2020-2021 Pre-Doctoral Fellows

2020-2021 Pre-Doctoral Fellow Projects by Research Category

Clinical and Translational Sciences (includes pharmacotherapy, experimental therapeutics, PK/PD, modeling and simulation)

Screen Shot 2020-06-17 at 11.23.43 AMDr. Karryn Crisamore, University of Pittsburgh, Second Year Fellow

Mentor: Dr. Philip Empey

Research Title: A Pharmacogenomic Approach to Explaining Pharmacokinetic Variability of Sedatives in the Pediatric Intensive Care Unit

“I aim to identify patient-specific factors that contribute to differences in response to sedative medications in critically ill children. My project goals are to determine if differences in how the body handles and eliminates medication are associated with patient response. I will also evaluate if genetics drives these differences. Identification of these factors can be translated into clinical practice to inform prescribing and improve medication outcomes.”

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Mansour Dughbaj ,University of Southern California, Dr. Paul B. Mydral Memorial Fellow

Mentor: Dr. Paul Beringer

Research Title: Design of Protegrin-1(PG-1)-based Cyclotides as a Therapeutics for Cystic Fibrosis Infection and Inflammation”

“The search for novel antimicrobial agents is dire due to the escalating prevalence of infections involving antibiotic resistance bacteria in the lungs of patients with cystic fibrosis (CF). CF is the most common Caucasian life-limiting genetic disorder and is characterized by a vicious cycle of airway obstruction, microbial infection, and inflammation. Microbial infection is one of the significant drivers of CF lung disease, antibiotics are responsible for a momentous increased survival in CF patients; however, pathogens render CF treatment ineffective by evolving antibiotic resistance. Chronic microbial infections exacerbate airway inflammation leading to lung injury and progressive loss of lung function. Hence, research into new safe and effective antimicrobial and anti-inflammatory therapeutics discoveries are critical for the treatment of CF lung disease. ”

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Mohammed Gbadamosi, University of Florida

Mentor: Dr. Jatinder Lamba

Research Title: Pharmacogenomic Drivers of Efficacy in Anti-CD33 Immunotherapeutic Treatment Strategies

“Immunotherapy leverages a patient’s immune system to kill cancer cells. In the context of acute myeloid leukemia (AML), immunotherapy shows great promise in addressing the longtime abysmal outcomes resulting from the heterogeneous nature of AML. Specifically, immunotherapy targeting CD33, a myeloid cell surface protein present on leukemic cells in > 85% of AML patients, has proven effective in some populations of AML patients. While CD33-directed therapies have revolutionized AML treatment strategies, studies have shown evidence of interpatient variation in CD33-directed immunotherapies. This project centers on understanding how genetics play a role in the interpatient variation in response to CD33-directed immunotherapies in the context of acute myeloid leukemia and using that information to improve treatment outcomes and efficacy. The Lamba Lab group is the first to study CD33 genetic variants in the context of CD33 immunotherapeutic response. In our previous work, we reported the occurrence of six genetic variations in CD33 with potential significant functional and clinical relevance. Subsequently, we developed a composite score using those genetic variants (CD33-PGx6 Score) that hold potential for predicting outcomes of pediatric AML patients treated with gemtuzumab ozogamicin, a CD33-directed therapy. The goal of this project is to validate that score in an independent cohort of pediatric AML patients and to mechanistically characterize the effects of three genetic variants included in the CD33-PGx6 Score on CD33 biology and CD33 immunotherapeutic efficacy using a panel of CRISPR/cas9 engineered cell lines. We anticipate that our study will elucidate mechanistic reasons behind changes in CD33-directed therapeutic efficacy as a result of CD33 variation and will establish the foundation for strategies to improve CD33 immunotherapeutic treatment strategies and guide novel CD33 immunotherapy development.”

