Digital Commons Network^™

Investigating The In Vivo Effects Of Anti-Prion Protein Nanobodies On Prion Disease With Aav Vector, Jingjing Zhang, Mengfei Wang, Dan Wang, Xiangyi Zhang, Yue Ma, Els Pardon, Jan Steyaert, Romany Abskharon, Fei Wang, Jiyan Ma

Faculty, Staff and Student Publications

Prion diseases are fatal neurodegenerative disorders affecting humans and animals, and the central pathogenic event is the conversion of normal prion protein (PrPC) into the pathogenic PrPSc isoform. Previous studies have identified nanobodies that specifically recognize PrPC and inhibit the PrPC to PrPSc conversion in vitro. In this study, we investigated the potential for in vivo expression of anti-PrPC nanobodies and evaluated their impact on prion disease. The coding sequences of three nanobodies were packaged into recombinant adeno-associated virus (rAAV) and were administered via intracerebroventricular (ICV) injection in newborn mice. We found that the expression of these nanobodies remained robust …

Dairy Consumption And The Colonic Mucosa-Associated Gut Microbiota In Humans-A Preliminary Investigation, Ellie Chen, Nadim J Ajami, Donna L White, Yanhong Liu, Shawn Gurwara, Kristi Hoffman, David Y Graham, Hashem B El-Serag, Joseph F Petrosino, Li Jiao

Faculty, Staff and Students Publications

Background: Dairy consumption has been associated with various health outcomes that may be mediated by changes in gut microbiota.

Methods: This cross-sectional study investigated the association between the colonic mucosa-associated gut microbiota and the self-reported intake of total dairy, milk, cheese, and yogurt. A total of 97 colonic mucosal biopsies collected from 34 polyp-free individuals were analyzed. Dairy consumption in the past year was assessed using a food frequency questionnaire. The 16S rRNA gene V4 region was amplified and sequenced. Operational taxonomic unit (OTU) classification was performed using the UPARSE and SILVA databases. OTU diversity and relative abundance were compared …

Cardiovascular Disease In Adults With Osteogenesis Imperfecta: Clinical Characteristics, Care Recommendations, And Research Priorities Identified Using A Modified Delphi Technique, Lars Folkestad, Siddharth K Prakash, Sandesh C S Nagamani, Niels Holmark Andersen, Erin Carter, Jannie Dahl Hald, Riley J Johnson, Bente Langdahl, Eleanor M Perfetto, Cathleen Raggio, Stuart H Ralston, Robert A Sandhaus, Oliver Semler, Laura Tosi, Eric Orwoll

Faculty, Staff and Student Publications

Osteogenesis imperfecta (OI) is a multisystem disorder most often caused by pathogenic variants in genes that encode type I collagen. Type I collagen is abundant not only in bone but also in multiple tissues including skin, tendons, cornea, blood vessels, and heart. Thus, OI can be expected to affect cardiovascular system, and there are numerous reports of cardiovascular disease (CVD) in people with OI. However, there is no consensus on how CVD in OI should be assessed or managed. To fill this gap, a multidisciplinary group was convened to develop clinical guidance. The work included a systematic review of the …

What We Mean When We Say Semantic: Toward A Multidisciplinary Semantic Glossary, Jamie Reilly, Cory Shain, Valentina Borghesani, Philipp Kuhnke, Gabriella Vigliocco, Jonathan E. Peelle, Bradford Z. Mahon, Laurel J. Buxbaum, Asifa Majid, Marc Brysbaert, Anna M. Borghi, Simon De Deyne, Guy Dove, Liuba Papeo, Penny M. Pexman, David Poeppel, Gary Lupyan, Paulo Boggio, Gregory Hickok, Laura Gwilliams, Leonardo Fernandino, Daniel Mirman, Evangelia G. Chrysikou, Chaleece W. Sandberg, Sebastian J. Crutch, Liina Pylkkänen, Eiling Yee, Rebecca L. Jackson, Jennifer M. Rodd, Marina Bedny, Louise Connell, Markus Kiefer, David Kemmerer, Greig De Zubicaray, Elizabeth Jefferies, Dermot Lynott, Cynthia S. Q. Siew, Rutvik H. Desai, Ken Mcrae, Michele T. Diaz, Marianna Bolognesi, Evelina Fedorenko, Swathi Kiran, Maria Montefinese, Jeffrey R. Binder, Melvin J. Yap, Gesa Hartwigsen, Jessica Cantlon, Yanchao Bi, Paul Hoffman, Frank E. Garcea, David Vinson

