Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Avaren-Fc, A Novel Immunotherapeutic, Recruits Nk Cells In B16f10 Melanoma Tumor Tissue, Sreevatsa Vemuri, Katarina Mayer, Nobuyuki Matoba

Posters-at-the-Capitol

Melanoma is the fifth most common cancer in the US, with limited effective immunotherapeutic options available for patients. Avaren-Fc (AvFc) is a novel experimental immunotherapeutic agent with a unique “lectibody” property. It is capable of targeting cancer cells through the selective recognition of high mannose glycans, which are aberrantly overrepresented on the surface of malignant cells. AvFc can interact with circulating effector immune cells equipped with Fc receptors, such as natural killer (NK) cells to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and kill cancer cells. Previous work has shown that AvFc effectively induces ADCC activity against B16F10 cancer cells in vitro …

Comparison Of Three Rapid Diagnostic Tests For Bloodstream Infections Using Benefit-Risk Evaluation Framework (Bed-Frame), Richard D Smith, Min Zhan, Shanshan Zhang, Surbhi Leekha, Anthony Harris, Yohei Doi, Scott Evans, J Kristie Johnson, Robert K Ernst

Faculty, Staff and Student Publications

Rapid diagnostic tests (RDTs) for bloodstream infections have the potential to reduce time to appropriate antimicrobial therapy and improve patient outcomes. Previously, an in-house, lipid-based, matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) method, Fast Lipid Analysis Technique (FLAT MS), has shown promise as a rapid pathogen identification method. In this study, FLAT MS for direct from blood culture identification was evaluated and compared to FDA-cleared identification methods using the Benefit-risk Evaluation Framework (BED-FRAME) analysis. FLAT MS was evaluated and compared to Bruker Sepsityper and bioMérieux BioFire FilmArray BCID2 using results from a previous study. For this study, 301 …

Development And Validation Of A Nomogram For Predicting Pulmonary Infection In Patients Receiving Immunosuppressive Drugs, Chuxuan Luo, Yue Zhang, Jiajie Zhang, Chen Jin, Xiaolan Ye, Yan Ren, Huajuan Shen, Maosheng Chen, Yiwen Li, Qiang He, Guangbiao Xu, Lina Shao

Faculty, Staff and Student Publications

Objective: Pulmonary infection (PI), a severe complication of immunosuppressive therapy, affects patients' prognosis. As part of this study, we aimed to construct a pulmonary infection prediction (PIP) model and validate it in patients receiving immunosuppressive drugs (ISDs). Methods: Totally, 7,977 patients being treated with ISDs were randomised 7:3 to the developing (n = 5,583) versus validation datasets (n = 2,394). Our predictive nomogram was established using the least absolute shrinkage and selection operator (LASSO) and multivariate COX regression analyses. With the use of the concordance index (C-index) and calibration curve, the prediction performance of the final model was …

Expanded T Lymphocytes In The Cerebrospinal Fluid Of Multiple Sclerosis Patients Are Specific For Epstein-Barr-Virus-Infected B Cells, Assaf Gottlieb, H Phuong T Pham, Jerome G Saltarrelli, J William Lindsey

Faculty, Staff and Student Publications

Epstein-Barr virus (EBV) infection has long been associated with multiple sclerosis (MS), but the role of EBV in the pathogenesis of MS is not clear. Our hypothesis is that a major fraction of the expanded clones of T lymphocytes in the cerebrospinal fluid (CSF) are specific for autologous EBV-infected B cells. We obtained blood and CSF samples from eight relapsing-remitting patients in the process of diagnosis. We stimulated cells from the blood with autologous EBV-infected lymphoblastoid cell lines (LCL), EBV, varicella zoster virus, influenza, and candida and sorted the responding cells with flow cytometry after 6 d. We sequenced the …

