Digital Commons Network^™

Immune Evasion And Membrane Fusion Of Sars-Cov-2 Xbb Subvariants Eg51 And Xbb23, Julia N Faraone, Panke Qu, Negin Goodarzi, Yi-Min Zheng, Claire Carlin, Linda J Saif, Eugene M Oltz, Kai Xu, Daniel Jones, Richard J Gumina, Shan-Lu Liu

Faculty, Staff and Student Publications

Immune evasion by SARS-CoV-2 paired with immune imprinting from monovalent mRNA vaccines has resulted in attenuated neutralizing antibody responses against Omicron subvariants. In this study, we characterized two new XBB variants rising in circulation - EG.5.1 and XBB.2.3, for their neutralization and syncytia formation. We determined the neutralizing antibody titers in sera of individuals that received a bivalent mRNA vaccine booster, BA.4/5-wave infection, or XBB.1.5-wave infection. Bivalent vaccination-induced antibodies neutralized ancestral D614G efficiently, but to a much less extent, two new EG.5.1 and XBB.2.3 variants. In fact, the enhanced neutralization escape of EG.5.1 appeared to be driven by its key …

Quantitative Dual-Energy Computed Tomography With Cesium As A Novel Contrast Agent For Localization Of Thermochemical Ablation In Phantoms And Ex Vivo Models, Emily A Thompson, Megan C Jacobsen, David T Fuentes, Rick R Layman, Erik N K Cressman

Faculty, Staff and Student Publications

Background: Thermochemical ablation (TCA) is a minimally invasive therapy under development for hepatocellular carcinoma. TCA simultaneously delivers an acid (acetic acid, AcOH) and base (sodium hydroxide, NaOH) directly into the tumor, where the acid/base chemical reaction produces an exotherm that induces local ablation. However, AcOH and NaOH are not radiopaque, making monitoring TCA delivery difficult.

Purpose: We address the issue of image guidance for TCA by utilizing cesium hydroxide (CsOH) as a novel theranostic component of TCA that is detectable and quantifiable with dual-energy CT (DECT).

Materials and methods: To quantify the minimum concentration of CsOH that can be positively …

Lessons For The Next Generation Of Scientists From The Second Annual Arthur And Sandra Irving Cancer Immunology Symposium, Christopher Alvarez-Breckenridge, Kristin G Anderson, Ana Luisa Correia, Shadmehr Demehri, Huy Q Dinh, Karen Olivia Dixon, Gavin P Dunn, Laura Evgin, Jeremy Goc, Zinaida Good, Nir Hacohen, Patrick Han, Pavel Hanč, John Hickey, Kelly Kersten, Beiyun C Liu, Aitziber Buque, Yuxuan 'Phoenix' Miao, J Justin Milner, Yuri Pritykin, Ferdinando Pucci, Nicole E Scharping, Lisa Sudmeier, Yufei Wang, Andreas Wieland, Michelle M Williams

Faculty, Staff and Student Publications

The Arthur and Sandra Irving Cancer Immunology Symposium has been created as a platform for established cancer immunologists to mentor trainees and young investigators as they launch their research career in the field. By sharing their different paths to success, the senior faculty mentors provide an invaluable resource to support the development of the next generation of leaders in the cancer immunology community. This Commentary describes some of the key topics that were discussed during the 2022 symposium: scientific and career trajectory, leadership, mentoring, collaborations, and publishing. For each of these topics, established investigators discussed the elements that facilitate success …

An Ace2 Decamer Viral Trap As A Durable Intervention Solution For Current And Future Sars-Cov, Hailong Guo, Bomsoo Cho, Paul R Hinton, Sijia He, Yongjun Yu, Ashwin Kumar Ramesh, Jwala Priyadarsini Sivaccumar, Zhiqiang Ku, Kristen Campo, Sarah Holland, Sameer Sachdeva, Christopher Mensch, Mohamed Dawod, Annalis Whitaker, Philip Eisenhauer, Allison Falcone, Rebekah Honce, Jason W Botten, Stephen F Carroll, Bruce A Keyt, Andrew W Womack, William R Strohl, Kai Xu, Ningyan Zhang, Zhiqiang An, Sha Ha, John W Shiver, Tong-Ming Fu

