Genetic Phenomena Commons^™

Long Covid Incidence Across Sars-Cov-2 Lineages And Identification Of Conserved Spike Targets For Multivalent Vaccines, Grace J. Kim, Md Ashad Alam, Judy S. Crabtree, Rebecca Rose, Susanna L. Lamers, San Chu, Ronald Horswell, Daniel Fort, Lucio Miele

School of Graduate Studies Faculty Publications

Background: Long COVID remains poorly characterized at the genomic level. The primary aim of this study was to examine the relationship between viral sequences and the incidence of Long COVID at a tertiary care center in Louisiana between April 2020 and December 2022. A secondary aim was analysis of the Spike protein to identify conserved regions for multivalent vaccine targets. Method: To estimate Long COVID incidence across variants, we linked 4,789 SARS-CoV-2 sequences to 3,090 de-identified patient electronic health record information. The base population was defined as any patient with an International Classification of Diseases-10-Clinical Modification COVID-19 diagnosis code (U07.1) …

Sars-Cov-2 Rna-Binding Protein Suppresses Extracellular Mirna Release, Hyejin Mun, Chang Hoon Shin, Qingxuan Fei, Andrea Estefania Lopez Giraldo, Kyoung-Min Choi, Ji Won Lee, Kyungmin Kim, Kyung-Won Min, Leilei Shi, Mark T Bedford, Dong-Chan Kim, Yoo Lim Chun, Seonghyun Ryu, Dongin Kim, Jeong Ho Chang, Ryan T Westrope, Michelle Shay, Edward Nguyen, Junho K Hur, Abigail Agyenda, Nam Chul Kim, Sung-Ung Kang, Woonghee Lee, Je-Hyun Yoon

Faculty, Staff and Student Publications

SARS-CoV-2 is the betacoronavirus causing the COVID-19 pandemic. Although the SARS-CoV-2 genome and transcriptome were reported previously, the function of individual viral proteins is largely unknown. Utilizing biochemical and molecular biology methods, we identified that four SARS-CoV-2 RNA-binding proteins (RBPs) regulate the host RNA metabolism by direct interaction with mature miRNA let-7b revealed by Nuclear Magnetic Resonance spectroscopy (NMR). SARS-CoV-2 RBP Nsp9 primarily binds mature miRNA let-7b, a direct ligand of the Toll-like Receptor 7 (TLR7), one of the potential SARS-CoV-2 therapeutics. Nsp9 suppresses host gene expression possibly by promoting let-7b-mediated silencing of a cellular RNA polymerase, POLR2D. In addition, …

Immunogenomic Diversity Of Triple-Negative Breast Cancers In Obese And Non-Obese Black And White Women, Fokhrul Hossain, Denise Danos, Jovanny Zabaleta, Xiao-Cheng Wu, Luis Del Valle, Chindo Hicks, Jiande Wu, Jerneja Tomsic, Susan Neuhausen, Yuan Chun Ding, Kavitha Mukund, Zahra Mesrizadeh, Shankar Subramaniam, Augusto Ochoa, Victoria Seewaldt, Lucio Miele

School of Medicine Faculty Publications

Racial disparities in incidence and outcomes of triple-negative breast cancer (TNBC) have been attributed to ancestry, socioeconomic factors and/or obesity. We studied 253 TNBCs from 128 Black and 125 White women. Arms were balanced for age, AJCC stage, histological grade and molecular subtypes, and differed significantly in BMI distribution, obesity, and Area Deprivation Index. We examined survival rates, whole-transcriptome RNASeq and genetic ancestry. In our sample, Black race or obesity were not intrinsically predictive of poor outcomes. TNBC molecular portraits varied with stage and biological aggressiveness, irrespective of race. We identified a novel group of TNBCs with a distinctive luminal-like …

Runx2 Cooperates With Srebp1 To Rewire Cancer Metabolism And Promote Aggressiveness, Emanuele Vitale, Mila Gugnoni, Veronica Manicardi, Silvia Muccioli, Federica Torricelli, Benedetta Donati, Simonetta Piana, Gloria Manzotti, Elisa Salviato, Francesca Reggiani, Cristian Ascione, Rebecca Vezzani, Moira Ragazzi, Mattia Forcato, Oriana Romano, Silvio Bicciato, Aaron Goldman, Marco Tigano, Alessia Ciarrocchi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Embryonic Transcription Factors (TFs) are often reactivated in cancer, driving developmental gene programs that support phenotypic plasticity. Metabolic adaptation fuels this plasticity by supplying energy and molecular building blocks for growth. RUNX2, the master regulator of bone morphogenesis, is ectopically expressed in epithelial cancer, promoting metastasis through trans-differentiation processes like Epithelial-to-Mesenchymal Transition (EMT) and osteomimicry. By combining omics data with functional validation, we demonstrated that RUNX2 drives cancer cell metabolic rewiring by repressing mitochondrial respiration while promoting anabolic processes. We showed that RUNX2 upregulates key genes of lipid biosynthesis by regulating and cooperating with SREBP1. In vivo expression analysis in …