Novel Species Of Triatoma (Hemiptera: Reduviidae) Identified In A Case Of Vectorial Transmission Of Chagas Disease In Northern Belize, Sarah M Gunter, Alisa Nelson, Alexander R Kneubehl, Silvia A Justi, Russell Manzanero, Emily Zielinski-Gutierrez, Claudia Herrera, Julie Thompson, Rajendra Mandage, Hans Desale, Adrianna Maliga, Kim Bautista, Shannon E Ronca, Francis Morey, Rafael Chacon Fuentes, Beatriz Lopez, Eric Dumonteil, Gerhaldine H Morazan, Kristy O Murray

Faculty, Staff and Students Publications

Chagas disease is a leading cause of non-ischemic cardiomyopathy in endemic regions of Central and South America. In Belize, Triatoma dimidiata sensu lato has been identified as the predominate taxon but vectorial transmission of Chagas disease is considered to be rare in the country. We recently identified an acute case of vector-borne Chagas disease in the northern region of Belize. Here we present a subsequent investigation of triatomines collected around the case-patient's home. We identified yet undescribed species, closely related to Triatoma huehuetenanguensis vector by molecular systematics methods occurring in the peridomestic environment. The identification of a T. cruzi-positive, novel …

The Pan-Microbiome Profiling System Taxa4meta Identifies Clinical Dysbiotic Features And Classifies Diarrheal Disease, Qinglong Wu, Shyam Badu, Sik Yu So, Todd J Treangen, Tor C Savidge

Faculty, Staff and Students Publications

Targeted metagenomic sequencing is an emerging strategy to survey disease-specific microbiome biomarkers for clinical diagnosis and prognosis. However, this approach often yields inconsistent or conflicting results owing to inadequate study power and sequencing bias. We introduce Taxa4Meta, a bioinformatics pipeline explicitly designed to compensate for technical and demographic bias. We designed and validated Taxa4Meta for accurate taxonomic profiling of 16S rRNA amplicon data acquired from different sequencing strategies. Taxa4Meta offers significant potential in identifying clinical dysbiotic features that can reliably predict human disease, validated comprehensively via reanalysis of individual patient 16S data sets. We leveraged the power of Taxa4Meta's pan-microbiome …

Gad65abs Are Not Associated With Beta-Cell Dysfunction In Patients With T2d In The Grade Study, Christiane S Hampe, Ali Shojaie, Barbara Brooks-Worrell, Sepideh Dibay, Kristina Utzschneider, Steven E Kahn, Mary E Larkin, Mary L Johnson, Naji Younes, Neda Rasouli, Cyrus Desouza, Robert M Cohen, Jean Y Park, Hermes J Florez, Willy Marcos Valencia, Robert Stempel, Jerry P Palmer, Ashok Balasubramanyam

Faculty, Staff and Students Publications

CONTEXT: Autoantibodies directed against the 65-kilodalton isoform of glutamic acid decarboxylase (GAD65Abs) are markers of autoimmune type 1 diabetes (T1D) but are also present in patients with Latent Autoimmune Diabetes of Adults and autoimmune neuromuscular diseases, and also in healthy individuals. Phenotypic differences between these conditions are reflected in epitope-specific GAD65Abs and anti-idiotypic antibodies (anti-Id) against GAD65Abs. We previously reported that 7.8% of T2D patients in the GRADE study have GAD65Abs but found that GAD65Ab positivity was not correlated with beta-cell function, glycated hemoglobin (HbA1c), or fasting glucose levels.

CONTEXT: In this study, we aimed to better characterize islet autoantibodies …

Novel Pan-Err Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism And Mitochondrial Function, Weiyi Xu, Cyrielle Billon, Hui Li, Andrea Wilderman, Lei Qi, Andrea Graves, Jernie Rae Dela Cruz Rideb, Yuanbiao Zhao, Matthew Hayes, Keyang Yu, Mckenna Losby, Carissa S Hampton, Christiana M Adeyemi, Seok Jae Hong, Eleni Nasiotis, Chen Fu, Tae Gyu Oh, Weiwei Fan, Michael Downes, Ryan D Welch, Ronald M Evans, Aleksandar Milosavljevic, John K Walker, Brian C Jensen, Liming Pei, Thomas Burris, Lilei Zhang

Faculty, Staff and Students Publications

BACKGROUND: Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available.