Moss-Magee Rehabilitation Papers

Tulving characterized semantic memory as a vast repository of meaning that underlies language and many other cognitive processes. This perspective on lexical and conceptual knowledge galvanized a new era of research undertaken by numerous fields, each with their own idiosyncratic methods and terminology. For example, "concept" has different meanings in philosophy, linguistics, and psychology. As such, many fundamental constructs used to delineate semantic theories remain underspecified and/or opaque. Weak construct specificity is among the leading causes of the replication crisis now facing psychology and related fields. Term ambiguity hinders cross-disciplinary communication, falsifiability, and incremental theory-building. Numerous cognitive subdisciplines (e.g., vision, …

Arginine Metabolism Is A Biomarker Of Red Blood Cell And Human Aging., Julie A Reisz, Eric J Earley, Travis Nemkov, Alicia Key, Daniel Stephenson, Gregory R Keele, Monika Dzieciatkowska, Steven L Spitalnik, Eldad A Hod, Steven Kleinman, Nareg H Roubinian, Mark T Gladwin, Kirk C Hansen, Philip J Norris, Michael P Busch, James C Zimring, Gary Churchill, Grier P Page, Angelo D'Alessandro

Faculty Research 2025

Increasing global life expectancy motivates investigations of molecular mechanisms of aging and age-related diseases. This study examines age-associated changes in red blood cells (RBCs), the most numerous host cell in humans. Four cohorts, including healthy individuals and patients with sickle cell disease, were analyzed to define age-dependent changes in RBC metabolism. Over 15,700 specimens from 13,757 humans were examined, a major expansion over previous studies of RBCs in aging. Multi-omics approaches identified chronological age-related alterations in the arginine pathway with increased arginine utilization in RBCs from older individuals. These changes were consistent across healthy and sickle cell disease cohorts and …

Polyploid Superficial Uroepithelial Bladder Barrier Cells Express Features Of Cellular Senescence Across The Lifespan And Are Insensitive To Senolytics., Iman M Al-Naggar, Maria Antony, Dylan Baker, Lichao Wang, Lucas Da Cunha Godoy, Chia-Ling Kuo, Matthew O Fraser, Phillip P Smith, Ming Xu, George A Kuchel

Faculty Research 2025

Lower urinary tract dysfunction (LUTD) increases with aging. Ensuing symptoms including incontinence greatly impact quality of life, isolation, depression, and nursing home admission. The aging bladder is hypothesized to be central to this decline, however, it remains difficult to pinpoint a singular strong driver of aging-related bladder dysfunction. Many molecular and cellular changes occur with aging, contributing to decreased resilience to internal and external stressors, affecting urinary control and exacerbating LUTD. In this study, we examined whether cellular senescence, a cell fate involved in the etiology of most aging diseases, contributes to LUTD. We found that umbrella cells (UCs), luminal …

Intrinsic-Dimension Analysis For Guiding Dimensionality Reduction And Data Fusion In Multi-Omics Data Processing., Jessica Gliozzo, Mauricio Soto-Gomez, Valentina Guarino, Arturo Bonometti, Alberto Cabri, Emanuele Cavalleri, Justin Reese, Peter N Robinson, Marco Mesiti, Giorgio Valentini, Elena Casiraghi

Faculty Research 2025

Multi-omics data have revolutionized biomedical research by providing a comprehensive understanding of biological systems and the molecular mechanisms of disease development. However, analyzing multi-omics data is challenging due to high dimensionality and limited sample sizes, necessitating proper data-reduction pipelines to ensure reliable analyses. Additionally, its multimodal nature requires effective data-integration pipelines. While several dimensionality reduction and data fusion algorithms have been proposed, crucial aspects are often overlooked. Specifically, the choice of projection space dimension is typically heuristic and uniformly applied across all omics, neglecting the unique high dimension small sample size challenges faced by individual omics. This paper introduces a …