A Social Media Campaign And Web-Based Survey About Prostate Cancer Genetics: Mixed Methods Study, Amy Leader, Stacy Loeb, Preethi Selvan, Ashley Hunter, Rebecca Hartman, Scott Keith, Veda Giri

Department of Medical Oncology Faculty Papers

BACKGROUND: Germline genetic variants are important for prostate cancer (PCa) management and hereditary cancer risk assessment, but testing is underused. Furthermore, patients are often unaware of the genetic connections to PCa. Social media is increasingly serving as a source of awareness for health information and a method to gather data from a large population.

OBJECTIVE: There were three objectives: to (1) create and test social media messages related to PCa genetics and genetic testing, (2) determine which social media message was most engaging, and (3) assess knowledge of and attitudes toward PCa genetic testing through an online survey using the …

Secretogranin 2 Binds Lilrb4 Resulting In Immunosuppression, Xing Yang, Ryan Huang, Meng Fang, Yubo He, Jingjing Xie, Xiaoye Liu, Chengcheng Zhang, Qi Lou, Mi Deng, Wei Xiong, Cheryl Lewis, Zade Sadek, Ankit Gupta, Lianqi Chen, Xuewu Zhang, Lei Guo, Lin Xu, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

Immunosuppressive myeloid cells are important in a variety of physiological and pathological contexts, including tumor development, but how hormones might regulate their activity is unclear. Secretogranins, a family of secretory proteins in endocrine and neuronal cells, are proposed to function as prohormones or hormones, but their specific receptors are unknown. Here we show that secretogranin 2 (SCG2), a granin family member, functionally interacts with leukocyte immunoglobulin-like receptor B4 (LILRB4) on monocytic cells. Tumor-derived SCG2 promotes tumor growth in myeloid-specific LILRB4 transgenic mice in a T cell-dependent manner, whereas SCG2 deficiency in host mice impairs tumor progression and reduces infiltration of …

Whole-Genome Sequence-Based Association Analysis Of African American Individuals With Bipolar Disorder And Schizophrenia, Runjia Li, Sarah A Gagliano Taliun, Kevin Liao, Matthew Flickinger, Janet L Sobell, Giulio Genovese, Adam E Locke, Rebeca Rothwell Chiu, Jonathon Lefaive, Jiongming Wang, Taylor Martins, Sinéad Chapman, Anna Neumann, Robert E Handsaker, Donna K Arnett, Kathleen C Barnes, Eric Boerwinkle, David Braff, Brian E Cade, Myriam Fornage, Richard A Gibbs, Karin F Hoth, Lifang Hou, Charles Kooperberg, Ruth J F Loos, Ginger A Metcalf, Courtney G Montgomery, Alanna C Morrison, Zhaohui S Qin, Susan Redline, Alexander P Reiner, Stephen S Rich, Jerome I Rotter, Kent D Taylor, Karine A Viaud-Martinez, Tim B Bigdeli, Stacey Gabriel, Sebastian Zollner, Albert V Smith, Goncalo Abecasis, Steve A Mccarroll, Michele T Pato, Carlos N Pato, Michael Boehnke, James Knowles, Hyun Min Kang, Roel A Ophoff, Jason Ernst, Laura J Scott

Faculty, Staff and Student Publications

In studies of individuals of primarily European genetic ancestry, common and low-frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole-genome sequencing (∼27X) of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study). We increased power by incorporating 14,812 jointly called psychiatrically unscreened ancestry-matched controls from the Trans-Omics for Precision Medicine (TOPMed) Program for a total of …

Causes Of Symptoms And Symptom Persistence In Long Covid And Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Anthony L Komaroff, Robert Dantzer