Faculty, Staff and Student Publications

The capacity of SARS-CoV-2 to evolve poses challenges to conventional prevention and treatment options such as vaccination and monoclonal antibodies, as they rely on viral receptor binding domain (RBD) sequences from previous strains. Additionally, animal CoVs, especially those of the SARS family, are now appreciated as a constant pandemic threat. We present here a new antiviral approach featuring inhalation delivery of a recombinant viral trap composed of ten copies of angiotensin-converting enzyme 2 (ACE2) fused to the IgM Fc. This ACE2 decamer viral trap is designed to inhibit SARS-CoV-2 entry function, regardless of viral RBD sequence variations as shown by …

Trehalose Enhances Mitochondria Deficits In Human Npc1 Mutant Fibroblasts But Disrupts Mouse Purkinje Cell Dendritic Growth Ex Vivo., Collin M Macleod, Fawad A K Yousufzai, Liam T Spencer, Sarah Kim, Lucianne A Rivera-Rosario, Zerian D Barrera, Lindsay Walsh, Claude Krummenacher, Benjamin Carone, Ileana Soto

College of Science & Mathematics Departmental Research

Lysosomes play important roles in catabolism, nutrient sensing, metabolic signaling, and homeostasis. NPC1 deficiency disrupts lysosomal function by inducing cholesterol accumulation that leads to early neurodegeneration in Niemann-Pick type C (NPC) disease. Mitochondria pathology and deficits in NPC1 deficient cells are associated with impaired lysosomal proteolysis and metabolic signaling. It is thought that activation of the transcription factor TFEB, an inducer of lysosome biogenesis, restores lysosomal-autophagy activity in lysosomal storage disorders. Here, we investigated the effect of trehalose, a TFEB activator, in the mitochondria pathology of NPC1 mutant fibroblasts in vitro and in mouse developmental Purkinje cells ex vivo. We …

The Non-Coding Rnome After Splenectomy, Yoshiki Kobayashi, Hanh Hong Chu, Dan Van Bui, Yasutaka Yun, Linh Manh Nguyen, Akitoshi Mitani, Kensuke Suzuki, Mikiya Asako, Akira Kanda, Hiroshi Iwai

Faculty, Staff and Student Publications

Eosinophilic airway inflammation, complicated by bronchial asthma and eosinophilic chronic rhinosinusitis (ECRS), is difficult to treat. The disease may become refractory when eosinophilic mucin associated with eosinophil peroxidase (EPX) and autoantibodies fills in the paranasal sinus and small airway. This study investigated the functional role of an anti-EPX antibody in eosinophilic mucin of ECRS in eosinophilic airway inflammation. Eosinophilic mucin was obtained from patients with ECRS. The effects of the anti-EPX antibody on dsDNA release from eosinophils and eosinophilic mucin decomposition were evaluated. Immunofluorescence or enzyme-linked immunosorbent assays were performed to detect the anti-EPX antibody and its supernatant and serum …

Functional Analysis Of Recurrent Cdc20 Promoter Variants In Human Melanoma, Paula M Godoy, Abimbola Oyedeji, Jacqueline L Mudd, Vasilios A Morikis, Anna P Zarov, Gregory D Longmore, Ryan C Fields, Charles K Kaufman

2020-Current year OA Pubs

Small nucleotide variants in non-coding regions of the genome can alter transcriptional regulation, leading to changes in gene expression which can activate oncogenic gene regulatory networks. Melanoma is heavily burdened by non-coding variants, representing over 99% of total genetic variation, including the well-characterized TERT promoter mutation. However, the compendium of regulatory non-coding variants is likely still functionally under-characterized. We developed a pipeline to identify hotspots, i.e. recurrently mutated regions, in melanoma containing putatively functional non-coding somatic variants that are located within predicted melanoma-specific regulatory regions. We identified hundreds of statistically significant hotspots, including the hotspot containing the TERT promoter variants, …

Precision Recruitment And Engagement Of Individuals At Risk For Diabetes And Hypertension In Clinical Trials (Predhict): A Randomized Trial For An E-Persuasive Mobile Application To Inform Decision Making About Clinical Trials, Azizi Seixas, Shannique Richards, Jesse Q Moore, Chigozirim Izeogu, Laronda A Hollimon, Peng Jin, Girardin Jean-Louis

