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Apurinic/Apyrimidinic Endonuclease 1 Restricts The Internalization Of Bacteria Into Human Intestinal Epithelial Cells Through The Inhibition Of Rac1, Gerco Den Hartog, Lindsay D Butcher, Amber L Ablack, Laura A Pace, Jailal N G Ablack, Richard Xiong, Soumita Das, Thaddeus S Stappenbeck, Lars Eckmann, Peter B Ernst, Sheila E Crowe

Open Access Publications

Pathogenic intestinal bacteria lead to significant disease in humans. Here we investigated the role of the multifunctional protein, Apurinic/apyrimidinic endonuclease 1 (APE1), in regulating the internalization of bacteria into the intestinal epithelium. Intestinal tumor-cell lines and primary human epithelial cells were infected with

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 …

Rna Based Approaches To Profile Oncogenic Pathways From Low Quantity Samples To Drive Precision Oncology Strategies, Anja Van De Stolpe, Wim Verhaegh, Jean-Yves Blay, Cynthia X Ma, Patrick Pauwels, Mark Pegram, Hans Prenen, Dirk De Ruysscher, Nabil F Saba, Susan F Slovin, Karen Willard-Gallo, Hatim Husain

Open Access Publications

Precision treatment of cancer requires knowledge on active tumor driving signal transduction pathways to select the optimal effective targeted treatment. Currently only a subset of patients derive clinical benefit from mutation based targeted treatment, due to intrinsic and acquired drug resistance mechanisms. Phenotypic assays to identify the tumor driving pathway based on protein analysis are difficult to multiplex on routine pathology samples. In contrast, the transcriptome contains information on signaling pathway activity and can complement genomic analyses. Here we present the validation and clinical application of a new knowledge-based mRNA-based diagnostic assay platform (OncoSignal) for measuring activity of relevant signaling …

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.

Nab-Paclitaxel Plus Durvalumab In Patients With Previously Treated Advanced Stage Non-Small Cell Lung Cancer (Abound.2l+), Daniel Morgensztern, Manuel Cobo Dols, Santiago Ponce Aix, Pieter E Postmus, Jaafar Bennouna, Jürgen R Fischer, Oscar Juan-Vidal, David J Stewart, Andrea Ardizzoni, Rafia Bhore, Marianne Wolfsteiner, Martin Reck, Denis Talbot, Ramaswamy Govindan, Teng Jin Ong

Open Access Publications

No abstract provided.

Treatment-Emergent Neuroendocrine Prostate Cancer: A Clinicopathological And Immunohistochemical Analysis Of 94 Cases, Qingfu Zhang, Yunan Han, Yao Zhang, Dan Liu, Jian Ming, Bo Huang, Xueshan Qiu

Open Access Publications

Purpose: This study aimed to evaluate the pathological characteristics, immunophenotype, and prognosis of treatment-emergent neuroendocrine prostate cancer (T-NEPC).

Materials and Methods: We collected 231 repeated biopsy specimens of castration-resistant prostate cancer (CRPC) cases between 2008 and 2019. We used histopathological and immunohistochemical evaluations of Synaptophysin (SYN), ChromograninA (CgA), CD56, androgen receptor (AR), and prostate

Results: Among the 231 CRPC cases, 94 (40.7%) cases were T-NEPC. T-NEPC were more likely to present with negative immunohistochemistry for AR (30.9%) and PSA (47.9%) than that of CRPC (8.8% and 17.5%, respectively). Kaplan-Meier analysis revealed that patients with T-NEPC (median overall survival [OS]: 17.6 …

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.

Dementia Research In The Caribbean Hispanic Islands: Present Findings And Future Trends, Daisy Acosta, Jorge J Llibre-Guerra, Ivonne Z Jiménez-Velázquez, Juan J Llibre-Rodríguez

Open Access Publications

During the last decade, the Caribbean Hispanic islands experienced accelerated demographic aging, representing the fastest aging region within Latin America. Age-related non-communicable diseases, including dementia, are now reported at high prevalence. The Caribbean islands share similar genetic ancestry, culture, migration patterns, and risk profiles, providing a unique setting to understand dementia in the Caribbean-Hispanics. This perspective article aimed to describe the impact of dementia in the Caribbean, at a local and regional level and reflect on research strategies to address dementia. We report on 10/66 project findings, described research projects and regional plans for the region. According to our results, …

Intensive Teenage Activity Is Associated With Greater Muscle Hyperintensity On T1w Magnetic Resonance Imaging In Adults With Dysferlinopathy, Ursula Moore, Alan Pestronk, Et Al

