Digital Commons Network^™

Neurofibromatosis Type 1 Has A Wide Spectrum Of Growth Hormone Excess, Fady Hannah-Shmouni, Giampaolo Trivellin, Pablo Beckers, Lefkothea P Karaviti, Maya Lodish, Christina Tatsi, Adekunle M Adesina, Fotini Adamidou, Gesthimani Mintziori, Jami L Josefson, Martha Quezado, Constantine A Stratakis

Faculty, Staff and Students Publications

Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3−5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29−52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH …

Targeting Non-Coding Rnas To Overcome Cancer Therapy Resistance, Baoqing Chen, Mihnea P Dragomir, Chen Yang, Qiaoqiao Li, David Horst, George A Calin

Faculty, Staff and Student Publications

It is now well known that non-coding RNAs (ncRNAs), rather than protein-coding transcripts, are the preponderant RNA transcripts. NcRNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation, apoptosis, invasion, metastasis, and genomic instability. Despite recent discoveries in cancer therapy, resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy continue to be a major setback. Recent studies have shown that ncRNAs also play a major role in resistance to different cancer therapies by rewiring essential signaling pathways. In this review, we present the intricate mechanisms through …

Closing The Loop: Automatically Identifying Abnormal Imaging Results In Scanned Documents, Akshat Kumar, Heath Goodrum, Ashley Kim, Carly Stender, Kirk Roberts, Elmer V Bernstam

Faculty, Staff and Student Publications

OBJECTIVES: Scanned documents (SDs), while common in electronic health records and potentially rich in clinically relevant information, rarely fit well with clinician workflow. Here, we identify scanned imaging reports requiring follow-up with high recall and practically useful precision.

MATERIALS AND METHODS: We focused on identifying imaging findings for 3 common causes of malpractice claims: (1) potentially malignant breast (mammography) and (2) lung (chest computed tomography [CT]) lesions and (3) long-bone fracture (X-ray) reports. We train our ClinicalBERT-based pipeline on existing typed/dictated reports classified manually or using ICD-10 codes, evaluate using a test set of manually classified SDs, and compare against …

Applying Requisite Imagination To Safeguard Electronic Health Record Transitions, Dean F Sittig, Priti Lakhani, Hardeep Singh

Faculty, Staff and Student Publications

Over the next decade, many health care organizations (HCOs) will transition from one electronic health record (EHR) to another; some forced by hospital acquisition and others by choice in search of better EHRs. Herein, we apply principles of Requisite Imagination, or the ability to imagine key aspects of the future one is planning, to offer 6 recommendations on how to proactively safeguard these transitions. First, HCOs should implement a proactive leadership structure that values communication. Second, HCOs should implement proactive risk assessment and testing processes. Third, HCOs should anticipate and reduce unwarranted variation in their EHR and clinical processes. Fourth, …

Cngpld: Case-Control Copy-Number Analysis Using Gaussian Process Latent Difference, David J H Shih, Ruoxing Li, Peter Müller, W Jim Zheng, Kim-Anh Do, Shiaw-Yih Lin, Scott L Carter

Faculty, Staff and Student Publications

MOTIVATION: Cross-sectional analyses of primary cancer genomes have identified regions of recurrent somatic copy-number alteration, many of which result from positive selection during cancer formation and contain driver genes. However, no effective approach exists for identifying genomic loci under significantly different degrees of selection in cancers of different subtypes, anatomic sites or disease stages.