METHODS: Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLU-PP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload-induced HF model in vivo. We …

A Novel Erβ High Throughput Microscopy Platform For Testing Endocrine Disrupting Chemicals, Derek A Abbott, Maureen G Mancini, Michael J Bolt, Adam T Szafran, Kaley A Neugebauer, Fabio Stossi, Daniel A Gorelick, Michael A Mancini

Faculty, Staff and Students Publications

In this study we present an inducible biosensor model for the Estrogen Receptor Beta (ERβ), GFP-ERβ:PRL-HeLa, a single-cell-based high throughput (HT) in vitro assay that allows direct visualization and measurement of GFP-tagged ERβ binding to ER-specific DNA response elements (EREs), ERβ-induced chromatin remodeling, and monitor transcriptional alterations via mRNA fluorescence in situ hybridization for a prolactin (PRL)-dsRED2 reporter gene. The model was used to accurately (Z' = 0.58-0.8) differentiate ERβ-selective ligands from ERα ligands when treated with a panel of selective agonists and antagonists. Next, we tested an Environmental Protection Agency (EPA)-provided set of 45 estrogenic reference chemicals with known …

Targeting Innate Immunity In Glioma Therapy, Andrew G Gillard, Dong Ho Shin, Lethan A Hampton, Andres Lopez-Rivas, Akhila Parthasarathy, Juan Fueyo, Candelaria Gomez-Manzano

Faculty, Staff and Student Publications

Currently, there is a lack of effective therapies for the majority of glioblastomas (GBMs), the most common and malignant primary brain tumor. While immunotherapies have shown promise in treating various types of cancers, they have had limited success in improving the overall survival of GBM patients. Therefore, advancing GBM treatment requires a deeper understanding of the molecular and cellular mechanisms that cause resistance to immunotherapy. Further insights into the innate immune response are crucial for developing more potent treatments for brain tumors. Our review provides a brief overview of innate immunity. In addition, we provide a discussion of current therapies …

Aging Fly Cell Atlas Identifies Exhaustive Aging Features At Cellular Resolution, Kenneth A Wilson, Sudipta Bar, Eric B Dammer, Enrique M Carrera, Brian A Hodge, Tyler A U Hilsabeck, Joanna Bons, George W Brownridge, Jennifer N Beck, Jacob Rose, Melia Granath-Panelo, Christopher S Nelson, Grace Qi, Akos A Gerencser, Jianfeng Lan, Alexandra Afenjar, Geetanjali Chawla, Rachel B Brem, Philippe M Campeau, Hugo J Bellen, Birgit Schilling, Nicholas T Seyfried, Lisa M Ellerby, Pankaj Kapahi

Faculty, Staff and Students Publications

Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects. Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function …

Exploiting The Carboxylate-Binding Pocket Of Β-Lactamase Enzymes Using A Focused Dna-Encoded Chemical Library, Suhyeorn Park, Jiayi Fan, Srinivas Chamakuri, Murugesan Palaniappan, Kiran Sharma, Xuan Qin, Jian Wang, Zhi Tan, Allison Judge, Liya Hu, Banumathi Sankaran, Feng Li, B V Venkataram Prasad, Martin M Matzuk, Timothy Palzkill

Faculty, Staff and Students Publications

β-Lactamase enzymes hydrolyze and thereby provide bacterial resistance to the important β-lactam class of antibiotics. The OXA-48 and NDM-1 β-lactamases cause resistance to the last-resort β-lactams, carbapenems, leading to a serious public health threat. Here, we utilized DNA-encoded chemical library (DECL) technology to discover novel β-lactamase inhibitors. We exploited the β-lactamase enzyme-substrate binding interactions and created a DECL targeting the carboxylate-binding pocket present in all β-lactamases. A library of 10