Open Access Publications

Practice of sports during childhood or adolescence correlates with an earlier onset and more rapidly progressing phenotype in dysferlinopathies. To determine if this correlation relates to greater muscle pathology that persists into adulthood, we investigated the effect of exercise on the degree of muscle fatty replacement measured using muscle MRI. We reviewed pelvic, thigh and leg T1W MRI scans from 160 patients with genetically confirmed dysferlinopathy from the Jain Foundation International clinical outcomes study in dysferlinopathy. Two independent assessors used the Lamminen-Mercuri visual scale to score degree of fat replacement in each muscle. Exercise intensity for each individual was defined …

Essential But Undefined — Reimagining How Policymakers Identify Safety-Net Hospitals, Paula Chatterjee, Benjamin D. Sommers, Karen E. Joynt Maddox

Open Access Publications

No abstract provided.

Sourcing Photoreceptor-Like Cells For Treating Vision Loss, Rajendra S. Apte

Open Access Publications

No abstract provided.

Killing The Pathogen And Sparing The Placenta, Indira U. Mysorekar

Open Access Publications

No abstract provided.

Effects Of Diet Versus Gastric Bypass On Metabolic Function In Diabetes, Mihoko Yoshino, Brandon D. Kayser, Jun Yoshino, Richard I. Stein, Dominic Reeds, J. Christopher Eagon, Shaina R. Eckhouse, Jeramie D. Watrous, Mohit Jain, Rob Knight, Kenneth Schechtman, Bruce W. Patterson, Samuel Klein

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 …

Hematopoeitic Cell Transplantation And Car T-Cell Therapy: Complements Or Competitors?, Scott R Goldsmith, Armin Ghobadi, John F Dipersio

Open Access Publications

Allogeneic hematopoietic cell transplantation (allo-HCT) and chimeric antigen receptor T cell (CAR T) therapy are the main modalities of adoptive cellular immunotherapy that have widely permeated the clinical space. The advent of both technologies revolutionized treatment of many hematologic malignancies, both offering the chance at sustained remissions for patients who would otherwise invariably succumb to their diseases. The understanding and exploitation of the nonspecific alloreactivity of allo-HCT and the graft-versus-tumor effect is contrasted by the genetically engineered precision of CAR T therapy. Historically, those with relapsed and refractory hematologic malignancies have often been considered for allo-HCT, although outcomes vary dramatically …

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 …

Sars-Cov-2 Viral Rna Shedding For More Than 87 Days In An Individual With An Impaired Cd8+ T Cell Response, Jackson S Turner, Aaron Day, Wafaa B Alsoussi, Zhuoming Liu, Jane A O'Halloran, Rachel M Presti, Bruce K Patterson, Sean P J Whelan, Ali H Ellebedy, Philip A Mudd

Open Access Publications

Prolonged shedding of viral RNA occurs in some individuals following SARS-CoV-2 infection. We perform comprehensive immunologic evaluation of one individual with prolonged shedding. The case subject recovered from severe COVID-19 and tested positive for SARS-CoV-2 viral RNA repeatedly as many as 87 days after the first positive test, 97 days after symptom onset. The subject did not have any associated rise in anti-Spike protein antibody titers or plasma neutralization activity, arguing against re-infection. This index subject exhibited a profoundly diminished circulating CD8+ T cell population and correspondingly low SARS-CoV-2-specific CD8+ T cell responses when compared with a cohort of other …

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

A Single Amino Acid Change To Taq Dna Polymerase Enables Faster Pcr, Reverse Transcription And Strand-Displacement, Wayne M Barnes, Zhian Zhang, Milko B Kermekchiev

Open Access Publications

A change of an aspartic acid to asparagine of Taq (

Blood Biomarkers For Detection Of Brain Injury In Covid-19 Patients, Steven T. Dekosky, Lawrence Lewis, Stacey House, Et Al.

Open Access Publications

No abstract provided.

Community Health Behaviors And Geographic Variation In Early-Onset Colorectal Cancer Survival Among Women, Andreana N. Holowatyj, Marvin E. Langston, Yunan Han, Richard Viskochil, Jose Perea, Yin Cao, Charles R. Rogers, Christopher H. Lieu, Justin X. Moore

Open Access Publications

No abstract provided.