RESULTS: CNGPLD is a new tool for performing case-control somatic copy-number analysis that facilitates the discovery of differentially amplified or deleted copy-number aberrations in a case group of cancer compared with a control group of cancer. This tool uses a Gaussian process statistical framework in order …

Variability Of Care And Access To Transplantation For Children With Biliary Atresia Who Need A Liver Replacement, Jean De Ville De Goyet, Toni Illhardt, Christophe Chardot, Peace N Dike, Ulrich Baumann, Katherine Brandt, Barbara E Wildhaber, Mikko Pakarinen, Fabrizio Di Francesco, Ekkehard Sturm, Marianna Cornet, Caroline Lemoine, Eva Doreen Pfister, Ana M Calinescu, Maria Hukkinen, Sanjiv Harpavat, Fabio Tuzzolino, Riccardo Superina

Faculty, Staff and Students Publications

Background & Aims: Biliary atresia (BA) is the commonest single etiology indication for liver replacement in children. As timely access to liver transplantation (LT) remains challenging for small BA children (with prolonged waiting time being associated with clinical deterioration leading to both preventable pre- and post-transplant morbidity and mortality), the care pathway of BA children in need of LT was analyzed—from diagnosis to LT—with particular attention to referral patterns, timing of referral, waiting list dynamics and need for medical assistance before LT. Methods: International multicentric retrospective study. Intent-to-transplant study analyzing BA children who had indication for LT early in life …

Human Pancreatic Microenvironment Promotes Β-Cell Differentiation Via Non-Canonical Wnt5a/Jnk And Bmp Signaling, Jolanta Chmielowiec, Wojciech J Szlachcic, Diane Yang, Marissa A Scavuzzo, Katrina Wamble, Alejandro Sarrion-Perdigones, Omaima M Sabek, Koen J T Venken, Malgorzata Borowiak

Faculty, Staff and Students Publications

In vitro derivation of pancreatic β-cells from human pluripotent stem cells holds promise as diabetes treatment. Despite recent progress, efforts to generate physiologically competent β-cells are still hindered by incomplete understanding of the microenvironment's role in β-cell development and maturation. Here, we analyze the human mesenchymal and endothelial primary cells from weeks 9-20 fetal pancreas and identify a time point-specific microenvironment that permits β-cell differentiation. Further, we uncover unique factors that guide in vitro development of endocrine progenitors, with WNT5A markedly improving human β-cell differentiation. WNT5A initially acts through the non-canonical (JNK/c-JUN) WNT signaling and cooperates with Gremlin1 to inhibit …

Autologous Stem Cell Transplantation For Large B-Cell Lymphoma With Secondary Central Nervous System Involvement, Serkan Akin, Chitra Hosing, Issa Khouri, Sairah Ahmed, Amin Alousi, Nathan Fowler, Jacinth Joseph, Jonathan Truxillo, Jeremy L Ramdial, Farzaneh Maadani, Gabriela Rondon, May Daher, Jin S Im, Raphael Steiner, Jason Westin, Swaminathan P Iyer, Bouthaina Dabaja, Paolo Anderlini, Uday R Popat, Muzaffar H Qazilbash, Christopher R Flowers, Elizabeth Shpall, Richard E Champlin, Yago Nieto, Samer A Srour

Faculty, Staff and Student Publications

Secondary central nervous system large B-cell lymphoma (SCNSL) is rare, with a generally poor prognosis. There is limited data about the role of autologous stem cell transplantation (ASCT) in these high-risk patients. We explored in this study treatment outcomes and prognostic factors for patients with SCNSL who underwent ASCT. We included all consecutive patients who underwent ASCT at our institution. Primary endpoints were progression-free survival (PFS) and overall survival (OS). One-hundred two patients were identified. Median age at transplant was 56 (range, 21-71) years. With a median follow-up of 56 (range, 1-256) months, the median PFS and OS were 40 …