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Jacqueline Gerhart, UNC-Chapel Hill, Dr. Fred Eshelman Fellow

Mentor: Dr. Daniel Gonzalez

Research Title: Application of Physiologically-Based Pharmacokinetic (PBPK) Modeling to Understand Drug Disposition in Children with Obesity

“One in six children in the United States are currently obese, but doctors have little guidance on if or how to adjust the dosing of medicines for these patients. This is because conducting the clinical trials necessary to determine the right dose in children, let alone children with obesity, is very ethically and logistically challenging. My project aims to use novel mathematical modeling and simulation techniques to optimize the dosing of six commonly used drugs in children with obesity. To do this, I will 1) develop a virtual population of children that reflects the actual demographics and physiology of actual children with obesity, 2) use this virtual population and what we know about the medicine in adults to develop these models, then 3) use the models to simulate different dosing scenarios in children with obesity in order to predict which dose results in concentrations that are both safe and efficacious for this vulnerable patient population.”

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Dr. Teddy Jennaro, University of Michigan, Regional Fellow

Mentor: Dr. Kathleen Stringer

Research Title: Identifying Altered Metabolic Signatures that Drive Mortality in Septic Shock: Steps Toward Precision Pharmacotherapy

“Sepsis is a life-threatening organ dysfunction that results from a bloodstream infection. The individual response to infection is highly variable, and the precise reasons why sepsis resolves in some individuals and is deadly in others is poorly understood. Sepsis is a ‘catabolic crisis’ and the body alters energy utilization pathways and perturbs metabolism to meet the rising energetic demand. I seek to apply novel statistical and bioinformatic approaches to understand metabolic changes over time in septic patients, which are related to mortality and drug response. I will use bioinformatic software to map these findings back to known biochemistry and molecular biology to inform rational drug discovery. I will also seek to explain interpatient variability in response to a promising, targeted sepsis-therapeutic, levo-carnitine, using patient-specific data.”

Screen Shot 2020-06-17 at 11.42.34 AMFabian Martinez, Oregon State University

Mentor: Dr. Aleksandra Sikora

Research Title: Protein Subunit Vaccine Delivery Platform for Development of Gonorrhea Vaccine

“Amongst the prevalent sexually transmitted infections (STIs), Gonorrhea has gained momentum in attention due to increasing rates of reported cases within the United States, according to the Centers for Disease Control and Prevention (CDC). The rise of antibiotic resistance in Neisseria gonorrhoeae (Ng) has led to resistance to CDC’s recommended dual antibiotic treatment; intramuscular ceftriaxone and oral azithromycin. According to the CDC and the world health organization (WHO), increased antibiotic resistance has classified Ng as a superbug and has become a significant public health risk. The project goal is to formulate a subunit vaccine for gonorrhea, using novel identified proteins discovered through a proteomic approach and displaying them on a nanodelivery system. The rationale for this study is clear, currently, no vaccines are available for gonorrhea and there is an imperative need for a long-term solution.”

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A young Park, University of Southern California, Second Year Fellow

Mentor: Dr. Paul Beringer

Research Title: “Pharmacokinetics/Pharmacodynamics of Vitamin D3 in Adults with Cystic Fibrosis”

“Currently, the best approach to treat vitamin D deficiency is via vitamin D supplementation. However, there is no proven treatment strategy that effectively achieves and maintains optimal vitamin D3 blood levels in cystic fibrosis (CF) patients. CF Foundation recommends 2,000 international units (IU) daily vitamin D3 supplementation for the treatment of vitamin D deficiency. Nonetheless, due to large individual variations in response to vitamin D supplementation, a fixed-dose approach to vitamin D3 therapy may not be efficacious in improving vitamin D status in CF patients. These issues highlight the need to identify the sources of variability and to determine the optimal dosing regimens that raise and maintains vitamin D3 status. Maintaining sufficient vitamin D3 status has shown to have beneficial effects on inflammation and infections in several patient populations. In order to individualize dosing regimens, the kinetic disposition of vitamin D3 and its metabolites must be well understood. Population pharmacokinetic approach allows to explain the sources of pharmacokinetic variability and guide clinicians to choose appropriate dosing regimen for a given population. In addition, PK/PD analysis of vitamin D3 guide clinicians to properly design clinical trials prior to the start of the study via clinical trial simulation and sample scheduling optimization to minimize failure. The use of modeling and simulation can greatly expedite the drug development or regimen optimization process while reducing the cost.”

