Digital Commons Network^™

Setd2 Suppresses Tumorigenesis In A Krasg12c-Driven Lung Cancer Model, And Its Catalytic Activity Is Regulated By Histone Acetylation, Ricardo J Mack, Natasha M Flores, Geoffrey C Fox, Hanyang Dong, Metehan Cebeci, Simone Hausmann, Tourkian Chasan, Jill M Dowen, Brian D Strahl, Pawel K Mazur, Or Gozani

Faculty, Staff and Student Publications

Histone H3 trimethylation at lysine 36 (H3K36me3) is a key chromatin modification that regulates fundamental physiological and pathological processes. In humans, SETD2 is the only known enzyme that catalyzes H3K36me3 in somatic cells and is implicated in tumor suppression across multiple cancer types. While there is considerable crosstalk between the SETD2-H3K36me3 axis and other epigenetic modifications, much remains to be understood. Here, we show that Setd2 functions as a potent tumor suppressor in a KRASG12C-driven lung adenocarcinoma (LUAD) mouse model, and that acetylation enhances SETD2 in vitro methylation of H3K36 on nucleosome substrates. In vivo, Setd2 ablation accelerates lethality in …

Developmental Transformations Of Purkinje Cells Tracked By Dna Electrokinetic Mobility, Cheryl Brandenburg, Garrett W Crutcher, Andrea J Romanowski, Sarah G Donofrio, Lita R Duraine, Richard N A Owusu-Mensah, Benjamin H Cooper, Izumi Sugihara, Gene J Blatt, Roy V Sillitoe, Alexandros Poulopoulos

Duncan NRI Faculty and Staff Publications

Brain development begins with neurogenesis in progenitor zones and ends with expansive, intricately-patterned cellular diversity in the adult brain. We took advantage of bioelectric interactions between DNA and embryonic tissue to perform "stereo-tracking," a developmental targeting strategy that differentially labels cells at different depths within progenitor zones. This 3D labeling was achieved by delivery of plasmids with distinct electrokinetic mobilities in utero. We applied stereo-tracking with light sheet imaging in the cerebellum and identified that Purkinje cells follow embryonically committed developmental trajectories, linking distinct progenitor zone subfields to the mature topography of the cerebellar cortex. We additionally identified an unexpected …

Regional Citrate Anticoagulation And Infectious Complications In Critically Ill Children And Young Adults Receiving Continuous Renal Replacement Therapy, Katja M Gist, Sai Prasad N Iyer, H David Humes, Stuart L Goldstein, Mihaela Damian, Andrea Cappoli, Catherine Joseph, Danielle E Soranno, Michelle Starr, Ashita Tolwani, Kevin K Chung, Theresa Mottes, Huaiyu Zang, Jangdong Seo, Nicholas J Ollberding, Shina Menon

Faculty, Staff and Students Publications

Introduction: Recent studies have identified an association between regional citrate anticoagulation (RCA) and subsequent infectious complications during continuous renal replacement therapy (CRRT). We aimed to determine if RCA was associated with infectious complications in children and young adults receiving CRRT.

Methods: A secondary analysis of the multinational Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK) registry (34 centers, 9 countries), was performed, including patients from 2015 to 2018. Patients were excluded if they (1) died within 72 h of CRRT initiation, had minor trauma or were postsurgical (analysis 1), or (2) met an exclusion in analysis 1 …

Preclinical Perspectives On Disorders Of The Temporomandibular Joint: Tracing The Past, Navigating The Present, And Shaping The Future, John K Neubert, Kyle Allen, Tamara Alliston, Alejandro J Almarza, Kyriacos A Athanasiou, Basak Donertas-Ayaz, Bruna Balbino De Paula, Roxanne Bavarian, Nidhi Bhutani, Brian E Cairns, Robert M Caudle, Yang Chai, Jian-Fu Chen, Yong Chen, Glenn T Clark, Yenisel Cruz-Almeida, Alexandre F Dasilva, Paul L Durham, Airam Vivanco Estela, Millie Embree, Roger Fillingim, Fernando Guastaldi, Shruti Handa, Sunil D Kapila, David Keith, Keith L Kirkwood, Phillip Kramer, Katherine T Martucci, Niall P Murphy, Andrea G Nackley, Richard Ohrbach, Benedikt Sagl, Shad B Smith, Feng Tao, Beth Winkelstein, Hai Yao, Simon Young, Michael S Gold