Faculty, Staff and Student Publications

Debilitating symptoms for many years can follow acute COVID-19 ("long COVID"), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and various post-acute infection syndromes (PAISs). Together, long COVID and ME/CFS affect 60-400 million individuals, globally. Many similar underlying biological abnormalities have been identified in both conditions including autoantibodies against neural targets, endothelial dysfunction, acquired mitochondrial dysfunction, and a pro-inflammatory gut microbiome. Each of these abnormalities may directly cause some of the symptoms. In addition, the symptoms also may be caused by ancient, evolutionarily conserved symptomatic and metabolic responses to vital threats-sickness behavior and torpor-responses mediated by specific, recently discovered neural circuits. These neural …

Sensory Neuron-Expressed Fgf13 Controls Nociceptive Signaling In Diabetic Neuropathy Models, Aditya K Singh, Matteo Bernabucci, Nolan M Dvorak, Zahra Haghighijoo, Jessica Di Re, Nana A Goode, Feni K Kadakia, Laura A Maile, Olumarotimi O Folorunso, Paul A Wadsworth, Cynthia M Tapia, Pingyuan Wang, Jigong Wang, Haiying Chen, Yu Xue, Jully Singh, Kali Hankerd, Isaac J Gamez, Makenna Kager, Vincent Truong, Patrick Walsh, Stephanie I Shiers, Nishka Kuttanna, Hanyue Liao, Margherita Marchi, Erika Salvi, Ilaria D'Amato, Daniela D'Amico, Parsa Arman, Catharina G Faber, Rayaz A Malik, Marina De Tommaso, Dan Ziegler, Krishna Rajarathnam, Thomas A Green, Peter M Grace, Matthew R Sapio, Michael J Iadarola, Gregory D Cuny, Diana S Chow, Giuseppe Lauria Pinter, Steve Davidson, Dustin P Green, Jun-Ho La, Jin Mo Chung, Jia Zhou, Theodore J Price, Elizabeth Salisbury, Subo Yuan, Fernanda Laezza

Faculty, Staff and Student Publications

Nociception involves complex signaling, yet intrinsic mechanisms bidirectionally regulating this process remain unexplored. Here, we show that the fibroblast growth factor 13 (FGF13)/Nav1.7 protein-protein interaction (PPI) complex bidirectionally modulates nociception, and that the FGF13/Nav1.7 ratio is upregulated in type 2 diabetic neuropathy (T2DN). PW164, an FGF13/Nav1.7 channel C-terminal tail domain (CTD) PPI interface inhibitor, which reduces complex assembly, selectively suppressed Na+ currents sensitized by capsaicin-induced activation of TRPV1 channels in human induced pluripotent stem cell-derived (hIPSC-derived) sensory neurons and inhibited mechanical and thermal hyperalgesia in mice. FGF13 silencing mimics PW164 activity in culture and in vivo. Conversely, ZL192, an FGF13 …

Investigation Of A Pathogenic Inversion In Unc13d And Comprehensive Analysis Of Chromosomal Inversions Across Diverse Datasets, Tugce Bozkurt-Yozgatli, Ming Yin Lun, Jesse D Bengtsson, Ugur Sezerman, Ivan K Chinn, Zeynep Coban-Akdemir, Claudia M B Carvalho

Faculty, Staff and Student Publications

Inversions are known contributors to the pathogenesis of genetic diseases. Identifying inversions poses significant challenges, making it one of the most demanding structural variants (SVs) to detect and interpret. Recent advancements in sequencing technologies and the development of publicly available SV datasets have substantially enhanced our capability to explore inversions. However, a cross-comparison in those datasets remains unexplored. In this study, we reported a proband with familial hemophagocytic lymphohistiocytosis type-3 carrying a splicing variant (c.1389+1G>A) in trans with an inversion present in 0.006345% of individuals in gnomAD (v4.0) that disrupts UNC13D. Based on this result, we investigate the features …

Shared Genetic Architecture Of Posttraumatic Stress Disorder With Cardiovascular Imaging, Risk, And Diagnoses, Jie Shen, Wander Valentim, Eleni Friligkou, Cassie Overstreet, Karmel W. Choi, Dora Koller, Christopher J. O’Donnell, Murray B. Stein, Joel Gelernter, Haitao Lv, Ling Sun, Guido J. Falcone, Renato Polimanti, Gita A. Pathak, Edward Trapido, Ariane Rung, Et Al.