Bacteriophage Sp01 Gene Product 56 Inhibits Bacillus Subtilis Cell Division By Interacting With Ftsl And Disrupting Pbp2b And Ftsw Recruitment, Amit Bhambhani, Isabella Iadicicco, Jules Lee, Syed Ahmed, Max Belfatto, David Held, Alexia Marconi, Aaron Parks, Charles R Stewart, William Margolin, Petra Anne Levin, Daniel P Haeusser

Open Access Publications

Previous work identified gene product 56 (gp56), encoded by the lytic bacteriophage SP01, as being responsible for inhibition of

The Alzheimer's Biomarker Consortium-Down Syndrome: Rationale And Methodology, Benjamin L Handen, Anne M Fagan, Beau Ances, Et Al

Open Access Publications

Introduction: Adults with Down syndrome (DS) are at exceptionally high risk for Alzheimer's disease (AD), with virtually all individuals developing key neuropathological features by age 40. Identifying biomarkers of AD progression in DS can provide valuable insights into pathogenesis and suggest targets for disease modifying treatments.

Methods: We describe the development of a multi-center, longitudinal study of biomarkers of AD in DS. The protocol includes longitudinal examination of clinical, cognitive, blood and cerebrospinal fluid-based biomarkers, magnetic resonance imaging and positron emission tomography measures (at 16-month intervals), as well as genetic modifiers of AD risk and progression.

Results: Approximately 400 individuals …

Cerebrospinal Fluid Biomarkers Of Alzheimer's Disease In A Cohort Of Adults With Down Syndrome, Rachel L Henson, Eric Doran, Bradley T Christian, Benjamin L Handen, William E Klunk, Florence Lai, Joseph H Lee, H Diana Rosas, Nicole Schupf, Shahid H Zaman, Ira T Lott, Anne M Fagan

Open Access Publications

Introduction: Virtually all individuals with Down syndrome (DS) will develop Alzheimer's disease (AD) pathology by age 40. Cerebrospinal fluid (CSF) biomarkers have characterized AD pathology in cohorts of late-onset AD (LOAD) and autosomal-dominant AD (ADAD). Few studies have evaluated such biomarkers in adults with DS.

Methods: CSF concentrations of amyloid beta (Aβ)40, Aβ42, tau, phospho-tau181 (p-tau), neurofilament light chain (NfL), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40), alpha synuclein (αSyn), neurogranin (Ng), synaptosomal-associated protein 25 (SNAP-25), and visinin-like protein 1 (VILIP-1) were assessed in CSF from 44 adults with DS from the Alzheimer's Biomarker …

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-

Monocyte Distribution Width Enhances Early Sepsis Detection In The Emergency Department Beyond Sirs And Qsofa, Elliott D Crouser, Joseph E Parrillo, Greg S Martin, David T Huang, Pierre Hausfater, Ilya Grigorov, Diana Careaga, Tiffany Osborn, Mohamad Hasan, Liliana Tejidor

Open Access Publications

BACKGROUND: The initial presentation of sepsis in the emergency department (ED) is difficult to distinguish from other acute illnesses based upon similar clinical presentations. A new blood parameter, a measurement of increased monocyte volume distribution width (MDW), may be used in combination with other clinical parameters to improve early sepsis detection. We sought to determine if MDW, when combined with other available clinical parameters at the time of ED presentation, improves the early detection of sepsis.

METHODS: A retrospective analysis of prospectively collected clinical data available during the initial ED encounter of 2158 adult patients who were enrolled from emergency …

Clearance Of Interstitial Fluid (Isf) And Csf (Clic) Group-Part Of Vascular Professional Interest Area (Pia): Cerebrovascular Disease And The Failure Of Elimination Of Amyloid-Β From The Brain And Retina With Age And Alzheimer's Disease-Opportunities For Therapy, Roxana O Carare, David Holtzman, Et Al

Open Access Publications

Two of the key functions of arteries in the brain are (1) the well-recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri-arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms …

Differentiating Among Stages Of Cognitive Impairment In Aging: Version 3 Of The Uniform Data Set (Uds) Neuropsychological Test Battery And Moca Index Scores, Hiroko H Dodge, John C Morris, Et Al

Open Access Publications

Introduction: Federally funded Alzheimer's Disease Centers in the United States have been using a standardized neuropsychological test battery as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) since 2005. Version 3 (V3) of the UDS replaced the previous version (V2) in 2015. We compared V2 and V3 neuropsychological tests with respect to their ability to distinguish among the Clinical Dementia Rating (CDR) global scores of 0, 0.5, and 1.

Methods: First, we matched participants receiving V2 tests (V2 cohort) and V3 tests (V3 cohort) in their cognitive functions using tests common to both versions. Then, we compared …