Distinct Molecular And Immune Hallmarks Of Inflammatory Arthritis Induced By Immune Checkpoint Inhibitors For Cancer Therapy, Sang T Kim, Yanshuo Chu, Mercy Misoi, Maria E Suarez-Almazor, Jean H Tayar, Huifang Lu, Maryam Buni, Jordan Kramer, Emma Rodriguez, Zulekha Hussain, Sattva S Neelapu, Jennifer Wang, Amishi Y Shah, Nizar M Tannir, Matthew T Campbell, Don L Gibbons, Tina Cascone, Charles Lu, George R Blumenschein, Mehmet Altan, Bora Lim, Vincente Valero, Monica E Loghin, Janet Tu, Shannon N Westin, Aung Naing, Guillermo Garcia-Manero, Noha Abdel-Wahab, Hussein A Tawbi, Patrick Hwu, Isabella C Glitza Oliva, Michael A Davies, Sapna P Patel, Jun Zou, Andrew Futreal, Adi Diab, Linghua Wang, Roza Nurieva

Faculty, Staff and Student Publications

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8

Predicting The Need For Therapeutic Intervention And Mortality In Acute Pancreatitis: A Two-Center International Study Using Machine Learning, Na Shi, Lan Lan, Jiawei Luo, Ping Zhu, Thomas R W Ward, Peter Szatmary, Robert Sutton, Wei Huang, John A Windsor, Xiaobo Zhou, Qing Xia

Faculty, Staff and Student Publications

BACKGROUND: Current approaches to predicting intervention needs and mortality have reached 65-85% accuracy, which falls below clinical decision-making requirements in patients with acute pancreatitis (AP). We aimed to accurately predict therapeutic intervention needs and mortality on admission, in AP patients, using machine learning (ML).

METHODS: Data were obtained from three databases of patients admitted with AP: one retrospective (Chengdu) and two prospective (Liverpool and Chengdu) databases. Intervention and mortality differences, as well as potential predictors, were investigated. Univariate analysis was conducted, followed by a random forest ML algorithm used in multivariate analysis, to identify predictors. The ML performance matrix was …

Role Of Drosophila In Human Disease Research 2.0, Masamitsu Yamaguchi, Shinya Yamamoto

Duncan NRI Faculty and Staff Publications

The fruit fly Drosophila melanogaster is a highly tractable animal model to study various human diseases [1]. Many biological pathways are highly conserved between humans and flies, and nearly 85% of human disease-causing genes have homologs in Drosophila. Drosophila has a relatively short life span and produces a large number of progenies, allowing researchers to perform rapid experiments that can easily be reproduced, allowing reliable statistical analyses of biological data. In addition, there are fewer ethical concerns when using Drosophila for biomedical research compared to mammalian models. Importantly, sophisticated genetic experiments can be designed to answer complicated …

An Imaging Biomarker Of Tumor-Infiltrating Lymphocytes To Risk-Stratify Patients With Hpv-Associated Oropharyngeal Cancer, Germán Corredor, Paula Toro, Can Koyuncu, Cheng Lu, Christina Buzzy, Kaustav Bera, Pingfu Fu, Mitra Mehrad, Kim A Ely, Mojgan Mokhtari, Kailin Yang, Deborah Chute, David J Adelstein, Lester D R Thompson, Justin A Bishop, Farhoud Faraji, Wade Thorstad, Patricia Castro, Vlad Sandulache, Shlomo A Koyfman, James S Lewis, Anant Madabhushi

Faculty, Staff and Students Publications

BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has excellent control rates compared to nonvirally associated OPSCC. Multiple trials are actively testing whether de-escalation of treatment intensity for these patients can maintain oncologic equipoise while reducing treatment-related toxicity. We have developed OP-TIL, a biomarker that characterizes the spatial interplay between tumor-infiltrating lymphocytes (TILs) and surrounding cells in histology images. Herein, we sought to test whether OP-TIL can segregate stage I HPV-associated OPSCC patients into low-risk and high-risk groups and aid in patient selection for de-escalation clinical trials.

METHODS: Association between OP-TIL and patient outcome was explored on whole slide …

Ndrg1 In Aggressive Breast Cancer Progression And Brain Metastasis, Emilly S Villodre, Xiaoding Hu, Bedrich L Eckhardt, Richard Larson, Lei Huo, Ester C Yoon, Yun Gong, Juhee Song, Shuying Liu, Naoto T Ueno, Savitri Krishnamurthy, Stefan Pusch, Debu Tripathy, Wendy A Woodward, Bisrat G Debeb

Faculty, Staff and Student Publications

BACKGROUND: N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies, including breast cancer, yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive.

