Digital Commons Network^™

Sting Agonist-Loaded Mesoporous Manganese-Silica Nanoparticles For Vaccine Applications, Cheng Xu, Hannah E Dobson, Mengjie Yu, Wang Gong, Xiaoqi Sun, Kyung Soo Park, Andrew Kennedy, Xingwu Zhou, Jin Xu, Yao Xu, Andrew W Tai, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Cyclic dinucleotides (CDNs), as one type of Stimulator of Interferon Genes (STING) pathway agonist, have shown promising results for eliciting immune responses against cancer and viral infection. However, the suboptimal drug-like properties of conventional CDNs, including their short in vivo half-life and poor cellular permeability, compromise their therapeutic efficacy. In this study, we have developed a manganese-silica nanoplatform (MnOx@HMSN) that enhances the adjuvant effects of CDN by achieving synergy with Mn2+ for vaccination against cancer and SARS-CoV-2. MnOx@HMSN with large mesopores were efficiently co-loaded with CDN and peptide/protein antigens. MnOx@HMSN(CDA) amplified the activation of the STING pathway and enhanced the …

Gwas And Meta-Analysis Identifies 49 Genetic Variants Underlying Critical Covid-19, Erola Pairo-Castineira, Konrad Rawlik, Andrew D Bretherick, Ting Qi, Yang Wu, Isar Nassiri, Glenn A Mcconkey, Marie Zechner, Lucija Klaric, Fiona Griffiths, Wilna Oosthuyzen, Athanasios Kousathanas, Anne Richmond, Jonathan Millar, Clark D Russell, Tomas Malinauskas, Ryan Thwaites, Kirstie Morrice, Sean Keating, David Maslove, Alistair Nichol, Malcolm G Semple, Julian Knight, Manu Shankar-Hari, Charlotte Summers, Charles Hinds, Peter Horby, Lowell Ling, Danny Mcauley, Hugh Montgomery, Peter J M Openshaw, Colin Begg, Timothy Walsh, Albert Tenesa, Carlos Flores, José A Riancho, Augusto Rojas-Martinez, Pablo Lapunzina, Genomicc Investigators, Scourge Consortium, Isaricc Investigators, 23andme Covid-19 Team, Jian Yang, Chris P Ponting, James F Wilson, Veronique Vitart, Malak Abedalthagafi, Andre D Luchessi, Esteban J Parra, Raquel Cruz, Angel Carracedo, Angie Fawkes, Lee Murphy, Kathy Rowan, Alexandre C Pereira, Andy Law, Benjamin Fairfax, Sara Clohisey Hendry, J Kenneth Baillie

Faculty, Staff and Student Publications

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a …

Translational Studies Using The Malt1 Inhibitor (S)-Mepazine To Induce Treg Fragility And Potentiate Immune Checkpoint Therapy In Cancer, Mauro Di Pilato, Yun Gao, Yi Sun, Amina Fu, Carina Grass, Thomas Seeholzer, Regina Feederle, Irina Mazo, Samuel W Kazer, Kevin Litchfield, Ulrich H Von Andrian, Thorsten R Mempel, Russell W Jenkins, Daniel Krappmann, Peter Keller

Faculty, Staff and Student Publications

Introduction

Regulatory T cells (Tregs) play a critical role in the maintenance of immune homeostasis but also protect tumors from immune-mediated growth control or rejection and pose a significant barrier to effective immunotherapy. Inhibition of MALT1 paracaspase activity can selectively reprogram immune-suppressive Tregs in the tumor microenvironment to adopt a proinflammatory fragile state, which offers an opportunity to impede tumor growth and enhance the efficacy of immune checkpoint therapy (ICT).

