Digital Commons Network^™

Control Of Acute Myeloid Leukemia And Generation Of Immune Memory In Vivo Using Amv564, A Bivalent Bispecific Cd33 X Cd3 T Cell Engager, Linda G. Eissenberg, Julie K. Ritchey, Michael P. Rettig, Dilan A. Patel, Kiran Vij, Feng Gao, Victoria Smith, Tae H Han, John F. Dipersio

2020-Current year OA Pubs

Off-the-shelf immunotherapeutics that suppress tumor growth and provide durable protection against relapse could enhance cancer treatment. We report preclinical studies on a CD33 x CD3 bivalent bispecific diabody, AMV564, that not only suppresses tumor growth, but also facilitates memory responses in a mouse model of acute myelogenous leukemia (AML). Mechanistically, a single 5-day treatment with AMV564 seems to reduce tumor burden by redirection of T cells, providing a time window for allogeneic or other T cells that innately recognize tumor antigens to become activated and proliferate. When the concentration of bispecific becomes negligible, the effector: target ratio has also shifted, …

Intermuscular Coherence As An Early Biomarker For Amyotrophic Lateral Sclerosis: The Protocol For A Prospective, Multicenter Study, Naoum P Issa, Serdar Aydin, Eric Polley, Nathan Carberry, Mark A. Garret, Sean Smith, Ali A. Habib, Nicholas W. Baumgartner, Betty Soliven, Kourosh Rezania

2020-Current year OA Pubs

OBJECTIVE: To describe the protocol of a prospective study to test the validity of intermuscular coherence (IMC) as a diagnostic tool and biomarker of upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS).

METHODS: This is a multicenter, prospective study. IMC of muscle pairs in the upper and lower limbs is gathered in ∼650 subjects across three groups using surface electrodes and conventional electromyography (EMG) machines. The following subjects will be tested: 1) neurotypical controls; 2) patients with symptomatology suggestive for early ALS but not meeting probable or definite ALS by Awaji Criteria; 3) patients with a known ALS mimic. …

Sillyputty: Improved Clustering By Optimizing The Silhouette Width, Polina Bombina, Dwayne Tally, Zachary B. Abrams, Kevin R. Coombes

2020-Current year OA Pubs

Clustering is an important task in biomedical science, and it is widely believed that different data sets are best clustered using different algorithms. When choosing between clustering algorithms on the same data set, reseachers typically rely on global measures of quality, such as the mean silhouette width, and overlook the fine details of clustering. However, the silhouette width actually computes scores that describe how well each individual element is clustered. Inspired by this observation, we developed a novel clustering method, called SillyPutty. Unlike existing methods, SillyPutty uses the silhouette width for individual elements as a tool to optimize the mean …

Adherence To Practice Parameters In Medicare Beneficiaries With Amyotrophic Lateral Sclerosis, Osvaldo J. Laurido-Soto, Irene M. Faust, Susan Searles Nielsen, Brad A. Racette

2020-Current year OA Pubs

OBJECTIVE: Physician adherence to evidence-based clinical practice parameters impacts outcomes of amyotrophic lateral sclerosis (ALS) patients. We sought to investigate compliance with the 2009 practice parameters for treatment of ALS patients in the United States, and sociodemographic and provider characteristics associated with adherence.

METHODS: In this population-based, retrospective cohort study of incident ALS patients in 2009-2014, we included all Medicare beneficiaries age ≥20 with ≥1 International Classification of Diseases, Ninth Revision, Clinical Modification ALS code (335.20) in 2009 and no prior years (N = 8,575). Variables of interest included race/ethnicity, sex, age, urban residence, Area Deprivation Index (ADI), and provider …

Stat1 Employs Myeloid Cell-Extrinsic Mechanisms To Regulate The Neutrophil Response And Provide Protection Against Invasive Klebsiella Pneumoniae Lung Infection, Shekina Gonzalez-Ferrer, Zeyu Xiong, Atish Gheware, Janet S Lee, Et Al.