School of Public Health Faculty Publications

Patients with post-traumatic stress disorder face increased cardiovascular risk. This study examines shared genetic regions between post-traumatic stress disorder and 246 cardiovascular conditions across electronic health records, 82 cardiac imaging, and health behaviors defined by Life’s Essential 8. Post-traumatic stress disorder is genetically correlated with cardiovascular diagnoses in 33 regions, imaging traits in 4 regions, and health behaviors in 44 regions. Potentially shared causal variants between post-traumatic stress disorder and 17 cardiovascular conditions were observed in 11 regions. Subsequent observational analysis in AllofUS cohort showed post-traumatic stress disorder is associated with 13 diagnoses even after accounting for socioeconomic factors and …

Developing Reference Plans For Evaluating Global Clinical Trials Credentialing And Psqa Systems, Fre'etta M D Brooks, Mohammad Hussein, Jessica Lye, Christopher L Nelson, Nakamura Mitsuhiro, Mallory C Glenn, Patricia Diez, Rushil Patel, Maddison Shaw, Ileana Silvestre Patallo, Miriam Barry, Catharine H Clark, Joerg Lehmann, Stephen F Kry

Faculty, Staff and Student Publications

Purpose: To develop a practical framework for creating a diverse set of validated reference plans (varying in complexity) and implement a workflow to introduce beam modeling, calibration, and delivery errors into the reference cohort to test and compare various dosimetry audit methodologies.

Methods: Sixteen IMRT and VMAT reference plans were created, using RayStation software, for four phantom geometries based on established credentialing cases from participating Global Harmonization Group (GHG) members. These reference plans were first validated in a multi-ion-chamber phantom. Nine dosimetric errors (perturbations) were introduced into the plans by modifying beam model and/or delivery parameters (MLC-offset, MLC-transmission, leaf-tip-width, PDD, …

Hyalinization-Based Pathologic Response And Immune Infiltration Following Neoadjuvant Radiotherapy With Or Without Immune-Checkpoint Blockade In Localized Undifferentiated Pleomorphic Sarcoma, R S Traweek, M Zoghbi, R Lazcano, B M Cope, A J Bishop, A Farooqi, D Mitra, A K Yoder, B A Guadagnolo, D R Ingram, K Wani, D Shamsutdinova, A J Lazar, W-L Wang, C P Scally, E Z Keung, K E Torres, K K Hunt, R Ratan, J A Livingston, M S Nakazawa, D M Araujo, S Patel, V Ravi, A P Conley, M A Zarzour, N Somaiah, C L Roland, E F Nassif Haddad

Faculty, Staff and Student Publications

BACKGROUND: Standard-of-care treatment of localized undifferentiated pleomorphic sarcoma (UPS) involves preoperative radiotherapy (RT) and surgery. Combination of RT with immune-checkpoint blockade (ICB) represents a promising new strategy.

METHODS: Our primary objective was to assess survival outcomes and pathologically documented response in patients receiving RT with or without ICB or chemotherapy.

RESULTS: In a retrospective cohort of 68 patients with primary or locally recurrent UPS who received neoadjuvant RT with or without ICB, the ICB group had greater tumor hyalinization than the non-ICB group (89% compared with 30%, P = 0.018). In the non-ICB group, 19/37 patients (51%) achieved hyalinization-based pathologic …

Citrullinated Eno1 Vaccine Enhances Pd-1 Blockade In Mice Implanted With Murine Triple-Negative Breast Cancer Cells, Ricardo A León-Letelier, Alejandro M Sevillano-Mantas, Yihui Chen, Soyoung Park, Jody Vykoukal, Johannes F Fahrmann, Edwin J Ostrin, Candace Garrett, Rongzhang Dou, Yining Cai, Fu-Chung Hsiao, Jennifer B Dennison, Eduardo Vilar, Banu K Arun, Samir Hanash, Hiroyuki Katayama

Faculty, Staff and Student Publications

Background/Objectives:Cancer vaccine targets mostly include mutations and overexpressed proteins. However, cancer-associated post-translational modifications (PTMs) may also induce immune responses. Previously, our group established the enzyme protein arginine deiminase type-2 (PADI2), which catalyzes citrullination modification, is highly expressed in triple-negative breast cancer (TNBC), promoting antigenicity.