Methods

We performed preclinical studies with the orally available allosteric MALT1 inhibitor (S)-mepazine as a single-agent and in combination with anti-programmed cell death protein 1 (PD-1) ICT to …

Hard To Swallow: A Review Of Interventions To Improve Swallowing Solid Medication, Caryn J Vandenberg, Alyssa Adams, Robyn Bockrath, Sanghee Kim, Giselle Rodriguez, Andrea Fawcett, Ravi Jhaveri

Faculty, Staff and Student Publications

Solid oral medications are preferred over intravenous or liquid formulations; however, difficulty swallowing solid medication remains a common barrier to adherence. Previous reviews have demonstrated limited evidence on interventions to improve solid medication swallowing abilities. PubMed, Medline (OVID), CINAHL, Scopus, and Web of Science databases were searched for interventions to improve the pediatric population's ability to swallow solid medications. We included studies in English published after the latest review, from January 2014 through April 2022, with pediatric patients not having comorbid conditions affecting swallowing ability. The authors independently reviewed each study's sampling strategy, study design, and the strength of outcome …

Sarcoidosis And Airway Disease After Immune Checkpoint Inhibitor Therapy: Case Study And Review Of The Literature, Felipe Soto, Luis F Torre-Sada, Frank E Mott, Sang T Kim, Roza Nurieva, Vickie R Shannon, Saadia A Faiz, Roberto F Casal, Mehmet Altan, Julie Lin, Ajay Sheshadri

Faculty, Staff and Student Publications

Pulmonary toxicity from immune checkpoint inhibitor therapy is typically a severe and potentially fatal complication, but these observations are driven by the most common toxicity, pneumonitis. Rarer pulmonary immune related adverse events, like airway disease and sarcoidosis, may have a more benign course. In this case report, we present a patient in whom therapy with the PD-1 inhibitor pembrolizumab resulted in severe eosinophilic asthma and sarcoidosis. This is the first case showing that anti-IL-5 inhibition may be safe in patients who develop eosinophilic asthma after ICI therapy. We further show that sarcoidosis does not necessarily require treatment cessation. This case …

Effect Of P2y12 Inhibitors On Organ Support-Free Survival In Critically Ill Patients Hospitalized For Covid-19: A Randomized Clinical Trial, Jeffrey S Berger, Matthew D Neal, Lucy Z Kornblith, Michelle N Gong, Harmony R Reynolds, Mary Cushman, Andrew D Althouse, Patrick R Lawler, Bryan J Mcverry, Keri S Kim, Lisa Baumann Kreuziger, Scott D Solomon, Mikhail N Kosiborod, Scott M Berry, Grant V Bochicchio, Marco Contoli, Michael E Farkouh, Joshua D Froess, Sheetal Gandotra, Yonatan Greenstein, Erinn M Hade, Nicholas Hanna, Kristin Hudock, Robert C Hyzy, Fátima Ibáñez Estéllez, Nicole Iovine, Ashish K Khanna, Pooja Khatri, Bridget-Anne Kirwan, Matthew E Kutcher, Eric Leifer, George Lim, Renato D Lopes, Jose L Lopez-Sendon, James F Luther, Lilia Nigro Maia, John G Quigley, Lana Wahid, Jennifer G Wilson, Ryan Zarychanski, Andrei Kindzelski, Mark W Geraci, Judith S Hochman, Activ-4a Investigators

Faculty, Staff and Students Publications

IMPORTANCE: Platelet activation is a potential therapeutic target in patients with COVID-19.

OBJECTIVE: To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19.

DESIGN, SETTING, AND PARTICIPANTS: This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients.

INTERVENTION: Participants were randomly assigned to receive a P2Y12 …

Qt-Prolonging Antibiotics, Serum-To-Dialysate Potassium Gradient, And Risk Of Sudden Cardiac Death Among Patients Receiving Maintenance Hemodialysis, Patrick H Pun, Magdalene M Assimon, Lily Wang, Sana M Al-Khatib, M Alan Brookhart, David J Weber, Wolfgang C Winkelmayer, Jennifer E Flythe

Faculty, Staff and Students Publications

RATIONALE & OBJECTIVE: Treatment with certain QT interval-prolonging antibiotics is associated with a higher risk of sudden cardiac death among individuals with hemodialysis-dependent kidney failure. Concurrent exposure to large serum-to-dialysate potassium gradients, which promote large potassium shifts, may augment the proarrhythmic effects of these medications. The primary objective of this study was to examine whether the serum-to-dialysate gradient modifies the cardiac safety of azithromycin, and separately, levofloxacin/moxifloxacin.

STUDY DESIGN: Retrospective observational cohort study using a new-user study design.

SETTING & POPULATION: Adult in-center hemodialysis patients with Medicare coverage in the US Renal Data System (2007-2017).