Genomic Reanalysis Of A Pan-European Rare-Disease Resource Yields New Diagnoses., Steven Laurie, Wouter Steyaert, Elke De Boer, Kiran Polavarapu, Nika Schuermans, Anna K Sommer, German Demidov, Kornelia Ellwanger, Ida Paramonov, Coline Thomas, Stefan Aretz, Jonathan Baets, Elisa Benetti, Gemma Bullich, Patrick F Chinnery, Jill Clayton-Smith, Enzo Cohen, Daniel Danis, Jean-Madeleine De Sainte Agathe, Anne-Sophie Denommé-Pichon, Jordi Diaz-Manera, Stephanie Efthymiou, Laurence Faivre, Marcos Fernandez-Callejo, Mallory Freeberg, José Garcia-Pelaez, Lena Guillot-Noel, Tobias B Haack, Mike Hanna, Holger Hengel, Rita Horvath, Henry Houlden, Adam Jackson, Lennart Johansson, Mridul Johari, Erik-Jan Kamsteeg, Melanie Kellner, Tjitske Kleefstra, Didier Lacombe, Hanns Lochmüller, Estrella López-Martín, Alfons Macaya, Anna Marcé-Grau, Aleš Maver, Heba Morsy, Francesco Muntoni, Francesco Musacchia, Isabelle Nelson, Vincenzo Nigro, Catarina Olimpio, Carla Oliveira, Jaroslava Paulasová Schwabová, Martje G Pauly, Borut Peterlin, Sophia Peters, Rolph Pfundt, Giulio Piluso, Davide Piscia, Manuel Posada, Selina Reich, Alessandra Renieri, Lukas Ryba, Karolis Šablauskas, Marco Savarese, Ludger Schöls, Leon Schütz, Verena Steinke-Lange, Giovanni Stevanin, Volker Straub, Marc Sturm, Morris A Swertz, Marco Tartaglia, Iris B A W Te Paske, Rachel Thompson, Annalaura Torella, Christina Trainor, Bjarne Udd, Liedewei Van De Vondel, Bart Van De Warrenburg, Jeroen Van Reeuwijk, Jana Vandrovcova, Antonio Vitobello, Janet Vos, Emílie Vyhnálková, Robin Wijngaard, Carlo Wilke, Doreen William, Jishu Xu, Burcu Yaldiz, Luca Zalatnai, Birte Zurek, Solve-Rd Ditf-Genturis, Solve-Rd Ditf-Ithaca, Solve-Rd Ditf-Euro-Nmd, Solve-Rd Ditf-Rnd, Solve-Rd Consortium, Anthony J Brookes, Teresinha Evangelista, Christian Gilissen, Holm Graessner, Nicoline Hoogerbrugge, Stephan Ossowski, Olaf Riess, Rebecca Schüle, Matthis Synofzik, Alain Verloes, Leslie Matalonga, Han G Brunner, Katja Lohmann, Richarda M De Voer, Ana Töpf, Lisenka E L M Vissers, Sergi Beltran, Alexander Hoischen

Faculty Research 2025

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.5% genomes), and performed systematic reanalysis for 6,447 individuals (3,592 male, 2,855 female) with previously undiagnosed rare diseases from 6,004 families. We established a collaborative, two-level expert review infrastructure that allowed a genetic diagnosis in 506 (8.4%) families. Of 552 disease-causing variants identified, 464 (84.1%) were single-nucleotide variants or short insertions/deletions. These variants were either located in recently published novel disease …

Prediction Of Lacosamide Concentrations To Support Dose Optimization During Pregnancy, Jessica M. Barry, Sílvia M. Illamola, Page B. Pennell, Catherine M.T. Sherwin, Kimford J. Meador, Angela K. Birnbaum

Pediatrics Faculty Publications

Objective: We aimed to quantify and predict lacosamide exposure during pregnancy by developing a pregnancy physiologically-based pharmacokinetic model, allowing the prediction of potential dose increases to support maintaining a patient's preconception lacosamide concentrations. Methods: Models for nonpregnant adults and pregnant female patients were constructed using physiochemical and pharmacological parameters identified from literature review. Evaluation of plasma concentration data from human males was digitized froM.T.he literature. Concentration data in nonpregnant and pregnant human females were available froM.T.he Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, a longitudinal observational study which followed 11 nonpregnant and 16 pregnant women receiving lacosamide. …

Palovarotene In Fibrodysplasia Ossificans Progressiva: Review And Perspective, Vincent Verheij, Robert Diecidue, Esmée Botman, Joseph Harrington, Nobuhiko Haga, Alberto Hidalgo-Bravo, Patricia Delai, Vrisha Madhuri, Mona Al Mukaddam, Keqin Zhang, Tae-Joon Cho, Rolf Morhart, Richard Keen, Carmen De Cunto, Clive Friedman, Zvi Grunwald, Michael Zasloff, J. Coen Netelenbos, Edward Hsiao, Frederick Kaplan, Robert Pignolo, Christiaan Scott, Elisabeth Marelise Eekhoff

Department of Oral and Maxillofacial Surgery Faculty Papers

INTRODUCTION: Palovarotene is a retinoic acid receptor gamma agonist that was studied in phase-2 and phase-3 clinical trials for the inhibition of new heterotopic ossification (HO) in fibrodysplasia ossificans progressiva (FOP). Despite numerous setbacks and regulatory delays, palovarotene is now the first approved FOP treatment in the U.S.A., Canada and Australia but remains unapproved in Europe where concerns surrounding the drug and its path to regional market authorization persist.

