Translational Medical Research Commons^™

Increased Glucose Availability Sensitizes Pancreatic Cancer To Chemotherapy, Ali Vaziri-Gohar, Jonathan J. Hue, Ata Abbas, Hallie J. Graor, Omid Hajihassani, Mehrdad Zarei, George Titomihelakis, John Feczko, Moeez Rathore, Sylwia Chelstowska, Alexander W. Loftus, Rui Wang, Mahsa Zarei, Maryam Goudarzi, Renliang Zhang, Belinda Willard, Li Zhang, Adam Kresak, Joseph E. Willis, Gi-Ming Wang, Curtis Tatsuoka, Joseph M. Salvino, Ilya Bederman, Henri Brunengraber, Costas A. Lyssiotis, Jonathan R. Brody, Jordan M. Winter

Student Papers, Posters & Projects

Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies …

A Review Of Isomirs In Colorectal Cancer, Molly A. Lausten, Bruce M. Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

As advancements in sequencing technology rapidly continue to develop, a new classification of microRNAs has occurred with the discovery of isomiRs, which are relatively common microRNAs with sequence variations compared to their established template microRNAs. This review article seeks to compile all known information about isomiRs in colorectal cancer (CRC), which has not, to our knowledge, been gathered previously to any great extent. A brief overview is given of the history of microRNAs, their implications in colon cancer, the canonical pathway of biogenesis and isomiR classification. This is followed by a comprehensive review of the literature that is available on …

Particle Arc Single-Isocenter Stereotactic Radiosurgery Of Multiple Brain Metastases, L Volz, S Mein, T Tessonnier, Peilin Liu, A Mairani, M Durante, Xuanfeng Ding, C Graeff, T Li

Conference Presentation Abstracts

Purpose: To develop spot-scanning proton (SPArc) and heavy ion (SHArc) arc therapy for single-isocenter stereotatic radiosurgery (SISRS) of multiple brain metastases (MBMs). First results achieved with dedicated planning infrastructure are compared to state-of-the -art volumetric modulated photon arc therapy (HA-VMAT). Methods: A multi-institutional collaboration was established to develop bespoke SPArc and SHArc SISRS infrastructure with available research and commercial treatment planning systems. Devised planning and delivery methods considered dedicated energy, spot, and multi-arc selection strategies. SPArc and SHArc (carbon and helium ions) plans were generated for MBM patients exhibiting 3-12 intracranial lesions with GTV volumes between 0.03ccm and 19.8ccm, at …

An Analytic Model Of The External Beam Dose Rate Effect On Immune Cells In Blood Dosimetry, Lili Zhao, Peilin Liu, G Liu, Xuanfeng Ding

Conference Presentation Abstracts

Purpose: Radiation therapy is a double-edged sword with regard to its immunomodulatory effect. It is critical to find how it is affected by dose rate. Thus, we developed an analytic model for calculating the number of immune cells receiving radiation. Methods: Suppose the blood is received radiation by constant dose rate. The blood is one-way flow without circulation in the radiation delivery at a constant velocity. Two kinds of lung treatment regimens were considered standard delivery 2Gy per fx total 30fx and hypo-fractionation SBRT 12 Gy per fx total 5 fx. Two different dose rates were simulated for standard treatment: …

Does Proton Arc Therapy Has Potential Clinical Benefits For Hepatocellular Carcinoma?, Peilin Liu, R Dalfsen, M Soukup, Shupeng Chen, Lili Zhao, Z Wang, X S. Gao, Thomas Quinn, Craig Stevens, Rohan Deraniyagala, Xiaoqiang Li, Xuanfeng Ding

Conference Presentation Abstracts

Purpose: To investigate the potential clinical benefits and dose-averaged Linear Energy Transfer (LETd) sparing, utilizing proton arc plan for Hepatocellular carcinoma (HCC) patients in comparison with Intensity Modulated Proton Therapy (IMPT). Methods: Ten HCC patients have been retrospectively selected. Two planning groups were created: Proton Arc plans using Monaco ver. 6 and the clinical IMPT plan. Both planning groups used the same robustness parameters. The prescription dose is 67.5 Gy (RBE) in 15 fractions/ 66 GyE in 10 fractions of the Clinical Target Volume (CTV) following clinical IMPT plan. Robustness evaluations were performed to ensure target dose coverage. Normal Tissue …