EXPOSURE: Initiation of azithromycin (or …

Adad2 Functions In Spermiogenesis And Pirna Biogenesis In Mice, Yonggang Lu, Ippei Nagamori, Hisato Kobayashi, Kanako Kojima-Kita, Kenjiro Shirane, Hsin-Yi Chang, Toru Nishimura, Takayuki Koyano, Zhifeng Yu, Julio M Castañeda, Makoto Matsuyama, Satomi Kuramochi-Miyagawa, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

BACKGROUND: Adenosine deaminase domain containing 2 (ADAD2) is a testis-specific protein composed of a double-stranded RNA binding domain and a non-catalytic adenosine deaminase domain. A recent study showed that ADAD2 is indispensable for the male reproduction in mice. However, the detailed functions of ADAD2 remain elusive.

OBJECTIVES: This study aimed to investigate the cause of male sterility in Adad2 mutant mice and to understand the molecular functions of ADAD2.

MATERIALS AND METHODS: Adad2 homozygous mutant mouse lines, Adad2

RESULTS: Adad2–/– and Adad2Δ/Δ mice exhibit male-specific sterility due to abnormal spermiogenesis. ADAD2 interacts with multiple RNA-binding proteins involved in …

Endogenous Interleukin-10 Contributes To Wound Healing And Regulates Tissue Repair, Walker D Short, Meredith Rae, Thomas Lu, Benjamin Padon, Tanuj J Prajapati, Fayiz Faruk, Oluyinka O Olutoye, Ling Yu, Paul Bollyky, Sundeep G Keswani, Swathi Balaji

Faculty, Staff and Students Publications

INTRODUCTION: Interleukin-10 (IL-10) is essential in fetal regenerative wound healing and likewise promotes a regenerative phenotype in adult dermal wounds. However, the role of endogenous IL-10 in postnatal dermal wound healing is not well-established. We sought to determine the function of endogenous IL-10 in murine full thickness excisional wounds that are splinted to prevent contracture and mimic human patterns of wound closure.

METHODS: Full-thickness excisional wounds were made in wildtype (WT) and IL-10

RESULTS: We observed no difference in wound healing rate between WT and IL-10

CONCLUSIONS: These data suggest that endogenous IL-10 expression does not alter closure of full …

Why The Vonoprazan Helicobacter Pylori Therapies In The Us-European Trial Produced Unacceptable Cure Rates, David Y Graham

Faculty, Staff and Students Publications

INTRODUCTION: Helicobacter pylori infects a large percentage of the world's population and is etiologically related to gastric cancer. The U.S. Food and Drug Administration recently approved two 14-day vonoprazan-containing regimens (vonoprazan-amoxicillin with or without clarithromycin) for H. pylori infections in the United States/Europe.

METHODS: We critically reviewed the trial methods to discover why the results were unacceptable low [i.e., no regimen achieved clinically acceptable (≥ 90%) or even conditionally acceptable cure rates (≥ 85%)]. Cure rates with antibiotic susceptible strains were 84.7 for vonoprazan triple therapy, 78.5 for vonoprazan-amoxicillin, and 78.7 for lansoprazole triple therapy, respectively. As was previously shown …

Leveraging The Electronic Health Record To Implement Emergency Department Delirium Screening, Anita N Chary, Elise Brickhouse, Beatrice Torres, Ilianna Santangelo, Christopher R Carpenter, Shan W Liu, Kyler M Godwin, Aanand D Naik, Hardeep Singh, Maura Kennedy

Faculty, Staff and Students Publications

OBJECTIVE: The aim of this study is to understand how emergency departments (EDs) use health information technology (HIT), and specifically the electronic health record (EHR), to support implementation of delirium screening.