Screen Shot 2020-06-17 at 11.58.18 AMJoshua Silva, University of Southern California, Second Year Fellow

Mentor: Dr. Daryl Davies

Research Title: Dihydromyricetin (DHM) Increases Alcohol Metabolism and Reduces Alcohol-Induced Liver Injury

“Every year millions of people suffer from alcohol use disorder (AUD) and alcoholism that contributes to organ injury. In particular, damage from repeated and excessive alcohol abuse is strongly associated with the development of alcoholic liver disease (ALD), due to the liver mainly being the site of ethanol metabolism. Dihydromyricetin (DHM), an herbal extract from the Ampelopsis grossedentata species has recently been proposed as an antioxidant and anti-inflammatory supplement that may play a role in reducing alcohol intoxication and liver disease in mice models. DHM has also shown the potential to provide anti-alcoholic effects on animal models, resulting in reduced alcohol intoxication, dependence, and a reduction in alcohol-mediated liver injury. At the cellular level, few studies, including data from our lab, suggest that DHM enhances the metabolism of alcohol and its toxic metabolites. Therefore, our studies that begin to investigate the mechanisms of DHM liver protective effects and its ability to reduce alcohol dependence would allow us to develop new drugs that are capable of preventing injury associated with alcohol metabolism and potentially reduce alcohol drinking behavior. Therefore, this project has two main points: 1) to better understand the mechanisms and ability of DHM to reduce/prevent ALD in alcohol use animal models 2) to help us identify the potential benefits of DHM in reducing alcohol dependence and alcohol-mediated anxiety/depression, potentially serving as a novel therapy for AUD. By investigating these effects using both cell culture models and animal models, we can better understand the potential of DHM to prevent ethanol-induced organ injuries and toxicities related to ethanol metabolism.”

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Dr. Meghan Whalen, University of California, San Francisco

Mentor: Dr. Francesca Aweeka

Research Title: Optimization of Malaria Treatment Strategies: A Pharmacokinetic/Pharmacodynamic Analysis of Artemisinin-Based Combination Therapies (ACTs) in the Context of HIV

“The overarching goal of my project is to make antimalarial medications safer and more effective in pediatric populations. My project focuses on studying drug-drug interactions between antimalarial medications and different HIV antiretroviral therapies. I will examine how these interactions can affect antimalarial drug concentrations in the body and drug efficacy. I want to determine the best antimalarial medication dosing strategies for children, with the goal being to decrease malaria treatment failure and drug toxicity, especially for children who are taking HIV antiretroviral therapies. There is currently a lack of research on this patient population and, as children have the highest malaria mortality risk, it is urgent that this gap in research be filled.”

Drug Delivery, Bioengineering (includes nanomedicine, devices, biotechnology, protein delivery and characterization, and biopharmaceuticals)

Screen Shot 2020-06-17 at 11.39.19 AMBrian Kiesel, University of Pittsburgh, Second Year Fellow

Mentor: Dr. Jan Beumer

Research Title: Comparative Pharmacology of ATR Inhibitors”

“Many cancer therapies like radiation or chemotherapy have been mainstays of cancer treatment due to their unparalleled efficacy, however, they often produce terrible side effects. A new group of drugs, known as chemoradiation sensitizers, can enhance the efficacy of primary cancer treatment and hopefully reduce the side-effects by limiting the effect to the site of cancer. My primary goals are to understand the duration and extent of chemoradiation sensitizers in cancer patients by examining the factors that influence these factors including physiology, anatomy, and co-medications as well as exploring the biological effects these drugs have when given in combination with chemotherapy or radiation.”

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Madeleine Landry, Oregon State University, Herb and Nina Demuth Memorial Fellow

Mentor: Dr. Conroy Sun

Title: Understanding the impact of radiation on endocytosis of small molecule therapies and their nanoformulations

“My lab is focused on employing nanotechnology to drug delivery systems that would serve to benefit from nanoscale size and high surface area to volume ratios of the drug carrier. Nanoparticles are especially beneficial in the field of cancer medicine due to the enhanced uptake in tumors and the limited solubility of chemotherapy drugs. A major limitation of chemotherapies is the poor delivery rate; very little administered drug actually reaches the desired tumor target(s). The drug passes through the body and is cleared out rapidly after the body recognizes it as foreign. The nanoparticles I make address this by shielding the drug from the body with a polymer coating that is not recognized by the immune system as foreign, slowing the clearance from the body. Additionally, nanoparticles are able to preferentially accumulate in tumors due to their optimal size. Tumor vasculature is both leaky, allowing nanoparticles to enter, while also having poor lymphatic drainage, preventing easy escape from the tissue. With my proposed project I’d like to investigate and clarify the effects of radiation on nanoparticle uptake. This has the potential to vastly improve the nanoparticle delivery, and thereby increase the drug delivery.”