Methods: Here, we show the workflow of designing citrullinated enolase 1 (citENO1) vaccine peptides identified from breast cancer cells by mass spectrometry and demonstrate TNBC vaccine efficacy in the mouse model. Immunized mice with citENO1 peptides or the corresponding unmodified peptides, plus Poly I:C as an adjuvant, were orthotopically implanted with a TNBC murine …

Aapm Task Group No 249b-Essentials And Guidelines For Clinical Medical Physics Residency Training Programs, Jonathon A Nye, Joseph P Dugas, William D Erwin, David P Gierga, Darryl G Kaurin, Stephanie M Leon, Ho-Ling Anthony Liu, Zheng Feng Lu, Alphonso W Magri, Lynn N Rill, Leah K Schubert, Beth A Schueler, Irina Vergalasova, John Vetter, Brian D Wichman, Amy Shu-Jung Yu, Dandan Zheng

Faculty, Staff and Student Publications

The establishment of guidelines and curriculum standards for medical physics residency training is a critical component of setting expectations and competencies for the profession. Since the last publication of these standards, residency training has become integrated into the eligibility criteria for most medical physics certification bodies. The rapid growth of medical physics requires periodic review of the curriculum to remove outdated approaches, update established knowledge, and add emerging technologies. The goal of this document is to provide a reference standard for residency training program directors, training mentors, and residents to guide creation and/or optimization of their program's curriculum. The document …

Clinical And Fundamental Research Progressions On Tumor-Infiltrating Lymphocytes Therapy In Cancer, Jiandong Hu, Mengli Jin, Weihong Feng, Barbara Nassif-Rausseo, Alexandre Reuben, Chunhua Ma, Gregory Lizee, Fenge Li

Faculty, Staff and Student Publications

Malignant tumors represent a significant threat to human health. Among the various therapeutic strategies available, cancer immunotherapy-encompassing adoptive cell transfer (ACT) and immune checkpoint blockade therapy-has emerged as a particularly promising approach following surgical resection, radiotherapy, chemotherapy, and molecular targeted therapies. This form of treatment elicits substantial antigen-specific immune responses, enhances or restores anti-tumor immunity, thereby facilitating the control and destruction of tumor cells, and yielding durable responses across a range of cancers, which can lead to the eradication of tumor lesions and the prevention of recurrence. Tumor-infiltrating lymphocytes (TILs), a subset of ACT, are characterized by their heterogeneity and …

Heart To Heart: Exploring Why Cardiovascular Risk Is Higher In South Asians, Jasjeet Kaur Dhaliwal

Rowan-Virtua Research Day

Cardiovascular disease (CVD) is a leading global cause of mortality, but South Asians experience a disproportionately high burden of disease, often developing CVD at younger ages and with lower body mass indices compared to other populations. This project explores the underlying genetic and lifestyle factors contributing to elevated cardiovascular risk in South Asians, aiming to highlight the need for targeted prevention strategies and policy reforms.

A literature review was conducted using peer-reviewed studies, meta-analyses, and reviews published between 2007 and 2024. After screening 47 initial articles, 18 were selected for analysis based on their relevance to genetic and lifestyle risk …

Dose Prediction Via Deep Learning To Enhance Treatment Planning Of Lung Radiotherapy Including Simultaneous Integrated Boost Techniques, Wenhua Cao, Mary Gronberg, Stephen Bilton, Hana Baroudi, Skylar Gay, Christopher Peeler, Zhongxing Liao, Thomas J Whitaker, Karen Hoffman, Laurence E Court

Faculty, Staff and Student Publications

Background: Recent studies have shown deep learning techniques are able to predict three-dimensional (3D) dose distributions of radiotherapy treatment plans. However, their use in dose prediction for treatments with varied prescription doses including simultaneous integrated boost (SIB), that is, using multiple prescription doses within the same plan, and benefit in improving plan quality should be validated.

Purpose: To investigate the feasibility and potential benefit of using deep learning to predict dose distribution of volumetric modulated arc therapy (VMAT) including SIB techniques and improve treatment planning for patients with lung cancer.

Methods: The dose prediction model was trained with 93 retrospective …

T2-Weighted Imaging Of Rectal Cancer Using A 3d Fast Spin Echo Sequence With And Without Deep Learning Reconstruction: A Reader Study, Dan Nguyen, Sarah Palmquist, Ken-Pin Hwang, Jingfei Ma, Usama Salem, Jia Sun, Xinzeng Wang, Jong Bum Son, Randy Ernst, Peng Wei, Harmeet Kaur, Nir Stanietzky

Faculty, Staff and Student Publications

Purpose: To compare image quality and clinical utility of a T2-weighted (T2W) 3-dimensional (3D) fast spin echo (FSE) sequence using deep learning reconstruction (DLR) versus conventional reconstruction for rectal magnetic resonance imaging (MRI).

