Digital Commons Network^™

Neurotoxins Subvert The Allosteric Activation Mechanism Of Sarm1 To Induce Neuronal Loss, Tong Wu, Jian Zhu, Amy Strickland, Kwang Woo Ko, Yo Sasaki, Caitlin B Dingwall, Yurie Yamada, Matthew D Figley, Xianrong Mao, Alicia Neiner, A Joseph Bloom, Aaron Diantonio, Jeffrey Milbrandt

Open Access Publications

SARM1 is an inducible TIR-domain NAD

Nrf2 Promotes Urothelial Cell Response To Bacterial Infection By Regulating Reactive Oxygen Species And Rab27b Expression, Chetanchandra S Joshi, Amy Mora, Paul A Felder, Indira U Mysorekar

Open Access Publications

Uropathogenic Escherichia coli (UPEC) cause urinary tract infections (UTIs) by invading urothelial cells. In response, the host mounts an inflammatory response to expel bacteria. Here, we show that the NF-E2-related factor 2 (NRF2) pathway is activated in response to UPEC-triggered reactive oxygen species (ROS) production. We demonstrate the molecular sequence of events wherein NRF2 activation in urothelial cells reduces ROS production, inflammation, and cell death, promotes UPEC expulsion, and reduces the bacterial load. In contrast, loss of NRF2 leads to increased ROS production, bacterial burden, and inflammation, both in vitro and in vivo. NRF2 promotes UPEC expulsion by regulating transcription …

Trem2 Modulates Differential Deposition Of Modified And Non-Modified Aβ Species In Extracellular Plaques And Intraneuronal Deposits, Pranav Joshi, Florian Riffel, Sathish Kumar, Nàdia Villacampa, Sandra Theil, Samira Parhizkar, Christian Haass, Marco Colonna, Michael T Heneka, Thomas Arzberger, Jochen Herms, Jochen Walter

2020-Current year OA Pubs

Progressive accumulation of Amyloid-β (Aβ) deposits in the brain is a characteristic neuropathological hallmark of Alzheimer's disease (AD). During disease progression, extracellular Aβ plaques undergo specific changes in their composition by the sequential deposition of different modified Aβ species. Microglia are implicated in the restriction of amyloid deposits and play a major role in internalization and degradation of Aβ. Recent studies showed that rare variants of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are associated with an increased risk for AD. Post-translational modifications of Aβ could modulate the interaction with TREM2, and the uptake by microglia. Here, we …

Aducanumab For Alzheimer Disease: The Amyloid Hypothesis Moves From Bench To Bedside, Erik S. Musiek, Teresa Gomez-Isla, David M Holtzman

Open Access Publications

No abstract provided.

Integrin Activation Is An Essential Component Of Sars-Cov-2 Infection, Peter Simons, Derek A. Rinaldi, Virginie Bondu, Alison M. Kell, Steven Bradfute, Diane S. Lidke, Tione Buranda

Pathology Research and Scholarship

SARS-CoV-2 infection depends on binding its spike (S) protein to angiotensin-converting enzyme 2 (ACE2). The S protein expresses an RGD motif, suggesting that integrins may be co-receptors. Here, we UV-inactivated SARS-CoV-2 and fluorescently labeled the envelope membrane with octadecyl rhodamine B (R18) to explore the role of integrin activation in mediating cell entry and productive infection. We used flow cytometry and confocal microscopy to show that SARS-CoV-2^R18 particles engage basal-state integrins. Furthermore, we demonstrate that Mn2+, which induces integrin extension, enhances cell entry of SARS-CoV-2^R18. We also show that one class of integrin antagonist, which binds to …

A Selective Antibiotic For Lyme Disease, Nadja Leimer, Xiaoqian Wu, Yu Imai, Madeleine Morrissette, Norman Pitt, Quentin Favre-Godal, Akira Iinishi, Samta Jain, Mariaelena Caboni, Inga V Leus, Vincent Bonifay, Samantha Niles, Rachel Bargabos, Meghan Ghiglieri, Rachel Corsetti, Megan Krumpoch, Gabriel Fox, Sangkeun Son, Dorota Klepacki, Yury S Polikanov, Cecily A Freliech, Julie E Mccarthy, Diane G Edmondson, Steven J Norris, Anthony D'Onofrio, Linden T Hu, Helen I Zgurskaya, Kim Lewis

