Digital Commons Network^™

Deconstructing Tumor Heterogeneity: The Stromal Perspective, Renee E. Vickman, Douglas V. Faget, Sheila A. Stewart, Et Al

Open Access Publications

Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive

Orsay Virus Cp-Δ Adopts A Novel Β-Bracelet Structural Fold And Incorporates Into Virions As A Head Fiber, Yusong R. Guo, Yanlin Fan, Ying Zhou, Miao Jin, Jim L. Zhang, Hongbing Jiang, Matthew V. Holt, Tao Wang, Nicolas L. Young, David Wang, Weiwei Zhong, Yizhi J. Tao

Open Access Publications

Fiber proteins are commonly found in eukaryotic and prokaryotic viruses, where they play important roles in mediating viral attachment and host cell entry. They typically form trimeric structures and are incorporated into virions via noncovalent interactions. Orsay virus, a small RNA virus which specifically infects the laboratory model nematode

Sex Differences In Population Dynamics During Formation Of Kidney Bacterial Communities By Uropathogenic Escherichia Coli, Lisa K. Mclellan, Allyssa L. Daugherty, David A. Hunstad

Open Access Publications

No abstract provided.

Campylobacter Colonization, Environmental Enteric Dysfunction, Stunting, And Associated Risk Factors Among Young Children In Rural Ethiopia: A Cross-Sectional Study From The Campylobacter Genomics And Environmental Enteric Dysfunction (Caged) Project, Dehao Chen, Mark J Manary, Et Al

Open Access Publications

Livestock farming provides a possible mechanism by which smallholder farmers can meet their household need for animal source foods (ASF), which may reduce the risk of stunting. However, direct/indirect contacts with domestic animals may increase colonization by

Cd4 Inhibits Helper T Cell Activation At Lower Affinity Threshold For Full-Length T Cell Receptors Than Single Chain Signaling Constructs, Deborah K Johnson, Wyatt Magoffin, Sheldon J Myers, Jordan G Finnell, John C Hancock, Taylor S Orton, Stephen P Persaud, Kenneth A Christensen, K Scott Weber

Open Access Publications

CD4

Insights From Genetic Studies Of Cerebral Palsy, Sara A Lewis, Sheetal Shetty, Bryce A Wilson, Aris J Huang, Sheng Chih Jin, Hayley Smithers-Sheedy, Michael C Fahey, Michael C Kruer

Open Access Publications

Cohort-based whole exome and whole genome sequencing and copy number variant (CNV) studies have identified genetic etiologies for a sizable proportion of patients with cerebral palsy (CP). These findings indicate that genetic mutations collectively comprise an important cause of CP. We review findings in CP genomics and propose criteria for CP-associated genes at the level of gene discovery, research study, and clinical application. We review the published literature and report 18 genes and 5 CNVs from genomics studies with strong evidence of for the pathophysiology of CP. CP-associated genes often disrupt early brain developmental programming or predispose individuals to known …

Nonmicrobial Activation Of Tlrs Controls Intestinal Growth, Wound Repair, And Radioprotection, William F Stenson, Matthew A Ciorba

Open Access Publications

TLRs, key components of the innate immune system, recognize microbial molecules. However, TLRs also recognize some nonmicrobial molecules. In particular, TLR2 and TLR4 recognize hyaluronic acid, a glycosaminoglycan in the extracellular matrix. In neonatal mice endogenous hyaluronic acid binding to TLR4 drives normal intestinal growth. Hyaluronic acid binding to TLR4 in pericryptal macrophages results in cyclooxygenase2- dependent PGE

Regulatory T Cells Developing Peri-Weaning Are Continually Required To Restrain Th2 Systemic Responses Later In Life, Kathryn A. Knoop, Keely G Mcdonald, Chyi-Song Hsieh, Phillip I Tarr, Rodney D Newberry

Open Access Publications

Atopic disorders including allergic rhinitis, asthma, food allergy, and dermatitis, are increasingly prevalent in Western societies. These disorders are largely characterized by T helper type 2 (Th2) immune responses to environmental triggers, particularly inhaled and dietary allergens. Exposure to such stimuli during early childhood reduces the frequency of allergies in at-risk children. These allergic responses can be restrained by regulatory T cells (Tregs), particularly Tregs arising in the gut. The unique attributes of how early life exposure to diet and microbes shape the intestinal Treg population is a topic of significant interest. While imprinting during early life promotes the development …

Using The Zebrafish Lateral Line To Understand The Roles Of Mitochondria In Sensorineural Hearing Loss, Melanie Holmgren, Lavinia Sheets

