Digital Commons Network^™

Ron Signalling Promotes Therapeutic Resistance In Esr1 Mutant Breast Cancer, Derek Dustin, Shunqiang Li, Et Al

Open Access Publications

BACKGROUND: Oestrogen Receptor 1 (ESR1) mutations are frequently acquired in oestrogen receptor (ER)-positive metastatic breast cancer (MBC) patients who were treated with aromatase inhibitors (AI) in the metastatic setting. Acquired ESR1 mutations are associated with poor prognosis and there is a lack of effective therapies that selectively target these cancers.

METHODS: We performed a proteomic kinome analysis in ESR1 Y537S mutant cells to identify hyperactivated kinases in ESR1 mutant cells. We validated Recepteur d'Origine Nantais (RON) and PI3K hyperactivity through phospho-immunoblot analysis, organoid growth assays, and in an in vivo patient-derived xenograft (PDX) metastatic model.

RESULTS: We demonstrated that RON …

Tlr3 Controls Constitutive Ifn-Β Antiviral Immunity In Human Fibroblasts And Cortical Neurons, Daxing Gao, Michael S Diamond, Et Al

Open Access Publications

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes …

Cd11c+ Cd88+ Cd317+ Myeloid Cells Are Critical Mediators Of Persistent Cns Autoimmunity, Navid Manouchehri, Rehana Z. Hussain, Petra D. Cravens, Ekaterina Esaulova, Maxim N. Artyomov, Brian T. Edelson, Gregory F. Wu, Anne H. Cross, Richard Doelger, Nicolas Loof, Todd N. Eagar, Thomas G. Forsthuber, Laurent Calvier, Joachim Herz, Olaf Stüve

Open Access Publications

No abstract provided.

Monitoring The Variation In The Gut Microbiota Of Captive Woolly Monkeys Related To Changes In Diet During A Reintroduction Process, Camilo Quiroga-González, Luis Alberto Chica Cardenas, Mónica Ramírez, Alejandro Reyes, Camila González, Pablo R. Stevenson

Open Access Publications

No abstract provided.

Inflammatory Signaling Sensitizes Piezo1 Mechanotransduction In Articular Chondrocytes As A Pathogenic Feed-Forward Mechanism In Osteoarthritis, Whasil Lee, Robert J. Nims, Alireza Savadipour, Qiaojuan Zhang, Holly A. Leddy, Fang Liu, Amy L. Mcnulty, Yong Chen, Farshid Guilak, Wolfgang B. Liedtke

Open Access Publications

No abstract provided.

Long, Noncoding Rna Dysregulation In Glioblastoma, Patrick A Desouza, Xuan Qu, Hao Chen, Bhuvic Patel, Christopher A Maher, Albert H Kim

Open Access Publications

Transcription occurs across more than 70% of the human genome and more than half of currently annotated genes produce functional noncoding RNAs. Of these transcripts, the majority-long, noncoding RNAs (lncRNAs)-are greater than 200 nucleotides in length and are necessary for various roles in the cell. It is increasingly appreciated that these lncRNAs are relevant in both health and disease states, with the brain expressing the largest number of lncRNAs compared to other organs. Glioblastoma (GBM) is an aggressive, fatal brain tumor that demonstrates remarkable intratumoral heterogeneity, which has made the development of effective therapies challenging. The cooperation between genetic and …

Mechanical Dysfunction Of The Sarcomere Induced By A Pathogenic Mutation In Troponin T Drives Cellular Adaptation, Sarah R. Clippinger, Paige E. Cloonan, Wei Wang, Lina Greenberg, W. Tom Stump, Paweorn Angsutararux, Jeanne M. Nerbonne, Michael J. Greenberg

Open Access Publications

Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales, from molecules to tissues. This makes it challenging to deconvolve the biophysical molecular defect that drives the disease pathogenesis from downstream changes in cellular function. In this study, we examine an HCM mutation in troponin T, R92Q, for which several models explaining its effects in disease have been put forward. We demonstrate that the primary molecular insult driving disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased …

Variables Associated With Intravenous Rehydration And Hospitalization In Children With Acute Gastroenteritis: A Secondary Analysis Of 2 Randomized Clinical Trials, Naveen Poonai, Philip Tarr, Et Al

Open Access Publications

Importance: Despite guidelines endorsing oral rehydration therapy, intravenous fluids are commonly administered to children with acute gastroenteritis in high-income countries.