Faculty, Staff and Student Publications

Lyme disease is on the rise. Caused by a spirochete Borreliella burgdorferi, it affects an estimated 500,000 people in the United States alone. The antibiotics currently used to treat Lyme disease are broad spectrum, damage the microbiome, and select for resistance in non-target bacteria. We therefore sought to identify a compound acting selectively against B. burgdorferi. A screen of soil micro-organisms revealed a compound highly selective against spirochetes, including B. burgdorferi. Unexpectedly, this compound was determined to be hygromycin A, a known antimicrobial produced by Streptomyces hygroscopicus. Hygromycin A targets the ribosomes and is taken up by B. burgdorferi, explaining …

Norovirus Protease Structure And Antivirals Development, Boyang Zhao, Liya Hu, Yongcheng Song, Ketki Patil, Sasirekha Ramani, Robert L Atmar, Mary K Estes, B V Venkataram Prasad

Faculty, Staff and Students Publications

Human norovirus (HuNoV) infection is a global health and economic burden. Currently, there are no licensed HuNoV vaccines or antiviral drugs available. The protease encoded by the HuNoV genome plays a critical role in virus replication by cleaving the polyprotein and is an excellent target for developing small-molecule inhibitors. The current strategy for developing HuNoV protease inhibitors is by targeting the enzyme's active site and designing inhibitors that bind to the substrate-binding pockets located near the active site. However, subtle differential conformational flexibility in response to the different substrates in the polyprotein and structural differences in the active site and …

Untargeted Metabolomic Analysis Of Human Milk From Mothers Of Preterm Infants, Lila S Nolan, Angela N Lewis, Qingqing Gong, James J Sollome, Olivia N Dewitt, Robert D Williams, Misty Good

2020-Current year OA Pubs

The application of metabolomics in neonatology offers an approach to investigate the complex relationship between nutrition and infant health. Characterization of the metabolome of human milk enables an investigation into nutrients that affect the neonatal metabolism and identification of dietary interventions for infants at risk of diseases such as necrotizing enterocolitis (NEC). In this study, we aimed to identify differences in the metabolome of breast milk of 48 mothers with preterm infants with NEC and non-NEC healthy controls. A minimum significant difference was observed in the human milk metabolome between the mothers of infants with NEC and mothers of healthy …

Tetraspanin Cd82 Regulates S1pr, Chelsea A. Saito-Reis, Victoria D. Balise, Erica M. Pascetti, Magdalena Jiminez, Jennifer M. Gillette

Pathology Research and Scholarship

Hematopoietic stem and progenitor cell (HSPC) mobilization into the blood occurs under normal physiological conditions and is stimulated in the clinic to enable the isolation of HSPCs for transplantation therapies. In the present study, we identify the tetraspanin CD82 as a novel regulator of HSPC mobilization. Using a global CD82 knockout (CD82KO) mouse, we measure enhanced HSPC mobilization after granulocyte-colony stimulating factor (G-CSF) or AMD3100 treatment, which we find is promoted by increased surface expression of the sphingosine 1-phosphate receptor 1 (S1PR

Project Earthrise: Proceedings Of The Ninth Annual Conference Of Invivo Planetary Health, Susan L. Prescott, Ganesa Wegienka, Remco Kort, David H. Nelson, Sabine Gabrysch, Trevor Hancock, Anita Kozyrskyj, Christopher A. Lowry, Nicole Redvers, Blake Poland, Jake Robinson, Jean-Claude Moubarac, Sara Warber, Janet Jansson, Aki Sinkkonen, John Penders, Susan Erdman, Ralph Nanan, Matilda Van Den Bosch, Kirk Schneider, Nicholas J. Schroeck, Tanja Sobko, Jamie Harvie, George A. Kaplan, Rob Moodie, Laura Lengnick, Isaac Prilleltensky, Yuria Celidwen, Susan H. Berman, Alan C. Logan, Brian Berman

Public Health Sciences Articles

The "Earthrise" photograph, taken on the 1968 Apollo 8 mission, became one of the most significant images of the 20th Century. It triggered a profound shift in environmental awareness and the potential for human unity-inspiring the first Earth Day in 1970. Taking inspiration from these events 50 years later, we initiated