Faculty, Staff and Student Publications

The primary objective of this randomized trial was to test the effectiveness of the PREDHiCT digital application, which provides educational and supportive navigation to increase willingness to participate in a future clinical trial. The second objective was to test whether PREDHiCT increased clinical trial literacy or enhanced psychological facilitators of clinical trial participation, such as altruism. To test these two objectives, we conducted a 1-month remote decentralized trial with 100 participants who either have a personal or family history of cardiometabolic health conditions, such as hypertension, diabetes, and obesity. Results indicated significant changes in altruism (mean: -2.94 vs. 0.83;

Formative Evaluation And Adaptation Of A Hypertension Extension For Community Health Outcomes Program For Healthcare Workers Within The Federal Capital Territory, Nigeria, Abigail S Baldridge, Nadia Goldstar, Grace C Bellinger, Abigail T Denoma, Ikechukwu A Orji, Gabriel L Shedul, Rosemary C B Okoli, Nanna R Ripiye, Adaora Odukwe, Olabisi Dabiri, L Nneka Mobisson, Dike B Ojji, Mark D Huffman, Namratha R Kandula, Lisa R Hirschhorn

2020-Current year OA Pubs

BACKGROUND: The Extension for Community Health Outcomes (ECHO) model has been used extensively to link care providers in rural communities with experts with the aim of improving local patient care.

OBJECTIVE: The aim of this qualitative research study was to assess the feasibility, acceptability, perceived needs, and contextual factors to guide implementation of a hypertension focused ECHO program for Community Health Extension Workers (CHEWs) in the Federal Capital Territory, Nigeria.

METHODS: From September 2020 to December 2020, key informant interviews were performed with seven global organizations (hubs) providing ECHO training focused on cardiovascular disease or nephrology to identify contextual factors …

Occlusive Membranes For Guided Regeneration Of Inflamed Tissue Defects., Woojin Choi, Utkarsh Mangal, Jin-Young Park, Ji-Yeong Kim, Taesuk Jun, Ju Won Jung, Moonhyun Choi, Sungwon Jung, Milae Lee, Ji-Yeong Na, Du Yeol Ryu, Jin Man Kim, Jae-Sung Kwon, Won-Gun Koh, Sangmin Lee, Patrick T J Hwang, Kee-Joon Lee, Ui-Won Jung, Jae-Kook Cha, Sung-Hwan Choi, Jinkee Hong

Henry M. Rowan College of Engineering Departmental Research

Guided bone regeneration aided by the application of occlusive membranes is a promising therapy for diverse inflammatory periodontal diseases. Symbiosis, homeostasis between the host microbiome and cells, occurs in the oral environment under normal, but not pathologic, conditions. Here, we develop a symbiotically integrating occlusive membrane by mimicking the tooth enamel growth or multiple nucleation biomineralization processes. We perform human saliva and in vivo canine experiments to confirm that the symbiotically integrating occlusive membrane induces a symbiotic healing environment. Moreover, we show that the membrane exhibits tractability and enzymatic stability, maintaining the healing space during the entire guided bone regeneration …

Genetic Separation Of Brca1 Functions Reveal Mutation-Dependent Polθ Vulnerabilities, John J Krais, Et Al.

2020-Current year OA Pubs

Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality. Surprisingly, homozygous Brca1 mutant, Polq

Chimeric Antigen Receptor T Cells To Target Cd79b In B-Ceall Lymphomas, Fuliang Chu, Jingjing Cao, Jingwei Liu, Haopeng Yang, Timothy J Davis, Shao-Qing Kuang, Xiaoyun Cheng, Zheng Zhang, Swathi Karri, Long T Vien, Laura Bover, Ryan Sun, Francisco Vega, Michael Green, Richard Eric Davis, Sattva S Neelapu

Faculty, Staff and Student Publications

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent and durable effects in B-cell malignancies. However, antigen loss or downregulation is a frequent cause of resistance. Here, we report development of a novel CAR T-cell therapy product to target CD79b, a pan B-cell antigen, widely expressed in most B-cell lymphomas.