Methods: The study included 50 patients with rectal cancer who underwent rectal MRI consecutively between July 7, 2020 and January 20, 2021 using a T2W 3D FSE sequence with DLR and conventional reconstruction. Three radiologists reviewed the two sets of images, scoring overall SNR, motion artifacts, and overall image quality on a 3-point scale and indicating clinical preference for DLR or conventional reconstruction based on those three …

A Pioneering Artificial Intelligence Tool To Predict Treatment Outcomes In Ovarian Cancer Via Diagnostic Laparoscopy, Xiaotian Ma, Yu-Chun Hsu, Amma Asare, Kai Zhang, Deanna Glassman, Katelyn F Handley, Katherine Foster, Khwahish Sharma, Shannon Westin, Amir Jazaeri, Nicole D Fleming, Pratip K Bhattacharya, Xiaoqian Jiang, Anil K Sood, Shayan Shams

Faculty, Staff and Student Publications

Ovarian cancer is associated with high rates of patient mortality and morbidity. Laparoscopic assessment of tumor localization can be used for treatment planning in newly diagnosed high-grade serous ovarian carcinoma (HGSOC). While spread to multiple intra-abdominal areas is correlated with worse outcomes, whether other morphological tumor differences are also associated with patient outcomes is unknown. Given the large volume of visual information in laparoscopic videos, we investigated whether deep-learning models can capture implicit features and predict treatment outcomes. We developed a novel deep-learning framework using pre-treatment laparoscopic images to assess clinical outcomes following upfront standard treatment, defined as short progression-free …

Dock2 Deficiency And Gata2 Haploinsufficiency Can Underlie Critical Coronavirus Disease 2019 (Covid-19) Pneumonia, Sajjad Biglari, Leila Youssefian, Mohammad Amin Tabatabaiefar, Amir Hossein Saeidian, Bahareh Abtahi-Naeini, Erfan Khorram, Roya Sherkat, Atefeh Sohanforooshan Moghaddam, Fatemeh Mohaghegh, Maziyar Rahimi, Hamid Rahimi, Sharareh Babaei, Mohammad Shahrooei, Nikoo Mozafari, Shirin Zaresharifi, Fatemeh Vahidnezhad, Vida Homayouni, Lam C Tsoi, Johann E Gudjonsson, Hakon Hakonarson, Jean-Laurent Casanova, Emmanuelle Jouanguy, Vivien Béziat, Qian Zhang, Aurélie Cobat, Hassan Vahidnezhad

Faculty, Staff and Students Publications

The life-threatening coronavirus disease 2019 (COVID-19) affects about 1 in 1,000 healthy people under 50 without underlying conditions. Among patients with critical COVID-19 pneumonia, rare germline variants at genes controlling type I IFN immunity have been reported in up to 5% of patients. Causal etiologies in 80-85% of cases are still unknown. We analyzed two families with hypoxemic COVID-19 pneumonia for known single-gene inborn errors of immunity. In Family 1, two siblings with critical COVID-19 were homozygous for a DOCK2 variant, c.3624+5G>A. DOCK2 deficiency is a known T-cell disorder underlying severe viral diseases. The variant resulted in skipping exon …

Rare Damaging Ccr2 Variants Are Associated With Lower Lifetime Cardiovascular Risk, Marios K Georgakis, Rainer Malik, Omar El Bounkari, Natalie R Hasbani, Jiang Li, Jennifer E Huffman, Gabrielle Shakt, Reinier W P Tack, Tamara N Kimball, Yaw Asare, Alanna C Morrison, Noah L Tsao, Renae Judy, Braxton D Mitchell, Huichun Xu, May E Montasser, Ron Do, Eimear E Kenny, Ruth J F Loos, James G Terry, John Jeffrey Carr, Joshua C Bis, Bruce M Psaty, W T Longstreth, Kendra A Young, Sharon M Lutz, Michael H Cho, Jai Broome, Alyna T Khan, Fei Fei Wang, Nancy Heard-Costa, Sudha Seshadri, Ramachandran S Vasan, Nicholette D Palmer, Barry I Freedman, Donald W Bowden, Lisa R Yanek, Brian G Kral, Lewis C Becker, Patricia A Peyser, Lawrence F Bielak, Farah Ammous, April P Carson, Michael E Hall, Laura M Raffield, Stephen S Rich, Wendy S Post, Russel P Tracy, Kent D Taylor, Xiuqing Guo, Michael C Mahaney, Joanne E Curran, John Blangero, Shoa L Clarke, Jeffrey W Haessler, Yao Hu, Themistocles L Assimes, Charles Kooperberg, Jürgen Bernhagen, Christopher D Anderson, Scott M Damrauer, Ramin Zand, Jerome I Rotter, Paul S De Vries, Martin Dichgans