Open Access Publications

Hair cells are the mechanosensory receptors of the inner ear and can be damaged by noise, aging, and ototoxic drugs. This damage often results in permanent sensorineural hearing loss. Hair cells have high energy demands and rely on mitochondria to produce ATP as well as contribute to intracellular calcium homeostasis. In addition to generating ATP, mitochondria produce reactive oxygen species, which can lead to oxidative stress, and regulate cell death pathways. Zebrafish lateral-line hair cells are structurally and functionally analogous to cochlear hair cells but are optically and pharmacologically accessible within an intact specimen, making the zebrafish a good model …

Advances In Modeling The Immune Microenvironment Of Colorectal Cancer, Paul Sukwoo Yoon, Nuala Del Piccolo, Venktesh S Shirure, Yushuan Peng, Amanda Kirane, Robert J Canter, Ryan C Fields, Steven C George, Sepideh Gholami

Open Access Publications

Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the US. CRC frequently metastasizes to the liver and these patients have a particularly poor prognosis. The infiltration of immune cells into CRC tumors and liver metastases accurately predicts disease progression and patient survival. Despite the evident influence of immune cells in the CRC tumor microenvironment (TME), efforts to identify immunotherapies for CRC patients have been limited. Here, we argue that preclinical model systems that recapitulate key features of the tumor microenvironment-including tumor, stromal, and immune cells; the extracellular matrix; and the vasculature-are …

Ige And T Cell Reactivity To A Comprehensive Panel Of Cockroach Allergens In Relation To Disease, Anna Pomés, Véronique Schulten, Jill Glesner, Ricardo Da Silva Antunes, Aaron Sutherland, Leonard B Bacharier, Avraham Beigelman, Paula Busse, April Frazier, Alessandro Sette

Open Access Publications

IgE sensitization to cockroach allergens is associated with development of allergic diseases, such as asthma. To understand the relevance of different cockroach allergens for diagnosis and immunotherapy, a comprehensive analysis of IgE antibody levels and T cell reactivity to an expanded set of cockroach allergens and their relationship to disease was performed in a cohort of USA cockroach sensitized patients. IgE antibody levels to recombinant chitinase and hemocyanin were measured for 23 subjects by custom-made ImmunoCAPs and compared with IgE levels to eight cockroach allergens we previously reported for the same cohort.

Affinity-Restricted Memory B Cells Dominate Recall Responses To Heterologous Flaviviruses, Rachel Wong, Julia A. Belk, Jennifer Govero, Jennifer L. Uhrlaub, Dakota Reinartz, Haiyan Zhao, John M. Errico, Lucas D'Souza, Tyler J. Ripperger, Janko Nikolich-Zugich, Mark J. Shlomchik, Ansuman T. Satpathy, Daved H. Fremont, Michael S. Diamond, Deepta Bhattacharya

Open Access Publications

No abstract provided.

Toxic Effects Of Endoplasmic Reticulum Stress Transducer Bbf2h7-Derived Small Peptide Fragments On Neuronal Cells, Koji Matsuhisa, Longjie Cai, Atsushi Saito, Fumika Sakaue, Yasunao Kamikawa, Sachiko Fujiwara, Rie Asada, Yukitsuka Kudo, Kazunori Imaizumi

Open Access Publications

No abstract provided.

Randomized Controlled Crossover Trials Of The Pharmacokinetics Of Prc-063, A Novel Multilayer Extended-Release Formulation Of Methylphenidate, In Healthy Adults, Martin A. Katzman, Greg Mattingly, Larry J. Klassen, Marc J. Cataldo, Graeme A. E. Donnelly

Open Access Publications

No abstract provided.

Krasg12c Inhibition With Sotorasib In Advanced Solid Tumors, David S. Hong, Ramaswamy Govindan, Et Al

Open Access Publications

No abstract provided.

Context Is Key: Delineating The Unique Functions Of Ifnα And Ifnβ In Disease, Lindsey E Fox, Marissa C Locke, Deborah J Lenschow

Open Access Publications

Type I interferons (IFNs) are critical effector cytokines of the immune system and were originally known for their important role in protecting against viral infections; however, they have more recently been shown to play protective or detrimental roles in many disease states. Type I IFNs consist of IFNα, IFNβ, IFNϵ, IFNκ, IFNω, and a few others, and they all signal through a shared receptor to exert a wide range of biological activities, including antiviral, antiproliferative, proapoptotic, and immunomodulatory effects. Though the individual type I IFN subtypes possess overlapping functions, there is growing appreciation that they also have unique properties. In …

Macrophages Respond Rapidly To Ototoxic Injury Of Lateral Line Hair Cells But Are Not Required For Hair Cell Regeneration, Mark E Warchol, Angela Schrader, Lavinia Sheets