METHODS: We conducted semi-structured interviews with 23 ED clinician-administrators, representing 20 EDs, about how they used HIT resources to implement delirium screening. Interviews focused on challenges participants experienced when implementing ED delirium screening and EHR-based strategies they used to overcome them. We coded interview transcripts using dimensions from the Singh and Sittig sociotechnical model, which addresses use of HIT in complex adaptive health care systems. Subsequently, we analyzed data …

Extracorporeal Membrane Oxygenation Characteristics And Outcomes In Children And Adolescents With Covid-19 Or Multisystem Inflammatory Syndrome Admitted To Us Icus, Melania M Bembea, Laura L Loftis, Ravi R Thiagarajan, Cameron C Young, Timothy P Mccadden, Margaret M Newhams, Suden Kucukak, Elizabeth H Mack, Julie C Fitzgerald, Courtney M Rowan, Aline B Maddux, Amanda R Kolmar, Katherine Irby, Sabrina Heidemann, Stephanie P Schwartz, Michele Kong, Hillary Crandall, Kevin M Havlin, Aalok R Singh, Jennifer E Schuster, Mark W Hall, Kari A Wellnitz, Mia Maamari, Mary G Gaspers, Ryan A Nofziger, Peter Paul C Lim, Ryan W Carroll, Alvaro Coronado Munoz, Tamara T Bradford, Melissa L Cullimore, Natasha B Halasa, Gwenn E Mclaughlin, Pia S Pannaraj, Natalie Z Cvijanovich, Matt S Zinter, Bria M Coates, Steven M Horwitz, Charlotte V Hobbs, Heda Dapul, Ana Lia Graciano, Andrew D Butler, Manish M Patel, Laura D Zambrano, Angela P Campbell, Adrienne G Randolph

Faculty, Staff and Students Publications

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) has been used successfully to support adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related cardiac or respiratory failure refractory to conventional therapies. Comprehensive reports of children and adolescents with SARS-CoV-2-related ECMO support for conditions, including multisystem inflammatory syndrome in children (MIS-C) and acute COVID-19, are needed.

DESIGN: Case series of patients from the Overcoming COVID-19 public health surveillance registry.

SETTING: Sixty-three hospitals in 32 U.S. states reporting to the registry between March 15, 2020, and December 31, 2021.

PATIENTS: Patients less than 21 years admitted to the ICU meeting Centers for Disease Control criteria …

Sars-Cov-2 Serostatus And Covid-19 Illness Characteristics By Variant Time Period In Non-Hospitalized Children And Adolescents, Sarah E Messiah, Michael D Swartz, Rhiana A Abbas, Yashar Talebi, Harold W Kohl, Melissa Valerio-Shewmaker, Stacia M Desantis, Ashraf Yaseen, Steven H Kelder, Jessica A Ross, Lindsay N Padilla, Michael O Gonzalez, Leqing Wu, David Lakey, Jennifer A Shuford, Stephen J Pont, Eric Boerwinkle

Faculty, Staff and Student Publications

OBJECTIVE: to describe COVID-19 illness characteristics, risk factors, and SARS-CoV-2 serostatus by variant time period in a large community-based pediatric sample.

DESIGN: Data were collected prospectively over four timepoints between October 2020 and November 2022 from a population-based cohort ages 5 to 19 years old.

SETTING: State of Texas, USA.

PARTICIPANTS: Participants ages 5 to 19 years were recruited from large pediatric healthcare systems, Federally Qualified Healthcare Centers, urban and rural clinical practices, health insurance providers, and a social media campaign.

EXPOSURE: SARS-CoV-2 infection.

MAIN OUTCOME(S) AND MEASURE(S): SARS-CoV-2 antibody status was assessed by the Roche Elecsys

RESULTS: Over half …

The Current State Of Prenatal Detection Of Genetic Conditions In Congenital Heart Defects, Areebah S Ahmad, Kathleen M Mulligan, David X Zheng, Katie A O'Connell, Benjamin Gallo Marin, Misha V Koshelev

Faculty, Staff and Student Publications

Interest in subspecialty training remains high for dermatology residency graduates. Fellowship program directors (FPDs) are largely responsible for fellowship organization and development. Here, we study the dermatology fellowship leadership landscape and identify notable differences in the characteristics of current dermatopathology, paediatric dermatology, and Mohs micrographic surgery and dermatologic oncology FPDs.