METHODS: We generated a novel anti-CD79b monoclonal antibody by hybridoma method. The specificity of the antibody was determined by testing against isogenic cell lines with human CD79b knock-in or knock-out. A single-chain variable fragment derived from the monoclonal antibody was used to make a panel of CD79b-targeting CAR …

Stratification Of Risk For Emergent Intracranial Abnormalities In Children With Headaches: A Pediatric Emergency Care Applied Research Network (Pecarn) Study Protocol, Daniel S Tsze, Nathan Kuppermann, T Charles Casper, Bradley J Barney, Lawrence P Richer, Danica B Liberman, Pamela J Okada, Claudia R Morris, Sage R Myers, Jane K Soung, Rakesh D Mistry, Lynn Babcock, Sandra P Spencer, Michael D Johnson, Eileen J Klein, Kimberly S Quayle, Dale W Steele, Andrea T Cruz, Alexander J Rogers, Danny G Thomas, Jacqueline M Grupp-Phelan, Tiffani J Johnson, Peter S Dayan, Pediatric Emergency Care Applied Research Network (Pecarn)

Faculty, Staff and Students Publications

INTRODUCTION: Headache is a common chief complaint of children presenting to emergency departments (EDs). Approximately 0.5%-1% will have emergent intracranial abnormalities (EIAs) such as brain tumours or strokes. However, more than one-third undergo emergent neuroimaging in the ED, resulting in a large number of children unnecessarily exposed to radiation. The overuse of neuroimaging in children with headaches in the ED is driven by clinician concern for life-threatening EIAs and lack of clarity regarding which clinical characteristics accurately identify children with EIAs. The study objective is to derive and internally validate a stratification model that accurately identifies the risk of EIA …

Stratification Of Risk For Emergent Intracranial Abnormalities In Children With Headaches: A Pediatric Emergency Care Applied Research Network (Pecarn) Study Protocol, Daniel S Tsze, Kimberly S Quayle, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Headache is a common chief complaint of children presenting to emergency departments (EDs). Approximately 0.5%-1% will have emergent intracranial abnormalities (EIAs) such as brain tumours or strokes. However, more than one-third undergo emergent neuroimaging in the ED, resulting in a large number of children unnecessarily exposed to radiation. The overuse of neuroimaging in children with headaches in the ED is driven by clinician concern for life-threatening EIAs and lack of clarity regarding which clinical characteristics accurately identify children with EIAs. The study objective is to derive and internally validate a stratification model that accurately identifies the risk of EIA …

Glial Cell Adhesion Molecule (Glialcam) Determines Proliferative Versus Invasive Cell States In Glioblastoma, Arpan De, John M Lattier, John E Morales, Jack R Kelly, Xiaofeng Zheng, Zhihua Chen, Sumod Sebastian, Zahra Nassiri Toosi, Jason T Huse, Frederick F Lang, Joseph H Mccarty

Faculty, Staff and Student Publications

The malignant brain cancer glioblastoma (GBM) contains groups of highly invasive cells that drive tumor progression as well as recurrence after surgery and chemotherapy. The molecular mechanisms that enable these GBM cells to exit the primary mass and disperse throughout the brain remain largely unknown. Here we report using human tumor specimens and primary spheroids from male and female patients that glial cell adhesion molecule (GlialCAM), which has normal roles in brain astrocytes and is mutated in the developmental brain disorder megalencephalic leukoencephalopathy with subcortical cysts (MLC), is differentially expressed in subpopulations of GBM cells. High levels of GlialCAM promote …

A Conceptual Framework For Nomenclatural Stability And Validity Of Medically Important Fungi: A Proposed Global Consensus Guideline For Fungal Name Changes Supported By Abp, Asm, Clsi, Ecmm, Escmid-Efisg, Eucast-Afst, Fdlc, Idsa, Isham, Mmsa, And Msgerc, Sybren De Hoog, Thomas J Walsh, Sarah A Ahmed, Ana Alastruey-Izquierdo, Barbara D Alexander, Maiken Cavling Arendrup, Esther Babady, Feng-Yan Bai, Joan-Miquel Balada-Llasat, Andrew Borman, Anuradha Chowdhary, Andrew Clark, Robert C Colgrove, Oliver A Cornely, Tanis C Dingle, Philippe J Dufresne, Jeff Fuller, Jean-Pierre Gangneux, Connie Gibas, Heather Glasgow, Yvonne Gräser, Jacques Guillot, Andreas H Groll, Gerhard Haase, Kimberly Hanson, Amanda Harrington, David L Hawksworth, Randall T Hayden, Martin Hoenigl, Vit Hubka, Kristie Johnson, Julianne V Kus, Ruoyu Li, Jacques F Meis, Michaela Lackner, Fanny Lanternier, Sixto M Leal, Francesca Lee, Shawn R Lockhart, Paul Luethy, Isabella Martin, Kyung J Kwon-Chung, Wieland Meyer, M Hong Nguyen, Luis Ostrosky-Zeichner, Elizabeth Palavecino, Preeti Pancholi, Peter G Pappas, Gary W Procop, Scott A Redhead, Daniel D Rhoads, Stefan Riedel, Bryan Stevens, Kaede Ota Sullivan, Paschalis Vergidis, Emmanuel Roilides, Amir Seyedmousavi, Lili Tao, Vania A Vicente, Roxana G Vitale, Qi-Ming Wang, Nancy L Wengenack, Lars Westblade, Nathan Wiederhold, Lewis White, Christina M Wojewoda, Sean X Zhang