Faculty, Staff and Student Publications

BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested …

Cracking The Code Of Hbv Persistence: Cutting-Edge Approaches To Targeting Cccdna In Chronic Hepatitis B With Or Without Pyogenic Liver Abscesses, Umar Saeed, Zahra Zahid Piracha, Mahmood Khan, Muhammad Nouman Tariq, Syed Shahan Gilani, Muhammad Raza, Rakshana Munuswamy, Naveen Bose, Dilber Uzun Ozsahin, Ilker Özşahin, Surya M. Nauli

Pharmacy Faculty Articles and Research

Chronic Hepatitis B Virus (HBV) infection remains a formidable global health challenge, driving severe liver complications such as hepatocellular carcinoma (HCC) and pyogenic liver abscesses (PLA). At the core of HBV persistence lies covalently closed circular DNA (cccDNA), a viral reservoir that fuels ongoing infection despite antiviral treatments. This review highlights molecular mechanisms governing cccDNA formation, maintenance, and clearance, spotlighting innovative therapeutic strategies to disrupt this key viral element. We explore cutting-edge approaches, including epigenetic modulation to silence cccDNA, RNA interference (RNAi) for viral RNA degradation, and CRISPR/Cas genome editing to excise cccDNA directly. Additionally, emerging antiviral therapies and immunotherapies, …

Bevacizumab Beyond Progression: Impact Of Subsequent Bevacizumab Re-Treatment In Patients With Ovarian, Fallopian Tube, And Peritoneal Cancer After Progression, Amma Asare, Rebecca Ann Previs, Daniel Spinosa, Bryan Fellman, Amelia L Scott, Isabelle Mulder, May Mahmoud, Ahmed Enbaya, Jean Hansen Siedel, Lauren Cobb, Pamela T Soliman, Anil K Sood, Robert L Coleman, Angeles Alvarez Secord, Shannon N Westin

Faculty, Staff and Student Publications

Background: This study evaluated whether patients with epithelial ovarian, fallopian tube, and primary peritoneal carcinoma (OC) who are immediately re-treated with bevacizumab derive benefit after disease progression on a bevacizumab-containing regimen.

Methods: This multi-institutional, retrospective study compared patients with high grade non-mucinous epithelial OC who received bevacizumab followed directly by another bevacizumab-containing treatment regimen to patients who received bevacizumab followed by a regimen that did not contain bevacizumab (or received no further treatment). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier product-limit estimator and modeled via Cox proportional hazards regression.

Results: Among 226 patients with OC …

An Automated Treatment Planning Portfolio For Whole Breast Radiotherapy, Hana Baroudi, Leonard Che Fru, Deborah Schofield, Dominique L Roniger, Callistus Nguyen, Donald Hancock, Christine Chung, Beth M Beadle, Kent A Gifford, Tucker Netherton, Joshua S Niedzielski, Adam Melancon, Manickam Muruganandham, Meena Khan, Simona F Shaitelman, Sanjay Shete, Patricia Murina, Daniel Venencia, Sheeba Thengumpallil, Conny Vrieling, Joy Zhang, Melissa P Mitchell, Laurence E Court

Faculty, Staff and Student Publications

Background: Automation in radiotherapy presents a promising solution to the increasing cancer burden and workforce shortages. However, existing automated methods for breast radiotherapy lack a comprehensive, end-to-end solution that meets varying standards of care.

Purpose: This study aims to develop a complete portfolio of automated radiotherapy treatment planning for intact breasts, tailored to individual patient factors, clinical approaches, and available resources.

Methods: We developed five automated conventional treatment approaches and utilized an established RapidPlan model for volumetric arc therapy. These approaches include conventional tangents for whole breast treatment, two variants for supraclavicular nodes (SCLV) treatment with/without axillary nodes, and two …

American Association Of Physicists In Medicine (Aapm) Chapter Climate Check: Mixed Methods Analysis Of Survey Responses, Ashley J Cetnar, Ghada Aldosary, Meghan C Koo, Holly Lincoln, Angélica Pérez-Andújar, Surendra Prajapati, Samantha J Simiele, Kristi R G Hendrickson

Faculty, Staff and Student Publications

Introduction: The American Association of Physicists in Medicine (AAPM) recently shared results and recommendations from its first Equity, Diversity, and Inclusion (EDI) Climate Survey, which was designed to assess the climate at the workplace, the AAPM organization, and the AAPM regional chapter level. This work further explores the status of EDI at the regional chapter level.