2020-Current year OA Pubs

Klebsiella pneumoniae (KP) is an extracellular Gram-negative bacterium that causes infections in the lower respiratory and urinary tracts and the bloodstream. STAT1 is a master transcription factor that acts to maintain T cell quiescence under homeostatic conditions. Although STAT1 helps defend against systemic spread of acute KP intrapulmonary infection, whether STAT1 regulation of T cell homeostasis impacts pulmonary host defense during acute bacterial infection and injury is less clear. Using a clinical KP respiratory isolate and a pneumonia mouse model, we found that STAT1 deficiency led to an early neutrophil-dominant transcriptional profile and neutrophil recruitment in the lung preceding widespread …

Usability Testing Of A Web Tool For Dissemination And Implementation Science Models, Rebekah Natalie Gomes, Bryan S Ford, Rachel G Tabak, Ross C Brownson, Sara Malone, Maggie Padek, Russell E Glasgow, Borsika Rabin

2020-Current year OA Pubs

UNLABELLED: Dissemination and Implementation science is dedicated to increasing the speed of evidence-based research translated into practice as guided by one or multiple D&I theories, models, and frameworks. The Dissemination and Implementation Models in Health Research and Practice web tool guides users on how to plan, select, combine, adapt, use, and assess theories, models, and frameworks. This paper describes usability testing to update the web tool. Iterative user testing was conducted with implementation science research and clinical participants to facilitate updates and optimize the functionality of the tool. A multi-step protocol involved quantitative and qualitative data collection including a survey, …

Protocol For A Pilot Clinical Trial Of The Senolytic Drug Combination Dasatinib Plus Quercetin To Mitigate Age-Related Health And Cognitive Decline In Mental Disorders [Version 2; Peer Review: 1 Approved, 2 Approved With Reservations], Abigail Schweiger, Breno Diniz, Ginger Nicol, Julie Schweiger, Andes E Dasklakis-Perez, Eric J Lenze

2020-Current year OA Pubs

BACKGROUND: Major depressive disorder (MDD) and schizophrenia are linked to accelerated aging leading to reduced lifespan, health span and cognitive decline. Cellular senescence, in which cells lose proliferative capacity and develop a senescence-associated secretory phenotype (SASP), plays a role in this process. Emerging research suggests that the senolytic regimen of dasatinib+quercetin (D+Q) reduces senescent cells, potentially mitigating age-related health and cognitive decline. This pilot study aims to assess the feasibility and safety of D+Q in older adults with schizophrenia, schizoaffective disorder, and treatment-resistant depression (TRD).

METHODS: This single-center study will recruit 30 participants total aged 50 years or older with …

Tourette Syndrome Research Highlights From 2023 [Version 2; Peer Review: 3 Approved], Andreas Hartmann, Per Andrén, Cyril Atkinson-Clement, Virginie Czernecki, Cécile Delorme, Nanette Mol Debes, Simon Morand-Beaulieu, Kirsten Müller-Vahl, Peristera Paschou, Natalia Szejko, Apostolia Topaloudi, Kevin J Black

2020-Current year OA Pubs

In this, the tenth annual update for the F1000Research Tics collection, we summarize research reports from 2023 on Gilles de la Tourette syndrome and other tic disorders. The authors welcome article suggestions and thoughtful feedback from readers.

Characterization And Z-Score Calculation Of Cardiovascular Magnetic Resonance Imaging Parameters In Patients After The Fontan Operation: A Fontan Outcome Registry Using Cardiovascular Magnetic Resonance Examinations Study, Tarek Alsaied, Manish Aggarwal, Et Al.

2020-Current year OA Pubs

BACKGROUND: Cardiac magnetic resonance (CMR) offers valuable hemodynamic insights post-Fontan, but is limited by the absence of normative single ventricle data. The Fontan Outcomes Registry using CMR Examinations (FORCE) is a large international Fontan-specific CMR registry. This study used FORCE registry data to evaluate expected CMR ventricular size/function and create Fontan-specific z-scores adjusting for ventricular morphology (VM) in healthier Fontan patients.