Human Sapovirus Replication In Human Intestinal Enteroids, Gabriel Euller-Nicolas, Cécile Le Mennec, Julien Schaeffer, Xi-Lei Zeng, Khalil Ettayebi, Robert L Atmar, Françoise S Le Guyader, Mary K Estes, Marion Desdouits

Faculty, Staff and Students Publications

Human sapoviruses (HuSaVs), like human noroviruses (HuNoV), belong to the Caliciviridae family and cause acute gastroenteritis in humans. Since their discovery in 1976, numerous attempts to grow HuSaVs in vitro were unsuccessful until 2020, when these viruses were reported to replicate in a duodenal cancer cell-derived line. Physiological cellular models allowing viral replication are essential to investigate HuSaV biology and replication mechanisms such as genetic susceptibility, restriction factors, and immune responses to infection. In this study, we demonstrate replication of two HuSaV strains in human intestinal enteroids (HIEs) known to support the replication of HuNoV and other human enteric viruses. …

Rapid Escape Of New Sars-Cov-2 Omicron Variants From Ba2-Directed Antibody Responses, Aiste Dijokaite-Guraliuc, Raksha Das, Daming Zhou, Helen M Ginn, Chang Liu, Helen M E Duyvesteyn, Jiandong Huo, Rungtiwa Nutalai, Piyada Supasa, Muneeswaran Selvaraj, Thushan I De Silva, Megan Plowright, Thomas A H Newman, Hailey Hornsby, Alexander J Mentzer, Donal Skelly, Thomas G Ritter, Nigel Temperton, Paul Klenerman, Eleanor Barnes, Susanna J Dunachie, Optic Consortium, Cornelius Roemer, Thomas P Peacock, Neil G Paterson, Mark A Williams, David R Hall, Elizabeth E Fry, Juthathip Mongkolsapaya, Jingshan Ren, David I Stuart, Gavin R Screaton

Faculty, Staff and Student Publications

In November 2021, Omicron BA.1, containing a raft of new spike mutations, emerged and quickly spread globally. Intense selection pressure to escape the antibody response produced by vaccines or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection then led to a rapid succession of Omicron sub-lineages with waves of BA.2 and then BA.4/5 infection. Recently, many variants have emerged such as BQ.1 and XBB, which carry up to 8 additional receptor-binding domain (RBD) amino acid substitutions compared with BA.2. We describe a panel of 25 potent monoclonal antibodies (mAbs) generated from vaccinees suffering BA.2 breakthrough infections. Epitope mapping shows potent …

Modeling Collective Cell Behavior In Cancer: Perspectives From An Interdisciplinary Conversation, Frederick R Adler, Alexander R A Anderson, Abhinav Bhushan, Paul Bogdan, Jose Javier Bravo-Cordero, Amy Brock, Yun Chen, Edna Cukierman, Kathleen E Delgiorno, Gerald V Denis, Meghan C Ferrall-Fairbanks, Zev Jordan Gartner, Ronald N Germain, Deborah M Gordon, Ginger Hunter, Mohit Kumar Jolly, Loukia Georgiou Karacosta, Karthikeyan Mythreye, Parag Katira, Rajan P Kulkarni, Matthew L Kutys, Arthur D Lander, Ashley M Laughney, Herbert Levine, Emil Lou, Pedro R Lowenstein, Kristyn S Masters, Dana Pe'er, Shelly R Peyton, Manu O Platt, Jeremy E Purvis, Gerald Quon, Jennifer K Richer, Nicole C Riddle, Analiz Rodriguez, Joshua C Snyder, Gregory Lee Szeto, Claire J Tomlin, Itai Yanai, Ioannis K Zervantonakis, Hannah Dueck

Faculty, Staff and Student Publications

Collective cell behavior contributes to all stages of cancer progression. Understanding how collective behavior emerges through cell-cell interactions and decision-making will advance our understanding of cancer biology and provide new therapeutic approaches. Here, we summarize an interdisciplinary discussion on multicellular behavior in cancer, draw lessons from other scientific disciplines, and identify future directions.