Faculty, Staff and Student Publications

The rapid pace of name changes of medically important fungi is creating challenges for clinical laboratories and clinicians involved in patient care. We describe two sources of name change which have different drivers, at the species versus the genus level. Some suggestions are made here to reduce the number of name changes. We urge taxonomists to provide diagnostic markers of taxonomic novelties. Given the instability of phylogenetic trees due to variable taxon sampling, we advocate to maintain genera at the largest possible size. Reporting of identified species in complexes or series should where possible comprise both the name of the …

Mediation Of The Association Between Social Environmental Characteristics Of Family Childcare Home And Weight Status In Children By Diet Quality., Qianxia Jiang, Patricia Markham Risica, Alison Tovar, Kristen Cooksey Stowers, Marlene B. Schwartz, Caitlin Lombardi, Kim M. Gans

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The food and beverages served in family childcare homes (FCCHs) may play an important role in the development of childhood overweight and obesity. This analysis examines whether children's diet quality mediates the relationship between foods and beverages served in FCCHs and preschool-aged children's weight status.

METHODS: Trained and certified staff conducted observations for two days in each FCCH, using the Environment and Policy Assessment and Observation (EPAO) measure to determine the foods and beverages served to children (N = 370) in FCCHs (N = 120). They also used the Dietary Observation in Child Care (DOCC) protocol to assess children's …

Multi-Center Clinical Evaluation Of The Panther Fusion Sars-Cov-2/Flu A/B/Rsv Assay In Nasopharyngeal Swab Specimens From Symptomatic Individuals., Anjana Sasidharan, Rangaraj Selvarangan, Kennah Konrad, Matthew L. Faron, Salika M. Shakir, David Hillyard, Robert K. Mccall, Ian H. Mchardy, David C. Goldberg, James J. Dunn, Alexander L. Greninger, Christine Lansang, Rachel Bogh, Carmelle V. Remillard

Manuscripts, Articles, Book Chapters and Other Papers

The symptomology is overlapping for respiratory infections due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), influenza A/B viruses, and respiratory syncytial virus (RSV). Accurate detection is essential for proper medical management decisions. This study evaluated the clinical performance of the Panther Fusion SARS-CoV-2/Flu A/B/RSV assay in nasopharyngeal swab (NPS) specimens from individuals of all ages with signs and symptoms of respiratory infection consistent with COVID-19, influenza, or RSV. Retrospective known-positive and prospectively obtained residual NPS specimens were collected during two respiratory seasons in the USA. Clinical performance was established by comparing Panther Fusion SARS-CoV-2/Flu assay results to a three-molecular assay …

Eicosanoid And Eicosanoid-Related Inflammatory Mediators And Exercise Intolerance In Heart Failure With Preserved Ejection Fraction, Emily S Lau, Athar Roshandelpoor, Shahrooz Zarbafian, Dongyu Wang, James S Guseh, Norrina Allen, Vinithra Varadarajan, Matthew Nayor, Ravi V Shah, Joao A C Lima, Sanjiv J Shah, Bing Yu, Mona Alotaibi, Susan Cheng, Mohit Jain, Gregory D Lewis, Jennifer E Ho