METHODS: To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test …

Bismuth Nanoparticle And Polyhydroxybutyrate Coatings Enhance The Radiopacity Of Absorbable Inferior Vena Cava Filters For Fluoroscopy-Guided Placement And Longitudinal Computed Tomography Monitoring In Pigs, Jossana A Damasco, Steven Y Huang, Joy Vanessa D Perez, John Andrew T Manongdo, Katherine A Dixon, Malea L Williams, Megan C Jacobsen, Roland Barbosa, Gino Martin Canlas, Gouthami Chintalapani, Adam D Melancon, Rick R Layman, Natalie W Fowlkes, Elizabeth M Whitley, Marites P Melancon

Faculty, Staff and Student Publications

Inferior vena cava filters (IVCFs) constructed with poly-

Racial Disparities In Prostate Cancer: A Complex Interplay Between Socioeconomic Inequities And Genomics, Dallin Lowder, Kinza Rizwan, Collin Mccoll, Alyssa Paparella, Michael Ittmann, Nicholas Mitsiades, Salma Kaochar

Faculty, Staff and Students Publications

The largest US cancer health disparity exists in prostate cancer, with Black men having more than a two-fold increased risk of dying from prostate cancer compared to all other races. This disparity is a result of a complex network of factors including socioeconomic status (SES), environmental exposures, and genetics/biology. Inequity in the US healthcare system has emerged as a major driver of disparity in prostate cancer outcomes and has raised concerns that the actual incidence rates may be higher than current estimates. However, emerging studies argue that equalizing healthcare access will not fully eliminate racial health disparities and highlight the …

Mechanistic Origin Of Different Binding Affinities Of Sars-Cov And Sars-Cov-2 Spike Rbds To Human Ace2, Zhi-Bi Zhang, Yuan-Ling Xia, Jian-Xin Shen, Wen-Wen Du, Yun-Xin Fu, Shu-Qun Liu

Faculty, Staff and Student Publications

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (RBDCoV2) has a higher binding affinity to the human receptor angiotensin-converting enzyme 2 (ACE2) than the SARS-CoV RBD (RBDCoV). Here, we performed molecular dynamics (MD) simulations, binding free energy (BFE) calculations, and interface residue contact network (IRCN) analysis to explore the mechanistic origin of different ACE2-binding affinities of the two RBDs. The results demonstrate that, when compared to the RBDCoV2-ACE2 complex, RBDCoV-ACE2 features enhanced dynamicsand inter-protein positional movements and increased conformational entropy and conformational diversity. Although the inter-protein electrostatic attractive interactions are the primary determinant for the high ACE2-binding affinities of …

Envisioning Future Urinary Tract Infection Diagnostics, Robin Patel, Christopher R Polage, Jennifer Dien Bard, Larissa May, Francesca M Lee, Valeria Fabre, Mary K Hayden, Sarah D B Doernberg, David A Haake, Barbara W Trautner, Larissa Grigoryan, Ephraim L Tsalik, Kimberly E Hanson

Faculty, Staff and Students Publications

Urinary tract infections (UTIs) are among the most common bacterial infections in the United States and are a major driver of antibiotic use, both appropriate and inappropriate, across healthcare settings. Novel UTI diagnostics are a strategy that might enable better UTI treatment. Members of the Antibacterial Resistance Leadership Group Laboratory Center and the Infectious Diseases Society of America Diagnostics Committee convened to envision ideal future UTI diagnostics, with a view towards improving delivery of healthcare, patient outcomes and experiences, and antibiotic use, addressing which types of UTI diagnostics are needed and how companies might approach development of novel UTI diagnostics.

