Digital Commons Network^™

Stat3-Mediated Atg7 Expression Regulates Anti-Tumor Immunity In Mouse Melanoma, Sarah M Zimmerman, Erin Suh, Sofia R Smith, George P Souroullas

2020-Current year OA Pubs

Epigenetic modifications to DNA and chromatin control oncogenic and tumor-suppressive mechanisms in melanoma. Ezh2, the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which mediates methylation of lysine 27 on histone 3 (H3K27me3), can regulate both melanoma initiation and progression. We previously found that mutant Ezh2

Left Coronary Artery Compression And Stent Fracture Following Self-Expanding Transcatheter Pulmonary Valve Implantation, Jeannette Wong-Siegel, Adam Naylor, David Balzer

2020-Current year OA Pubs

Coronary compression and vascular perforation have not been reported for self-expanding transcatheter pulmonary valves. We describe a patient with tetralogy of Fallot after self-expanding valve implantation who developed left coronary artery compression from the valve. In addition, a wire frame fracture resulted in perforation of the aorta.

A Genetic Screen In Drosophila Uncovers A Role For Senseless-2 In Surface Glia In The Peripheral Nervous System To Regulate Cns Morphology, Haluk Lacin, Yuqing Zhu, Jose T Dipaola, Beth A Wilson, Yi Zhu, James B Skeath

2020-Current year OA Pubs

Despite increasing in mass approximately 100-fold during larval life, the Drosophila CNS maintains its characteristic form. Dynamic interactions between the overlying basement membrane and underlying surface glia are known to regulate CNS structure in Drosophila, but the genes and pathways that establish and maintain CNS morphology during development remain poorly characterized. To identify genes that regulate CNS shape in Drosophila, we conducted an EMS-based, forward genetic screen of the second chromosome, uncovered 50 mutations that disrupt CNS structure, and mapped these alleles to 17 genes. Analysis of whole genome sequencing data wedded to genetic studies uncovered the affected gene for …

Prognostic Significance And Biologic Associations Of Senescence-Associated Secretory Phenotype Biomarkers In Heart Failure, Oday Salman, Ali Javaheri, Douglas L Mann, Et Al.

2020-Current year OA Pubs

BACKGROUND: The role of cellular senescence in human heart failure (HF) remains unclear. The senescence-associated secretory phenotype (SASP) is composed of proteins released by senescent cells. We assessed the prognostic significance and biologic pathways associated with the SASP in human HF using a plasma proteomics approach.

METHODS AND RESULTS: We measured 25 known SASP proteins among 2248 PHFS (Penn HF Study) participants using the SOMAScan V4 assay. We extracted the common variance in these proteins to generate SASP factor scores and assessed the relationship between these SASP factor scores and (1) all-cause death and (2) the composite of death or …

Hierarchical Tricarboxylic Acid Cycle Regulation By Hepatocyte Arginase 2 Links The Urea Cycle To Oxidative Metabolism, Yiming Zhang, Cassandra B Higgins, Stefani Tica, Joshua A Adams, Jiameng Sun, Shannon C Kelly, Xiaoyu Zong, Dennis J Dietzen, Terri Pietka, Samuel J Ballentine, Leah P Shriver, Gary J Patti, Yin Cao, Brian J Debosch

2020-Current year OA Pubs

Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2

Stabilization Of Interdomain Closure By A G Protein Inhibitor, Tyson D Todd, Neha Vithani, Sukrit Singh, Gregory R Bowman, Kendall J Blumer, Andrea Soranno

2020-Current year OA Pubs

Inhibitors of heterotrimeric G proteins are being developed as therapeutic agents. Epitomizing this approach are YM-254890 (YM) and FR900359 (FR), which are efficacious in models of thrombosis, hypertension, obesity, asthma, uveal melanoma, and pain, and under investigation as an FR-antibody conjugate in uveal melanoma clinical trials. YM/FR inhibits the Gq/11/14 subfamily by interfering with GDP (guanosine diphosphate) release, but by an unknown biophysical mechanism. Here, we show that YM inhibits GDP release by stabilizing closure between the Ras-like and α-helical domains of a Gα subunit. Nucleotide-free Gα adopts an ensemble of open and closed configurations, as indicated by single-molecule Förster …