AREAS COVERED: The developmental history of palovarotene and an overview of the clinical trials and the regulatory approval journey are discussed by global FOP experts.

EXPERT OPINION: While post hoc analyses …

Extracellular Vesicles Released By All Patients Contain Hne-Adducted Proteins: Implications Of Collateral Damage., Jenni Ho, Suriyan Sukati, Tamara Taylor, Sherry Carter, Brittany Fuller, Amy Marmo, Caryn Sorge, John D'Orazio, D Allan Butterfield, Subbarao Bondada, Heidi Weiss, Daret K St Clair, Luksana Chaiswing

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Off-target neuronal injury is a serious side-effect observed in cancer survivors. It has previously been shown that pediatric acute lymphoblastic leukemia (ALL) survivors have a decline in neurocognition compared to healthy age-matched counterparts. Elevated oxidative stress has been documented to be a mediator in off-target tissue damage in cancer survivors. Early detection of oxidative stress markers may provide an opportunity to prevent off-target tissue damage. Extracellular vesicles (EVs) have surfaced as a potential diagnostic tool due to molecular cargo they contain. We investigated the potential for EVs to be a sensitive indicator of oxidative stress and off-target tissue damage by …

Multi-Institutional Retrospective Study On Opioid Prescribing Patterns Of Oral And Maxillofacial Surgeons, Steven J D Zbarsky, Issa A Hanna, Je Dong Ryu, Audra Boehm, Simon Young, Gary Yu, Minh Phuong Dong, Minh Chau Joe Tran, Alan Herford, Samuel Young, Chi T Viet

Faculty, Staff and Student Publications

BACKGROUND: The opioid epidemic is a serious crisis in the United States. It has been proposed that opioid prescriptions after dental procedures are a major contributor to opioid use and abuse. The American Dental Association has been working to educate dental care providers about safe opioid prescribing practices. The authors hypothesized that oral and maxillofacial surgeons, following the efforts and publications from the American Dental Association, have been prescribing fewer postoperative opioids.

METHODS: This was a multi-institutional retrospective study with a total of 3,710 patients from Loma Linda University and University of Texas Health Science Center at Houston undergoing ambulatory …

Nrf2/Cyclooxygenase 2 Signaling In Cr(Vi)-Induced Carcinogenesis, Lei Zhao, Yi-Fang Wang, Andrea Adamcakova-Dodd, Peter Thorne, Ranakul Islam, Ke Jian Liu, Fei Chen, Jia Luo, Ling-Zhi Liu

Kimmel Cancer Center Faculty Papers

Long-term exposure to hexavalent chromium [Cr(VI)] has been linked to lung cancer, and cyclooxygenase-2 (COX-2) is a well-known inflammatory factor. However, the role and mechanism of COX-2 in Cr(VI)-induced carcinogenesis are not clear yet. To address this question, we employed a mouse model exposed to Cr(VI) through intranasal instillation of particulate zinc chromate (ZnCrO4) for 12 weeks. Metabolomics and RNA-seq assays revealed enhanced activity of the arachidonic acid (AA)/eicosanoid metabolism pathway in lung tissues from mice exposed to Cr(VI). COX-2, the key enzyme of the AA/eicosanoid pathway, was significantly upre- gulated in Cr(VI)-exposed lung tissues, as well as in the …

Five-Year Outcomes Of Lenadogene Nolparvovec Gene Therapy In Leber Hereditary Optic Neuropathy, Patrick Yu-Wai-Man, Nancy Newman, Valérie Biousse, Valerio Carelli, Mark Moster, Catherine Vignal-Clermont, Thomas Klopstock, Alfredo Sadun, Robert C Sergott, Rabih Hage, Simona Degli Esposti, Chiara La Morgia, Claudia Priglinger, Rustum Karanja, Magali Taiel, José-Alain Sahel

Department of Neurology Faculty Papers

IMPORTANCE: Limited studies have assessed the long-term benefit/risk of gene therapy for Leber hereditary optic neuropathy (LHON).

OBJECTIVE: To determine the safety and efficacy of lenadogene nolparvovec in patients with LHON due to the MT-ND4 gene variant for up to 5 years after administration.