Faculty, Staff and Student Publications

Temporomandibular disorders (TMDs) are complex conditions characterized by orofacial pain and dysfunction, affecting a significant portion of the population. TMDs may involve joint and/or muscle pain, dysfunction (e.g., noise, limited or altered jaw movements), or both, leading to a marked decrease in quality of life. Patients often experience functional limitations that hinder eating, speaking, and daily activities. Additionally, TMDs are frequently associated with psychological distress, including anxiety and depression, which further impacts overall well-being. Despite the profound individual and societal impact of TMDs, effective therapies remain elusive, partly due to deficiencies in translational research. A primary limitation in the TMD …

Potential For Therapeutic Alteration Of The Underlying Biology Of Epilepsy, Michael R. Sperling, Jurriaan M. Peters, Qian Wu, Michelle Guignet, H. Steve White, Evelyn K. Shih, Leock Y. Ngo, Enrique Carrazana, Adrian L. Rabinowicz

Department of Neurology Faculty Papers

Approximately 30-35% of people with epilepsy experience seizures despite taking antiseizure medications. Recurrent seizures that are independent of status epilepticus can be associated with neuronal injury and structural changes to the brain, as well as diminished cognitive function, mood, and quality of life. A treatment that alters the underlying biology of epilepsy, thereby reducing the seizure burden and its attendant consequences, would be of great value in preventing these detrimental effects. In this review, we summarize preclinical and clinical research on pharmacological treatments that may favorably alter the underlying biology of epilepsy (i.e., disease modification or antiepileptogenesis). A reduction in …

Distinct Transcriptional Regulation Of The Wnt And Tgfβ Signaling Families Associated With Wound Healing And Fibrotic Outcomes To Lens Injury, Catherine Lalman, Kylie R. Stabler, Joshua Disatham, Lisa A. Brennan, Marc Kantorow, Janice L. Walker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Posterior capsule opacification (PCO) is a fibrotic complication of cataract surgery caused by aberrant repair of residual lens cells. It remains unclear how the lens injury response shifts toward a pathological repair process. Here, we performed a transcriptional analysis of two major pro-fibrotic pathways, the TGF-β superfamily and Wnt signaling pathways to determine how they are differentially regulated during regenerative wound healing versus fibrosis in a lens injury model. For these studies, RNA sequencing was performed on an ex vivo lens explant system that models post-surgical healing within regenerative and fibrotic microenvironments, from 0 to 3 days post-injury. Fibrotic conditions …

A Novel Sialylation Pathway Mediated By Extracellular Vesicles In Aggressive Prostate Cancer, Camila A. Bach, Md Niamat Hossain, Ishan J. Chaudhari, Cecilia E. Verrillo, Nicole M. Naranjo, Isabella Amoroso, Anna Testa, Samuel Sey, W. Kevin Kelly, Susan L. Bellis, Aurelio Lorico, Ada G. Blidner, Gabriel A. Rabinovich, Lucia R. Languino

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Altered cell surface glycosylation is a hallmark of cancer; among aberrant glycan structures, hypersialylated proteins contribute to disease progression. The enzyme ST6 β-galactoside α2,6-sialyltransferase 1 (ST6GAL1) mediates α2,6-linked sialylation of N-glycosylated proteins and is upregulated in many cancers, including prostate cancer (PrCa). We propose that ST6GAL1 may be released by cancer cells in small extracellular vesicles (sEVs) in the PrCa tumor microenvironment to potentially modulate cell surface sialylation in recipient cells. We isolated sEVs from PrCa cells by density gradient separation and characterized them by nanoparticle tracking analysis using ZetaView and immunoblotting analysis. We identified ST6GAL1 in both its membrane-bound …