Framework Of The Centralized Interactive Phenomics Resource (Cipher) Standard For Electronic Health Data-Based Phenomics Knowledgebase, Jacqueline Honerlaw, Yuk-Lam Ho, Francesca Fontin, Jeffrey Gosian, Monika Maripuri, Michael Murray, Rahul Sangar, Ashley Galloway, Andrew J Zimolzak, Stacey B Whitbourne, Juan P Casas, Rachel B Ramoni, David R Gagnon, Tianxi Cai, Katherine P Liao, J Michael Gaziano, Sumitra Muralidhar, Kelly Cho

Faculty, Staff and Students Publications

The development of phenotypes using electronic health records is a resource-intensive process. Therefore, the cataloging of phenotype algorithm metadata for reuse is critical to accelerate clinical research. The Department of Veterans Affairs (VA) has developed a standard for phenotype metadata collection which is currently used in the VA phenomics knowledgebase library, CIPHER (Centralized Interactive Phenomics Resource), to capture over 5000 phenotypes. The CIPHER standard improves upon existing phenotype library metadata collection by capturing the context of algorithm development, phenotyping method used, and approach to validation. While the standard was iteratively developed with VA phenomics experts, it is applicable to the …

Extended Analysis Of Hiv Infection In Cisgender Men And Transgender Women Who Have Sex With Men Receiving Injectable Cabotegravir For Hiv Prevention: Hptn 083, Mark A Marzinke, Jessica M Fogel, Zhe Wang, Estelle Piwowar-Manning, Ryan Kofron, Amber Moser, Pradip Bhandari, Ryann Gollings, Lane R Bushman, Lei Weng, Elias K Halvas, John Mellors, Peter L Anderson, Deborah Persaud, Craig W Hendrix, Marybeth Mccauley, Alex R Rinehart, Marty St Clair, Susan L Ford, James F Rooney, Adeola Adeyeye, Suwat Chariyalertsak, Kenneth Mayer, Roberto C Arduino, Myron S Cohen, Beatriz Grinsztejn, Brett Hanscom, Raphael J Landovitz, Susan H Eshleman

Faculty, Staff and Student Publications

HPTN 083 demonstrated that injectable cabotegravir (CAB) was superior to oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for HIV prevention in cisgender men and transgender women who have sex with men. We previously analyzed 58 infections in the blinded phase of HPTN 083 (16 in the CAB arm and 42 in the TDF-FTC arm). This report describes 52 additional infections that occurred up to 1 year after study unblinding (18 in the CAB arm and 34 in the TDF-FTC arm). Retrospective testing included HIV testing, viral load testing, quantification of study drug concentrations, and drug resistance testing. The new CAB arm infections …

Zoster-Associated Prothrombotic Plasma Exosomes And Increased Stroke Risk, Andrew N Bubak, Christina Coughlan, Janelle Posey, Anthony J Saviola, Christy S Niemeyer, Serena W R Lewis, Sara Bustos Lopez, Adriana Solano, Stephen K Tyring, Cassidy Delaney, Keith B Neeves, Ravi Mahalingam, Kirk C Hansen, Maria A Nagel

Faculty, Staff and Student Publications

Herpes zoster (HZ; shingles) caused by varicella zoster virus reactivation increases stroke risk for up to 1 year after HZ. The underlying mechanisms are unclear, however, the development of stroke distant from the site of zoster (eg, thoracic, lumbar, sacral) that can occur months after resolution of rash points to a long-lasting, virus-induced soluble factor (or factors) that can trigger thrombosis and/or vasculitis. Herein, we investigated the content and contributions of circulating plasma exosomes from HZ and non-HZ patient samples. Compared with non-HZ exosomes, HZ exosomes (1) contained proteins conferring a prothrombotic state to recipient cells and (2) activated platelets …

Safety And Immunogenicity Of Multimeric-001 (M-001) Followed By Seasonal Quadrivalent Inactivated Influenza Vaccine In Young Adults – A Randomized Clinical Trial, Robert L Atmar, David I Bernstein, Patricia Winokur, Sharon E Frey, Laura S Angelo, Christopher Bryant, Tammy Ben-Yedidia, Paul C Roberts, Hana M El Sahly, Wendy A Keitel

Faculty, Staff and Students Publications

BACKGROUND: The continuing evolution of influenza viruses poses a challenge to vaccine prevention, highlighting the need for a universal influenza vaccine. We evaluated the safety and immunogenicity of one such candidate, Multimeric-001 (M-001), when used as a priming vaccine prior to administration of quadrivalent inactivated influenza vaccine (IIV4).