Screen Shot 2020-06-04 at 1.59.54 PM Jordan Pritts, University of Maryland, Second Year Fellow

Mentor: Dr. Sarah Michel

Research Title: Understanding how the human influenza virus protein NS1A targets the nuclear protein CPSF30 to promote virulence: A novel druggable protein-protein interaction

“The influenza virus (‘the flu’) contributes to substantial economic and social impact each year. Generally, the symptoms of the flu are mild with fatigue, muscle/joint aches, fever, and sinus discomfort. However, there are strains of the flu that can be deadly such as the 1918 Spanish flu that resulted in high death tolls. Currently, our main line of defense against the flu is yearly vaccinations. These are helpful in controlling large outbreaks of seasonal flu strains but have some limitations. First, influenza A is a virus that is always mutating and adapting to become stronger and more resistant to our defenses. This makes predicting the strains to include in the vaccines difficult. Second, it takes time to generate and distribute these vaccines to affected areas and this would not be feasible for new strains that make their way to human pathogenicity. This is where anti-influenza drugs come into play. Drugs are needed as a first line of defense for ameliorating outbreaks of new strains of the flu, as protection for populations that cannot be vaccinated, or as a prophylactic treatment for populations at high risk of exposure of newly virulent strains. Currently, there are a few anti-influenza drugs on the market including M2 ion channel inhibitors Amantadine and Rimantadine as well as neuraminidase inhibitors such as Oseltamivir and Zamanivir. However, new strains of the flu are increasingly becoming more resistant to these drugs and new lines of defense are becoming an urgent public health concern. This proposal focuses on characterizing one of the main pathways to influenza virulence in humans to lay a foundation for targeting the flu with novel therapeutics. Additionally, FDA approved drugs that may be able to be repurposed to fight influenza A will be identified and novel drugs will be synthesized, optimized, and assessed as novel anti-influenza A drugs.”

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Andrew Zhou, University of Minnesota, Second Year Fellow

Mentor: Dr. Karunya Kandimalla

Research Title: Development of a PET imaging agent for early diagnosis of brain insulin resistance in Alzheimer’s disease

“We propose to develop an insulin-conjugated radiotracer that will be used for PET imaging studies in animal models and subsequently in Alzheimer’s disease (AD) patients. Our preliminary data provide evidence that insulin radiotracers can be used to detect changes in the blood-to-brain transport kinetics of insulin in healthy vs. AD mouse models, which exhibit brain insulin resistance. The PET tracer will be synthesized and developed under good manufacturing practice (GMP) conditions, and the safety and efficacy of the tracer will be established in mice to enable translation into the clinic.”

Drug discovery/medicinal chemistry

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Jack Henderson, University of Maryland

Mentor: Dr. Jana Shen

Research Title: Unveiling Proton-Coupled Mechanisms of Malarial Proteases and Sodium-Proton Antiporters to Advance Structure-Based Drug Design

“The overall goal of this dissertation is to aid the design of novel therapeutic agents by gaining detailed mechanistic insights into two important classes of drug targets through computer simulations. With malarial drug resistance on the rise, there is a need for novel antimalarial drugs. In recent years, a family of malarial aspartyl protease proteins called plasmepsins has been identified as new antimalarial targets. The goal of aim 1 is to aid the design of potent and selective inhibitors targeting plasmepsins by performing state-of-the-art constant pH molecular dynamics simulations. These simulations will allow us to identify the catalytic acid and base and decipher unique ligand binding modes to enable selective inhibitor design. The human sodium-proton antiporter protein is linked to heart failure, hypertension, and diabetes. The function of the antiporter is realized through ion-proton transport and conformational transitions between active and inactive states; however, detailed mechanisms remain unresolved. The goal of aim 2 is to gain detailed insight into the ion-proton transport and conformational transition mechanisms of the human analog, the E. coli sodium-proton antiporter NhaA, which has an inactive crystal structure. Our study will resolve the controversy regarding the proton binding sites and elucidate the pathway of conformational activation of NhaA. Our work will provide a mechanistic basis to inform future drug design efforts targeting the human sodium-proton antiporter.”