Objective: To identify factors associated with intravenous fluid administration and hospitalization in children with acute gastroenteritis.

Design, Setting, and Participants: This study is a planned secondary analysis of the Pediatric Emergency Research Canada (PERC) and Pediatric Emergency Care Applied Research Network (PECARN) probiotic trials. Participants include children aged 3 to 48 months with 3 or more watery stools in 24 hours between November 5, 2013, and April 7, 2017, for the PERC study and July 8, 2014, and June 23, …

Lysis Of Arterial Thrombi By Perfusion Of N,N'-Diacetyl-L-Cystine (Dinac), Dongjune Kim, Susan M. Shea, David N. Ku

Open Access Publications

The search persists for a safe and effective agent to lyse arterial thrombi in the event of acute heart attacks or strokes due to thrombotic occlusion. The culpable thrombi are composed either primarily of platelets and von Willebrand Factor (VWF), or polymerized fibrin, depending on the mechanism of formation. Current thrombolytics were designed to target red fibrin-rich clots, but may be not be efficacious on white VWF-platelet-rich arterial thrombi. We have developed an in vitro system to study the efficacy of known and proposed thrombolytic agents on white clots formed from whole blood in a stenosis with arterial conditions. The …

Cannabis-Induced Hypodopaminergic Anhedonia And Cognitive Decline In Humans: Embracing Putative Induction Of Dopamine Homeostasis, Kenneth Blum, Jag Khalsa, Jean Lud Cadet, David Baron, Abdalla Bowirrat, Brent Boyett, Lisa Lott, Raymond Brewer, Marjorie Gondré-Lewis, Gregory Bunt, Shan Kazmi, Mark S Gold

Open Access Publications

Over years, the regular use of cannabis has substantially increased among young adults, as indicated by the rise in cannabis use disorder (CUD), with an estimated prevalence of 8. 3% in the United States. Research shows that exposure to cannabis is associated with hypodopaminergic anhedonia (depression), cognitive decline, poor memory, inattention, impaired learning performance, reduced dopamine brain response-associated emotionality, and increased addiction severity in young adults. The addiction medicine community is increasing concern because of the high content of delta-9-tetrahydrocannabinol (THC) currently found in oral and vaping cannabis products, the cognitive effects of cannabis may become more pronounced in young …

Thermoneutrality Alters Gastrointestinal Antigen Passage Patterning And Predisposes To Oral Antigen Sensitization In Mice, Taeko K Noah, Jee-Boong Lee, Christopher A Brown, Amnah Yamani, Sunil Tomar, Varsha Ganesan, Rodney D Newberry, Gary B Huffnagle, Senad Divanovic, Simon P Hogan

Open Access Publications

Food allergy is an emerging epidemic, and the underlying mechanisms are not well defined partly due to the lack of robust adjuvant free experimental models of dietary antigen sensitization. As housing mice at thermoneutrality (Tn) - the temperature of metabolic homeostasis (26-30°C) - has been shown to improve modeling various human diseases involved in inflammation, we tested the impact of Tn housing on an experimental model of food sensitization. Here we demonstrate that WT BALB/c mice housed under standard temperature (18-20°C, Ts) conditions translocated the luminal antigens in the small intestine (SI) across the epithelium

The Dystonia Coalition: A Multicenter Network For Clinical And Translational Studies, Gamze Kilic-Berkmen, Laura J Wright, Joel S Perlmutter, Cynthia Comella, Mark Hallett, Jan Teller, Sarah Pirio Richardson, David A Peterson, Carlos Cruchaga, Codrin Lungu, H A Jinnah

Open Access Publications

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal postures, repetitive movements, or both. Research in dystonia has been challenged by several factors. First, dystonia is uncommon. Dystonia is not a single disorder but a family of heterogenous disorders with varied clinical manifestations and different causes. The different subtypes may be seen by providers in different clinical specialties including neurology, ophthalmology, otolaryngology, and others. These issues have made it difficult for any single center to recruit large numbers of subjects with specific types of dystonia for research studies in a timely manner. The Dystonia Coalition …

Myosin V Regulates Spatial Localization Of Different Forms Of Neurotransmitter Release In Central Synapses, Dario Maschi, Michael W Gramlich, Vitaly A Klyachko