DESIGN, SETTING, AND PARTICIPANTS: The RESCUE and REVERSE Long-Term Follow-up Study (RESTORE), conducted from 2018 to 2022, is the 5-year follow-up study of the 2 phase 3 clinical studies RESCUE (Efficacy Study of Lenadogene Nolparvovec for the Treatment of Vision Loss Up to 6 Months From Onset in LHON Due to the MT-ND4 Mutation) and REVERSE …

Multi-Cancer Early Detection Tests: Attributes For Clinical Implementation, Jon O. Ebbert, Ernest T. Hawk, Christopher V. Chambers, Margaret A. Tempero, Elliot K. Fishman, Jospeh E. Ravenell, Tomasz M. Beer, Seema P. Rego

Department of Family & Community Medicine Faculty Papers

Guideline-recommended screening programs exist for only a few single-cancer types, and these cancers represent less than one-half of all new cancer cases diagnosed each year in the U.S. In addition, these "single-cancer" standard of care (SoC) screening tests vary in accuracy, adherence, and effectiveness, though all are generally understood to lead to reductions in cancer-related mortality. Recent advances in high-throughput technologies and machine learning have facilitated the development of blood-based multi-cancer early detection (MCED) tests. The opportunity for early detection of multiple cancers with a single blood test holds promise in addressing the current unmet need in cancer screening. By …

Notch3 Deletion Regulates Hiv-1 Gene Expression And Systemic Inflammation To Ameliorate Chronic Kidney Disease, Mackenzie Thornton, Nicole Sommer, Mercedes Mcgonigle, Anil Kumar Ram, Sireesha Yerrathota, Henrietta Ehirim, Aakriti Chaturvedi, Johnny Dinh Phan, Anubhav Chakraborty, V. Praveen Chakravarthi, Sumedha Gunewardena, Mudit Tyagi, Jaya Talreja, Tao Wang, Pravin Singhal, Pamela V. Tran, Timothy A. Fields, Patricio E. Ray, Navneet K. Dhillon, Madhulika Sharma

Center for Translational Medicine Faculty Papers

Anti-retroviral therapy (ART) has decreased human immunodeficiency virus (HIV)-1-associated morbidity. However, despite ART, immune cells remain latently infected, leading to chronic inflammation and HIV-1-associated comorbidities. New strategies are needed to target viral proteins and inflammation. We found activation of Notch3 in renal cells of the HIV-1 transgenic mouse model (HIV-Tg26) and in patients with HIV-associated nephropathy. We hypothesized that targeting NOTCH3 activation constitutes an effective therapy for HIV-related chronic kidney disease. We generated HIV-Tg26 mice with Notch3 knocked out (Tg-N3KO). Compared to HIV-Tg26 mice at 3 months, Tg-N3KO mice showed a marked reduction in renal injury, skin lesions and mortality …

Tracking Community Outreach And Engagement Activities Among National Cancer Institute-Designated Cancer Centers, Todd Burus, Caree Mcafee, Pamela Hull, Amy Leader, Christopher Mcnair

Kimmel Cancer Center Faculty Papers

The National Cancer Institute's (NCI) Cancer Center Support Grant mandates that NCI-designated cancer centers establish a Community Outreach and Engagement (COE) component to help direct efforts at reducing cancer burden within their catchment areas. Despite the critical role of COE offices, little is known about how they track and evaluate outreach activities and outcomes. We gathered information on current practices from representatives of 40 out of 65 COE offices using an online survey. Although nearly all responding centers (97.5%) tracked COE activities, no consensus existed on resources used, and satisfaction with current solutions was mixed (51.0% not satisfied). Respondents expressed …

Bayesian Population Pharmacokinetic Modeling Of Ondansetron For Neonatal Opioid Withdrawal Syndrome, Kevin Lam, John Mondick, Gary Peltz, Manhong Wu, Walter Kraft

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Ondansetron is an anti-emetic 5-HT3 receptor antagonist being investigated for treating neonatal opioid withdrawal syndrome (NOWS). Sparse PK data were analyzed from a multicenter, double-blind clinical trial with 98 mother/neonate dyads. Pregnant women with opioid use disorder were randomized to receive either placebo or ondansetron 8 mg intravenously within 4 h of delivery. Neonates born to mothers who were randomized to ondansetron received 0.07 mg/kg orally once every 24 h for up to five doses. Using current PK data, model parameters from a two-compartmental structural model from the literature (i.e., a priori model) were updated with the Metropolis-Hastings Markov-chain Monte …