Infusion Of Blood From Young And Old Mice Modulates Amyloid Pathology, Matias Pizarro, Ruben Gomez-Gutierrez, Ariel Caviedes, Catalina Valdes, Ute Woehlbier, Cristian Vargas, Mauricio Hernandez, Claudia Duran-Aniotz, Rodrigo Morales

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of misfolded proteins in the brain. Recently, the impact of blood components in the progression of this disease has come to attention. This study investigates the effects of infusing blood from young and old wild-type mice into transgenic mice that model AD brain amyloidosis. Impaired memory and Aβ accumulation were observed in mice infused with blood from old donors. A proteomic analysis in the brain of these mice identified alterations in components related to synaptogenesis and the endocannabinoid system. The α2δ2 protein, associated with neuronal calcium regulation, was validated …

Loss Of Ptdss1 In Tumor Cells Improves Immunogenicity And Response To Anti-Pd-1 Therapy, Jielin Liu, Shelley Herbrich, Sreyashi Basu, Yulong Chen, Ashwat Nagarajan, Swetha Anandhan, Sangeeta Goswami, Liangwen Xiong, Baoxiang Guan, Padmanee Sharma

Faculty, Staff and Student Publications

PTDSS1 (phosphatidylserine synthase 1) encodes an enzyme that facilitates production of phosphatidylserine (PS), which mediates a global immunosuppressive signal. Here, based on in vivo CRISPR screen, we identified PTDSS1 as a target to improve anti-PD-1 therapy. Depletion of Ptdss1 in tumor cells increased expression of interferon-γ (IFN-γ)-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1, even in the absence of IFN-γ stimulation in vitro. Loss of Ptdss1 in tumor cells also led to increased expression of MHC-I, enhanced cytotoxicity of CD8+ T cells, and increased frequency of an iNOS+ myeloid subset. A gene signature derived from the …

The Colonic Crypt: Cellular Dynamics And Signaling Pathways In Homeostasis And Cancer, Anh L. Nguyen, Molly A. Lausten, Bruce M. Boman

College of Life Sciences Faculty Papers

The goal of this review is to expand our understanding of how the cellular organization of the normal colonic crypt is maintained and elucidate how this intricate architecture is disrupted during tumorigenesis. Additionally, it will focus on implications for new therapeutic strategies targeting Epithelial-Mesenchymal Transition (EMT). The colonic crypt is a highly structured epithelial unit that functions in maintaining homeostasis through a complex physiological function of diverse cell types: SCs, transit-amplifying (TA) progenitors, goblet cells, absorptive colonocytes, Paneth-like cells, M cells, tuft cells, and enteroendocrine cells. These cellular subpopulations are spatially organized and regulated by multiple crucial signaling pathways, including …

The Hidden Link Between Hiv And Cardiomyopathy: Unraveling Hiv's Impact On The Heart, Toluwalase Awoyemi, Oluwaremilekun Zeth Tolu-Akinnawo, Andrew Greek, Oluwakemi Adenuga, Chukwuebuka Asogwa, Isaac Ekundayo, Olamide Odusola, Oyinlola O. Fasehun, Mercy Ajayi, Onyinye Ugoala

School of Medicine Publications

This comprehensive review examines the complex relationship between human immunodeficiency virus (HIV) and cardiomyopathy, focusing on the underlying molecular mechanisms, clinical manifestations, diagnostic approaches, and treatment strategies. It highlights the significant global health burden posed by HIV and its potential to cause long-term cardiovascular complications. The review investigates the pathogenesis of HIV-associated cardiomyopathy. It elucidates the intricate cellular and molecular pathways involved, including the actions of neutrophils, monocytes, macrophages, and lymphocytes in cardiac inflammation. Key signaling pathways such as TNF-NF-κB and the caspase-1 inflammasome are detailed, as they contribute to cardiac infection and injury. The clinical manifestations of HIV-associated cardiomyopathy …