METHODS: Healthy adults 18 to 49 years of age were enrolled in a phase 2 randomized, double-blind placebo-controlled trial. Participants received two doses of either 1.0-mg M-001 or saline placebo (60 per study arm) on Days 1 and 22 followed by a single dose of IIV4 on about Day 172. Safety, reactogenicity, …

Serinc5 Restricts Hiv Membrane Fusion By Altering Lipid Order And Heterogeneity In The Viral Membrane, Amanda E Ward, Daria Sokovikova, Melvin Neal Waxham, Frederick A Heberle, Ilya Levental, Kandice R Levental, Volker Kiessling, Judith M White, Lukas K Tamm

Faculty, Staff and Student Publications

The host restriction factor, Serinc5, incorporates into budding HIV particles and inhibits their infection by an incompletely understood mechanism. We have previously reported that Serinc5 but not its paralogue, Serinc2, blocks HIV cell entry by membrane fusion, specifically by inhibiting fusion pore formation and dilation. A body of work suggests that Serinc5 may alter the conformation and clustering of the HIV fusion protein, Env. To contribute an additional perspective to the developing model of Serinc5 restriction, we assessed Serinc2 and Serinc5's effects on HIV pseudoviral membranes. By measuring pseudoviral membrane thickness via cryo-electron microscopy and order via the fluorescent dye, …

The Abscopal Effect In Patients With Cancer Receiving Immunotherapy, Blessie Elizabeth Nelson, Jacob J Adashek, Steven H Lin, Vivek Subbiah

Faculty, Staff and Student Publications

Interest in the abscopal effect has been rekindled over the past decade with the advent of immunotherapy. Although purportedly elusive, this phenomenon is being increasingly reported. Venturing further using a multimodality approach with an array of systemic agents and unconventional modalities is direly needed. In this perspective, we describe the fundamentals of abscopal responses (ARs), explore combinations with systemic therapies that hold promise in eliciting ARs, and reconnoiter unconventional modalities that may induce ARs. Finally, we scrutinize prospective agents and modalities that exhibit preclinical ability to elicit ARs and discuss prognostic biomarkers, their limitations, and pathways of abscopal resistance for …

Low And Differential Polygenic Score Generalizability Among African Populations Due Largely To Genetic Diversity, Lerato Majara, Allan Kalungi, Nastassja Koen, Kristin Tsuo, Ying Wang, Rahul Gupta, Lethukuthula L Nkambule, Heather Zar, Dan J Stein, Eugene Kinyanda, Elizabeth G Atkinson, Alicia R Martin

Faculty, Staff and Students Publications

African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across …

One Population, Multiple Lifestyles: Commensalism And Pathogenesis In The Human Mycobiome, Diana M Proctor, Rebecca A Drummond, Michail S Lionakis, Julia A Segre

Faculty, Staff and Student Publications

Candida auris and Candida albicans can result in invasive fungal diseases. And yet, these species can stably and asymptomatically colonize human skin and gastrointestinal tracts. To consider these disparate microbial lifestyles, we first review factors shown to influence the underlying microbiome. Structured by the damage response framework, we then consider the molecular mechanisms deployed by C. albicans to switch between commensal and pathogenic lifestyles. Next, we explore this framework with C. auris to highlight how host physiology, immunity, and/or antibiotic receipt are associated with progression from colonization to infection. While treatment with antibiotics increases the risk an individual will succumb …

Development Of A Corticosteroid-Immunosuppressed Mouse Model To Study The Pathogenesis And Therapy Of Influenza-Associated Pulmonary Aspergillosis, Sebastian Wurster, Jezreel Pantaleón García, Nathaniel D Albert, Ying Jiang, Keerthi Bhoda, Vikram V Kulkarni, Yongxing Wang, Thomas J Walsh, Scott Evans, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Influenza-associated pulmonary aspergillosis (IAPA) is a feared complication in patients with influenza tracheobronchitis, especially those receiving corticosteroids. Herein, we established a novel IAPA mouse model with low-inoculum Aspergillus infection and compared outcomes in mice with and without cortisone acetate (CA) immunosuppression. CA was an independent predictor of increased morbidity/mortality in mice with IAPA. Early antifungal treatment with liposomal amphotericin B was pivotal to improve IAPA outcomes in CA-immunosuppressed mice, even after prior antiviral therapy with oseltamivir. In summary, our model recapitulates key clinical features of IAPA and provides a robust preclinical platform to study the pathogenesis and treatment of IAPA.