Genome-Wide Study Investigating Effector Genes And Polygenic Prediction For Kidney Function In Persons With Ancestry From Africa And The Americas, Odessica Hughes, Amy R Bentley, Charles E Breeze, Francois Aguet, Xiaoguang Xu, Girish Nadkarni, Quan Sun, Bridget M Lin, Thomas Gilliland, Mariah C Meyer, Jiawen Du, Laura M Raffield, Holly Kramer, Robert W Morton, Mateus H Gouveia, Elizabeth G Atkinson, Adan Valladares-Salgado, Niels Wacher-Rodarte, Nicole D Dueker, Xiuqing Guo, Yang Hai, Adebowale Adeyemo, Lyle G Best, Jianwen Cai, Guanjie Chen, Michael Chong, Ayo Doumatey, James Eales, Mark O Goodarzi, Eli Ipp, Marguerite Ryan Irvin, Minzhi Jiang, Alana C Jones, Charles Kooperberg, Jose E Krieger, Ethan M Lange, Matthew B Lanktree, James P Lash, Paulo A Lotufo, Ruth J F Loos, Vy Thi Ha My, Jesús Peralta-Romero, Lihong Qi, Leslie J Raffel, Stephen S Rich, Erik J Rodriquez, Eduardo Tarazona-Santos, Kent D Taylor, Jason G Umans, Jia Wen, Bessie A Young, Zhi Yu, Ying Zhang, Yii-Der Ida Chen, Tanja Rundek, Jerome I Rotter, Miguel Cruz, Myriam Fornage, Maria Fernanda Lima-Costa, Alexandre C Pereira, Guillaume Paré, Pradeep Natarajan, Shelley A Cole, April P Carson, Leslie A Lange, Yun Li, Eliseo J Perez-Stable, Ron Do, Fadi J Charchar, Maciej Tomaszewski, Josyf C Mychaleckyj, Charles Rotimi, Andrew P Morris, Nora Franceschini

Faculty, Staff and Students Publications

Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p < 5 × 10−8), of which two have not been previously reported in any ancestry group. We integrated fine-mapped loci with epigenomic and transcriptomic resources to highlight potential effector genes relevant to kidney physiology and disease, and reveal key regulatory elements and pathways involved in renal function and development. We demonstrate the varying but increased predictive power offered by a multi-ancestry polygenic score for eGFR and highlight the importance of population diversity in GWASs and multi-omics resources to enhance opportunities for clinical translation for all.

Delineating The Mechanism Of Fragility At Bcl6 Breakpoint Region Associated With Translocations In Diffuse Large B Cell Lymphoma, Vidya Gopalakrishnan, Urbi Roy, Shikha Srivastava, Khyati M Kariya, Shivangi Sharma, Saniya M Javedakar, Bibha Choudhary, Sathees C Raghavan

Faculty, Staff and Student Publications

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5' UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into …

Variants In The Wdr44 Wd40-Repeat Domain Cause A Spectrum Of Ciliopathy By Impairing Ciliogenesis Initiation, Andrea Accogli, Saurabh Shakya, Taewoo Yang, Christine Insinna, Soo Yeon Kim, David Bell, Kirill R Butov, Mariasavina Severino, Marcello Niceta, Marcello Scala, Hyun Sik Lee, Taekyeong Yoo, Jimmy Stauffer, Huijie Zhao, Chiara Fiorillo, Marina Pedemonte, Maria C Diana, Simona Baldassari, Viktoria Zakharova, Anna Shcherbina, Yulia Rodina, Christina Fagerberg, Laura Sønderberg Roos, Jolanta Wierzba, Artur Dobosz, Amanda Gerard, Lorraine Potocki, Jill A Rosenfeld, Seema R Lalani, Tiana M Scott, Daryl Scott, Mahshid S Azamian, Raymond Louie, Hannah W Moore, Neena L Champaigne, Grace Hollingsworth, Annalaura Torella, Vincenzo Nigro, Rafal Ploski, Vincenzo Salpietro, Federico Zara, Simone Pizzi, Giovanni Chillemi, Marzia Ognibene, Erin Cooney, Jenny Do, Anders Linnemann, Martin J Larsen, Suzanne Specht, Kylie J Walters, Hee-Jung Choi, Murim Choi, Marco Tartaglia, Phillippe Youkharibache, Jong-Hee Chae, Valeria Capra, Sung-Gyoo Park, Christopher J Westlake