Investigate The Delivery Efficiency Improvement For Sparc Compared To Impt, Peilin Liu, B A. De Jong, S Chang, Lili Zhao, G Liu, Craig Stevens, Rohan Deraniyagala, E W. Korevaar, J A. Langendijk, Xiaoqiang Li, Xuanfeng Ding

Conference Presentation Abstracts

Purpose: To assess the efficiency improvement of SPArc compared to IMPT in proton clinical operation.Methods: A random clinical operation day at a proton therapy center with a two room system. Aa total of 10 Head & Neck cancer cases treated on Jan 6th, 2021were selected and SPArc plans were generated for all the cases with similar target coverage and dose constraints of organ at risk (OARs). 3% range uncertainties and 3mm setup uncertainties were applied for robust optimization. The log files of clinical IMPT were exported to calculate true treatment delivery time. The machine-specific delivery sequence model was utilized to …

A Comprehensive Investigation Of Linear Energy Transfer Optimization Effectiveness In Intensity-Modulated Proton Therapy Via Alternating Direction Method Of Multipliers (Impt Let-Admm), Q Fan, G Liu, Lili Zhao, Xiaoqiang Li, Xuanfeng Ding, S Dai

Conference Presentation Abstracts

Linear energy transfer (LET)-guided optimization in intensity-modulated proton therapy (IMPT) via alternating direction method of multipliers (ADMM) has the potential to improve its biological effectiveness (IMPTLET- ADMM), in which the LET distribution in target can be escalated, while the LET distribution in the organs at risk can be mitigated. This study aims to quantitatively investigate the effectiveness of LET optimization in IMPT via ADMM with different solvers in its iteration loop. Methods: The clinical dose-volume-histogram (DVH) constraint noted dose sub-problem and clinical LET -volume-histogram (LVH) constraint noted LET sub-problem are combined to generate a composite objective function, which is available …

Expansion Of The Detrusor Muscular Ring Surrounding The Bladder Neck On Mri: Moving Beyond The Prostate As An Etiology Of Lower Urinary Tract Symptoms Due To Benign Prostatic Hyperplasia, Kiran Nandalur, David Walker, Hong Ye, Sayf A. Al-Katib, Brian Seifman, David Gangwish, Abhay Dhaliwal, Connor Ervin, Kayla Dobies, Channing Sesoko, Sirisha Nandalur, Bernadette Zwaans, Jennifer Nguyen, Jason Hafron

Conference Presentation Abstracts

Purpose: The etiology of lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH) remains uncertain. The purpose of our study was to quantitatively analyze pelvic anatomic characteristics on magnetic resonance imaging (MRI) to assess for independent factors for symptoms.
*Methods and Materials: This retrospective single-institution study evaluated treatment-naïve men who underwent prostate MRI within 3 months of International Prostate Symptom Score (IPSS) from June 2021 to February 2022. Factors measured on MRI included: detrusor muscular ring surrounding the bladder neck measured as area and alternatively diameter, central gland (CG) mean apparent diffusion coefficient (ADC), levator hiatus (LH) volume, intrapelvic …

Sexual Dysfunction After Rectal Cancer Treatment, Sarah M. Popek

Clinical and Translational Science Center Scholarly Output

Introduction: Treatment for rectal cancer results in sexual dysfunction. Sexual function is a component of the HR-QOL (health related quality of life) measures. The incidence of sexual dysfunction following treatment for rectal cancer and its impact on the HR-QOL is not well delineated, particularly on women.

Objectives: To prospectively assess the degree of sexual dysfunction that occurs after treatment for Stage I-III rectal cancer and the corresponding short term (<3 months) and long term (<2 years) effect on the Quality of Life measure for oncology (QOL-30).