Open Access Publications

Synaptic active zone (AZ) contains multiple specialized release sites for vesicle fusion. The utilization of release sites is regulated to determine spatiotemporal organization of the two main forms of synchronous release, uni-vesicular (UVR) and multi-vesicular (MVR). We previously found that the vesicle-associated molecular motor myosin V regulates temporal utilization of release sites by controlling vesicle anchoring at release sites in an activity-dependent manner. Here we show that acute inhibition of myosin V shifts preferential location of vesicle docking away from AZ center toward periphery, and results in a corresponding spatial shift in utilization of release sites during UVR. Similarly, inhibition …

Comprehensive Mirnome-Wide Profiling In A Neuronal Cell Model Of Synucleinopathy Implies Involvement Of Cell Cycle Genes, Elisabeth Findeiss, Sigrid C Schwarz, Valentin Evsyukov, Thomas W Rösler, Matthias Höllerhage, Tasnim Chakroun, Niko-Petteri Nykänen, Yimin Shen, Wolfgang Wurst, Michael Kohl, Jörg Tost, Günter U Höglinger

Open Access Publications

Growing evidence suggests that epigenetic mechanisms like microRNA-mediated transcriptional regulation contribute to the pathogenesis of parkinsonism. In order to study the influence of microRNAs (miRNAs), we analyzed the miRNome 2 days prior to major cell death in α-synuclein-overexpressing Lund human mesencephalic neurons, a well-established cell model of Parkinson's disease (PD), by next-generation sequencing. The expression levels of 23 miRNAs were significantly altered in α-synuclein-overexpressing cells, 11 were down- and 12 upregulated (

Initial Clinical Experience Of Mr-Guided Radiotherapy For Non-Small Cell Lung Cancer, Cathryn B Crockett, Pamela Samson, Robert Chuter, Michael Dubec, Corinne Faivre-Finn, Olga L Green, Sara L Hackett, Fiona Mcdonald, Clifford Robinson, Anna-Maria Shiarli, Michael W Straza, Joost J C Verhoeff, Maria Werner-Wasik, Gregory Vlacich, David Cobben

Open Access Publications

Curative-intent radiotherapy plays an integral role in the treatment of lung cancer and therefore improving its therapeutic index is vital. MR guided radiotherapy (MRgRT) systems are the latest technological advance which may help with achieving this aim. The majority of MRgRT treatments delivered to date have been stereotactic body radiation therapy (SBRT) based and include the treatment of (ultra-) central tumors. However, there is a move to also implement MRgRT as curative-intent treatment for patients with inoperable locally advanced NSCLC. This paper presents the initial clinical experience of using the two commercially available systems to date: the ViewRay MRIdian and …

Whipworm-Associated Intestinal Microbiome Members Consistent Across Both Human And Mouse Hosts, Bruce A Rosa, Caroline Snowden, John Martin, Kerstin Fischer, Jonah Kupritz, Ethiopia Beshah, Taniawati Supali, Lincoln Gankpala, Peter U Fischer, Joseph F Urban, Makedonka Mitreva

Open Access Publications

The human whipworm

De Novo Synthesis Of Phosphatidylcholine Is Essential For The Promastigote But Not Amastigote Stage In Leishmania Major, Samrat Moitra, Somrita Basu, Mattie Pawlowic, Fong-Fu Hsu, Kai Zhang

Open Access Publications

Phosphatidylcholine (PC) is the most abundant type of phospholipids in eukaryotes constituting ~30% of total lipids in

Neuroscience Of Object Relations In Health And Disorder: A Proposal For An Integrative Model, Dragan M Svrakic, Charles F Zorumski

Open Access Publications

Recent advances in the neuroscience of episodic memory provide a framework to integrate object relations theory, a psychoanalytic model of mind development, with potential neural mechanisms. Object relations are primordial cognitive-affective units of the mind derived from survival- and safety-level experiences with caretakers during phase-sensitive periods of infancy and toddlerhood. Because these are learning experiences, their neural substrate likely involves memory, here affect-enhanced episodic memory. Inaugural object relations are encoded by the hippocampus-amygdala synaptic plasticity, and systems-consolidated by medial prefrontal cortex (mPFC). Self- and object-mental representations, extracted from these early experiences, are at first dichotomized by contradictory affects evoked by …

Therapeutic Ultrasound-Enhanced Immune Checkpoint Inhibitor Therapy, Jinyun Yuan, Dezhuang Ye, Si Chen, Hong Chen

Open Access Publications

No abstract provided.