A Switch Protein Adapter For Anti-Lilrb4 Car-T Cells, Ryan Huang, Heyu Chen, Jingjing Xie, Qi Lou, Lingxiao Tan, Ningyan Zhang, Zhiqiang An, Samuel John, Cheng Cheng Zhang

The Brown Foundation: Institute of Molecular Medicine

Chimeric antigen receptor-T cell (CAR-T) immunotherapy has shown remarkable results for the treatment of certain hematologic malignancies. A redirection strategy that utilizes clinically relevant CAR-T cells in combination with adapter proteins may be an effective strategy to target other hematologic and solid cancers. We established a fusion antibody-based strategy with flexibility to target multiple tumor types in combination with a novel anti-leukocyte immunoglobulin-like receptor-B 4 (LILRB4) CAR-T cell. Specifically, we engineered switch protein (SwP) adapters containing the LILRB4 extracellular domain fused to either an anti-CD19 or anti-CD20 single-chain variable fragment (scFv). These SwPs were sufficient to stimulate anti-LILRB4 CAR-T cells …

Leucine-Rich Alpha-2-Glycoprotein 1 Promotes Metastatic Colorectal Cancer Growth Through Human Epidermal Growth Factor Receptor 3 Signaling, Moeez Rathore, Kimberly Curry, Wei Huang, Michel'le Wright, Daniel Martin, Jiyeon Baek, Derek Taylor, Masaru Miyagi, Wen Tang, Hao Feng, Yamu Li, Zhenghe Wang, Hallie Graor, Joseph Willis, Elizabeth Bryson, Christina S Boutros, Omkar Desai, Bianca N Islam, Lee M Ellis, Stephen E Moss, Jordan M Winter, John Greenwood, Rui Wang

Faculty, Staff and Student Publications

Background & aims: Therapy failure in patients with metastatic colorectal cancer (mCRC, ∼80% occur in the liver) remains an overarching challenge. Preclinical studies demonstrated that human epidermal growth factor receptor 3 (HER3) promotes colorectal cancer (CRC) cell survival, but therapies blocking the neuregulin-induced canonical HER3 signaling have made little impact in the clinic. Recent studies suggest that the liver microenvironment promotes CRC growth by activating HER3 in a neuregulin-independent fashion, thus elucidation of these mechanisms may reveal new strategies for treating patients with mCRC.

Methods: Patient-derived primary liver endothelial cells (ECs) were used to interrogate EC-CRC crosstalk. We conducted proteomic …

In Vitro Hydrolysis Of Areca Nut Xenobiotics In Human Liver, Vincenzo Paolillo, Mahendran Jayakumar, Colton Sheperd, Andrew Tran, Stephanie Hoang, Nhu Dao, Parag Jain, Alan L Myers

Faculty, Staff and Student Publications

Areca nut (AN) is a substance of abuse consumed by millions worldwide, in spite of established oral and systemic toxicities associated with its use. Previous research demonstrates methyl ester alkaloids in the AN, such as arecoline and guvacoline, exhibit mood-altering and toxicological effects. Nonetheless, their metabolism has not been fully elucidated in humans. In the present study, an HPLC-UV bioanalytical method was developed to evaluate the hydrolytic kinetics and clearance rates of arecoline and guvacoline in human liver microsomes (HLM) and cytosol (HLC). The bioassay was capable of quantifying arecoline and guvacoline (and carboxylate metabolites arecaidine and guvacine, respectively) with …

Plasma Proteomic Characterization Of Motoric Cognitive Risk And Mild Cognitive Impairment, Gabriela T Gomez, Sanish Sathyan, Jingsha Chen, Myriam Fornage, Pascal Schlosser, Zhongsheng Peng, Jenifer Cordon, Priya Palta, Kevin J Sullivan, Adrienne Tin, B Gwen Windham, Rebecca F Gottesman, Nir Barzilai, Sofiya Milman, Joe Verghese, Josef Coresh, Keenan A Walker

Faculty, Staff and Student Publications

INTRODUCTION: Motoric cognitive risk (MCR) is a pre-dementia syndrome characterized by mobility and cognitive dysfunction. This study conducted a proteome-wide study of MCR and compared the proteomic signatures of MCR to that of mild cognitive impairment (MCI).

METHODS: Participants were classified as MCR using a memory questionnaire and 4-meter walk. We measured 4877 plasma proteins collected during late-life and midlife. Multivariable logistic regression related each protein to late-life MCR/MCI. MCR-associated proteins were replicated internally at midlife and in an external cohort.