A Quantitative Look At Incarcerated Parents And Their Parenting Responsibilities In An Urban County Jail, Nancy P. Correa, Avni M. Bhalakia, Keisha White, Beth Van Horne

Journal of Applied Research on Children: Informing Policy for Children at Risk

An emerging body of research has shown that parental incarceration can negatively impact the emotional, social, and developmental health of children. However, most of the research has been conducted within prison populations. To better understand the scope and potential impact of parental incarceration in a large urban county jail, we surveyed 1,404 inmates in a county jail on their children, parenting responsibilities, and history of incarceration. Nearly half of respondents stated they were parents of at least one child under the age of 18. Over 90% of the incarcerated parents had been to jail or prison previously, 61% reported being …

Mendelian Randomization Supports Bidirectional Causality Between Telomere Length And Clonal Hematopoiesis Of Indeterminate Potential, Tetsushi Nakao, Alexander G Bick, Margaret A Taub, Seyedeh M Zekavat, Md M Uddin, Abhishek Niroula, Cara L Carty, John Lane, Michael C Honigberg, Joshua S Weinstock, Akhil Pampana, Christopher J Gibson, Gabriel K Griffin, Shoa L Clarke, Romit Bhattacharya, Themistocles L Assimes, Leslie S Emery, Adrienne M Stilp, Quenna Wong, Jai Broome, Cecelia A Laurie, Alyna T Khan, Albert V Smith, Thomas W Blackwell, Veryan Codd, Christopher P Nelson, Zachary T Yoneda, Juan M Peralta, Donald W Bowden, Marguerite R Irvin, Meher Boorgula, Wei Zhao, Lisa R Yanek, Kerri L Wiggins, James E Hixson, C Charles Gu, Gina M Peloso, Dan M Roden, Muagututi'a S Reupena, Chii-Min Hwu, Dawn L Demeo, Kari E North, Shannon Kelly, Solomon K Musani, Joshua C Bis, Donald M Lloyd-Jones, Jill M Johnsen, Michael Preuss, Russell P Tracy, Patricia A Peyser, Dandi Qiao, Pinkal Desai, Joanne E Curran, Barry I Freedman, Hemant K Tiwari, Sameer Chavan, Jennifer A Smith, Nicholas L Smith, Tanika N Kelly, Bertha Hidalgo, L Adrienne Cupples, Daniel E Weeks, Nicola L Hawley, Ryan L Minster, Samoan Obesity, Lifestyle And Genetic Adaptations Study (Olaga) Group, Ranjan Deka, Take T Naseri, Lisa De Las Fuentes, Laura M Raffield, Alanna C Morrison, Paul S Vries, Christie M Ballantyne, Eimear E Kenny, Stephen S Rich, Eric A Whitsel, Michael H Cho, M Benjamin Shoemaker, Betty S Pace, John Blangero, Nicholette D Palmer, Braxton D Mitchell, Alan R Shuldiner, Kathleen C Barnes, Susan Redline, Sharon L R Kardia, Gonçalo R Abecasis, Lewis C Becker, Susan R Heckbert, Jiang He, Wendy Post, Donna K Arnett, Ramachandran S Vasan, Dawood Darbar, Scott T Weiss, Stephen T Mcgarvey, Mariza De Andrade, Yii-Der Ida Chen, Robert C Kaplan, Deborah A Meyers, Brian S Custer, Adolfo Correa, Bruce M Psaty, Myriam Fornage, Joann E Manson, Eric Boerwinkle, Barbara A Konkle, Ruth J F Loos, Jerome I Rotter, Edwin K Silverman, Charles Kooperberg, John Danesh, Nilesh J Samani, Siddhartha Jaiswal, Peter Libby, Patrick T Ellinor, Nathan Pankratz, Benjamin L Ebert, Alexander P Reiner, Rasika A Mathias, Ron Do, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Pradeep Natarajan

Faculty, Staff and Student Publications

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD.

