciences (UAMS) to advance his research of DNA damage response (DDR) in cancer and genetic disorders.

Justin Leung, Ph.D., received the five-year grant for his project titled “Deciphering the Chromatin-based DNA Damage Response Pathway.” NIGMS, a part of the National Institutes of Health, supports basic research that improves understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment and prevention. ​

“DNA damage is a constant threat to our genetic material, so our bodies evolved a surveillance system called the DDR pathway. This pathway maintains our genome integrity by protecting our cells from damage to the genetic information that results in mutations and cell malignancies,” said Leung, assistant professor in the UAMS College of Medicine Department of Radiation Oncology and researcher in the UAMS Winthrop P. Rockefeller Cancer Institute.

An intact DDR pathway and network of DNA-repair proteins are essential for maintaining genome stability. When any component of the DDR pathway is compromised, DNA mutations will accumulate in cells, which potentially lead to diseases including cancer and genetic disorders.

“Our lab aims to understand how cells precisely repair DNA damage at the right place and right time. We investigate how the DDR is initiated and the mechanism by which DNA repair proteins are brought to the DNA breaks,” Leung said.

Leung’s grant, known as an R35 Maximizing Investigators’ Research Award, will be used to build a roadmap of the chromatin-based DDR pathway. The study will potentially provide insight into the causes of cancer and DDR-related genetic diseases. It will also help to develop therapeutic strategies for cancer treatment.

Research Findings Published

Findings from a collaborative project on DNA damage response conducted by Leung and Michael Huen, Ph.D., of the University of Hong Kong, was published July 1 in the scientific journal PNAS (Proceedings of the National Academy of Sciences of the United States of America).

The article titled “Screen identifies DYRK1B network as mediator of transcription repression on damaged chromatin,” outlines the team’s identification of a protein called DYRK1B and its functional network as a new branch of the DNA damage response to protect our genetic materials.

“Our work explains how DYRK1B dysregulation may fuel cancer progression. It also guides the development of a therapeutic strategy for the treatment of cancer and several rare genome instability-associated diseases,” Leung said.

The study uses a comprehensive proteomics approach supported by the IDeA (Institutional Development Award) National Resource for Quantitative Proteomics at UAMS to build an atlas for DYRK1B functions through profiling the potential biological pathways in which DYRK1B is involved.

“This study will open up new avenues for scientific discovery to study not only DNA repair but also a wide range of protein modifications in diverse cellular functions,” Leung said.

Postdoctoral fellow Kirk West, Ph.D., is the UAMS author of the study.

Genome-wide Cas9 binding specificity in Saccharomyces cerevisiae.

Waldrip ZJ, Jenjaroenpun P, DeYoung O, Nookaew I, Taverna SD, Raney KD, Tackett AJ.

PeerJ.

Frequent expression of activation induced cytidine deaminase in diffuse large B-cell lymphoma tissues from persons living with HIV.

Shponka V, Reveles CY, Alam S, Jaramillo M, Maguire A, Rimsza LM, Kendrick S.

AIDS.

Metabolism, CB1 cannabinoid receptor binding and in vivo activity of synthetic cannabinoid 5F-AKB48: Implications for toxicity.

Pinson A, Yarbrough AL, Bush JM, Cabanlong CV, Shoeib A, Jackson BK, Fukuda S, Gogoi J, Fantegrossi WE, McCain K, Prather PL, Fujiwara R, Radominska-Pandya A.

Pharmacol Biochem Behav.