Faculty, Staff and Students Publications

WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of …

Fusionpdb:: A Knowledgebase Of Human Fusion Proteins, Himansu Kumar, Lin-Ya Tang, Chengyuan Yang, Pora Kim

Faculty, Staff and Student Publications

Tumorigenic functions due to the formation of fusion genes have been targeted for cancer therapeutics (i.e. kinase inhibitors). However, many fusion proteins involved in various cellular processes have not been studied for targeted therapeutics. This is because the lack of complete fusion protein sequences and their whole 3D structures has made it challenging to develop new therapeutic strategies. To fill these critical gaps, we developed a computational pipeline and a resource of human fusion proteins named FusionPDB, available at https://compbio.uth.edu/FusionPDB. FusionPDB is organized into four levels: 43K fusion protein sequences (14.7K in-frame fusion genes, Level 1), over 2300 + 1267 …

Clinicalomicsdb: Exploring Molecular Associations Of Oncology Drug Responses In Clinical Trials, Chang In Moon, John Michael Elizarraras, Jonathan Thomas Lei, Byron Jia, Bing Zhang

Faculty, Staff and Students Publications

Matching patients to optimal treatment is challenging, in part due to the limited availability of real-world clinical datasets for predictive biomarker identification. The growing integration of omics profiling into clinical trials presents a new opportunity to tackle this challenge. Here, we introduce ClinicalOmicsDB, a web application for exploring molecular associations of oncology drug responses in clinical trials. This database includes transcriptomic data from 40 clinical trial studies, with 5913 patients spanning 11 cancer types. These studies include 67 treatment arms with a variety of chemotherapy, targeted therapy and immunotherapy drugs, and their combinations, which we organize based on an established …

A Syndromic Neurodevelopmental Disorder Caused By Rare Variants In Ppfia3, Maimuna S Paul, Sydney L Michener, Hongling Pan, Hiuling Chan, Jessica M Pfliger, Jill A Rosenfeld, Vanesa C Lerma, Alyssa Tran, Megan A Longley, Richard A Lewis, Monika Weisz-Hubshman, Mir Reza Bekheirnia, Nasim Bekheirnia, Lauren Massingham, Michael Zech, Matias Wagner, Hartmut Engels, Kirsten Cremer, Elisabeth Mangold, Sophia Peters, Jessica Trautmann, Jessica L Mester, Maria J Guillen Sacoto, Richard Person, Pamela P Mcdonnell, Stacey R Cohen, Laina Lusk, Ana S A Cohen, Jean-Baptiste Le Pichon, Tomi Pastinen, Dihong Zhou, Kendra Engleman, Caroline Racine, Laurence Faivre, Sébastien Moutton, Anne-Sophie Denommé-Pichon, Hyun Yong Koh, Annapurna Poduri, Jeffrey Bolton, Cordula Knopp, Dong Sun Julia Suh, Andrea Maier, Mehran Beiraghi Toosi, Ehsan Ghayoor Karimiani, Reza Maroofian, Gerald Bradley Schaefer, Vijayalakshmi Ramakumaran, Pradeep Vasudevan, Chitra Prasad, Matthew Osmond, Sarah Schuhmann, Georgia Vasileiou, Sophie Russ-Hall, Ingrid E Scheffer, Gemma L Carvill, Heather Mefford, Undiagnosed Diseases Network, Carlos A Bacino, Brendan H Lee, Hsiao-Tuan Chao