Metabolic Dysregulation Impairs Lymphocyte Function During Severe Sars-Cov-2 Infection, Sanjeev Gurshaney, Anamaria Morales-Alvarez, Kevin Ezhakunnel, Andrew Manalo, Thien-Huong Huynh, Jun-Ichi Abe, Nhat-Tu Le, Daniela Weiskopf, Alessandro Sette, Daniel S Lupu, Stephen J Gardell, Hung Nguyen

Faculty, Staff and Student Publications

Cellular metabolic dysregulation is a consequence of SARS-CoV-2 infection that is a key determinant of disease severity. However, how metabolic perturbations influence immunological function during COVID-19 remains unclear. Here, using a combination of high-dimensional flow cytometry, cutting-edge single-cell metabolomics, and re-analysis of single-cell transcriptomic data, we demonstrate a global hypoxia-linked metabolic switch from fatty acid oxidation and mitochondrial respiration towards anaerobic, glucose-dependent metabolism in CD8+Tc, NKT, and epithelial cells. Consequently, we found that a strong dysregulation in immunometabolism was tied to increased cellular exhaustion, attenuated effector function, and impaired memory differentiation. Pharmacological inhibition of mitophagy with mdivi-1 reduced excess glucose …

A Dynamic Risk Model For Multitype Recurrent Events, Alokananda Ghosh, Wenyaw Chan, Naji Younes, Barry R Davis

Faculty, Staff and Student Publications

Recurrent events can occur more than once in the same individual; such events may be of different types, known as multitype recurrent events. They are very common in longitudinal studies. Often there is a terminating event, after which no further events can occur. The risk of any event, including terminating events such as death or cure, is typically affected by prior events. We propose a flexible joint multitype recurrent-events model that explicitly provides estimates of the change in risk for each event due to subject characteristics, including number and type of prior events and the absolute risk for every event …

Bi-Allelic Snapc4 Variants Dysregulate Global Alternative Splicing And Lead To Neuroregression And Progressive Spastic Paraparesis, F Graeme Frost, Marie Morimoto, Prashant Sharma, Lyse Ruaud, Newell Belnap, Daniel G Calame, Yuri Uchiyama, Naomichi Matsumoto, Machteld M Oud, Elise A Ferreira, Vinodh Narayanan, Sampath Rangasamy, Matt Huentelman, Lisa T Emrick, Ikuko Sato-Shirai, Satoko Kumada, Nicole I Wolf, Peter J Steinbach, Yan Huang, Undiagnosed Diseases Network, Barbara N Pusey, Sandrine Passemard, Jonathan Levy, Séverine Drunat, Marie Vincent, Agnès Guet, Emanuele Agolini, Antonio Novelli, Maria Cristina Digilio, Jill A Rosenfeld, Jennifer L Murphy, James R Lupski, Gilbert Vezina, Ellen F Macnamara, David R Adams, Maria T Acosta, Cynthia J Tifft, William A Gahl, May Christine V Malicdan

Faculty, Staff and Students Publications

The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development …

Longitudinal Global Transcriptomic Profiling Of Preclinical Systemic Sclerosis Reveals Molecular Changes Associated With Disease Progression, Chiara Bellocchi, Lorenzo Beretta, Xuan Wang, Marka A Lyons, Maurizio Marchini, Maurizio Lorini, Vincenzo Carbonelli, Nicola Montano, Shervin Assassi

Faculty, Staff and Student Publications

Objective: To investigate peripheral blood cell (PBCs) global gene expression profile of SSc at its preclinical stage (PreSSc) and to characterize the molecular changes associated with progression to a definite disease over time.

Material and methods: Clinical data and PBCs of 33 participants with PreSSc and 16 healthy controls (HCs) were collected at baseline and follow-up (mean 4.2 years). Global gene expression profiling was conducted by RNA sequencing and a modular analysis was performed.

Results: Comparison of baseline PreSSc to HCs revealed 2889 differentially expressed genes. Interferon signalling was the only activated pathway among top over-represented pathways. Moreover, 10 modules …