Screen Shot 2020-06-17 at 11.46.49 AMLogan Neel, Auburn University, Second Year Fellow

Mentor: Dr. Forrest Smith

Research Title: Computational Design and Synthesis of Novel Cannabinoid Receptor 2 Selective Agonists.

“The computational design of a three-dimensional protein, CB2,  will allow for a better understanding of the active site. The CB2 model will be a predicted structure based on a known crystal structure with high sequence identities compared to CB2. Once an accurate model has been created, it is a goal for the model to be able to depict between an agonist and an antagonist. Another goal would be to design a selective agonist with a high affinity for the CB2 receptor and to synthesize the compound within the laboratory.”

 

Screen Shot 2020-06-17 at 11.51.36 AMChristine Nervig, The University of Utah

Mentor: Dr. Shawn Owen

Research Title: Antibody-drug conjugates as enhanced therapeutics against the drug-resistant bacteria Pseudomonas aeruginosa

“A common goal in medicinal chemistry is to increase drug activity while limiting the side effects they cause. My dissertation work focuses on the development of targeted drug delivery strategies to address this challenge by attaching drugs to a protein that targets specific cells or tissues, thus limiting off-target effects and lowering required doses. Multidrug-resistant bacterial infections are a growing concern around the world. To address these ‘superbugs’, I am developing antibody-drug conjugates (ADCs) against Pseudomonas aeruginosa, a bacterial strain that evades treatment by pumping common antibiotics out of their cells. I synthesize ADCs that deliver efflux pump inhibitors that, on their own, have had too many side effects to be used clinically. Antibody targeting bypasses detrimental off-target effects by delivering drugs directly to the infection. Further, this platform can be adapted to a variety of combination therapies, which are becoming standard for difficult-to-treat infections and diseases.”

 

Pharmacology, Toxicology (includes cell biology, chemical biology, and pharmacognosy)

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Ariana Brice-Tutt, University of Florida

Mentor: Dr. Jay McLaughlin

Research Title: Therapeutic and mechanistic evaluation of multifunctional opioids as improved treatments for pain and substance abuse

“The opioid epidemic has had a disastrous impact on human health and civil society. Through collaboration with medicinal chemists, pharmacologists, and neuroscientists, the goal of my project is to screen and validate novel multifunctional opioids for efficacy in preclinical models of pain and substance use. Compounds that demonstrate promise for these treatments without typical opioid-related side effects, such as respiratory depression and abuse potential, will then be thoroughly characterized to understand how they are working to retain therapeutic activity without undesired effects.”

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Anna M. Gutridge, Purdue University

Mentor: Dr. Richard van Rijn

Research Title: Investigation of biased signaling at opioid receptors for improved chronic pain therapeutics

“Chronic pain affects approximately 20% of adults in the United States and forces many to seek medical care where they are often prescribed opioids. Opioids are among the most effective pain treatments, but their prolonged use is hindered by harmful side effects such as respiratory depression, tolerance (causing reduced drug efficacy), and dependence. For individuals seeking long-term pain relief, there remains a critical need to develop safer analgesics. One goal of this project is to investigate whether the benefits of G-protein biased MOR drugs can be extended to those with chronic pain. Because individuals with chronic pain use opioids over an extended amount of time, they have a higher risk of adverse side effects. Using a mouse model of chronic pain, I will assess whether prolonged administration of G-protein biased MOR drugs increases opioid tolerance and reward liability when compared to traditional opioids. Conditions of chronic pain induce protein expression changes in the brain that can influence drug pharmacology. Because the bias profile of biased drugs is reliant on the activity of downstream signaling partners, it follows that changes in protein expression following chronic pain may influence the effectiveness of biased therapeutics. An additional goal in my research is to investigate how pain pathophysiology affects the pharmacology of biased ligands.  I will assess protein expression changes induced by chronic pain, then duplicate the changes in validated signaling assays to determine how the environment changes drug activity. The scope of this project begins by investigating the potential benefits of biased opioids in chronic pain and concludes with an in-depth look at the cellular context within which these opioids are acting.”