METHODS: "Healthier" Fontan patients were defined as patients free of adverse outcomes, who are New York Heart Association class I, have mild or less valve disease, and < 30% aortopulmonary collateral burden. General linear modeling was performed on 70% of the dataset to create z-scores for volumes and function. Models were tested using the remainder (30%) of the data. The z-scores were compared between children and adults. The z-scores were also compared between "healthier" Fontan and patients with adverse outcomes (death, listing for transplantation, or multiorgan disease).

RESULTS: The "healthier" Fontan population included 885 patients (15.0 ± 7.6 years) …

Neurosteroids: Mechanistic Considerations And Clinical Prospects, Jamie L Maguire, Steven Mennerick

2020-Current year OA Pubs

Like other classes of treatments described in this issue's section, neuroactive steroids have been studied for decades but have risen as a new class of rapid-acting, durable antidepressants with a distinct mechanism of action from previous antidepressant treatments and from other compounds covered in this issue. Neuroactive steroids are natural derivatives of progesterone but are proving effective as exogenous treatments. The best understood mechanism is that of positive allosteric modulation of GABA

Shared And Unique Heritability Of Hippocampal Subregion Volumes In Children And Adults, Jacob G Pine, Arpana Agrawal, Ryan Bogdan, Sridhar Kandala, Shelly Cooper, Deanna M Barch

2020-Current year OA Pubs

Behavioral genetic analyses have not demonstrated robust, unique, genetic correlates of hippocampal subregion volume. Genetic differentiation of hippocampal longitudinal axis subregion volume has not yet been investigated in population-based samples, although this has been demonstrated in rodent and post-mortem human tissue work. The following study is the first population-based investigation of genetic factors that contribute to gray matter volume along the hippocampal longitudinal axis. Twin-based biometric analyses demonstrated that longitudinal axis subregions are associated with significant, unique, genetic variance, and that longitudinal axis subregions are also associated with significant shared, hippocampus-general, genetic factors. Our study's findings suggest that genetic differences …

The Response Of Dual-Leucine Zipper Kinase (Dlk) To Nocodazole: Evidence For A Homeostatic Cytoskeletal Repair Mechanism, Laura Devault, Chase Mateusiak, John Palucki, Michael Brent, Jeffrey Milbrandt, Aaron Diantonio

2020-Current year OA Pubs

Genetic and pharmacological perturbation of the cytoskeleton enhances the regenerative potential of neurons. This response requires Dual-leucine Zipper Kinase (DLK), a neuronal stress sensor that is a central regulator of axon regeneration and degeneration. The damage and repair aspects of this response are reminiscent of other cellular homeostatic systems, suggesting that a cytoskeletal homeostatic response exists. In this study, we propose a framework for understanding DLK mediated neuronal cytoskeletal homeostasis. We demonstrate that low dose nocodazole treatment activates DLK signaling. Activation of DLK signaling results in a DLK-dependent transcriptional signature, which we identify through RNA-seq. This signature includes genes likely …

Shared Decision-Making During Virtual Care Regarding Rheumatologic And Chronic Conditions: Qualitative Study Of Benefits, Pitfalls, And Optimization, Lisa Zickuhr, Catherine Mccarthy, Emma Nolan-Thomas, Tiffany Westrich-Robertson, Elizabeth A Baker, Janice L Hanson

2020-Current year OA Pubs

OBJECTIVE: Virtual care (VC) is an accepted modality of care delivery, and shared decision-making (SDM) benefits patients with rheumatologic and chronic conditions (RCCs). Unfortunately, research suggests reduced quality of SDM during VC. This study explores the benefits and shortcomings of SDM regarding RCCs during VC with suggestions for optimally using VC during SDM.