Nmr-Based Metabolomic Profiling For Brain Cancer Diagnosis And Treatment Guidance, Julia R Zickus, José S Enriquez, Paytience Smith, Bill T Sun, Muxin Wang, Aldo Morales, Pratip K Bhattacharya, Shivanand Pudakalakatti

Faculty, Staff and Student Publications

Nuclear magnetic resonance (NMR) spectroscopy is a routinely used analytical tool for studying chemical entities of varying molecular sizes, ranging from approximately 20 Da to ~45 kDa, and in some cases even larger. Over the past two decades, the use of NMR spectroscopy has significantly expanded to the study of metabolomics. In this medium-sized review, the application of NMR-based metabolomics in the diagnosis, therapeutic intervention, and guidance of therapy for various types of brain cancer is discussed.

Ubiquitination-Targeted Therapies Improve Bmd Ipsc Myogenic Cell Engraftment And Dystrophin Expression In Vivo, Muchen Liu, Somik Chatterjee, Jianbo Wu, Zeinab Kashaniasl, Ashok Kumar, Chunru Lin, Radbod Darabi

Faculty, Staff and Student Publications

Becker muscular dystrophy (BMD) is caused by in-frame mutations in dystrophin gene, leading to progressive muscle weakness, and cardiac and respiratory complications. Currently, there is no cure. We have recently identified the importance of poly-ubiquitination in regulating dystrophin stability through the binding of lncRNA H19 to the dystrophin C-terminal zinc-finger domain (ZNF), inhibiting TRIM63-mediated poly-ubiquitination. We also demonstrated that BMD mutations lead to conformational changes in ZNF domain, reduced lncRNA H19 binding and increased dystrophin ubiquitination. Here we used BMD iPSCs to investigate the in vitro myogenic potential of BMD myogenic cells, as well as in vitro and in vivo …

Neurotransmitter Signaling In Molecular And Behavioral Immune Responses To Pathogens In C Elegans, Benson Otarigho, Alejandro Aballay

Faculty, Staff and Student Publications

Neurotransmitter signaling pathways play major roles in both molecular and behavioral defenses against pathogen invasion, shaping the ability of Caenorhabditis elegans to sense and respond to environmental challenges. Given the conservation of neurotransmitter signaling pathways, their understanding may not only provide insights into the neurobiology of C. elegans but also has broader implications for our understanding of neural-immune interactions and host defense mechanisms in higher organisms. In this review, we discussed the literature on various neurotransmitter signaling pathways, including serotonergic, dopaminergic/octopaminergic, GABAergic, and glutamatergic pathways, and how these pathways modulate molecular and behavioral immune defense against pathogens.

Human Toxocariasis, Susana Lopez-Alamillo, Pravallika Padyala, Megan Carey, Megan M Duffey, Jill E Weatherhead

Faculty, Staff and Students Publications

Human toxocariasis is a globally prevalent zoonotic parasitic infection caused by larvae of Toxocara species, primarily Toxocara canis and Toxocara cati. Toxocariasis is commonly transmitted to humans through the ingestion of embryonated Toxocara eggs found in contaminated soil, water, or on surfaces contaminated with animal feces. Unlike in dogs and cats, humans are not definitive hosts for Toxocara spp., and, as a result, Toxocara larvae do not complete their life cycle in humans. Instead, following accidental oral ingestion of embryonated eggs, Toxocara larvae undergo an aberrant larval migratory cycle to various organs including the lungs, liver, muscles, and central …

Infectious Prions In Brains And Muscles Of Domestic Pigs Experimentally Challenged With The Bse, Scrapie, And Cwd Agents, Francisca Bravo-Risi, Fraser Brydon, Angela Chong, Kane Spicker, Justin J Greenlee, Glenn Telling, Claudio Soto, Sandra Pritzkow, Marcelo A Barria, Rodrigo Morales