Faculty, Staff and Students Publications

PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Seventeen unique PPFIA3 variants were detected in 18 families. To determine the pathogenicity …

Preclinical Repurposing Of Sitagliptin As A Drug Candidate For Colorectal Cancer By Targeting Cd24/Ctnnb1/Sox4-Centered Signaling Hub, Jing-Wen Shih, Alexander T H Wu, Ntlotlang Mokgautsi, Po-Li Wei, Yan-Jiun Huang

Faculty, Staff and Student Publications

Despite significant advances in treatment modalities, colorectal cancer (CRC) remains a poorly understood and highly lethal malignancy worldwide. Cancer stem cells (CSCs) and the tumor microenvironment (TME) have been shown to play critical roles in initiating and promoting CRC progression, metastasis, and treatment resistance. Therefore, a better understanding of the underlying mechanisms contributing to the generation and maintenance of CSCs is crucial to developing CSC-specific therapeutics and improving the current standard of care for CRC patients. To this end, we used a bioinformatics approach to identify increased CD24/SOX4 expression in CRC samples associated with poor prognosis. We also …

An Evolutionary Perspective On Complex Neuropsychiatric Disease, Jon M Mcclellan, Anthony W Zoghbi, Joseph D Buxbaum, Carolina Cappi, James J Crowley, Jonathan Flint, Dorothy E Grice, Suleyman Gulsuner, Conrad Iyegbe, Sanjeev Jain, Po-Hsiu Kuo, Maria Claudia Lattig, Maria Rita Passos-Bueno, Meera Purushottam, Dan J Stein, Anna B Sunshine, Ezra S Susser, Christopher A Walsh, Olivia Wootton, Mary-Claire King

Faculty, Staff and Students Publications

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields …

Antiviral Effects Of Micafungin Against Pteropine Orthoreovirus, An Emerging Zoonotic Virus Carried By Bats, Eiichi Hondo, Tetsufumi Katta, Ayato Sato, Naoya Kadofusa, Tomoki Ishibashi, Hiroshi Shimoda, Hirokazu Katoh, Atsuo Iida

Faculty, Staff and Student Publications

Bat-borne emerging zoonotic viruses cause major outbreaks, such as the Ebola virus, Nipah virus, and/or beta coronavirus. Pteropine orthoreovirus (PRV), whose spillover event occurred from fruits bats to humans, causes respiratory syndrome in humans widely in South East Asia. Repurposing approved drugs against PRV is an effective tool to confront future PRV pandemics. We screened 2,943 compounds in an FDA-approved drug library and identified eight hit compounds that reduce viral cytopathic effects on cultured Vero cells. Real-time quantitative PCR analysis revealed that six of eight hit compounds significantly inhibited PRV replication. Among them, micafungin used clinically as an antifungal drug, …

Tim/Tam Receptors: A Potential Biomarker For Predicting Sensitivity To Zika Virus-Induced Oncolysis In Non-Small Cell Lung Cancers, Shankari Somasekar

Honors Undergraduate Theses

Non-small cell lung cancers (NSCLC) constitute 80-85% of lung cancers and are the leading cause of cancer-related deaths globally. The most common cause is prolonged smoking. Current treatment options for NSCLC include surgery, radiation, chemotherapy, targeted drug therapy, and immunotherapy. Although these medications are effective in the short term, patients often face issues of drug resistance and debilitating side effects with prolonged use. Currently, the use of Zika virus (ZIKV) is being researched as a possible alternative treatment for cancer, which minimizes side effects and the risk of drug resistance. TIM/TAM proteins are identified as the putative ZIKV receptors on …

Prioritizing Clinically Significant Lung Cancer Somatic Mutations For Targeted Therapy Through Efficient Ngs Data Filtering System, Jinlian Wang, Hui Li, Hongfang Liu