Targeting Akr1b10 By Drug Repurposing With Epalrestat Overcomes Chemoresistance In Non-Small Cell Lung Cancer Patient-Derived Tumor Organoids, Kanve N Suvilesh, Yariswamy Manjunath, Yulia I Nussbaum, Mohamed Gadelkarim, Murugesan Raju, Akhil Srivastava, Guangfu Li, Wesley C Warren, Chi-Ren Shyu, Feng Gao, Matthew A Ciorba, Jonathan B Mitchem, Satyanarayana Rachagani, Jussuf T Kaifi

2020-Current year OA Pubs

PURPOSE: Systemic treatments given to patients with non-small cell lung cancer (NSCLC) are often ineffective due to drug resistance. In the present study, we investigated patient-derived tumor organoids (PDTO) and matched tumor tissues from surgically treated patients with NSCLC to identify drug repurposing targets to overcome resistance toward standard-of-care platinum-based doublet chemotherapy.

EXPERIMENTAL DESIGN: PDTOs were established from 10 prospectively enrolled patients with non-metastatic NSCLC from resected tumors. PDTOs were compared with matched tumor tissues by histopathology/immunohistochemistry, whole exome sequencing, and transcriptome sequencing. PDTO growths and drug responses were determined by measuring 3D tumoroid volumes, cell viability, and proliferation/apoptosis. Differential …

Diurnal Rhythms In Varicella Vaccine Effectiveness, Dana Danino, Yoav Kalron, Jeffrey A. Haspel, Guy Hazan

2020-Current year OA Pubs

BACKGROUNDImmune processes are influenced by circadian rhythms. We evaluate the association between varicella vaccine administration time of day and vaccine effectiveness.METHODSA national cohort, children younger than 6 years, were enrolled between January 2002 and December 2023. We compared children vaccinated during morning (7:00-10:59), late morning to afternoon (11:00-15:59), or evening hours (16:00-19:59). A Cox proportional hazards regression model was used to adjust for ethnicity, sex, and comorbidities. The first varicella infection occurring at least 14 days after vaccination and a second dose administration were treated as terminal events.RESULTSOf 251,141 vaccinated children, 4,501 (1.8%) experienced breakthrough infections. Infection rates differed based …

Use Of Palliative Care Among Adults With Newly Diagnosed Heart Failure: Insights From A Us National Insured Patient Sample, Zidong Zhang, Divya S Subramaniam, Steven W Howard, Kenton J Johnston, William H Frick, Kimberly Enard, Leslie Hinyard

2020-Current year OA Pubs

BACKGROUND: Despite the known benefits for individuals with heart failure (HF), incomplete data suggest a low use of palliative care (PC) for HF in the United States. We aimed to investigate the national PC use for adults with HF by determining when they received their first PC consultation (PCC) and the associations with clinical factors following diagnosis of HF.

METHODS AND RESULTS: We conducted a retrospective cohort study in a national all-payer electronic health record database to identify adults (aged ≥18 years) with newly diagnosed HF between 2011 and 2018. The proportion of those who received PCC within 5 years …

Proteomic Correlates And Prognostic Significance Of Kidney Injury In Heart Failure With Preserved Ejection Fraction, Oday Salman, Ali Javaheri, Douglas L Mann, Et Al.

2020-Current year OA Pubs

BACKGROUND: Kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and prognostic significance of kidney injury (KI), in HFpEF, beyond the estimated glomerular filtration rate (eGFR), are unclear.

METHODS AND RESULTS: Using baseline plasma samples from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, we measured the following KI biomarkers: cystatin-C, fatty acid-binding protein-3, Beta-2 microglobulin, neutrophil gelatinase-associated lipocalin, and kidney-injury molecule-1. Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between the KI-factor score and the risk of death …

Concurrent Ependymal And Ganglionic Differentiation In A Subset Of Supratentorial Neuroepithelial Tumors With Ewsr1-Plagl1 Rearrangement, Julieann C Lee, Sonika Dahiya, Kaleigh Roberts, Et Al.