Faculty, Staff and Student Publications

Experimental studies suggest that animal species not previously described as naturally infected by prions are susceptible to prion diseases affecting sheep, cattle, and deer. These interspecies transmissions may generate prions with unknown host ranges. Pigs are susceptible to prions from different origins, including deer chronic wasting disease (CWD), sheep scrapie, and bovine spongiform encephalopathy (BSE). Here, we studied prions in brains and muscles from pigs previously infected with these different prion sources. Specifically, we measured the total prion protein (PrP) and PK-resistant PrP by western blot. Seeding activity in these tissues was evaluated using the protein misfolding cyclic amplification (PMCA) …

Inhibition Of The Ufd-1-Npl-4 Complex Triggers An Aberrant Immune Response In Caenorhabditis Elegans, Rajneesh Rao, Alejandro Aballay, Jogender Singh

Faculty, Staff and Student Publications

The UFD-1 (ubiquitin fusion degradation 1)-NPL-4 (nuclear protein localization homolog 4) heterodimer is involved in extracting ubiquitinated proteins from several plasma membrane locations, including the endoplasmic reticulum. This heterodimer complex helps in the degradation of ubiquitinated proteins via the proteasome with the help of the AAA+ATPase CDC-48. While the ubiquitin-proteasome system is known to have important roles in maintaining innate immune responses, the role of the UFD-1-NPL-4 complex in regulating immunity remains elusive. In this study, we investigate the role of the UFD-1-NPL-4 complex in maintaining

Testis Expressed 50 Is Essential For Maintaining Sperm Acrosome Integrity During Epididymal Transit, Saori Haga, Kaori Nozawa, Ferheen Abbasi, Katarzyna Kent, Naoko Nagasawa, Tsutomu Endo, Haruhiko Miyata, Masahito Ikawa, Martin M Matzuk, Yoshitaka Fujihara

Faculty, Staff and Students Publications

In mammals, sperm formation is completed in the seminiferous tubules within the testis, and sperm maturation occurs during the epididymal transit of the spermatozoa. Sperm morphology drastically changes when abnormal spermatozoa migrate from the testis to the epididymis. Detailed molecular mechanisms for sperm survival in the epididymis have not been determined yet. Globozoospermia is a cause of male infertility and is characterized by round-headed spermatozoa without acrosomes, an abnormal sperm nuclear membrane, and sperm midpiece defects. Testis expressed 50 (Tex50) is a testis-enriched gene that is expressed in mice and humans. Using CRISPR-Cas9, we generated Tex50 knockout (KO) …

Computationally Resolved Neuroprogenitor Cell Biomarkers Associate With Human Disorders, Gerarda Cappuccio, William T Choi, Fatih Semerci, Jill A Rosenfeld, Toni Claire Tacorda, Guantong Qi, Anthony W Zoghbi, Yi Zhong, Hu Chen, Pengfei Liu, Zhandong Liu, Mirjana Maletić-Savatić

Duncan NRI Faculty and Staff Publications

Adult hippocampal neurogenesis, the process of generating new neurons, relies on a rare population of neural stem and progenitor cells (NPCs) within the dentate gyrus complex microenvironment. Discovering the specific genes that define these cells is vital yet challenging due to overlapping expression patterns, limiting detection of rare cell populations using traditional approaches. By employing the computational digital sorting algorithm (DSA) that deconvolves complex gene expression data based on pattern recognition, we identified 129 genes enriched in murine NPCs. We validated these genes against published single-cell RNA sequencing (scRNA-seq) data and discovered that 25 human orthologs were known to cause …

Dissecting The Effect Of Mitochondrial Bcat Inhibition In Methylmalonic Acidemia, Madeline G Hemmingsen, Guo-Fang Zhang, Yunhan Ma, Hannah Marchuk, Kalyani R Patel, Tong Chen, Xinning Li, Mark Chapman, Sabrina Collias, Dolores H Lopez-Terrada, James Beasley, Ashlee R Stiles, Randy J Chandler, Charles P Venditti, Sarah P Young, Mercedes Barzi, Beatrice Bissig-Choisat, Doug Krafte, Christopher B Newgard, Karl-Dimiter Bissig