Methods: Validated questionnaires will be administered to assess sexual function and quality of life. The International Index of Erectile Dysfunction will be administered to male patients and …

Impact Of In-House Specialty Pharmacy On Access To Novel Androgen Axis Inhibitors In Men With Advanced Prostate Cancer, Anna Driscoll, Nathan Handley, Md, Mba, Adam Binder, Siobhan Henry, W. Kevin Kelly, Do

Phase 1

Introduction: Novel androgen axis inhibitors are standard of care treatments in advanced prostate cancer. The billed amounts for these medications are often very high, which may create significant financial toxicity for patients and lead to delays in treatment. Our institution implemented an in-house specialty pharmacy in 2014, that provides these medications and evaluates copay assistance options for all patients. We evaluated the program’s impact on out of pocket cost (OOP) and turnaround time (TAT).

Methods: We reviewed available internal specialty pharmacy records to identify prescriptions for abiraterone or enzalutamide filled between 1/1/17 and 12/31/18. Payments were stratified by primary payment …

Manipulation Of Genome Integrity Signaling Axes Contributing To Prostate Cancer Aggressiveness, Frank Duan, Veronica Rodriguez-Bravo, Phd

Phase 1

Introduction: Prostate cancer (PC) is one of the leading causes of death in men, and despite current treatment options patients can develop aggressive disease that spreads to other parts of the body. Little research has focused to date on the effect of centrosome biology in the pathogenesis of PC.

Methods: Two metastatic PC cell lines, DU145 and 22Rv1, as well as highly aggressive derivatives generated in Dr. Rodriguez-Bravo lab (docetaxel-resistant; (DR) variants) were compared through various experiments to determine differences in centrosome proteins expression and functionality. All cells (DU145 /DR and 22Rv1 /DR) underwent electroporations with siRNAs to knockout …

Determining The Role Of Surgery In Diagnosis And Treatment Of Primary Cns Lymphoma, Tyler Fox, Michael Baldassari, Lohit Velagapudi, Karim Hafazalla, Christopher J. Farrell, Md, James J. Evans, Md, David W. Andrews, Md, Kevin Judy, Md, Donald Ye, Md

Phase 1

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare entity typically treated with a combination of chemotherapy and radiation. The role of surgery is controversial, and biopsy may be non-definitive or injurious. We review our series of stereotactic and excisional biopsy as well as surgical debulking of PCNSL to quantify overall risk and benefits.

Methods: Patients with biopsy-confirmed intracranial PCNSL were identified from a large singlecenter academic institution between 2012-2018. Preoperative factors and perioperative outcomes were retrospectively reviewed.

Results: A total of 61 cases of PCNSL were identified. Most patients presented with confusion (23.0%), weakness/paralysis (19.7%), and gait disturbance …

Protocol For Ground Glass Opacity, Elissa Goldman

Phase 1

Rationale: Pure ground glass opacities (GGO), identified incidentally or on lung cancer screening, may indicate pre-invasive subtypes of lung adenocarcinoma. These neoplasms typically demonstrate indolent patterns of growth, and Fleischner Society guidelines recommend up to five years of serial imaging. Our aim was to determine the frequency of diagnosed lung adenocarcinoma arising from GGO detected beyond 5 years of CT surveillance.

Methods: We reviewed all pathologic diagnoses of lung adenocarcinoma (n=442) between 2016 and 2018 of a tertiary academic hospital and National Cancer Institute-designated cancer center to identify all cancers that arose from ground glass opacities detected on CT scan. …

Early Perioperative Fluid Benchmarking To Predict Pancreaticoduodenectomy (Pd) Outcomes, David Moskal, Carrie D. Walsh, Sofia Duque, Charles Yeo, Md, Facs, Harish Lavu, Md, Facs

Phase 1

Introduction: PD is a complex operation associated with a marked systemic inflammatory response and significant fluid shifts. Establishing a benchmark for ideal perioperative fluid management is critical to optimising PD patient recovery.