2020-Current year OA Pubs

Neuroepithelial tumors with fusion of PLAGL1 or amplification of PLAGL1/PLAGL2 have recently been described often with ependymoma-like or embryonal histology respectively. To further evaluate emerging entities with PLAG-family genetic alterations, the histologic, molecular, clinical, and imaging features are described for 8 clinical cases encountered at St. Jude (EWSR1-PLAGL1 fusion n = 6; PLAGL1 amplification n = 1; PLAGL2 amplification n = 1). A histologic feature observed on initial resection in a subset (4/6) of supratentorial neuroepithelial tumors with EWSR1-PLAGL1 rearrangement was the presence of concurrent ependymal and ganglionic differentiation. This ranged from prominent clusters of ganglion cells within ependymoma/subependymoma-like areas, …

Fetal Mavs And Type I Ifn Signaling Pathways Control Zikv Infection In The Placenta And Maternal Decidua, Yael Alippe, Leran Wang, Reyan Coskun, Stéfanie P Muraro, Fang R Zhao, Michelle Elam-Noll, J Michael White, Daiana M Vota, Vanesa C Hauk, Jeffrey I Gordon, Scott A Handley, Michael S Diamond

2020-Current year OA Pubs

The contribution of placental immune responses to congenital Zika virus (ZIKV) syndrome remains poorly understood. Here, we leveraged a mouse model of ZIKV infection to identify mechanisms of innate immune restriction exclusively in the fetal compartment of the placenta. ZIKV principally infected mononuclear trophoblasts in the junctional zone, which was limited by mitochondrial antiviral-signaling protein (MAVS) and type I interferon (IFN) signaling mechanisms. Single nuclear RNA sequencing revealed MAVS-dependent expression of IFN-stimulated genes (ISGs) in spongiotrophoblasts but not in other placental cells that use alternate pathways to induce ISGs. ZIKV infection of Ifnar1-/- or Mavs-/- placentas was associated with greater …

Analysis Of Ductal Carcinoma In Situ By Self-Reported Race Reveals Molecular Differences Related To Outcome, Siri H Strand, Graham A Colditz, Et Al.

2020-Current year OA Pubs

BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer (IBC). Studies have indicated differences in DCIS outcome based on race or ethnicity, but molecular differences have not been investigated.

METHODS: We examined the molecular profile of DCIS by self-reported race (SRR) and outcome groups in Black (n = 99) and White (n = 191) women in a large DCIS case-control cohort study with longitudinal follow up.

RESULTS: Gene expression and pathway analyses suggested that different genes and pathways are involved in diagnosis and ipsilateral breast outcome (DCIS or IBC) after DCIS treatment in White versus …

American Association Of Plastic Surgeons Consensus On Breast Implant-Associated Anaplastic Large-Cell Lymphoma, Mark W. Clemens, Terence M. Myckatyn, Arianna Di Napoli, Andrew L. Feldman, Elaine S. Jaffe, Cara L. Haymaker, Steven M. Horwitz, Kelly K. Hunt, Marshall E. Kadin, Colleen M Mccarthy, Roberto N. Miranda, H. Miles Prince, Fabio Santanelli Di Pompeo, Sari D. Holmes, Linda G. Phillips

2020-Current year OA Pubs

BACKGROUND: In the absence of high-quality evidence, there is a need for guidelines and multidisciplinary consensus recommendations on breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL). The purpose of this expert consensus conference was to evaluate the existing evidence regarding the diagnosis and management of BIA-ALCL caused by textured implants. This article aims to provide evidence-based recommendations regarding the management and prevention of BIA-ALCL.

METHODS: A comprehensive search was conducted in the MEDLINE, Cochrane Library, and Embase databases, and supplemented by manual searches of relevant English-language articles and "related articles" sections. Studies focusing on breast surgery and lymphoma associated with breast implants …

Surgeon Recommendations For Physical Activity In Patients With Pediatric Hip Conditions, Jacqueline Li, Emily K. Schaeffer, Stacey Miller, Verena M. Schreiber, Yasmin D. Hailer, John C. Clohisy, Harry K. W. Kim, Kishore Mulpuri

2020-Current year OA Pubs

BACKGROUND: While physical activity (PA) is important during youth, it is unclear if children and adolescents with developmental dysplasia of the hip (DDH), Legg-Calvé-Perthes disease (LCPD), or slipped capital femoral epiphysis (SCFE) are expected or encouraged to return to PA once they have healed. This study examines the orthopaedic surgeons' role in advising pediatric hip patients on the PA they should engage in, assessing their practice, opinions, and consensus when making recommendations.