Faculty, Staff and Student Publications

In the realm of lung cancer treatment, where genetic heterogeneity presents formidable challenges, precision oncology demands an exacting approach to identify and hierarchically sort clinically significant somatic mutations. Current Next-Generation Sequencing (NGS) data filtering pipelines, while utilizing various external databases for mutation screening, often fall short in comprehensive integration and flexibility needed to keep pace with the evolving landscape of clinical data. Our study introduces a sophisticated NGS data filtering system, which not only aggregates but effectively synergizes diverse data sources, encompassing genetic variants, gene functions, clinical evidence, and an extensive body of literature. This system is distinguished by a …

Synergistic Effects Of Antimicrobial Components Of The Human-Derived Composite Amnion-Chorion Membrane On Bacterial Growth, Alexandra Su Brummerhop, Chun-Teh Lee, Robin Weltman, Gena D Tribble, Ransome Van Der Hoeven, Yulun Chiu, Jianming Hong, Bing-Yan Wang

Faculty, Staff and Student Publications

Introduction: The human-derived amnion-chorion membrane (ACM) has endogenous antimicrobial properties, which are important for preventing the colonization and survival of oral bacteria on exposed membranes. This project aimed to decipher the underlying mechanism by identifying the components of ACM that confer antibacterial properties. In addition, the antimicrobial efficacy of these identified components on oral bacteria was assessed.

Methods: Four antimicrobial proteins, histone H2A/H2B, cathelicidin LL-37, lactoferrin, and lysozyme, were identified via mass spectrometry in ACM. These proteins were then assessed for their efficacy in killing Streptococcus gordonii Challis. Log-phased bacterial cells were cultured with the commercially available proteins that were …

Artificial Intelligence-Powered Discovery Of Small Molecules Inhibiting Ctla-4 In Cancer, Navid Sobhani, Dana Rae Tardiel-Cyril, Dafei Chai, Daniele Generali, Jian-Rong Li, Jonathan Vazquez-Perez, Jing Ming Lim, Rachel Morris, Zaniqua N Bullock, Aram Davtyan, Chao Cheng, William K Decker, Yong Li

Faculty, Staff and Students Publications

BACKGROUND/OBJECTIVES: Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially for monoclonal antibody treatment directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with the B7 proteins CD80 and CD86. Small molecules impairing the CTLA-4/CD80 interaction have been developed; however, they directly target CD80, not CTLA-4.

SUBJECTS/METHODS: In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to identify those targeting CTLA-4. We validated the …

Does An Early, Balanced Resuscitation Strategy Reduce The Incidence Of Hypofibrinogenemia In Hemorrhagic Shock?, David T Lubkin, Krislynn M Mueck, Gabrielle E Hatton, Jason B Brill, Mariela Sandoval, Jessica C Cardenas, Charles E Wade, Bryan A Cotton

Faculty, Staff and Student Publications

OBJECTIVES: Some centers have recommended including concentrated fibrinogen replacement in massive transfusion protocols (MTPs). Given our center's policy of aggressive early balanced resuscitation (1:1:1), beginning prehospital, we hypothesized that our rates of hypofibrinogenemia may be lower than those previously reported.

METHODS: In this retrospective cohort study, patients presenting to our trauma center November 2017 to April 2021 were reviewed. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen

RESULTS: Of 29 782 patients, 6618 level 1 activations, and 1948 patients receiving emergency release blood,

CONCLUSIONS: Low rates of hypofibrinogenemia were found in our center which treats hemorrhage with early, balanced …

The Kidney In Heart Failure: The Role Of Venous Congestion, Oluwaseun Adebayo Bamodu, Chen-Chih Chung, Thomas R Pisanic, Alexander T H Wu

Faculty, Staff and Student Publications

BACKGROUND: Cancer stem cells (CSCs) have emerged as pivotal players in tumorigenesis, disease progression, and resistance to therapies.

OBJECTIVE: This comprehensive review delves into the intricate relationship between CSCs and the cell-of-origin in diverse cancer types.

DESIGN: Comprehensive review of thematically-relevant literature.