Faculty, Staff and Student Publications

Systemic inflammation has been implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). Here, we examine the association of upstream mediators of inflammation as ascertained by fatty-acid derived eicosanoid and eicosanoid-related metabolites with HFpEF status and exercise manifestations of HFpEF. Among 510 participants with chronic dyspnea and preserved LVEF who underwent invasive cardiopulmonary exercise testing, we find that 70 of 890 eicosanoid and related metabolites are associated with HFpEF status, including 17 named and 53 putative eicosanoids (FDR q-value < 0.1). Prostaglandin (15R-PGF2α, 11ß-dhk-PGF2α) and linoleic acid derivatives (12,13 EpOME) are associated with greater odds of HFpEF, while epoxides (8(9)-EpETE), docosanoids (13,14-DiHDPA), and oxylipins (12-OPDA) are associated with lower odds of HFpEF. Among 70 metabolites, 18 are associated with future development of heart failure in the community. Pro- and anti-inflammatory eicosanoid and related metabolites may contribute to the pathogenesis of HFpEF and serve as potential targets for intervention.

Mechanism Of Stepwise Electron Transfer In Six-Transmembrane Epithelial Antigen Of The Prostate (Steap) 1 And 2, Kehan Chen, Lie Wang, Jiemin Shen, Ah-Lim Tsai, Ming Zhou, Gang Wu

Faculty, Staff and Student Publications

Six transmembrane epithelial antigen of the prostate (STEAP) 1-4 are membrane-embedded hemoproteins that chelate a heme prosthetic group in a transmembrane domain (TMD). STEAP2-4, but not STEAP1, have an intracellular oxidoreductase domain (OxRD) and can mediate cross-membrane electron transfer from NADPH via FAD and heme. However, it is unknown whether STEAP1 can establish a physiologically relevant electron transfer chain. Here, we show that STEAP1 can be reduced by reduced FAD or soluble cytochrome b5 reductase that serves as a surrogate OxRD, providing the first evidence that STEAP1 can support a cross-membrane electron transfer chain. It is not clear whether …

Vaginal Microbial Dynamics And Pathogen Colonization In A Humanized Microbiota Mouse Model, Marlyd E Mejia, Vicki Mercado-Evans, Jacob J Zulk, Samantha Ottinger, Korinna Ruiz, Mallory B Ballard, Stephanie W Fowler, Robert A Britton, Kathryn A Patras

Faculty, Staff and Students Publications

Vaginal microbial composition is associated with differential risk of urogenital infection. Although Lactobacillus spp. are thought to confer protection against infection, the lack of in vivo models resembling the human vaginal microbiota remains a prominent barrier to mechanistic discovery. Using 16S rRNA amplicon sequencing of C57BL/6J female mice, we found that vaginal microbial composition varies within and between colonies across three vivaria. Noting vaginal microbial plasticity in conventional mice, we assessed the vaginal microbiome of humanized microbiota mice (

Safety And Immunogenicity Of Etvax®, An Oral Inactivated Vaccine Against Enterotoxigenic Escherichia Coli Diarrhoea: A Double-Blinded, Randomized, Placebo-Controlled Trial Amongst Finnish Travellers To Benin, West Africa, Anu Kantele, Marianna Riekkinen, T Sakari Jokiranta, Sari H Pakkanen, Jukka-Pekka Pietilä, Anu Patjas, Mari Eriksson, Tamim Khawaja, Peter Klemets, Kati Marttinen, Heli Siikamäki, Anna Lundgren, Jan Holmgren, Agneta Lissmats, Nils Carlin, Ann-Mari Svennerholm

Faculty and Staff Publications

Background: No licensed human vaccines are available against enterotoxigenic Escherichia coli (ETEC), a major diarrhoeal pathogen affecting children in low- and middle-income countries and foreign travellers alike. ETVAX®, a multivalent oral whole-cell vaccine containing four inactivated ETEC strains and the heat-labile enterotoxin B subunit (LTB), has proved promising in Phase 1 and Phase 1/ 2 studies.