METHODS: Orthopaedic surgeons were invited from member lists of 4 hip study groups. The survey included demographics, opinions regarding PA, and 10 case scenarios that queried respondents on …

Teaching Application Of 3d-Printed Models For Nasal Analysis, Nneoma S. Wamkpah, Robert T. Cristel, Zachary O'Connor, Andrea Hanick, Dennis Nguyen, John J. Chi

2020-Current year OA Pubs

BACKGROUND: A major challenge in learning rhinoplasty is correlating patients' external and internal nasal structures. We aim to explore the application of three dimensional (3D)-printed models of nasal bony-cartilaginous structures in identifying accurate nasal anatomy.

METHODS: Otolaryngology-head and neck surgery and plastic and reconstructive surgery residents matched patient photograph models, described relative nasal bony-cartilaginous anatomy, completed pre- and postactivity self-evaluations (based on otolaryngology "nasal deformity" milestones including "anatomy," "function," "aesthetic," and "etiology"), and rated the 3D-printed models' usefulness. Descriptive statistics were measured.

RESULTS: Thirty-seven residents correctly matched four of six model-photograph pairs and correctly described 15 of 30 anatomic relationships, …

Single-Isocenter, Multiple-Target Abdominal Cone-Beam Computed Tomography (Cbct)-Guided Online Adaptive Stereotactic Body Radiotherapy (Sbrt), Chipo Raranje, Thomas R. Mazur, Allen Mo, Eric Laugeman

2020-Current year OA Pubs

Stereotactic body radiotherapy (SBRT) is increasingly being prescribed for treating patients with multiple metastases, especially in the setting of oligometastatic disease. Treating multiple targets presents unique challenges in radiotherapy planning and delivery, including practical considerations relating to treatment time, resource allocation, and treatment planning complexity. Treating targets in a common isocenter reduces the time required for treatment and simplifies planning, but historically, it has often not been feasible due to inter- and intra-fractional variation in relative target positions. With online adaptation, individual targets can be re-contoured on each treatment fraction to obviate inter-fractional variation, and with appropriate margin selection intra-fractional …

Plasma Phosphorylated Tau 217 And Aβ42/40 To Predict Early Brain Aβ Accumulation In People Without Cognitive Impairment, Shorena Janelidze, Nicolas R Barthélemy, Suzanne E Schindler, Vitaliy Ovod, James G Bollinger, Yingxin He, Yan Li, Cyrus A Raji, John C Morris, David M Holtzman, Randall J Bateman, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain β-amyloid (Aβ) levels who are at high risk of accumulating Aβ.

OBJECTIVE: To investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aβ pathology in CU individuals with subthreshold brain Aβ levels (defined as Aβ levels < 40 Centiloids) at baseline.

DESIGN, SETTING, AND PARTICIPANTS: This was a longitudinal study …

Evaluating The Psychometric Structure Of The Hamilton Rating Scale For Depression Pre- And Post-Treatment In Antidepressant Randomised Trials: Secondary Analysis Of 6843 Individual Participants From 20 Trials, David Byrne, Frank Doyle, Susan Brannick, Robert M Carney, Pim Cuijpers, Alexandra L Dima, Kenneth Freedland, Suzanne Guerin, David Hevey, Bishember Kathuria, Emma Wallace, Fiona Boland

2020-Current year OA Pubs

BACKGROUND: The 17-item Hamilton Rating Scale for Depression (HRSD-17) is the most popular depression measure in antidepressant clinical trials. Prior evidence indicates poor replicability and inconsistent factorial structure. This has not been studied in pooled randomised trial data, nor has a psychometrically optimal model been developed.

AIMS: To examine the psychometric properties of the HRSD-17 for pre-treatment and post-treatment clinical trial data in a large pooled database of antidepressant randomised controlled trial participants, and to determine an optimal abbreviated version.

METHOD: Data for 6843 participants were obtained from the data repository Vivli.org and randomly split into groups for exploratory (n …

The Long And Winding Road Towards New Treatments Against Lymphatic Filariasis And Onchocerciasis, Frederic Risch, Alexander Kazakov, Sabine Specht, Kenneth Pfarr, Peter U Fischer, Achim Hoerauf, Marc P Hübner

2020-Current year OA Pubs

Although lymphatic filariasis and onchocerciasis have been targeted for global elimination, these helminth infections are still a major public health problem across the tropics and subtropics. Despite decades of research, treatment options remain limited and drugs that completely clear the infections, and can be used on a large scale, are still unavailable. In the present review we discuss the strengths and weaknesses of currently available treatments and new ones in development. Novel candidates (corallopyronin A, DNDi-6166, emodepside, and oxfendazole) are currently moving through (pre)clinical development, while the development of two candidates (AWZ1066S and ABBV-4083/flubentylosin) was recently halted. The preclinical R&D …