Faculty, Staff and Students Publications

Methylmalonic acidemia (MMA) is a severe metabolic disorder affecting multiple organs because of a distal block in branched-chain amino acid (BCAA) catabolism. Standard of care is limited to protein restriction and supportive care during metabolic decompensation. Severe cases require liver/kidney transplantation, and there is a clear need for better therapy. Here, we investigated the effects of a small molecule branched-chain amino acid transaminase (BCAT) inhibitor in human MMA hepatocytes and an MMA mouse model. Mitochondrial BCAT is the first step in BCAA catabolism, and reduction of flux through an early enzymatic step is successfully used in other amino acid metabolic …

Reasons For Maintaining The Classification Of Esmethadone As An Investigational Uncompetitive Nmdar Antagonist Rapid Antidepressant: Reply To Ferré And Michaelides, Sara De Martin, Stefano Comai, Andrea Mattarei, Thomas R Kosten, Frank J Vocci, Charles W Gorodetzky, Marco Pappagallo, Paolo L Manfredi

Faculty, Staff and Students Publications

No abstract provided.

Gene Context Drift Identifies Drug Targets To Mitigate Cancer Treatment Resistance, Amir Jassim, Birgit V Nimmervoll, Sabrina Terranova, Erica Nathan, Linda Hu, Jessica T Taylor, Katherine E Masih, Lisa Ruff, Matilde Duarte, Elizabeth Cooper, Gunjan Katyal, Melika Akhbari, Reuben J Gilbertson, Jennifer C Coleman, Joseph S Toker, Colton Terhune, Gabriel Balmus, Stephen P Jackson, Hailong Liu, Tao Jiang, Michael D Taylor, Kui Hua, Jean E Abraham, Mariella G Filbin, Anthony Hill, Anarita Patrizi, Neil Dani, Aviv Regev, Maria K Lehtinen, Richard J Gilbertson

Faculty, Staff and Students Publications

Cancer treatment often fails because combinations of different therapies evoke complex resistance mechanisms that are hard to predict. We introduce REsistance through COntext DRift (RECODR): a computational pipeline that combines co-expression graph networks of single-cell RNA sequencing profiles with a graph-embedding approach to measure changes in gene co-expression context during cancer treatment. RECODR is based on the idea that gene co-expression context, rather than expression level alone, reveals important information about treatment resistance. Analysis of tumors treated in preclinical and clinical trials using RECODR unmasked resistance mechanisms -invisible to existing computational approaches- enabling the design of highly effective combination treatments …

Establishing Best Practices Guidelines For Collaborative Research In Global Surgery: Developing A Delphi Survey, Ramitha Eshan Ruwanpathirana, Swati Deshpande, Sophia Abdulhai, Mathilde Djeneba Billau, Sumeja Catic, Theresa L Chin, Julia N Harrison, Pratyush Kumar, Maria Cecilia T Leyson, Helen W Li, Katayoun S Madani, Arthur Serumaga, Margaret Tarpley, Grayson Wright, Nia N Zalamea, Joshua S Ng-Kamstra

Faculty, Staff and Students Publications

Background: Collaborative research in global surgery has resulted in the rapid development of the field via knowledge creation and dissemination, research capacity building, and direct improvements in the delivery of clinical care. Yet the establishment and maintenance of trans-boundary collaborations carries significant risk to health systems, clinicians, patients, and researchers, particularly if such collaborations are not developed thoughtfully and with appropriate guardrails. In recent years, there has been significant growth in the literature on the pervasiveness and impact of neocolonialism on global health research.

Methods: To harness the benefits of global surgery research collaboration while mitigating these risks, we reviewed …

Incidence And Risk Factors Of Developing A Dysrhythmia After Blunt Thoracic Trauma., Jessica Jowers, Kevin Van Derveer, Katherine Moore, Nathaniel Harshaw, Julie M Reichert, Hannah Karr, Urhum Khaliq, David J Cziperle, Lindsey L Perea