Social and Administrative Sciences

Screen Shot 2020-06-17 at 11.21.01 AMBrandy Davis, Auburn University

Mentor: Dr. Kimberly Garza

Research Title: Implementing a depression screening and referral service in rural community pharmacies: A mixed-methods comparative case study

“The broad goal of my project is to improve mental health outcomes in rural populations. The specific goal is to implement a depression screening and referral service in rural pharmacies. Long-term benefits will include increased awareness of rural populations towards depression screening as a common practice and the role pharmacists can play in mental health care. Knowledge gained from this study can inform future research to implement collaborative care among rural healthcare providers.”

 

Cassidi McDaniel, Auburn University

Mentor: Dr. Chou Chiahung

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Research Title: Improving access to quality care for rural residents with diabetes: developing a framework for care transitions and policy implications

“Patients with diabetes who are transitioning from hospital care back to their home are vulnerable to hospital readmissions, and this transitioning is referred to as transitions of care. A gold st

andard for transitions of care practices in patients with diabetes is lacking. Therefore, the goals of the proposed project are to develop an understanding of how to improve transitions of care in patients with diabetes and provide scientific knowledge to identify the gold standard for transitions of care practices. Through a mixed-methods approach, we will consider both large population-based data and perspectives of healthcare providers and patients to identify factors impacting the risk of high readmission rates among populations with diabetes. Machine learning techniques will be applied to population-based data to identify the factors attributing to patients’ risks for hospital readmissions, and framework analysis will be applied to provider and patient perspectives to understand how transitions of care may be improved among these patients. Through the integration of these results, we will gain a better understanding of how to improve transitions of care in patients with diabetes. Findings from this work will inform the design of a transition of care program, and the program will be examined for effectiveness to reduce hospital readmission rates in clinical practice. Overall, this study aims to determine which factors should be considered in intervention design and how these factors inform framework and program development. In conclusion, the overall goal of the proposed project is to provide further direction towards developing a gold standard intervention for transitions of care to advance health outcomes through amelioration of hospital readmissions for patients with diabetes.”

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Dr. Summer Tran, University of Minnesota, ASHP-AFPE Fellow

Mentor: Dr. David Stenhjem

Research Title: Impact of Concurrent Antibiotic Use on Effectiveness of Immune Checkpoint Inhibitors in Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC)

“There were almost 200,000 new cases of non-small cell lung cancer (NSCLC) in the U.S. in 2018. Prior to 2011, platinum-based chemotherapy was the standard of care for NSCLC, yet most patients did not survive for more than one year. The first drug in a new class, known as immune checkpoint inhibitors (ICIs or immunotherapies), entered the market in 2011 and since then six other ICIs have been approved by the FDA. The effectiveness of ICIs in patients with advanced NSCLC is proven to significantly improve both progression-free survival and the overall survival rate. While these new ICIs are promising, they face some challenges. First, more than 50% of NSCLC patients experience infections and are treated with antibiotics. However, animal studies and lab findings suggest that the use of antibiotics may limit, or even inhibit, the effectiveness of the otherwise promising ICIs. Second, these therapies are very expensive, with costs of over $200,000 for a year of treatment.
As a result, there is a pressing need for evidence-based clinical guidance on the use of ICI agents, including appropriate use when prescribed concurrently with antibiotics. The overall objective of my research is to determine if the use of antibiotics concurrently with ICI therapy in advanced NSCLC patients affects the outcome of ICI therapy. Previous clinical trials, with relatively small sample sizes of just 30-100 patients, have been inconclusive. This research project will use real-world data from the SEER database-a large registry of cancer patients covering a period of more than five years. This data will be used to evaluate three specific aims: (1) determine the prevalence of antibiotic use concurrent with ICI initiation in metastatic NSCLC patients; (2) compare the duration of ICI therapy (i.e., effectiveness) between metastatic NSCLC patients who are receiving current antibiotic treatment at the time of ICI initiation and the ICI duration in similar patients who do not use antibiotics concurrently; and (3) evaluate the relationship between duration of concurrent antibiotic use and duration of ICI therapy in metastatic NSCLC patients.”