A Systematic Review To Compare Electrical, Magnetic, And Optogenetic Stimulation For Peripheral Nerve Repair, Priya Kaluskar, Dhruv Bharadwaj, K Swaminathan Iyer, Christopher Dy, Minghao Zheng, David M Brogan

2020-Current year OA Pubs

The purpose of this systematic review was to assess the currently available evidence for the use of external stimulation to modulate neural activity and promote peripheral nerve regeneration. The most common external stimulations are electrical stimulation (ES), optogenetic stimulation (OS), and magnetic stimulation (MS). Understanding the comparative effectiveness of these stimulation methods is pivotal in advancing therapeutic interventions for peripheral nerve injuries. This systematic review focused on these three external stimulation modalities as potential strategies to enhance peripheral nerve repair (PNR). We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework to systematically evaluate and compare the efficiency …

Concepts Of Pain Management Following Nerve Injuries: Multidisciplinary Approach, Amanda Faust, Stephen J Demartini, Abigail Carey-Ewend, Lara W Crock, Sarah K Buday, David M Brogan, Christopher J Dy

2020-Current year OA Pubs

PURPOSE: A systematic review to identify treatment approaches for the management of pain following peripheral nerve injury.

METHODS: A published literature search was performed for the concepts of peripheral nerve injury and pain management with related synonyms. The strategies were created using a combination of controlled vocabulary terms and keywords and were executed in Embase.com, Ovid-Medline All, and Scopus from database inception. Database searches were completed on August 22, 2023.

RESULTS: The initial search resulted in a total of 1,793 citations. In total, 724 duplicates were removed, leaving 1,069 unique citations remaining for analysis. This review excluded all papers that …

The Physiologic Basis Of Molecular Therapeutics For Peripheral Nerve Injury: A Primer, Marie C Spezia, Christopher J Dy, David M Brogan

2020-Current year OA Pubs

Peripheral nerve injuries affect a significant number of patients who experience trauma affecting the hand and upper extremity. Improving unsatisfactory outcomes from repair of these injuries remains a clinical challenge despite advancements in microsurgical repair. Imperfections of the nerve regeneration process, including imprecise reinnervation, distal axon degradation, and muscular atrophy, complicate the repair process. However, the capacity for peripheral nerves to regenerate offers an avenue for therapeutic advancement. Regeneration is a temporally and spatially dynamic process coordinated by Schwann cells and neurons among other cell types. Neurotrophic factors are a primary means of controlling cell growth and differentiation in the …

Psychological Aspects Of Nerve Gap Reconstruction: Addressing Patient Perspectives And Expectations, Stephen Demartini, Amanda Faust, Brendan Navarro, Christopher J Dy

2020-Current year OA Pubs

PURPOSE: Preoperative expectations play a major role in determining patient satisfaction after surgery. The aim of this study was to characterize patient's preoperative expectations and postoperative perceptions of nerve gap repair surgery.

METHODS: We conducted a search of Embase, Scopus, and Web of Science databases for peer-reviewed articles that studied patient expectations, perceptions, and impressions of nerve gap repair in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies related to lumbar plexus radiculopathy, reimplantation, or patient satisfaction scores without patient testimony were excluded. Primary and secondary outcomes were patient's preoperative expectations and postoperative perceptions of …

Endogenous Base Damage As A Driver Of Genomic Instability In Homologous Recombination-Deficient Cancers, Lindsey N Aubuchon, Priyanka Verma

2020-Current year OA Pubs

Homologous recombination (HR) is a high-fidelity DNA double-strand break (DSB) repair pathway. Both familial and somatic loss of function mutation(s) in various HR genes predispose to a variety of cancer types, underscoring the importance of error-free repair of DSBs in human physiology. While environmental sources of DSBs have been known, more recent studies have begun to uncover the role of endogenous base damage in leading to these breaks. Base damage repair intermediates often consist of single-strand breaks, which if left unrepaired, can lead to DSBs as the replication fork encounters these lesions. This review summarizes various sources of endogenous base …

Etomoxir-Carnitine, A Novel Pharmaco-Metabolite Of Etomoxir, Inhibits Phospholipases A2 And Mitochondrial Respiration, Sung Ho Moon, Xinping Liu, Christopher M Jenkins, Beverly Gibson Dilthey, Gary J Patti, Richard W Gross