Open Access Publications

The sensory organs of the inner ear contain resident populations of macrophages, which are recruited to sites of cellular injury. Such macrophages are known to phagocytose the debris of dying cells but the full role of macrophages in otic pathology is not understood. Lateral line neuromasts of zebrafish contain hair cells that are nearly identical to those in the inner ear, and the optical clarity of larval zebrafish permits direct imaging of cellular interactions. In this study, we used larval zebrafish to characterize the response of macrophages to ototoxic injury of lateral line hair cells. Macrophages migrated into neuromasts within …

The Complex Interactions Between Rotavirus And The Gut Microbiota, Andrew Hyoungjin Kim, Michael P Hogarty, Vanessa C Harris, Megan T Baldridge

Open Access Publications

Human rotavirus (HRV) is the leading worldwide cause of acute diarrhea-related death in children under the age of five. RV infects the small intestine, an important site of colonization by the microbiota, and studies over the past decade have begun to reveal a complex set of interactions between RV and the gut microbiota. RV infection can temporarily alter the composition of the gut microbiota and probiotic administration alleviates some symptoms of infection

Consumptive Coagulopathy Of Severe Yellow Fever Occurs Independently Of Hepatocellular Tropism And Massive Hepatic Injury, Adam L. Bailey, Liang-I Kang, Luiz Gonzaga Francisco De Assis Barros D'Elia Zanella, Cássia G. T. Silveira, Yeh-Li Ho, Lander Foquet, Greg Bial, Broc T. Mccune, Amaro Nunes Duarte-Neto, Archana Thomas, Hans-Peter Raué, Kathleen Byrnes, Esper G. Kallas, Mark K. Slifka, Michael S. Diamond

Open Access Publications

No abstract provided.

Postural Directionality And Head Tremor In Cervical Dystonia, Qiyu Chen, Jeanne P Vu, Elizabeth Cisneros, Casey N Benadof, Zheng Zhang, Richard L Barbano, Christopher G Goetz, Joseph Jankovic, Hyder A Jinnah, Joel S Perlmutter, Mark I Appelbaum, Glenn T Stebbins, Cynthia L Comella, David A Peterson

Open Access Publications

Background: Although abnormal head and neck postures are defining features of cervical dystonia (CD), head tremor (HT) is also common. However, little is known about the relationship between abnormal postures and HT in CD.

Methods: We analyzed clinical data and video recordings from 185 patients enrolled by the Dystonia Coalition. We calculated the likelihood of their HT and HT type ("regular" vs. "jerky") given directionality of abnormal head postures, disease duration, sex, and age.

Results: Patients with retrocollis were more likely to have HT than patients with anterocollis (X

Discussion: We found that HT is more likely for CD patients …

Insights Into The Role Of The Jak/Stat Signaling Pathway In Graft-Versus-Host Disease, Ramzi Abboud, Jaebok Choi, Peter Ruminski, Mark A Schroeder, Sena Kim, Camille N Abboud, John F Dipersio

Open Access Publications

Allogeneic hematopoietic transplantation (allo-HCT) is a curative therapy for a variety of hematologic malignancies, primarily through immune-mediated clearance of malignant cells. This graft-

Humanized Zebrafish Enhance Human Hematopoietic Stem Cell Survival And Promote Acute Myeloid Leukemia Clonal Diversity, Vinothkumar Rajan, Nicole Melong, Wing Hing Wong, Benjamin King, R. Spencer Tong, Nithin Mahajan, Daniel Gaston, Troy Lund, David Rittenberg, Graham Dellaire, Clinton J. V. Campbell, Todd Druley, Jason N. Berman

Open Access Publications

Xenograft models are invaluable tools in establishing the current paradigms of hematopoiesis and leukemogenesis. The zebrafish has emerged as a robust alternative xenograft model but, like mice, lack specific cytokines that mimic the microenvironment found in human patients. To address this critical gap, we generated the first humanized zebrafish that express human hematopoietic-specific cytokines (GM-CSF, SCF, and SDF1α). Termed GSS fish, these zebrafish promote survival, self-renewal and multilineage differentiation of human hematopoietic stem and progenitor cells and result in enhanced proliferation and hematopoietic niche-specific homing of primary human leukemia cells. Using error-corrected RNA sequencing, we determined that patient-derived leukemias transplanted …

The Role Of Glia In Epilepsy, Intellectual Disability, And Other Neurodevelopmental Disorders In Tuberous Sclerosis Complex, Michael Wong