Exploring Preventive Healthcare In A High-Risk Vulnerable Population, Trisha L Amboree, Jane R Montealegre, Kayo Fujimoto, Osaro Mgbere, Charles Darkoh, Paige Padgett Wermuth

Faculty, Staff and Student Publications

This study describes preventive care behaviors and explores opportunities to deliver preventive sexual healthcare to a high-risk vulnerable population. Data from the National HIV Behavioral Surveillance (NHBS) system high-risk heterosexuals (HET) cycle (2019) in Houston, Texas, was used to describe preventive care utilization and assess the relationship between healthcare utilization and sociodemographic characteristics. More than 47% reported having no usual source of healthcare, and 94.6% reported receiving no non-HIV STI testing in the past 12 months. Additionally, many sociodemographic factors were associated with healthcare utilization and having a usual source of healthcare. Future efforts should be targeted at increasing preventive …

Meta-Analysis Of Genome-Wide Association Studies Identifies Ancestry-Specific Associations Underlying Circulating Total Tau Levels, Chloé Sarnowski, Mohsen Ghanbari, Joshua C Bis, Mark Logue, Myriam Fornage, Aniket Mishra, Shahzad Ahmad, Alexa S Beiser, Eric Boerwinkle, Vincent Bouteloup, Vincent Chouraki, L Adrienne Cupples, Vincent Damotte, Charles S Decarli, Anita L Destefano, Luc Djoussé, Alison E Fohner, Carol E Franz, Tiffany F Kautz, Jean-Charles Lambert, Michael J Lyons, Thomas H Mosley, Kenneth J Mukamal, Matthew P Pase, Eliana C Portilla Fernandez, Robert A Rissman, Claudia L Satizabal, Ramachandran S Vasan, Amber Yaqub, Stephanie Debette, Carole Dufouil, Lenore J Launer, William S Kremen, William T Longstreth, M Arfan Ikram, Sudha Seshadri

Faculty, Staff and Student Publications

Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10-8. We additionally detected 14 novel loci at P < 5 × 10-7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer's, and Parkinson's (F5, MAP1B, and BCAS3), with Alzheimer's pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.

Exploiting 4–1bb Immune Checkpoint To Enhance The Efficacy Of Oncolytic Virotherapy For Diffuse Intrinsic Pontine Gliomas, Virginia Laspidea, Montserrat Puigdelloses, Sara Labiano, Lucía Marrodán, Marc Garcia-Moure, Marta Zalacain, Marisol Gonzalez-Huarriz, Naiara Martínez-Vélez, Iker Ausejo-Mauleon, Daniel De La Nava, Guillermo Herrador-Cañete, Javier Marco-Sanz, Elisabeth Guruceaga, Carlos E De Andrea, María Villalba, Oren Becher, Massimo Squatrito, Verónica Matía, Jaime Gállego Pérez-Larraya, Ana Patiño-García, Sumit Gupta, Candelaria Gomez-Manzano, Juan Fueyo, Marta M Alonso

Faculty, Staff and Student Publications

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors, and patient survival has not changed despite many therapeutic efforts, emphasizing the urgent need for effective treatments. Here, we evaluated the anti-DIPG effect of the oncolytic adenovirus Delta-24-ACT, which was engineered to express the costimulatory ligand 4-1BBL to potentiate the antitumor immune response of the virus. Delta-24-ACT induced the expression of functional 4-1BBL on the membranes of infected DIPG cells, which enhanced the costimulation of CD8+ T lymphocytes. In vivo, Delta-24-ACT treatment of murine DIPG orthotopic tumors significantly improved the survival of treated mice, leading to long-term survivors that developed …

In-Depth Analysis Of Sars-Cov-2-Specific T Cells Reveals Diverse Differentiation Hierarchies In Vaccinated Individuals, Li Li, Muharrem Muftuoglu, Shaoheng Liang, Mahesh Basyal, Jiangxing Lv, Mehmet Emin Akdogan, Ken Chen, Michael Andreeff, Christopher R Flowers, Simrit Parmar