Methods: In this retrospective study, we evaluated perioperative fluid data for patients undergoing PD. We compared an optimal benchmark group who were discharged home by postoperative day five (≤5day) to a group of patients with an in hospital recovery greater than ten days (≥10day).

Results: Seventy-six patients who underwent PD between June 2015 and November 2016 were evaluated. The ≤5day group had a significantly lower intraoperative fluid administration …

Surgical Resection Of Convexity Meningiomas: A Single Center Retrospective Analysis, Haley Wendt, Michael Baldassari, Donald Ye, Kevin Judy

Phase 1

Introduction: Dural convexity meningiomas (CMs) are the most common primary intracranial tumors. Although surgical resection carries relatively low risk, it is necessary to quantify perioperative risks from a large patient cohort and identify factors contributing to short-term and long-term outcomes.

Methods: Patients who underwent craniotomy for resection of CMs between January 2012-December 2018 at a single large academic center were reviewed for pre-operative demographics, radiographic characteristics, and post-operative outcomes.

Results: 122 cases of CMs were identified. Common presenting symptoms included headache (39.3%), seizure (27.0%) and weakness/paralysis (18%). CMs were located over frontal, parietal, temporal, and occipital lobes in 57.4%, …

Hepatocellular Carcinoma Treated With Microwave Ablation Prior To Liver Transplantation, Nicole Wagner, Amanda Smolock, Michael Markovitz, Varun Danda, Christopher Neely, Warren Maley, Jesse Civan, Colette Shaw

Phase 1

Introduction: Ablation is a minimally invasive procedure that limits local liver tumor progression and prolongs patients’ transplantation eligibility. Microwave ablation (MWA) utilizes higher temperatures than the standard of care, radiofrequency ablation (RFA), which increases efficiency. Meta-analyses compared MWA with RFA for the treatment of HCC and showed similar efficacy and safety between these modalities. However, limited pathologic data exists determining whether explanted tumors remained viable after MWA.

Methods: Our database was reviewed retrospectively for patients with HCC who underwent MWA prior to liver transplantation between 2013 and 2019. Patient demographics, etiology of disease, tumor size, procedure details, bilirubin, MELD, …

Conjunctival Melanoma: Features Based On The Fitzpatrick Skin Type (Fst) In 540 Patients At A Single Ocular Oncology Center, Sunihidi Ramesh, Antonio Yaghy, Lauren A. Dalvin, Sara E. Lally, Jerry A. Shields, Carol L. Shields

Phase 1

Background: The Fitzpatrick skin type (FST) is a classification system for skin pigmentation that has been used to stratify risk for cutaneous melanoma; however, it has not yet been explored in the context of conjunctival melanoma. Herein, we examine FST and its association with the clinical features of conjunctival melanoma.

Methods: A retrospective review was conducted on 540 medical records of patients with pathologic diagnosis of conjunctival melanoma. The patients were categorized according to the FST classification based on their external facial photographs at presentation. This includes: Type I (white skin color), Type II (fair skin color), Type III (average …

The Presence Of Gc-C In Extracellular Vesicles Secreted By Colorectal Cancer Cells, Alexandre Martinez, Adam E. Snook

Phase 1

Background: Guanylyl Cyclase C (GC-C) is a membrane-bound protein found on intestinal epithelial cells involved in the activation of CFTR. This protein has previously been involved in the development of colorectal cancer.

Extracellular vesicles (EVs) are bilayered vesicles of varying size (30 to 1,000 + nm in diameter) that believed to be secreted by all cells in the human body. In the past decade, EVs have garnered attention due to their impact in the field of oncology, where they have been shown to potentially serve as biomarkers for various cancers.

In this study, we looked at the EVs secreted …

Statistics Of Tumor Micro-Environment, Brenton Maisel, Inna Chervoneva

Phase 1

Introduction: Immune cells play a prominent role in keeping tumors suppressed, but how the distribution of these immune cells within a tumor’s microenvironment remains poorly understood. The long-term goal of this project is to study how statistical spatial distributions of different immune cells is associated with clinical outcome. The first objective is developing an algorithm for identifying different types of immune cells.