Cerebrospinal Fluid Ncam-1 Concentration Is Associated With Neurodevelopmental Outcome In Post-Hemorrhagic Hydrocephalus Of Prematurity, David D. Limbrick, Diego M. Morales, Et Al.

Open Access Publications

OBJECTIVE: Efforts directed at mitigating neurological disability in preterm infants with intraventricular hemorrhage (IVH) and post hemorrhagic hydrocephalus (PHH) are limited by a dearth of quantifiable metrics capable of predicting long-term outcome. The objective of this study was to examine the relationships between candidate cerebrospinal fluid (CSF) biomarkers of PHH and neurodevelopmental outcomes in infants undergoing neurosurgical treatment for PHH.

STUDY DESIGN: Preterm infants with PHH were enrolled across the Hydrocephalus Clinical Research Network. CSF samples were collected at the time of temporizing neurosurgical procedure (n = 98). Amyloid precursor protein (APP), L1CAM, NCAM-1, and total protein (TP) were compared …

Clinical Prediction Rule For Sars-Cov-2 Infection From 116 U.S. Emergency Departments 2-22-2021, Jeffrey A. Kline, Stacey House, Et Al.

Open Access Publications

OBJECTIVES: Accurate and reliable criteria to rapidly estimate the probability of infection with the novel coronavirus-2 that causes the severe acute respiratory syndrome (SARS-CoV-2) and associated disease (COVID-19) remain an urgent unmet need, especially in emergency care. The objective was to derive and validate a clinical prediction score for SARS-CoV-2 infection that uses simple criteria widely available at the point of care.

METHODS: Data came from the registry data from the national REgistry of suspected COVID-19 in EmeRgency care (RECOVER network) comprising 116 hospitals from 25 states in the US. Clinical variables and 30-day outcomes were abstracted from medical records …

Genetic Association Analysis Of The Cardiovascular Biomarker: N-Terminal Fragment Of Pro-B-Type Natriuretic Peptide (Nt-Probnp), Yuan Yang, Joseph M. Zmuda, Mary K. Wojczynski, Bharat Thyagarajan, Kaare Christensen, Ryan K. Cvejkus, Allison L. Kuipers

Open Access Publications

BACKGROUND: NT-proBNP is a biomarker of cardiovascular disease (CVD). Little is known about the heritability and genetic variants associated with NT-proBNP. Therefore, we estimated the heritability of and examined genetic associations of SNPs in the BNP gene region with circulating NT-proBNP and prevalent CVD in 4,331 participants from the Long Life Family Study (LLFS).

METHODS AND RESULTS: Genotypes of 10 SNPs from the NPPB and NPPA regions that encode BNP and A-type natriuretic peptide, respectively, were tested for association with NT-proBNP and prevalent cardiovascular disease and risk factors. We performed analyses using the Sequential Oligogenic Linkage Analysis (SOLAR) program to …

Acute Symptoms Of Mild To Moderate Covid-19 Are Highly Heterogeneous Across Individuals And Over Time, Thomas L. Rodebaugh, Madelyn R. Frumkin, Angela M. Reiersen, Eric J. Lenze, Michael S. Avidan, J. Philip Miller, Jay F. Piccirillo, Charles F. Zorumski, Caline Mattar

Open Access Publications

Background: The symptoms of coronavirus disease 2019 (COVID-19) appear to be heterogenous, and the typical course of these symptoms is unknown. Our objectives were to characterize the common trajectories of COVID-19 symptoms and to assess how symptom course predicts other symptom changes as well as clinical deterioration.

Methods: One hundred sixty-two participants with acute COVID-19 responded to surveys up to 31 times for up to 17 days. Several statistical methods were used to characterize the temporal dynamics of these symptoms. Because 9 participants showed clinical deterioration, we explored whether these participants showed any differences in symptom profiles.