Faculty, Staff and Student Publications

SARS-CoV-2 vaccines pose as the most effective approach for mitigating the COVID-19 pandemic. High-degree efficacy of SARS-CoV-2 vaccines in clinical trials indicates that vaccination invariably induces an adaptive immune response. However, the emergence of breakthrough infections in vaccinated individuals suggests that the breadth and magnitude of vaccine-induced adaptive immune response may vary. We assessed vaccine-induced SARS-CoV-2 T cell response in 21 vaccinated individuals and found that SARS-CoV-2-specific T cells, which were mainly CD4+ T cells, were invariably detected in all individuals but the response was varied. We then investigated differentiation states and cytokine profiles to identify immune features associated with …

Lymphocyte Depletion Rate As A Biomarker Of Radiation Dose To Circulating Lymphocytes During Fractionated Partial-Body Radiation Therapy, Susannah G Ellsworth, Anirudh Yalamanchali, Tim Lautenschlaeger, Stuart A Grossman, Clemens Grassberger, Steven H Lin, Radhe Mohan

Faculty, Staff and Student Publications

Purpose: Radiation causes exponential depletion of circulating lymphocyte populations; in turn, radiation-induced lymphopenia is associated with worse survival for many solid tumors, possibly owing to attenuated antitumor immune responses. Identifying reliable and reproducible methods of calculating the radiation dose to circulating immune cells may facilitate development of techniques to reduce the risk and severity of radiation-induced toxic effects to circulating lymphocytes.

Methods and materials: Patient-specific lymphocyte loss rates were derived from a clinical data set including 684 adult patients with solid tumors. Multivariable linear regression was used to model the relationship between the lymphocyte loss rate and physical parameters of …

Retention Of Physician Assistants Within A Specialty After Completion Of A Postgraduate Training Program, John Ansiaux Pa-C, Carly Farrell Pa-C, Kathryn Hess Pa-C, Aubrey White Pa-C, Charlotte Peeters Pa-C, Jill Schulten Pa-C, Ryan Krasnosky Mpas, Pa-C, Dfaapa, Drph

Journal of Nursing & Interprofessional Leadership in Quality & Safety

Background: The advantages of a specialized training program have led to over 84 postgraduate training programs for Physician Assistants (PAs) covering over 25 specialties. Employee lateral mobility is more prevalent within the PA profession, which allows PA providers to switch between medical specialties. The versatility of PAs promotes higher turnover rates compared to physician counterparts. These high turnover rates can result in increased institutional burden. Postgraduate PA programs provide pre-employment exposure to more in-depth medical training, enabling a well-rounded knowledge base of the PA’s roles and responsibilities, minimizing turnover rates.

Purpose: The goal of this survey study is to identify …

Repurposing Probenecid For The Treatment Of Heart Failure (Re-Prosper-Hf): A Study Protocol For A Randomized Placebo-Controlled Clinical Trial, Jack Rubinstein, Nathan Robbins, Karen Evans, Gabrielle Foster, Kevin Mcconeghy, Toluwalope Onadeko, Julie Bunke, Melanie Parent, Xi Luo, Jacob Joseph, Wen-Chih Wu

Faculty, Staff and Student Publications

BACKGROUND: Improving contractility in heart failure with reduced ejection fraction (HFrEF) has resurfaced as a potential treatment goal. Inotropic therapy is now better understood through its underlying mechanism as opposed to the observed effect of increasing contractility. Calcitropes are a subgroup of inotropes that largely depend on the stimulation of adenylyl cyclase to transform ATP into cyclic adenosine monophosphate (cAMP). At least two clinically relevant calcitropes-istaroxime and probenecid-improve contractility through an increase in systolic intracellular calcium without activating cAMP production. Probenecid, which has been safely used clinically for decades in non-cardiac conditions, has recently been identified as an agonist of …