Methods: The data motivating this project includes spatial localization information (x-y coordinates) and expression levels of immune cell CD markers quantified by immunofluorescence immunohistochemistry (IF-IHC) in ~1,500 cases of invasive breast cancer. Using expression levels of CD markers …

The Role Of Rassf5 On Cell Growth And Hippo Signaling In Rhabdomyosarcoma, Megan Garver, Lee Helman, Md, Katrina Slemmons, Phd

Phase 1

Introduction: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Dysregulation of the Hippo pathway, a signaling cascade that regulates many biological processes, is associated with many human cancers. The goal of my project was to delete RASSF5, a regulator of the Hippo pathway, in RMS cells utilizing CRISPR/Cas9 and then to evaluate how the absence of RASSF5 affects RMS cell growth and Hippo signaling, with and without DNMTi Tx.

Methods: A lipofectamine transfection was performed in two different RMS cell lines, Rh30 & RD, in which two different CRIPSR/Cas9 vectors with RASSF5 guide RNA were introduced. …

Ethnic Differences In Germline Genetic Testing For Breast Cancer, Kathryn Dent, Rebecca J. Jaslow, Md

Phase 1

Introduction: Ethnic variations in uptake of genetic testing and differences in findings of germline mutations within ethnic groups, are not well understood. The goal of this research is to assess for any such differences or similarities within a genetic counseling and testing program at an urban Cancer Center.

Methods: This is a non-comparative, descriptive epidemiology study assessing individuals with a diagnosis of breast cancer undergoing genetic counseling at the TJUH Sidney Kimmel Cancer Center in Philadelphia between 2014 and 2019. Data were compiled onto Research Electronic Data Capture (REDCAP) and analyzed statistically.

Results: Patients with Breast Cancer (n=1075) were included …

Differential Iron Regulatory Genetics In 2d & 3d Culture Of Breast Cancer Cells, Tyler Hanna, Suzy Torti Ph. D, Frank Torti M.D., Mph, Nicole Farra Ph. D.

Honors Scholar Theses

The iron regulatory axis has consistently been shown to be perturbed in cancer cell lines relative to non-cancerous cell lines. As cancer cells rapidly divide and grow, they require iron to fuel many intracellular processes, including DNA replication and protein synthesis. Three-dimensional cell culture is an increasingly popular method of culture that purportedly more accurately mimics the in vivo microenvironment of cancers over traditional two-dimensional culture. This project was prompted by previous lab results to investigate differential iron regulatory gene expression in 2D and 3D spheroid culture models. We replicated the findings that the gene hepcidin is induced in 3D …

Cyclin D1-Mediated Microrna Expression Signature Predicts Breast Cancer Outcome, Guangxue Wang, Michael Gormley, Jing Qiao, Qian Zhao, Min Wang, Gabriele Disante, Shengqiong Deng, Lin Dong, Timothy G. Pestell, Xiaoming Ju, Mathew C. Casimiro, Sankar Addya, Adam Ertel, Ayden Tozeren, Qinchuan Li, Zuoren Yu, Richard G. Pestell

Department of Cancer Biology Faculty Papers

Background: Genetic classification of breast cancer based on the coding mRNA suggests the evolution of distinct subtypes. Whether the non-coding genome is altered concordantly with the coding genome and the mechanism by which the cell cycle directly controls the non-coding genome is poorly understood.

Methods: Herein, the miRNA signature maintained by endogenous cyclin D1 in human breast cancer cells was defined. In order to determine the clinical significance of the cyclin D1-mediated miRNA signature, we defined a miRNA expression superset from 459 breast cancer samples. We compared the coding and non-coding genome of breast cancer subtypes.