General Surgery Resident Research

Background/Objectives: The incidence of dysrhythmia after blunt thoracic trauma varies in the literature from 8-75%, and the complication rate from these dysrhythmias is not well studied. The aims of this study are to (1) identify the incidence of dysrhythmia following blunt thoracic trauma, (2) identify risk factors associated with developing a dysrhythmia, and (3) identify the incidence of cardiac intervention after developing a dysrhythmia. We hypothesize that blunt thoracic trauma may result in post-injury dysrhythmias. Methods: This is a retrospective review of trauma patients ≥ 18 years with a blunt mechanism of injury at a Level 1 Trauma …

Lewy Body Dementia Promotion By Air Pollutants, Xiaodi Zhang, Haiqing Liu, Xiao Wu, Longgang Jia, Kundlik Gadhave, Lena Wang, Kevin Zhang, Hanyu Li, Rong Chen, Ramhari Kumbhar, Ning Wang, Chantelle E Terrillion, Bong Gu Kang, Bin Bai, Minhan Park, Ma Cristine Faye Denna, Shu Zhang, Wenqiang Zheng, Denghui Ye, Xiaoli Rong, Liu Yang, Lili Niu, Han Seok Ko, Weiyi Peng, Lingtao Jin, Mingyao Ying, Liana S Rosenthal, David W Nauen, Alex Pantelyat, Mahima Kaur, Kezia Irene, Liuhua Shi, Rahel Feleke, Sonia García-Ruiz, Mina Ryten, Valina L Dawson, Francesca Dominici, Rodney J Weber, Xuan Zhang, Pengfei Liu, Ted M Dawson, Shizhong Han, Xiaobo Mao

Faculty, Staff and Student Publications

Evidence links air pollution to dementia, yet its role in Lewy body dementia (LBD) remains unclear. Here we showed in a cohort of 56.5 million individuals across the U.S. that PM2.5 exposure raises LBD risk. Mechanistically, we found PM2.5 exposure led to brain atrophy in wild-type mice, an effect not seen in α-synuclein (αSyn)-deficient mice. PM2.5 exposure generated a highly pathogenic αSyn strain, PM-PFF, with enhanced proteinase K-resistance and neurotoxicity, resembling αSyn LBD strains. PM2.5 samples from China, the U.S., and Europe consistently induced proteinase-resistant αSyn strains and in vivo pathology. Transcriptomic analyses revealed shared responses between PM2.5-exposed mice and …

Dissecting Microbial Communities With Single-Cell Transcriptome Analysis, Andrew W Pountain, Itai Yanai

Faculty, Staff and Student Publications

Revealing insights into the function of microbial communities requires moving beyond measuring bulk taxonomic composition to detecting interactions between subpopulations. Following the transformative impact of single-cell gene expression profiling techniques on numerous fields of human biology, recent years have seen increased application to microbes. We review progress in the development of these techniques and discuss challenges in applying them to microbial communities. We highlight applications for dissecting the microbiome in human health and disease that reveal functional heterogeneity within gut communities, antibiotic responses, and the dynamics of mobile genetic elements. As single-cell gene expression technologies continue to develop, they are …

Human Papillomavirus Integration Induces Oncogenic Host Gene Fusions In Oropharyngeal Cancers, Nusrat Khan, Keiko Akagi, Shiming Jiang, Joe Dan Dunn, Bo Jiang, Weihong Xiao, Madison P O'Hara, Li Shen, Qi Wang, Vakul Mohanty, Jing Wang, Sara Goodwin, Jamie L Hutchins, Kevin R Coombes, Jagannadha K Sastry, David E Symer, Maura L Gillison

Faculty, Staff and Student Publications

HPV integration disrupts host genomic structure and expression, but whether these alterations promote cancer development remains unclear. Multiple genomic analyses of oropharyngeal cancers identified several host fusion genes, including recurrent FGFR3-TACC3 fusions, expressed from rearranged genomic loci adjacent to HPV integration sites. Evolutionary modeling implicated integration of virus concatemers into the host genome as a common initiating event in fusion formation. Co-expression of HPV16 E6/E7 and FGFR3-TACC3, but neither alone, was sufficient for tumor development in both xenograft and syngeneic mouse models and led to unique transcriptional programs implicated in carcinogenesis. FGFR3-TACC3 expression decreased the ubiquitination and degradation of …

Left Atrial Thrombus In Rheumatic Mitral Stenosis: A Case Of Therapeutic International Normalized Ratio Failure, Muhammad Salman Sabri, Carly Weber, Yanis Belkadi, Donald C. Haas, Yasotha Rajeswaran

Division of Internal Medicine Faculty Papers & Presentations

BACKGROUND: Atrial fibrillation or flutter in rheumatic mitral stenosis (MS) increases left atrial appendage (LAA) thrombus risk despite therapeutic anticoagulation.