Predicted Gene Expression In Ancestrally Diverse Populations Leads To Discovery Of Susceptibility Loci For Lifestyle And Cardiometabolic Traits, Heather M Highland, Genevieve L Wojcik, Mariaelisa Graff, Katherine K Nishimura, Chani J Hodonsky, Antoine R Baldassari, Alanna C Cote, Iona Cheng, Christopher R Gignoux, Ran Tao, Yuqing Li, Eric Boerwinkle, Myriam Fornage, Jeffrey Haessler, Lucia A Hindorff, Yao Hu, Anne E Justice, Bridget M Lin, Danyu Lin, Daniel O Stram, Christopher A Haiman, Charles Kooperberg, Loic Le Marchand, Tara C Matise, Eimear E Kenny, Christopher S Carlson, Eli A Stahl, Christy L Avery, Kari E North, Jose Luis Ambite, Steven Buyske, Ruth J Loos, Ulrike Peters, Kristin L Young, Stephanie A Bien, Laura M Huckins

Faculty, Staff and Student Publications

One mechanism by which genetic factors influence complex traits and diseases is altering gene expression. Direct measurement of gene expression in relevant tissues is rarely tenable; however, genetically regulated gene expression (GReX) can be estimated using prediction models derived from large multi-omic datasets. These approaches have led to the discovery of many gene-trait associations, but whether models derived from predominantly European ancestry (EA) reference panels can map novel associations in ancestrally diverse populations remains unclear. We applied PrediXcan to impute GReX in 51,520 ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) participants (35% African American, 45% Hispanic/Latino, 10% Asian, …

Loss-Of-Function Variants In Tiam1 Are Associated With Developmental Delay, Intellectual Disability, And Seizures, Shenzhao Lu, Rebecca Hernan, Paul C Marcogliese, Yan Huang, Tracy S Gertler, Meltem Akcaboy, Shiyong Liu, Hyung-Lok Chung, Xueyang Pan, Xiaoqin Sun, Melahat Melek Oguz, Ulkühan Oztoprak, Jeroen H F De Baaij, Jelena Ivanisevic, Erin Mcginnis, Maria J Guillen Sacoto, Wendy K Chung, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in …

The Impact Of Pediatric Opioid-Related Visits On Us Emergency Departments, Tiffany Champagne-Langabeer, Marylou Cardenas-Turanzas, Irma T Ugalde, Christine Bakos-Block, Angela L Stotts, Lisa Cleveland, Steven Shoptaw, James R Langabeer

Faculty, Staff and Student Publications

BACKGROUND: While there is significant research exploring adults' use of opioids, there has been minimal focus on the opioid impact within emergency departments for the pediatric population.

METHODS: We examined data from the Agency for Healthcare Research, the National Emergency Department Sample (NEDS), and death data from the Centers for Disease Control and Prevention. Sociodemographic and financial variables were analyzed for encounters during 2014-2017 for patients under age 18, matching diagnoses codes for opioid-related overdose or opioid use disorder.

RESULTS: During this period, 59,658 children presented to an ED for any diagnoses involving opioids. The majority (68.5%) of visits were …

Gestational Age Variation In Human Placental Drug Transporters, Laura Goetzl, Nune Darbinian, Nana Merabova, Lindsay C Devane, Sammanda Ramamoorthy

Faculty, Staff and Student Publications

Patient and providers' fear of fetal exposure to medications may lead to discontinuation of treatment, disease relapse, and maternal morbidity. Placental drug transporters play a critical role in fetal exposure through active transport but the majority of data are limited to the 3rd trimester, when the majority of organogenesis has already occurred. Our objective was to define gestational age (GA) dependent changes in protein activity, expression and modifications of five major placental drug transporters: SERT, P-gp, NET, BCRP and MRP3. Apical brush border membrane fractions were prepared from fresh 1st, 2nd and 3rd trimester human placentas collected following elective pregnancy …