METHODS: Following Stiggelbout's framework for SDM, we conducted focus groups of patients with RCCs and providers to understand their experiences with SDM during VC, probing for facilitating and challenging factors. We conducted content analysis of the transcripts, defining themes, and inductively reasoned to identify relationships among themes. …

Arid1a Loss Is Associated With Increased Nrf2 Signaling In Human Head And Neck Squamous Cell Carcinomas, Vinh Nguyen, Travis P. Schrank, Michael B. Major, Bernard E. Weissman

2020-Current year OA Pubs

Prior to the next generation sequencing and characterization of the tumor genome landscape, mutations in the SWI/SNF chromatin remodeling complex and the KEAP1-NRF2 signaling pathway were underappreciated. While these two classes of mutations appeared to independently contribute to tumor development, recent reports have demonstrated a mechanistic link between these two regulatory mechanisms in specific cancer types and cell models. In this work, we expand upon these data by exploring the relationship between mutations in BAF and PBAF subunits of the SWI/SNF complex and activation of NRF2 signal transduction across many cancer types. ARID1A/B mutations were strongly associated with NRF2 transcriptional …

Comparison Of Cerebrospinal Fluid, Plasma And Neuroimaging Biomarker Utility In Alzheimer's Disease, Karin L Meeker, Patrick H Luckett, Nicolas R Barthélemy, Diana A Hobbs, Charles Chen, James Bollinger, Vitaliy Ovod, Shaney Flores, Sarah Keefe, Rachel L Henson, Elizabeth M Herries, Eric Mcdade, Jason J Hassenstab, Chengjie Xiong, Carlos Cruchaga, Tammie L S Benzinger, David M Holtzman, Suzanne E Schindler, Randall J Bateman, John C Morris, Brian A Gordon, Beau M Ances

2020-Current year OA Pubs

Alzheimer's disease biomarkers are crucial to understanding disease pathophysiology, aiding accurate diagnosis and identifying target treatments. Although the number of biomarkers continues to grow, the relative utility and uniqueness of each is poorly understood as prior work has typically calculated serial pairwise relationships on only a handful of markers at a time. The present study assessed the cross-sectional relationships among 27 Alzheimer's disease biomarkers simultaneously and determined their ability to predict meaningful clinical outcomes using machine learning. Data were obtained from 527 community-dwelling volunteers enrolled in studies at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington …

Multiple Genes Core To Erad, Macroautophagy And Lysosomal Degradation Pathways Participate In The Proteostasis Response In Α1-Antitrypsin Deficiency, Jie Li, Tunda Hidvegi, Sanja Sviben, James A J Fitzpatrick, Hemalatha Sundaramoorthi, Stephen C Pak, Gary A Silverman, David H Perlmutter, Et Al.

2020-Current year OA Pubs

BACKGROUND & AIMS: In the classic form of α1-antitrypsin deficiency (ATD), the misfolded α1-antitrypsin Z (ATZ) variant accumulates in the endoplasmic reticulum (ER) of liver cells. A gain-of-function proteotoxic mechanism is responsible for chronic liver disease in a subgroup of homozygotes. Proteostatic response pathways, including conventional endoplasmic reticulum-associated degradation and autophagy, have been proposed as the mechanisms that allow cellular adaptation and presumably protection from the liver disease phenotype. Recent studies have concluded that a distinct lysosomal pathway called endoplasmic reticulum-to-lysosome completely supplants the role of the conventional macroautophagy pathway in degradation of ATZ. Here, we used several state-of-the-art approaches …

Factors Associated With Never Treatment And Acceptability Of Mass Drug Administration For The Elimination Of Lymphatic Filariasis In Guyana, 2021, Claudia Duguay, Reza A. Niles-Robin, Charles R. Thickstun, Horace Cox, Annastacia Sampson, Jean Seme-Fils Alexandre, Nathely Caleb-Mars, Charles W. Goss, Ana Morice, Ronaldo G. Carvalho Scholte, Alison Krentel

2020-Current year OA Pubs

Guyana remains one of four countries in the Americas endemic for lymphatic filariasis (LF). Elimination of LF requires repeated annual mass drug administration (MDA) with sufficient levels of coverage for success. This study assesses the acceptability and never treatment of LF MDA using data from a routine assessment survey in 2021. A subset of individuals, over 20 years of age (n = 2498), were selected to receive an expanded questionnaire to examine factors associated with acceptability and never treatment. Assessed factors include respondent demographics, knowledge, risk perceptions of LF, and opinions on the MDA programme. The majority (73%) of those …