Methods: We conducted a Phase 2b double-blinded, randomized, placebo-controlled trial amongst Finnish travellers to Benin, West Africa. This report presents study design and safety and immunogenicity data. Volunteers aged 18-65 years were randomized 1:1 to receive ETVAX® or placebo. They visited Benin for 12 …

Perceptions Of Nigerian Medical Students Regarding Their Preparedness For Precision Medicine: A Cross-Sectional Survey In Lagos, Nigeria, Chibuzor Ogamba, Alero Roberts, Sharon Ajudua, Mosopefoluwa Akinwale, Fuhad Jeje, Festus Ibe, Moses Afolayan, Yetunde Kuyinu

Einstein Health Papers

BACKGROUND: Advances in precision medicine in Nigeria suggest improving genomics education and competency among healthcare practitioners to facilitate clinical translation. Due to the scarcity of research in this area, this study aimed to assess Nigerian medical students' perceptions about their preparedness to integrate precision medicine into their future clinical practice.

METHODS: This was an institution-based cross-sectional study of medicine and surgery students in their clinical years attending the two fully accredited colleges of medicine in Lagos, Nigeria, between April and October 2022 using an adapted tool administered via Google Forms. The survey assessed their awareness, perceptions about knowledge, ability, and …

Mechanisms Of Endothelial Cell Membrane Repair: Progress And Perspectives., Duoduo Zha, Shizhen Wang, Paula Monaghan-Nichols, Yisong Qian, Venkatesh Sampath, Mingui Fu

Manuscripts, Articles, Book Chapters and Other Papers

Endothelial cells are the crucial inner lining of blood vessels, which are pivotal in vascular homeostasis and integrity. However, these cells are perpetually subjected to a myriad of mechanical, chemical, and biological stresses that can compromise their plasma membranes. A sophisticated repair system involving key molecules, such as calcium, annexins, dysferlin, and MG53, is essential for maintaining endothelial viability. These components orchestrate complex mechanisms, including exocytosis and endocytosis, to repair membrane disruptions. Dysfunctions in this repair machinery, often exacerbated by aging, are linked to endothelial cell death, subsequently contributing to the onset of atherosclerosis and the progression of cardiovascular diseases …

First-Line Selpercatinib Or Chemotherapy And Pembrolizumab In Ret Fusion-Positive Nsclc, Caicun Zhou, Benjamin Solomon, Herbert H Loong, Keunchil Park, Maurice Pérol, Edurne Arriola, Silvia Novello, Baohui Han, Jianying Zhou, Andrea Ardizzoni, M Perez Mak, Fernando C Santini, Yasir Y Elamin, Alexander Drilon, Jürgen Wolf, Nalin Payakachat, Minji K Uh, Deborah Rajakumar, Hongmei Han, Tarun Puri, Victoria Soldatenkova, A Bence Lin, Boris K Lin, Koichi Goto, Libretto-431 Trial Investigators

Faculty, Staff and Student Publications

Background: Selpercatinib, a highly selective potent and brain-penetrant RET inhibitor, was shown to have efficacy in patients with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) in a nonrandomized phase 1-2 study.

Methods: In a randomized phase 3 trial, we evaluated the efficacy and safety of first-line selpercatinib as compared with control treatment that consisted of platinum-based chemotherapy with or without pembrolizumab at the investigator's discretion. The primary end point was progression-free survival assessed by blinded independent central review in both the intention-to-treat-pembrolizumab population (i.e., patients whose physicians had planned to treat them with pembrolizumab in the event that they were …

Tlr7 Promotes Smoke-Induced Experimental Lung Damage Through The Activity Of Mast Cell Tryptase, Gang Liu, Tatt Jhong Haw, Malcolm R Starkey, Ashleigh M Philp, Stelios Pavlidis, Christina Nalkurthi, Prema M Nair, Henry M Gomez, Irwan Hanish, Alan Cy Hsu, Elinor Hortle, Sophie Pickles, Joselyn Rojas-Quintero, Raul San Jose Estepar, Jacqueline E Marshall, Richard Y Kim, Adam M Collison, Joerg Mattes, Sobia Idrees, Alen Faiz, Nicole G Hansbro, Ryutaro Fukui, Yusuke Murakami, Hong Sheng Cheng, Nguan Soon Tan, Sanjay H Chotirmall, Jay C Horvat, Paul S Foster, Brian Gg Oliver, Francesca Polverino, Antonio Ieni, Francesco Monaco, Gaetano Caramori, Sukhwinder S Sohal, Ken R Bracke, Peter A Wark, Ian M Adcock, Kensuke Miyake, Don D Sin, Philip M Hansbro