Methods: AAPM's EDI Survey was distributed to 5500 members and had a response rate of 25%. In the survey, three open-ended comment boxes were provided for feedback, including one for regional AAPM members. Sixty-four percent of respondents indicated they were part of a regional …

Clinical Use Of Gafchromic Ebt4 Film For In Vivo Dosimetry For Total Body Irradiation, Emily Draeger, Fada Guan, Min-Young Lee, Dae Yup Han, William Donahue, Zhe Jay Chen

Faculty, Staff and Student Publications

Purpose: In vivo dosimetry is a common requirement to validate dose accuracy/uniformity in total body irradiation (TBI). Several detectors can be used for in vivo dosimetry, including thermoluminescent dosimeters (TLDs), diodes, ion chambers, optically stimulated luminescent dosimeters (OSLDs), and film. TLDs are well established for use in vivo but required expertise and clinical system availability may make them impractical for multifractionated TBI. OSLDs offer quick readout, but recalls have restricted their use. The purpose of this work was to validate the newly available Gafchromic EBT4 film for TBI in vivo dosimetry.

Methods: Film calibration curves were created under standard conditions …

Iroc Phantoms Accurately Detect Mlc Delivery Errors, Sharbacha S Edward, Julianne M Pollard-Larkin, Peter A Balter, Rebecca M Howell, Christine B Peterson, Stephen F Kry

Faculty, Staff and Student Publications

Purpose: We evaluated the impact of random and whole-bank multileaf collimator (MLC) delivery errors on dosimetric delivery accuracy in the Imaging and Radiation Oncology Core (IROC) phantom audits, as well as differences in delivery accuracy between the IROC phantom prescription and typical clinical fraction sizes.

Methods and materials: Plans were created for the IROC IMRT head and neck (H&N) and SBRT spine phantoms. MLC leaf errors were introduced into the plans: random shifts between -2 and 2 mm, and whole bank shifts of 0.5, 1, and 2 mm. Plans were recalculated and delivered on a Varian Truebeam, and the log …

A Randomized, Double-Blind, Placebo-Controlled Trial Of Il-7 In Critically Ill Patients With Covid-19, Manu Shankar-Hari, Bruno Francois, Kenneth E Remy, Cristina Gutierrez, Stephen Pastores, Thomas Daix, Robin Jeannet, Jane Blood, Andrew H Walton, Reinaldo Salomao, Georg Auzinger, David Striker, Robert S Martin, Nitin J Anand, James Bosanquet, Teresa Blood, Scott Brakenridge, Lyle L Moldawer, Vidula Vachharajani, Cassian Yee, Felipe Dal-Pizzol, Michel Morre, Frederique Berbille, Marcel Van Den Brink, Richard Hotchkiss

Faculty, Staff and Student Publications

Background: Lymphopenia and failure of lymphocytes to mount an early IFN-γ response correlate with increased mortality in COVID-19. Given the essential role of CD4 helper and CD8 cytotoxic cells in eliminating viral pathogens, this profound loss in lymphocytes may impair patients' ability to eliminate the virus. IL-7 is a pleiotropic cytokine that is obligatory for lymphocyte survival and optimal function.

Methods: We conducted a prospective, double-blind, randomized, placebo-controlled trial of CYT107, recombinant human IL-7, in 109 critically ill, patients with lymphopenia who have COVID-19. The primary endpoint was to assess CYT107's effect on lymphocyte recovery with secondary clinical endpoints including …

Rapidbrachyivbt: A Dosimetry Software For Patient-Specific Intravascular Brachytherapy Dose Calculations On Optical Coherence Tomography Images, Maryam Rahbaran, Jonathan Kalinowski, Joseph M Decunha, Kevin J Croce, Brian A Bergmark, James M G Tsui, Phillip M Devlin, Shirin A Enger

Faculty, Staff and Student Publications

Background: Coronary artery disease is the most common form of cardiovascular disease. It is caused by excess plaque along the arterial wall, blocking blood flow to the heart (stenosis). A percutaneous coronary intervention widens the arterial wall with the inflation of a balloon inside the lesion area and leaves behind a metal stent to prevent re-narrowing of the artery (restenosis). However, in-stent restenosis may occur due to damage to the arterial wall tissue, triggering neointimal hyperplasia, producing fibrotic and calcified plaques and narrowing the artery again. Drug-eluting stents, which slowly release medication to inhibit neointimal hyperplasia, are used to prevent …