Microstructural Analysis Does Not Support Altered Interhemispheric Wiring Of The Human Anterior Commissure In Corpus Callosum Dysgenesis, Timothy J Edwards, Ryan J Dean, Gail A Robinson, Jacquelyn Knight, Simone A Mandelstam, Linda J Richards

2020-Current year OA Pubs

BACKGROUND: Individuals with corpus callosum dysgenesis (CCD) lack the clear disconnection syndrome that is characteristic of individuals in whom the corpus callosum has been surgically severed. One potential explanation for this paradox is that the anterior commissure undergoes neuroplastic remodeling in CCD to improve interhemispheric communication between the brain hemispheres.

METHODS: A cohort of sixteen individuals with CCD (and sixteen sex and age-matched neurotypical controls) underwent multi-shell diffusion magnetic resonance high-field imaging (dMRI) at 7-Tesla to assess the anatomy of the anterior commissure for evidence of neuroplasticity.

RESULTS: No significant group-wise differences in midsagittal anterior commissure volumes were detected between …

Multi-Peptide Characterization Of Plasma Neurofilament Light Chain In Preclinical And Mild Alzheimer's Disease, John B Coulton, Yingxin He, Nicolas R Barthélemy, Hong Jiang, David M Holtzman, Randall J Bateman

2020-Current year OA Pubs

Although neurofilament light chain is a well-known marker of neuronal damage, its characterization at the proteoform level is underdeveloped. Here, we describe a new method to profile and quantify neurofilament light chain in plasma at the peptide level, using three in-house monoclonal antibodies targeting distinct protein domains and nano-liquid chromatography coupled to high-resolution tandem mass spectrometry. This study profiled and compared plasma neurofilament light chain to CSF in 102 older individuals (73.9 ± 6.3 years old), 37 of which had a clinical dementia rating greater than 0. We observed elevated neurofilament light chain in preclinical Alzheimer's disease plasma for two …

The Involvement Of The Piriform Cortex In Non-Lesional Temporal Lobe Epilepsy: An Uncommon Component Of The Epileptogenic Network, Nigel P Pedersen, Ashley Raghu, Veeresh Kumar N Shivamurthy, Joshua J Chern, Robert E Gross, Jon T Willie, Raymond J Dingledine, Ammar Kheder

2020-Current year OA Pubs

The piriform cortex is recognized as highly epileptogenic in rodents, yet its electrophysiological role in human epilepsy remains understudied. Recent surgical outcomes have suggested potential benefits in resecting the piriform cortex for cases of medial temporal lobe epilepsy. However, little is known about its electrophysiological activity in human epilepsy. This case-series study aimed to explore the electrophysiological role of the piriform cortex within the epileptogenic network among patients with suspected temporal lobe epilepsy. Participants were recruited from Emory University Hospital or Children's Healthcare of Atlanta, with non-lesional frontotemporal or temporal lobe hypotheses, undergoing stereoelectroencephalographic studies. Specifically, focus was placed on …

Mosgraphgen: A Novel Tool To Generate Multi-Omics Signaling Graphs To Facilitate Integrative And Interpretable Graph Ai Model Development, Heming Zhang, Dekang Cao, Zirui Chen, Xiuyuan Zhang, Yixin Chen, Cole Sessions, Carlos Cruchaga, Philip Payne, Guangfu Li, Michael Province, Fuhai Li

2020-Current year OA Pubs

MOTIVATION: Multi-omics data, i.e. genomics, epigenomics, transcriptomics, proteomics, characterize cellular complex signaling systems from multi-level and multi-view and provide a holistic view of complex cellular signaling pathways. However, it remains challenging to integrate and interpret multi-omics data for mining critical biomarkers. Graph AI models have been widely used to analyze graph-structure datasets, and are ideal for integrative multi-omics data analysis because they can naturally integrate and represent multi-omics data as a biologically meaningful multi-level signaling graph and interpret multi-omics data via graph node and edge ranking analysis. Nevertheless, it is nontrivial for graph-AI model developers to pre-analyze multi-omics data and …