METHODS: We explore the underlying molecular mechanisms that drive the conversion of normal cells into CSCs and the impact of the cell-of-origin on CSC properties, tumor initiation, and therapeutic responses. Moreover, we discuss potential therapeutic interventions targeting CSCs based on their distinct cell-of-origin characteristics.

RESULTS: Accruing evidence suggest that the cell-of-origin, the cell type from which the tumor …

Measurement Of 8-Hydroxy-2′-Deoxyguanosine In Serum And Cerebrospinal Fluid Of Horses With Neuroaxonal Degeneration And Other Causes Of Proprioceptive Ataxia, Megan Palmisano, Jeaneen Kulp, Susan Bender, Darko Stefanovski, Mary Robinson, Amy Johnson

Faculty, Staff and Student Publications

BACKGROUND: Eight-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative damage evaluated in human neurodegenerative disease, has potential to correlate with postmortem diagnosis of neuroaxonal dystrophy/degenerative myeloencephalopathy (NAD/DM) in horses.

HYPOTHESIS: We hypothesized that 8-OHdG will be higher in CSF and serum from NAD/DM horses compared with horses with other neurologic diseases (CVSM, EPM) and a control group of neurologically normal horses. We also hypothesized that 8-OHdG will be higher in CSF compared with serum from NAD/DM horses.

ANIMALS: Fifty client-owned horses with postmortem diagnoses: 20 NAD/DM, 10 CVSM, 10 EPM, and 10 control horses. Serum and CSF samples were obtained between November …

Persistent Microbial Infections And Idiopathic Pulmonary Fibrosis – An Insight Into Non-Typeable Haemophilus Influenza Pathogenesis, Anthony Shadid, Haydn E Rich, Hunter Devaughn, Aleksey Domozhirov, Marie-Françoise Doursout, Tingting Weng-Mills, Kristin L Eckel-Mahan, Harry Karmouty-Quintana, Marcos I Restrepo, Pooja Shivshankar

Faculty, Staff and Student Publications

Interstitial lung disease (ILD) is characterized by chronic inflammation and scarring of the lungs, of which idiopathic pulmonary fibrosis (IPF) is the most devastating pathologic form. Idiopathic pulmonary fibrosis pathogenesis leads to loss of lung function and eventual death in 50% of patients, making it the leading cause of ILD-associated mortality worldwide. Persistent and subclinical microbial infections are implicated in the acute exacerbation of chronic lung diseases. However, while epidemiological studies have highlighted pollutants, gastric aspirate, and microbial infections as major causes for the progression and exacerbation of IPF, the role of persistent microbial infections in the pathogenesis of IPF …

Using A Collaborative Learning Health System Approach To Improve Disease Activity Outcomes In Children With Juvenile Idiopathic Arthritis In The Pediatric Rheumatology Care And Outcomes Improvement Network, Julia G Harris, Catherine A Bingham, Sheetal S Vora, Cagri Yildirim-Toruner, Michelle Batthish, Danielle R Bullock, Jon M Burnham, Danielle C Fair, Kerry Ferraro, Suhas Ganguli, Mileka Gilbert, Beth S Gottlieb, Olha Halyabar, Melissa M Hazen, Ronald M Laxer, Tzielan C Lee, Alice Liu, Daniel J Lovell, Melissa L Mannion, Edward J Oberle, Nancy Pan, Michael Shishov, Jennifer E Weiss, Esi M Morgan

Faculty, Staff and Students Publications

INTRODUCTION: The Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) is a North American learning health network focused on improving outcomes of children with juvenile idiopathic arthritis (JIA). JIA is a chronic autoimmune disease that can lead to morbidity related to persistent joint and ocular inflammation. PR-COIN has a shared patient registry that tracks twenty quality measures including ten outcome measures of which six are related to disease activity. The network's global aim, set in 2021, was to increase the percent of patients with oligoarticular or polyarticular JIA that had an inactive or low disease activity state from 76% to …