Nuclear-Localized Human Respiratory Syncytial Virus Ns1 Protein Modulates Host Gene Transcription, Jingjing Pei, Nina R Beri, Angela J Zou, Philipp Hubel, Hannah K Dorando, Valter Bergant, Rebecca D Andrews, Jiehong Pan, Jared M Andrews, Kathleen C F Sheehan, Andreas Pichlmair, Gaya K Amarasinghe, Steven L Brody, Jacqueline E Payton, Daisy W Leung

Open Access Publications

Human respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in the pediatric, elderly, and immunocompromised individuals. RSV non-structural protein NS1 is a known cytosolic immune antagonist, but how NS1 modulates host responses remains poorly defined. Here, we observe NS1 partitioning into the nucleus of RSV-infected cells, including the human airway epithelium. Nuclear NS1 coimmunoprecipitates with Mediator complex and is chromatin associated. Chromatin-immunoprecipitation demonstrates enrichment of NS1 that overlaps Mediator and transcription factor binding within the promoters and enhancers of differentially expressed genes during RSV infection. Mutation of the NS1 C-terminal helix reduces NS1 impact on …

Prioritization Of Molecular Targets For Antimalarial Drug Discovery, Barbara Forte, Daniel E Goldberg, Eva S Istvan, Et Al

2020-Current year OA Pubs

There is a shift in antimalarial drug discovery from phenotypic screening toward target-based approaches, as more potential drug targets are being validated in

Rn7sk Small Nuclear Rna Controls Bidirectional Transcription Of Highly Expressed Gene Pairs In Skin, Roberto Bandiera, Rebecca E Wagner, Thiago Britto-Borges, Christoph Dieterich, Sabine Dietmann, Susanne Bornelöv, Michaela Frye

Open Access Publications

Pausing of RNA polymerase II (Pol II) close to promoters is a common regulatory step in RNA synthesis, and is coordinated by a ribonucleoprotein complex scaffolded by the noncoding RNA RN7SK. The function of RN7SK-regulated gene transcription in adult tissue homoeostasis is currently unknown. Here, we deplete RN7SK during mouse and human epidermal stem cell differentiation. Unexpectedly, loss of this small nuclear RNA specifically reduces transcription of numerous cell cycle regulators leading to cell cycle exit and differentiation. Mechanistically, we show that RN7SK is required for efficient transcription of highly expressed gene pairs with bidirectional promoters, which in the epidermis …

Inhibition Of The Nlrp3 Inflammasome Improves Lifespan In Animal Murine Model Of Hutchinson-Gilford Progeria, Alvaro González-Dominguez, Raúl Montañez, Beatriz Castejón-Vega, Jéssica Nuñez-Vasco, Débora Lendines-Cordero, Chun Wang, Gabriel Mbalaviele, José M Navarro-Pando, Elísabet Alcocer-Gómez, Mario D Cordero

Open Access Publications

Inflammation is a hallmark of aging and accelerated aging syndromes such as Hutchinson-Gilford progeria syndrome (HGPS). In this study, we present evidence of increased expression of the components of the NLRP3 inflammasome pathway in HGPS skin fibroblasts, an outcome that was associated with morphological changes of the nuclei of the cells. Lymphoblasts from HGPS patients also showed increased basal levels of NLRP3 and caspase 1. Consistent with these results, the expression of caspase 1 and Nlrp3, but not of the other inflammasome receptors was higher in the heart and liver of Zmpste24

Neuron-Specific Imp2 Overexpression By Synapsin Promoter-Driven Aav9: A Tool To Study Its Role In Axon Regeneration., Sarah Blizard, Danielle Park, Natalie O'Toole, Sheeva Norooz, Martin Dela Torre, Young Son, Adam Holstein, Scarlett Austin, Joshua Harman, Samantha Haraszti, Daved Fared, Mei Xu

PCOM Scholarly Works

Insulin-like growth factor II mRNA-binding protein (IMP) 2 is one of the three homologues (IMP1-3) that belong to a conserved family of mRNA-binding proteins. Its alternative splice product is aberrantly expressed in human hepatocellular carcinoma, and it is therefore identified as HCC. Previous works have indicated that IMP1/ZBP1 (zipcode binding protein) is critical in axon guidance and regeneration by regulating localization and translation of specific mRNAs. However, the role of IMP2 in the nervous system is largely unknown. We used the synapsin promoter-driven adeno-associated viral (AAV) 9 constructs for transgene expression both in vitro and in vivo. These viral vectors …