Results: Trajectories varied …

Genomic And Neoantigen Evolution From Primary Tumor To First Metastases In Head And Neck Squamous Cell Carcinoma, Charles R. Schutt, Hua Sun, Jaya Sarin Pradhan, Yvonne Saenger, Jessica Ley, Douglas Adkins, Matthew Ingham, Li Ding, Brian A. Van Tine

Open Access Publications

Head and neck cell squamous-cell carcinomas (HNSCC) are a group of common cancers typically associated with tobacco use and human papilloma virus infection. Up to half of all cases will suffer a recurrence after primary treatment. As such, new therapies are needed, including therapies which promote the anti-tumor immune response. Prior work has characterized changes in the mutation burden between primary and recurrent tumors; however, little work has characterized the changes in neoantigen evolution. We characterized genomic and neoantigen changes between 23 paired primary and recurrent HNSCC tumors. Twenty-three biopsies from patients originally diagnosed with locally advanced disease were identified …

Cognitive Gain Or Handicap: Magical Ideation And Self-Absorption In Clinical And Non-Clinical Participants, János Kállai, Gábor Vincze, Imre András Török, Rita Hargitai, Sándor Rózsa, István Hartung, István Tamás, András Láng, Róbert Herold

Open Access Publications

No abstract provided.

Correspondence Between Perceived Pubertal Development And Hormone Levels In 9-10 Year-Olds From The Adolescent Brain Cognitive Development Study, Megan M. Herting, Andrey P. Anokhin, Deanna M. Barch, Nico Dosenbach, Paul E.A. Glaser, Andrew C. Heath, Nicole R. Karcher, Et Al

Open Access Publications

No abstract provided.

Mr-Guided Adaptive Radiotherapy For Bladder Cancer, Adham Hijab, Boris Tocco, Ian Hanson, Hanneke Meijer, Christina Junker Nyborg, Anders Smedegaard Bertelsen, Robert Jan Smeenk, Gillian Smith, Jeff Michalski, Brian C Baumann, Shaista Hafeez

Open Access Publications

Radiotherapy has an important role in the curative and palliative treatment settings for bladder cancer. As a target for radiotherapy the bladder presents a number of technical challenges. These include poor tumor visualization and the variability in bladder size and position both between and during treatment delivery. Evidence favors the use of magnetic resonance imaging (MRI) as an important means of tumor visualization and local staging. The availability of hybrid systems incorporating both MRI scanning capabilities with the linear accelerator (MR-Linac) offers opportunity for in-room and real-time MRI scanning with ability of plan adaption at each fraction while the patient …

Transcriptome Analysis Of Dnmt3l Knock-Out Mice Derived Multipotent Mesenchymal Stem/Stromal Cells During Osteogenic Differentiation, Chih-Yi Yang, Rita Jui-Hsien Lu, Ming-Kang Lee, Felix Shih-Hsian Hsiao, Ya-Ping Yen, Chun-Chun Cheng, Pu-Sheng Hsu, Yi-Tzang Tsai, Shih-Kuo Chen, I-Hsuan Liu, Pao-Yang Chen, Shau-Ping Lin

Open Access Publications

Multipotent mesenchymal stem/stromal cells (MSCs) exhibit great potential for cell-based therapy. Proper epigenomic signatures in MSCs are important for the maintenance and the subsequent differentiation potential. The DNA methyltransferase 3-like (DNMT3L) that was mainly expressed in the embryonic stem (ES) cells and the developing germ cells plays an important role in shaping the epigenetic landscape. Here, we report the reduced colony forming ability and impaired

Gestational Age-Specific Complete Blood Count Signatures In Necrotizing Enterocolitis, Julia M Pantalone, Silvia Liu, Oluwabunmi O Olaloye, Erica C Prochaska, Toby Yanowitz, Melissa M Riley, Justin R Buland, Beverly S Brozanski, Misty Good, Liza Konnikova

Open Access Publications

No abstract provided.

Machine Learning Analytics Of Resting-State Functional Connectivity Predicts Survival Outcomes Of Glioblastoma Multiforme Patients, Bidhan Lamichhane, Andy G S Daniel, John J Lee, Daniel S Marcus, Joshua S Shimony, Eric C Leuthardt

Open Access Publications

Glioblastoma multiforme (GBM) is the most frequently occurring brain malignancy. Due to its poor prognosis with currently available treatments, there is a pressing need for easily accessible, non-invasive techniques to help inform pre-treatment planning, patient counseling, and improve outcomes. In this study we determined the feasibility of resting-state functional connectivity (rsFC) to classify GBM patients into short-term and long-term survival groups with respect to reported median survival (14.6 months). We used a support vector machine with rsFC between regions of interest as predictive features. We employed a novel hybrid feature selection method whereby features were first filtered using correlations between …