RESULTS: Proteome-wide analysis (n = 4076) identified 25 MCR-associated proteins. Eight of these proteins remained associated with late-life MCR …

Association Of Systemic Inflammation And Long-Term Dysfunction In Covid-19 Patients: A Prospective Cohort, Felipe Dal-Pizzol, Bruno Kluwe-Schiavon, Henrique Ritter Dal-Pizzol, Gabriele Da Silveira Prestes, Diogo Dominguini, Carolina Saibro Girardi, Lucas Santos, José Cláudio Fonseca Moreira, Daniel Pens Gelain, Roger Walz, Tatiana Barichello, Cristiane Ritter

Faculty, Staff and Student Publications

COVID-19 has significant long-term impacts, including a chronic syndrome known as long-COVID, characterized by persistent symptoms post-recovery. The inflammatory response during acute infection is hypothesized to influence long-term outcomes. This study aimed to identify inflammatory biomarkers predictive of functional outcomes one year after hospital discharge. A prospective cohort study was conducted with 213 COVID-19 patients admitted to ICUs in Southern Brazil between June and November 2020. After exclusions and follow-ups, 109 patients were evaluated for one-year post-discharge. Plasma levels of Th1 (TNF-α, INF-γ, IL-12), Th2 (IL-4, IL-5, IL-6, IL-10, IL-13), and Th17 (IL-17, IL-22) cytokines were measured. Functional outcomes in …

Transcriptome Size Matters For Single-Cell Rna-Seq Normalization And Bulk Deconvolution, Songjian Lu, Jiyuan Yang, Lei Yan, Jingjing Liu, Judy Jiaru Wang, Rhea Jain, Jiyang Yu

Faculty, Staff and Student Publications

The variation of transcriptome size across cell types significantly impacts single-cell RNA sequencing (scRNA-seq) data normalization and bulk RNA-seq cellular deconvolution, yet this intrinsic feature is often overlooked. Here we introduce ReDeconv, a computational algorithm that incorporates transcriptome size into scRNA-seq normalization and bulk deconvolution. ReDeconv introduces a scRNA-seq normalization approach, Count based on Linearized Transcriptome Size (CLTS), which corrects differential expressed genes typically misidentified by standard count per 10 K normalization, as confirmed by orthogonal validations. By maintaining transcriptome size variation, CLTS-normalized scRNA-seq enhances the accuracy of bulk deconvolution. Additionally, ReDeconv mitigates gene length effects and models expression variances, …

Pharmacologic Management Of Heart Failure With Preserved Ejection Fraction (Hfpef) In Older Adults, Ashkan Hashemi, Min Ji Kwak, Parag Goyal

Faculty, Staff and Student Publications

There are several pharmacologic agents that have been touted as guideline-directed medical therapy for heart failure with preserved ejection fraction (HFpEF). However, it is important to recognize that older adults with HFpEF also contend with an increased risk for adverse effects from medications due to age-related changes in pharmacokinetics and pharmacodynamics of medications, as well as the concurrence of geriatric conditions such as polypharmacy and frailty. With this review, we discuss the underlying evidence for the benefits of various treatments in HFpEF and incorporate key considerations for older adults, a subpopulation that may be at higher risk for adverse drug …

Immunogenomic Determinants Of Exceptional Response To Immune Checkpoint Inhibition In Renal Cell Carcinoma, Tejas Jammihal, Renee Maria Saliby, Chris Labaki, Hanna Soulati, Juan Gallegos, Arnau Peris, Dustin Mccurry, Chunlei Yu, Valisha Shah, Deepak Poduval, Talal El Zarif, Nourhan El Ahmar, Yasmin Nabil Laimon, Marc Eid, Aseman Bagheri Sheshdeh, Katherine M Krajewski, Florian A Büttner, Matthias Schwab, Daniel Heng, Rafael C Casellas, Kunal Rai, Niki M Zacharias Millward, Pavlos Msaouel, Jose Karam, Sabina Signoretti, Eliezer Van Allen, Toni K Choueiri, David A Braun, Sachet A Shukla

Faculty, Staff and Student Publications

Immune checkpoint inhibitors can lead to 'exceptional', durable responses in a subset of persons. However, the molecular basis of exceptional response (ER) to immunotherapy in metastatic clear cell renal cell carcinoma (mccRCC) has not been well characterized. Here we analyzed pretherapy genomic and transcriptomic data in treatment-naive persons with mccRCC treated with standard-of-care immunotherapies: (1) combination of programmed cell death protein and ligand 1 (PD1/PDL1) and cytotoxic T lymphocyte-associated protein 4 inhibitors (IO/IO) or (2) combination of PD1/PDL1 and vascular endothelial growth factor (VEGF) receptor inhibitors (IO/VEGF). In the IO/IO cohort, clonal neoantigen load was significantly higher in persons with …