A Guide For Authors And Readers Of The American Society For Nutrition Journals On The Proper Use Of P Values And Strategies That Promote Transparency And Improve Research Reproducibility, John D Sorkin, Mark Manary, Paul A M Smeets, Amanda J Macfarlane, Arne Astrup, Ronald L Prigeon, Beth B Hogans, Jack Odle, Teresa A Davis, Katherine L Tucker, Christopher P Duggan, Deirdre K Tobias

Children’s Nutrition Research Center Staff Publications

Two questions regarding the scientific literature have become grist for public discussion: 1) what place should P values have in reporting the results of studies? 2) How should the perceived difficulty in replicating the results reported in published studies be addressed? We consider these questions to be 2 sides of the same coin; failing to address them can lead to an incomplete or incorrect message being sent to the reader. If P values (which are derived from the estimate of the effect size and a measure of the precision of the estimate of the effect) are used improperly, for example …

Tet2 And Dnmt3a Mutations Exert Divergent Effects On Dna Repair And Sensitivity Of Leukemia Cells To Parp Inhibitors, Silvia Maifrede, Bac Viet Le, Margaret Nieborowska-Skorska, Konstantin Golovine, Katherine Sullivan-Reed, Wangisa M B Dunuwille, Joseph Nacson, Michael Hulse, Kelsey Keith, Jozef Madzo, Lisa Beatrice Caruso, Zachary Gazze, Zhaorui Lian, Antonella Padella, Kumaraswamy N. Chitrala, Boris A. Bartholdy, Ksenia Matlawska-Wasowska, Daniela Di Marcantonio, Giorgia Simonetti, Georg Greiner, Stephen M Sykes, Peter Valent, Elisabeth M. Paietta, Martin S. Tallman, Hugo F. Fernandez, Mark R. Litzow, Mark D. Minden, Jian Huang, Giovanni Martinelli, George S. Vassiliou, Italo Tempera, Katarzyna Piwocka, Neil Johnson, Grant A. Challen, Tomasz Skorski

Pediatrics Research and Scholarship

Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F , and MPLW515L , or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52 . Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK-mediated non-homologous …

Structure Of Venezuelan Equine Encephalitis Virus In Complex With The Ldlrad3 Receptor, Katherine Basore, Hongming Ma, Natasha M Kafai, Samantha Mackin, Arthur S Kim, Christopher A Nelson, Michael S Diamond, Daved H Fremont

Open Access Publications

LDLRAD3 is a recently defined attachment and entry receptor for Venezuelan equine encephalitis virus (VEEV)

Chemotherapy-Induced Cognitive Impairment: Focus On The Intersection Of Oxidative Stress And Tnfα., Nicole G Rummel, Luksana Chaiswing, Subbarao Bondada, Daret K St Clair, D Allan Butterfield

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Chemotherapy-induced cognitive impairment (CICI) has been observed in a large fraction of cancer survivors. Although many of the chemotherapeutic drugs do not cross the blood-brain barrier, following treatment, the structure and function of the brain are altered and cognitive dysfunction occurs in a significant number of cancer survivors. The means by which CICI occurs is becoming better understood, but there still remain unsolved questions of the mechanisms involved. The hypotheses to explain CICI are numerous. More than 50% of FDA-approved cancer chemotherapy agents are associated with reactive oxygen species (ROS) that lead to oxidative stress and activate a myriad of …

Immune Responses To Injury And Their Links To Eye Disease., Mary Ann Stepp, A Sue Menko

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The eye is regarded as an immune privileged site. Since the presence of a vasculature would impair vision, the vasculature of the eye is located outside of the central light path. As a result, many regions of the eye evolved mechanisms to deliver immune cells to sites of dysgenesis, injury, or in response to the many age-related pathologies. While the purpose of these immune responses is reparative or protective, cytokines released by immune cells compromise visual acuity by inducing inflammation and fibrosis. The response to traumatic or pathological injury is distinct in different regions of the eye. Age-related diseases impact …