CASE SUMMARY: A 72-year-old woman on warfarin with moderate MS and atrial flutter presented with dyspnea. Transesophageal echocardiogram (TEE) showed a large LAA thrombus despite an international normalized ratio >2.5. Cardioversion was deferred, and the international normalized ratio target was raised to a range of 2.5 to 3.5.

TAKE-HOME MESSAGES: While cardioversion can be considered in patients with uninterrupted anticoagulation without TEE, those with rheumatic MS are at high risk of LAA and LA thrombus and should undergo TEE before …

Nebulization Of An Mrna-Encoded Monoclonal Antibody For Passive Immunization Of Foals Against Rhodococcus Equi, Rebecca M Legere, Jeannine A Ott, Cristina Poveda, Daryll Vanover, Karin E R Borba, Jae Yeon Joo, Cameron L Martin, Bibiana P Da Silveira, Jocelyne M Bray, Kerstin Landrock, Gus A Wright, J Chistensen Blazier, Andrew E Hillhouse, Ashley L Benham-Duret, Brandon Mistretta, Rafaela L Klein, Sarah M Thompson, Amelia R Woolums, Michael F Criscitiello, Luc R Berghman, Angela I Bordin, Philip J Santangelo, Jeroen Pollet, Noah D Cohen

Faculty, Staff and Students Publications

Inhalation of Rhodococcus equi causes severe pneumonia in humans and animals worldwide, most commonly affecting horse foals. The standard for preventing R. equi pneumonia in foals is transfusion of hyperimmune plasma, which is expensive and carries the risk of adverse effects. Our goal was to passively immunize foals against R. equi by nebulizing mRNA encoding an equine monoclonal antibody (mAb) against the virulence-associated protein A (VapA) directly into the lungs. VapA-specific memory B cells from an immunized horse were used to identify and select the sequence for an equine immunoglobulin (Ig)G1 mAb. In vitro-transcribed mRNA encoding this sequence expressed …

An Allele-Agnostic Mutant-Kras Inhibitor Suppresses Tumor Maintenance Signals And Reprograms Tumor Immunity In Pancreatic Cancer, Kathleen M Mcandrews, Francesca Paradiso, Clint A Stalnecker, Benson S Chellakkan, Fredrik I Thege, David H Peng, Barbara A Moreno Diaz, Hikaru Sugimoto, Sarah I Patel, Krishnan K Mahadevan, Michelle L Kirtley, Danielle Wills, Amari M Sockwell, Andre Luis F Fonseca, Yunhe Liu, Kimal I Rajapakshe, Nathaniel G Yee, Phuong Thao Tran, Huda Alchikh Omar, Antonio Tedeschi, Fiorella Schischlik-Siegl, Andrew S Boghossian, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Dorothea Rudolph, Martin Aichinger, Florian Ebner, Artem V Artemov, Jesse Lipp, Laura Pisarsky, Valerie Laura Herrmann, John Park, Jörg F Rippmann, Otmar Schaaf, Vanessa Chandler, Mariah Williams, Charles E Deckard, Linghua Wang, Channing J Der, Christopher Vellano, Paola A Guerrero, Timothy P Heffernan, Raghu Kalluri, Anirban Maitra

Faculty, Staff and Student Publications

KRAS is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluate the pre-clinical efficacy of BI-2493 a panKRASi, a first-in-class allele agnostic mutant KRAS inhibitor, in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), syngeneic orthotopic models, and prolonged survival in genetically engineered mouse …