Faculty, Staff and Students Publications

Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. …

Tumor-Resident Lactobacillus Iners Confer Chemoradiation Resistance Through Lactate-Induced Metabolic Rewiring, Lauren E Colbert, Molly B El Alam, Rui Wang, Tatiana Karpinets, David Lo, Erica J Lynn, Timothy A Harris, Jacob H Elnaggar, Kyoko Yoshida-Court, Katarina Tomasic, Julianna K Bronk, Julie Sammouri, Ananta V Yanamandra, Adilene V Olvera, Lily G Carlin, Travis Sims, Andrea Y Delgado Medrano, Tatiana Cisneros Napravnik, Madison O'Hara, Daniel Lin, Chike O Abana, Hannah X Li, Patricia J Eifel, Anuja Jhingran, Melissa Joyner, Lilie Lin, Lois M Ramondetta, Andrew M Futreal, Kathleen M Schmeler, Geena Mathew, Stephanie Dorta-Estremera, Jianhua Zhang, Xiaogang Wu, Nadim J Ajami, Matthew Wong, Cullen Taniguchi, Joseph F Petrosino, K Jagannadha Sastry, Pablo C Okhuysen, Sara A Martinez, Lin Tan, Iqbal Mahmud, Philip L Lorenzi, Jennifer A Wargo, Ann H Klopp

Faculty, Staff and Student Publications

Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other …

A Cre-Dependent Massively Parallel Reporter Assay Allows For Cell-Type Specific Assessment Of The Functional Effects Of Non-Coding Elements In Vivo, Tomas Lagunas Jr, Stephen P Plassmeyer, Anthony D Fischer, Ryan Z Friedman, Michael A Rieger, Din Selmanovic, Simona Sarafinovska, Yvette K Sol, Michael J Kasper, Stuart B Fass, Alessandra F Aguilar Lucero, Joon-Yong An, Stephan J Sanders, Barak A Cohen, Joseph D Dougherty

2020-Current year OA Pubs

The function of regulatory elements is highly dependent on the cellular context, and thus for understanding the function of elements associated with psychiatric diseases these would ideally be studied in neurons in a living brain. Massively Parallel Reporter Assays (MPRAs) are molecular genetic tools that enable functional screening of hundreds of predefined sequences in a single experiment. These assays have not yet been adapted to query specific cell types in vivo in a complex tissue like the mouse brain. Here, using a test-case 3'UTR MPRA library with genomic elements containing variants from autism patients, we developed a method to achieve …

Targeting The Αvβ3/Ngr2 Pathway In Neuroendocrine Prostate Cancer, Anna Testa, Fabio Quaglia, Nicole M. Naranjo, Cecilia E. Verrillo, Christopher D. Shields, Stephen Lin, Maxwell W. Pickles, Drini F. Hamza, Tami Von Schalscha, David A. Cheresh, Benjamin E Leiby, Qin Liu, Jianyi Ding, William K. Kelly, D. Craig Hooper, Eva Corey, Edward F. Plow, Dario C. Altieri, Lucia R. Languino

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy, is associated with limited treatment options and hence poor prognosis. We have previously demonstrated that the αVβ3 integrin is over-expressed in neuroendocrine prostate cancer. We now show that LM609, a monoclonal antibody that specifically targets the human αVβ3 integrin, hinders the growth of neuroendocrine prostate cancer patient-derived xenografts in vivo. Our group has recently identified a novel αVβ3 integrin binding partner, NgR2, responsible for regulating the expression of neuroendocrine markers and for inducing neuroendocrine differentiation in prostate cancer cells. Through in …

Mucopolysaccharidosis Iva: Current Disease Models And Drawbacks, Andrés Felipe Leal, Carlos Javier Alméciga-Díaz, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Mucopolysaccharidosis IVA (MPS IVA) is a rare disorder caused by mutations in the N-acetylgalactosamine-6-sulfate-sulfatase (GALNS) encoding gene. GALNS leads to the lysosomal degradation of the glycosaminoglyccreasans keratan sulfate and chondroitin 6-sulfate. Impaired GALNS enzymes result in skeletal and non-skeletal complications in patients. For years, the MPS IVA pathogenesis and the assessment of promising drugs have been evaluated using in vitro (primarily fibroblasts) and in vivo (mainly mouse) models. Even though value information has been raised from those studies, these models have several limitations. For instance, chondrocytes have been well recognized as primary cells affected in MPS IVA and responsible for …