Rare Variants In Kdr, Encoding Vegf Receptor 2, Are Associated With Tetralogy Of Fallot., Doris Škorić-Milosavljević, Najim Lahrouchi, Fernanda M. Bosada, Gregor Dombrowsky, Simon G. Williams, Robert Lesurf, Fleur V Y Tjong, Roddy Walsh, Ihssane El Bouchikhi, Jeroen Breckpot, Enrique Audain, Aho Ilgun, Leander Beekman, Ilham Ratbi, Alanna Strong, Maximilian Muenke, Solveig Heide, Alison M. Muir, Mariam Hababa, Laura A. Cross, Dihong Zhou, T Pastinen, German Competence Network For Congenital Heart Defects, Elaine Zackai, Samir Atmani, Karim Ouldim, Najlae Adadi, Katharina Steindl, Anita Rauch, David Brook, Anna Wilsdon, Irene Kuipers, Nico A. Blom, Barbara J. Mulder, Heather C. Mefford, Boris Keren, Pascal Joset, Paul Kruszka, Isabelle Thiffault, Sarah E. Sheppard, Amy Roberts, Elisabeth M. Lodder, Bernard D. Keavney, Sally-Ann B. Clur, Seema Mital, Marc-Philip Hitz, Vincent M. Christoffels, Alex V. Postma, Connie R. Bezzina

Manuscripts, Articles, Book Chapters and Other Papers

Purpose: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear.

Methods: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF.

Results: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in …

Development Of Food Pattern Recommendations For Infants And Toddlers 6-24 Months Of Age To Support The Dietary Guidelines For Americans, 2020-2025, Kathryn G Dewey, Tusarebecca Pannucci, Kellie O Casavale, Teresa A Davis, Sharon M Donovan, Ronald E Kleinman, Elsie M Taveras, Regan L Bailey, Rachel Novotny, Barbara O Schneeman, Jamie Stang, Janet De Jesus, Eve E Stoody

Children’s Nutrition Research Center Staff Publications

Background: Developing food-based dietary guidelines (FBDGs) for infants and toddlers is a complex task that few countries have attempted.

Objectives: Our objectives are to describe the process of food pattern modeling (FPM) conducted to develop FBDGs for the Dietary Guidelines for Americans, 2020-2025 for infants 6 to <12 mo and toddlers 12 to <24 mo of age, as well as the implications of the results and areas needing further work.

Methods: The US 2020 Dietary Guidelines Advisory Committee, with the support of federal staff, conducted FPM analyses using 5 steps: 1) identified energy intake targets; 2) established nutritional goals; 3) identified food groupings and expected amounts, using 3 options for the amount of energy from human milk in each age interval; 4) estimated …

Dicer1 Tumor Predisposition Syndrome: An Evolving Story Initiated With The Pleuropulmonary Blastoma, Iván A González, Douglas R Stewart, Kris Ann P Schultz, Amanda P Field, D Ashley Hill, Louis P Dehner

Open Access Publications

DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4-5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation …

Advances In Optical Gastrointestinal Endoscopy: A Technical Review, Yubo Tang, Sharmila Anandasabapathy, Rebecca Richards-Kortum

Faculty, Staff and Students Publications

Optical endoscopy is the primary diagnostic and therapeutic tool for management of gastrointestinal (GI) malignancies. Most GI neoplasms arise from precancerous lesions; thus, technical innovations to improve detection and diagnosis of precancerous lesions and early cancers play a pivotal role in improving outcomes. Over the last few decades, the field of GI endoscopy has witnessed enormous and focused efforts to develop and translate accurate, user-friendly, and minimally invasive optical imaging modalities. From a technical point of view, a wide range of novel optical techniques is now available to probe different aspects of light-tissue interaction at macroscopic and microscopic scales, complementing …

Perspectives From The Society For Pediatric Research: Advice On Sustaining Science And Mentoring During Covid-19, Catherine S Forster, Suong T Nguyen, Weston T Powell, Daniel J Moore, Jacqueline Ho, Melvin B Heyman, Tara L Wenger, Fernando Gonzalez, Margaret Hostetter, Andrew Nowalk, Caroline E Rassbach, Debra Boyer, Pnina Weiss, Rebecca L Blankenburg, Jordan S Orange, Kate G Ackerman, Audrea M Burns, National Pediatric Physician-Scientist Collaborative Workgroup

Faculty, Staff and Students Publications

The COVID-19 pandemic will leave an indelible mark on the careers of current medical trainees. Given the disruptions to medical education, economic impact on institutions, and the uncertainties around future job prospects, trainees are facing unprecedented challenges. This situation is especially concerning for futures of pediatric physician-scientist trainees, where concerns regarding maintaining the pipeline were well documented prior to the emergence of COVID-19. In this Perspectives article, we leverage the unique expertise of our workgroup to address concerns of physician-scientist trainees and to provide suggestions on how to navigate career trajectories in the post-COVID-19 era. We identified and addressed four …