Results: Hierarchical clustering of …

Beta-Catenin Cleavage Enhances Transcriptional Activation, Tatiana Goretsky, Emily M. Bradford, Qing Ye, Olivia F. Lamping, Tomas Vanagunas, Mary Pat Moyer, Patrick C. Keller, Preetika Sinh, Josep M. Llovet, Tianyan Gao, Qing-Bai She, Linheng Li, Terrence A. Barrett

Internal Medicine Faculty Publications

Nuclear activation of Wnt/β-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that β-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of β-catenin phosphorylated at serine 552 (pβ-Cat⁵⁵²). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pβ-Cat⁵⁵², increased to the exclusion of full size (FS) forms of β-catenin. LMW β-catenin lacks both termini, leaving residues in the armadillo repeat intact. Further experiments showed that TCF4 predominantly binds LMW pβ-Cat⁵⁵² in the nucleus of inflamed and …

Electrotransfer Of Different Control Plasmids Elicits Different Antitumor Effectiveness In B16.F10 Melanoma, Masa Bosnjak, Tanjo Jesenko, Urska Kamensek, Gregor Sersa, Jaka Lavrencak, Loree Heller, Maja Cemazar

Bioelectrics Publications

Several studies have shown that different control plasmids may cause antitumor action in different murine tumor models after gene electrotransfer (GET). Due to the differences in GET protocols, plasmid vectors, and experimental models, the observed antitumor effects were incomparable. Therefore, the current study was conducted comparing antitumor effectiveness of three different control plasmids using the same GET parameters. We followed cytotoxicity in vitro and the antitumor effect in vivo after GET of control plasmids pControl, pENTR/U6 scr and pVAX1 in B16.F10 murine melanoma cells and tumors. Types of cell death and upregulation of selected cytosolic DNA sensors and cytokines were …

Glypican-3 And Cd81 Promote Development Of Hepatocellular Carcinoma And Hepatoblastoma Through Negative Selection., Yuhua Xue, Wendy Mars, William Bowen, Aatur D. Singhi, Sarangarajan Ranganathan, George K. Michalopoulos

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

Frontiers In Precision Medicine Ii: Cancer, Big Data And The Public, Emily Coonrod, Jorge L. Contreras, Willard Dere, Jeffrey Botkin, Leslie Francis, Jim Tabery

Utah Law Faculty Scholarship

Precision medicine is being developed within a complex landscape of public policy, science, economics, law, and regulation. In these and other policy areas, the goal of developing individually-tailored therapies poses novel challenges for health care research, delivery and policy. In this symposium, a range of experts in genetics, medicine, bioinformatics, intellectual property, health economics and bioethics identified and discussed many of the pressing questions raised by the development and practice of precision medicine. These and other issues will need to be taken into account as precision medicine moves ahead and becomes the standard of medical practice and care in the …

The Role Of Ng2 Proteoglycan In Glioma., Sridevi Yadavilli, Eugene I Hwang, Roger J. Packer, Javad Nazarian

Neurology Faculty Publications

Neuron glia antigen-2 ((NG2), also known as chondroitin sulphate proteoglycan 4, or melanoma-associated chondroitin sulfate proteoglycan) is a type-1 membrane protein expressed by many central nervous system (CNS) cells during development and differentiation and plays a critical role in proliferation and angiogenesis. 'NG2' often references either the protein itself or the highly proliferative and undifferentiated glial cells expressing high levels of NG2 protein. NG2 glia represent the fourth major type of neuroglia in the mammalian nervous system and are classified as oligodendrocyte progenitor cells by virtue of their committed oligodendrocyte generation in developing and adult brain. Here, we discuss NG2 …

Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer

University Scholar Projects

Somatic mutations may drive tumorigenesis or lead to new, immunogenic epitopes (neoantigens). The immune system is thought to represses neoplastic growths through the recognition of neoantigens presented only by tumor cells. To study mutations as well as the immune response to mutation-generated antigens, we have created a conditional knockin mouse line with a gene encoding, 5’ to 3’, yellow fluorescent protein (YFP), ovalbumin (which is processed to the immunologically recognizable peptide, SIINFEKL), and cyan fluorescent protein (CFP), or, YFP-ovalbumin-CFP. A frame shift mutation has been created at the 5’ end of the ovalbumin gene, hence YFP should always be expressed, …