Emapalumab Treatment In Patients With Rheumatologic Disease-Associated Hemophagocytic Lymphohistiocytosis In The United States: A Retrospective Medical Chart Review Study., Shanmuganathan Chandrakasan, Carl E. Allen, Deepika Bhatla, John Carter, May Chien, Robert Cooper, Lauren Draper, Olive S. Eckstein, Rabi Hanna, J Allyson Hays, Michelle L. Hermiston, Ashley P. Hinson, Patricia M. Hobday, Michael S. Isakoff, Michael B. Jordan, Jennifer W. Leiding, Renee Modica, Taizo A. Nakano, Abiola Oladapo, Sachit A. Patel, Priti Pednekar, Mona Riskalla, Susmita N. Sarangi, Prakash Satwani, Anand Tandra, Kelly J. Walkovich, John D. Yee, Adi Zoref-Lorenz, Edward M. Behrens, Real‐Hlh Investigators

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: Rheumatologic disease-associated hemophagocytic lymphohistiocytosis (HLH), a rare, life-threatening, systemic hyperinflammatory syndrome, occurs as a complication of underlying rheumatologic disease. Real-world evidence is lacking on emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon-γ, approved for treating patients with primary HLH.

METHODS: REAL-HLH, a retrospective medical chart review study conducted across 33 US hospitals, assessed real-world treatment patterns and outcomes in patients with HLH treated with one or more dose of emapalumab between November 20, 2018, and October 31, 2021. Data are presented for the subset of patients with rheumatologic disease-associated HLH.

RESULTS: Fifteen of 105 patients …

The Metabolic Basis Of Cancer-Related Fatigue, Robert Dantzer, Brandon Chelette, Elisabeth G Vichaya, A Phillip West, Aaron Grossberg

Faculty, Staff and Student Publications

Although we are all familiar with the sensation of fatigue, there are still profound divergences on what it represents and its mechanisms. Fatigue can take various forms depending on the condition in which it develops. Cancer-related fatigue is considered a symptom of exhaustion that is often present at the time of diagnosis, increases in intensity during cancer therapy, and does not always recede after completion of treatment. It is usually attributed to the inflammation induced by damage-associated molecular patterns released by tumor cells during cancer progression and in response to its treatment. In this review, we argue that it is …

Rapid And Scalable Personalized Aso Screening In Patient-Derived Organoids., John C. Means, Anabel L. Martinez-Bengochea, Daniel A. Louiselle, Jacqelyn Nemechek, John M. Perry, Emily G. Farrow, Tomi Pastinen, Scott T. Younger

Manuscripts, Articles, Book Chapters and Other Papers

Personalized antisense oligonucleotides (ASOs) have achieved positive results in the treatment of rare genetic disease. As clinical sequencing technologies continue to advance, the ability to identify patients with rare disease harbouring pathogenic genetic variants amenable to this therapeutic strategy will probably improve. Here we describe a scalable platform for generating patient-derived cellular models and demonstrate that these personalized models can be used for preclinical evaluation of patient-specific ASOs. We describe protocols for delivery of ASOs to patient-derived organoid models and confirm reversal of disease-associated phenotypes in cardiac organoids derived from a patient with Duchenne muscular dystrophy (DMD) with a structural …

Structural Polymorphism And Diversity Of Human Segmental Duplications., Hyeonsoo Jeong, Philip C. Dishuck, Dongahn Yoo, William T. Harvey, Katherine M. Munson, Alexandra P. Lewis, Jennifer Kordosky, Gage H. Garcia, Human Genome Structural Variation Consortium (Hgsvc), Feyza Yilmaz, Pille Hallast, Charles Lee, Tomi Pastinen, Evan E. Eichler

Manuscripts, Articles, Book Chapters and Other Papers

Segmental duplications (SDs) contribute significantly to human disease, evolution and diversity but have been difficult to resolve at the sequence level. We present a population genetics survey of SDs by analyzing 170 human genome assemblies (from 85 samples representing 38 Africans and 47 non-Africans) in which the majority of autosomal SDs are fully resolved using long-read sequence assembly. Excluding the acrocentric short arms and sex chromosomes, we identify 173.2 Mb of duplicated sequence (47.4 Mb not present in the telomere-to-telomere reference) distinguishing fixed from structurally polymorphic events. We find that intrachromosomal SDs are among the most variable, with rare events …