A Human Ipsc-Derived Inducible Neuronal Model Of Niemann-Pick Disease, Type C1, Anika V Prabhu, Insung Kang, Raffaella De Pace, Christopher A Wassif, Hideji Fujiwara, Pamela Kell, Xuntian Jiang, Daniel S Ory, Juan S Bonifacino, Michael E Ward, Forbes D Porter

2020-Current year OA Pubs

BACKGROUND: Niemann-Pick disease, type C (NPC) is a childhood-onset, lethal, neurodegenerative disorder caused by autosomal recessive mutations in the genes NPC1 or NPC2 and characterized by impaired cholesterol homeostasis, a lipid essential for cellular function. Cellular cholesterol levels are tightly regulated, and mutations in either NPC1 or NPC2 lead to deficient transport and accumulation of unesterified cholesterol in the late endosome/lysosome compartment, and progressive neurodegeneration in affected individuals. Previous cell-based studies to understand the NPC cellular pathophysiology and screen for therapeutic agents have mainly used patient fibroblasts. However, these do not allow modeling the neurodegenerative aspect of NPC disease, highlighting …

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, And Rezafungin, Martin Hoenigl, Rosanne Sprute, Matthias Egger, Amir Arastehfar, Oliver A Cornely, Robert Krause, Cornelia Lass-Flörl, Juergen Prattes, Andrej Spec, George R Thompson 3rd, Nathan Wiederhold, Jeffrey D Jenks

2020-Current year OA Pubs

The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a …

Clinical Trial And Postmarketing Safety Of Onasemnogene Abeparvovec Therapy, John W Day, Jerry R Mendell, Eugenio Mercuri, Richard S Finkel, Kevin A Strauss, Aaron Kleyn, Sitra Tauscher-Wisniewski, Francis Fonyuy Tukov, Sandra P Reyna, Deepa H Chand

2020-Current year OA Pubs

INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy.

OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data.

METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign …

Gut Microbiota-Derived Short-Chain Fatty Acids Protect Against The Progression Of Endometriosis, Sangappa B Chadchan, Pooja Popli, Chandrasekhar R Ambati, Eric Tycksen, Sang Jun Han, Serdar E Bulun, Nagireddy Putluri, Scott W Biest, Ramakrishna Kommagani

2020-Current year OA Pubs

Worldwide, ∼196 million are afflicted with endometriosis, a painful disease in which endometrial tissue implants and proliferates on abdominal peritoneal surfaces. Theories on the origin of endometriosis remained inconclusive. Whereas up to 90% of women experience retrograde menstruation, only 10% develop endometriosis, suggesting that factors that alter peritoneal environment might contribute to endometriosis. Herein, we report that whereas some gut bacteria promote endometriosis, others protect against endometriosis by fermenting fiber to produce short-chain fatty acids. Specifically, we found that altered gut microbiota drives endometriotic lesion growth and feces from mice with endometriosis contained less of short-chain fatty acid and n-butyrate …

Management And Outcomes Of Cardiogenic Shock In Cardiac Icus With Versus Without Shock Teams., Alexander I Papolos, Benjamin B Kenigsberg, David D Berg, Carlos L Alviar, Erin Bohula, James A Burke Md, Anthony P Carnicelli, Sunit-Preet Chaudhry, Stavros Drakos, Daniel A Gerber, Jianping Guo, James M Horowitz, Jason N Katz, Ellen C Keeley, Thomas S Metkus, Jose Nativi-Nicolau, Jeffrey R Snell, Shashank S Sinha, Wayne J Tymchak, Sean Van Diepen, David A Morrow, Christopher F Barnett

Cardiology Division

BACKGROUND: Single-center studies suggest that implementation of multidisciplinary cardiogenic shock (CS) teams is associated with improved CS survival.

OBJECTIVES: The aim was to characterize practice patterns and outcomes in the management of CS across multiple centers with versus without shock teams.

METHODS: The Critical Care Cardiology Trials Network is a multicenter network of cardiac intensive care units (CICUs) in North America. All consecutive medical admissions to each CICU (n = 24) were captured during annual 2-month collection periods (2017-2019; n = 6,872). Shock management and CICU mortality among centers with versus without shock teams were compared using inverse probability weighting. …