2020-Current year OA Pubs

Mitochondrial fatty acid oxidation serves as an essential process for cellular survival, differentiation, proliferation, and energy metabolism. Numerous studies have utilized etomoxir (ETO) for the irreversible inhibition of carnitine palmitoylcarnitine transferase 1 (CPT1), which catalyzes the rate-limiting step for mitochondrial long-chain fatty acid β-oxidation to examine the bioenergetic roles of mitochondrial fatty acid metabolism in many tissues in multiple diverse disease states. Herein, we demonstrate that intact mitochondria robustly metabolize ETO to etomoxir-carnitine (ETO-carnitine) prior to nearly complete ETO-mediated inhibition of CPT1. The novel pharmaco-metabolite, ETO-carnitine, was conclusively identified by accurate mass, fragmentation patterns, and isotopic fine structure. On the …

Trem2 On Microglia Cell Surface Binds To And Forms Functional Binary Complexes With Heparan Sulfate Modified With 6-O-Sulfation And Iduronic Acid, Ilayda Ozsan Mcmillan, Li Liang, Guowei Su, Xuehong Song, Kelly Drago, Hua Yang, Claudia Alvarez, Amika Sood, James Gibson, Robert J Woods, Chunyu Wang, Jian Liu, Fuming Zhang, Tom J Brett, Lianchun Wang

2020-Current year OA Pubs

The triggering receptor expressed on myeloid cells-2 (TREM2), a pivotal innate immune receptor, orchestrates functions such as inflammatory responses, phagocytosis, cell survival, and neuroprotection. TREM2 variants R47H and R62H have been associated with Alzheimer's disease, yet the underlying mechanisms remain elusive. Our previous research established that TREM2 binds to heparan sulfate (HS) and variants R47H and R62H exhibit reduced affinity for HS. Building upon this groundwork, our current study delves into the interplay between TREM2 and HS and its impact on microglial function. We confirm TREM2's binding to cell surface HS and demonstrate that TREM2 interacts with HS, forming HS-TREM2 …

Quantitative Gradient Recalled Echo (Qgre) Mri Enables In Vivo Measurement Of Pre-Atrophic Neurodegeneration In A Mouse Model Of Alzheimer's Disease, Michal R Tomaszewski, Alexander L Sukstanskii, Hyking Haley, Xiangjun Meng, Corin O Miller, Dmitriy A Yablonskiy

2020-Current year OA Pubs

Robust methods are needed for preclinical evaluation of novel Alzheimer Disease (AD) therapies to accelerate drug discovery. Quantitative Gradient Recalled Echo (qGRE) MRI has shown promise to provide insight into neurodegeneration in AD prior to atrophy development in humans, highlighting areas of low neuronal density. In this study a novel qGRE method (20 echoes, TE=2-40ms) is shown to non-invasively measure the longitudinal neuronal loss in the hippocampus of a mouse model of AD tauopathy Tg4510. Tg4510 (n=10) and wild type (WT, n=6) mice underwent MRI (7T field strength) at 3-7 months old. 3D qGRE approach was used to generate brain-specific …

Low-Dose Ondansetron: A Candidate Prospective Precision Medicine To Treat Alcohol Use Disorder Endophenotypes, Bankole Johnson, Hannu Alho, Giovanni Addolorato, Otto Michael Lesch, Jonathan Chick, Lei Liu, Vinzant Schuyler

2020-Current year OA Pubs

BACKGROUND: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise …

Utility Of Eosinophil Peroxidase As A Biomarker Of Eosinophilic Inflammation In Asthma, Monica Tang, Kaharu Sumino, Et Al.

2020-Current year OA Pubs

BACKGROUND: The relative utility of eosinophil peroxidase (EPX) and blood and sputum eosinophil counts as disease biomarkers in asthma is uncertain.

OBJECTIVE: We sought to determine the utility of EPX as a biomarker of systemic and airway eosinophilic inflammation in asthma.

METHODS: EPX protein was measured by immunoassay in serum and sputum in 110 healthy controls to establish a normal reference range and in repeated samples of serum and sputum collected during 3 years of observation in 480 participants in the Severe Asthma Research Program 3.

RESULTS: Over 3 years, EPX levels in patients with asthma were higher than normal …