Open Access Publications

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by severe neurological manifestations, including epilepsy, intellectual disability, autism, and a range of other behavioral and psychiatric symptoms, collectively referred to as TSC-associated neuropsychiatric disorders (TAND). Various tumors and hamartomas affecting different organs are the pathological hallmarks of the disease, especially cortical tubers of the brain, but specific cellular and molecular abnormalities, such as involving the mechanistic target of rapamycin (mTOR) pathway, have been identified that also cause or contribute to neurological manifestations of TSC independent of gross structural lesions. In particular, while neurons are immediate mediators of neurological symptoms, …

Regional Gene Repression By Dna Double-Strand Breaks In G1 Phase Cells, Caitlin E. Purman, Patrick L. Collins, Sofia I. Porter, Ankita Saini, Harshath Gupta, Barry P. Sleckman, Eugene M. Oltz

Open Access Publications

DNA damage responses (DDR) to double-strand breaks (DSBs) alter cellular transcription programs at the genome-wide level. Through processes that are less well understood, DSBs also alter transcriptional responses locally, which may be important for efficient DSB repair. Here, we developed an approach to elucidate the

Clearance Of Chikungunya Virus Infection In Lymphoid Tissues Is Promoted By Treatment With An Agonistic Anti-Cd137 Antibody, Jun P Hong, Mary K Mccarthy, Bennett J Davenport, Thomas E Morrison, Michael S Diamond

Open Access Publications

CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV …

Dosimetric Feasibility Of Utilizing The Viewray Magnetic Resonance Guided Linac System For Image-Guided Spine Stereotactic Body Radiation Therapy, Gage Redler, Tynan Stevens, Jochen Cammin, Martha Malin, Olga Green, Sasa Mutic, Sean Pitroda, Bulent Aydogan

Open Access Publications

INTRODUCTION: Spine stereotactic body radiation therapy (SBRT) achieves favorable outcomes compared to conventional radiotherapy doses/fractionation. The spinal cord is the principal dose-limiting organ-at-risk (OAR), and safe treatment requires precise immobilization/localization. Therefore, image guidance is paramount to successful spine SBRT. Conventional X-ray imaging and alignment to surrogate bony anatomy may be inadequate, whereas magnetic resonance imaging (MRI) directly visualizes the dose-limiting cord. This work assessed the dosimetric capability of the ViewRay (ViewRay Inc. Oakwood Village, OH) magnetic resonance (MR) guided linac (MR-Linac) for spine SBRT.

METHODS: Eight spine SBRT patients without orthopedic hardware who were previously treated on a TrueBeam using …

Distinct Roles Of Interferon Alpha And Beta In Controlling Chikungunya Virus Replication And Modulating Neutrophil-Mediated Inflammation, Lindsey E Cook, Marissa C Locke, Alissa R Young, Kristen Monte, Matthew L Hedberg, Raeann M Shimak, Kathleen C F Sheehan, Deborah J Veis, Michael S Diamond, Deborah J Lenschow

Open Access Publications

Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice …

The Local Translation Of Kna In Dendritic Projections Of Auditory Neurons And The Roles Of Kna In The Transition From Hidden To Overt Hearing Loss, Jeong Han Lee, Mincheol Kang, Seojin Park, Maria C. Perez-Flores, Xiao-Dong Zhang, Wenying Wang, Michael Anne Gratton, Nipavan Chiamvimonvat, Ebenezer N. Yamoah

Open Access Publications

Local and privileged expression of dendritic proteins allows segregation of distinct functions in a single neuron but may represent one of the underlying mechanisms for early and insidious presentation of sensory neuropathy. Tangible characteristics of early hearing loss (HL) are defined in correlation with nascent hidden hearing loss (HHL) in humans and animal models. Despite the plethora of causes of HL, only two prevailing mechanisms for HHL have been identified, and in both cases, common structural deficits are implicated in inner hair cell synapses, and demyelination of the auditory nerve (AN). We uncovered that Na

Sik3 Suppresses Neuronal Hyperexcitability By Regulating The Glial Capacity To Buffer K+ And Water, Hailun Li, Alexandra Russo, Aaron Diantonio

Open Access Publications

Glial regulation of extracellular potassium (K

Disease-Associated Mutations In Niemann-Pick Type C1 Alter Er Calcium Signaling And Neuronal Plasticity, Scott A. Tiscione, Oscar Vivas, Kenneth S. Ginsburg, Donald M. Bers, Daniel S. Ory, Luis F. Santana, Rose E. Dixon, Eamonn J. Dickson

Open Access Publications

Niemann-Pick type C1 (NPC1) protein is essential for the transport of externally derived cholesterol from lysosomes to other organelles. Deficiency of NPC1 underlies the progressive NPC1 neurodegenerative disorder. Currently, there are no curative therapies for this fatal disease. Given the Ca