Digital Commons Network^™

Impact Of Site-Specific Conjugation Strategies On The Pharmacokinetics Of Antibody Conjugated Radiotherapeutics, Ábel Nagy, David Ulmert, Wahed Zedan, Claire M Storey, Julie Park, Susanne Geres, Katharina Lückerath, Kjell Sjöström, Hadis Westin, Norbert Peekhaus, Daniel Lj Thorek, Amelie Eriksson Karlström, Mohamed Altai

2020-Current year OA Pubs

Antibody radionuclide conjugates are an emerging modality for targeted imaging and potent therapy of disseminated disease. Coupling of radionuclides to monoclonal antibodies (mAbs) is typically achieved by applying non-site-specific labelling techniques. With the ambition of reducing variability, increasing labelling efficacy and stability, several site-specific conjugation strategies have been developed in recent years for toxin- and fluorophore-mAb conjugates. In this study, we studied two site-specific labelling strategies for the conjugation of the macrocyclic chelating agent, DOTA, to the anti-Leucine Rich Repeat Containing 15 (LRRC15) mAb DUNP19. Specifically, one approach utilized a DOTA-bearing peptide (FcIII) with a strong affinity for the fragment …

A Practical Clinical Approach To Navigate Pulmonary Embolism Management: A Primer And Narrative Review Of The Evolving Landscape, Kevin Benavente, Bradley Fujiuchi, Hafeez Ul Hassan Virk, Pavan K Kavali, Walter Ageno, Geoffrey D Barnes, Marc Righini, Mahboob Alam, Rachel P Rosovsky, Chayakrit Krittanawong

2020-Current year OA Pubs

Advances in imaging, pharmacological, and procedural technologies have rapidly expanded the care of pulmonary embolism. Earlier, more accurate identification and quantification has enhanced risk stratification across the spectrum of the disease process, with a number of clinical tools available to prognosticate outcomes and guide treatment. Direct oral anticoagulants have enabled a consistent and more convenient long-term therapeutic option, with a greater shift toward outpatient treatment for a select group of low-risk patients. The array of catheter-directed therapies now available has contributed to a more versatile and nuanced armamentarium of treatment options, including ultrasound-facilitated thrombolysis and mechanical thrombectomy. Research into supportive …

Transcriptomic Landscape Of Mammalian Ventral Pallidum At Single-Cell Resolution, Lite Yang, Lisa Z Fang, Michelle R Lynch, Chang S Xu, Hannah J Hahm, Yufen Zhang, Monique R Heitmeier, Vincent D Costa, Vijay K Samineni, Meaghan C Creed

2020-Current year OA Pubs

The ventral pallidum (VP) is critical for motivated behaviors. While contemporary work has begun to elucidate the functional diversity of VP neurons, the molecular heterogeneity underlying this functional diversity remains incompletely understood. We used single-nucleus RNA sequencing and in situ hybridization to define the transcriptional taxonomy of VP cell types in mice, macaques, and baboons. We found transcriptional conservation between all three species, within the broader neurochemical cell types. Unique dopaminoceptive and cholinergic subclusters were identified and conserved across both primate species but had no homolog in mice. This harmonized consensus VP cellular atlas will pave the way for understanding …

Out-Of-Focus Signal Rejection For In Vivo Po2 Measurements Using Two-Photon Phosphorescence Lifetime Microscopy, Qi Pian, Baoqiang Li, Ikbal Şencan-Eğilmez, Xiaojun Cheng, Jay Dubb, Xinyue Huang, Buyin Fu, Srinivasa Rao Allu, Mohammad Abbas Yaseen, Anna Devor, Sergei A Vinogradov, Sava Sakadžić

2020-Current year OA Pubs

Two-photon phosphorescence lifetime microscopy has been a key tool for studying cerebral oxygenation in mice. However, the accuracy of the partial pressure of oxygen (pO

Estimation Of Prevalence Of Autoimmune Diseases In The United States Using Electronic Health Record Data, Aaron H. Abend, Albert M. Lai, Et Al.

2020-Current year OA Pubs

BACKGROUNDPrevious epidemiologic studies of autoimmune diseases in the US have included a limited number of diseases or used metaanalyses that rely on different data collection methods and analyses for each disease.METHODSTo estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from 6 large medical systems in the US. We developed a software program using common methodology to compute the estimated prevalence of autoimmune diseases alone and in aggregate that can be readily used by other investigators to replicate or modify the analysis over time.RESULTSOur findings indicate that over 15 million people, or 4.6% of …

A Potent Pan-Sarbecovirus Neutralizing Antibody Resilient To Epitope Diversification, Laura E Rosen, Zhuoming Liu, Sean P J Whelan, Et Al.

2020-Current year OA Pubs

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing coronavirus mAbs that are sufficiently potent for clinical development and retain activity despite viral evolution remain elusive. We identified a human mAb, designated VIR-7229, which targets the viral receptor-binding motif (RBM) with unprecedented cross-reactivity to all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently neutralizing SARS-CoV-2 variants since 2019, including the recent EG.5, BA.2.86, and JN.1. VIR-7229 tolerates extraordinary epitope variability, partly attributed to its high binding affinity, …

Genomic Surveillance Of Sars-Cov-2 In Nepal, Binod Khadka, Kathie A Mihindukulasuriya, Lindsay Droit, Anne M Paredes, Scott A Handley, David Wang, Et Al.

2020-Current year OA Pubs

During the COVID-19 pandemic, Nepal, like other countries, faced emerging SARS-CoV-2 variants. To evaluate the circulating variants, 278 samples collected between September 2021 and March 2022 were sequenced in the country. From these, 229 high-quality genomes were obtained (82.97% Omicron and 17.03% Delta) highlighting the genomic diversity of SARS-CoV-2 in Nepal.

Incidence, Healthcare And Out-Of-Pocket Costs, And Mortality Of Clostridioides Difficile Infection Among Us Adults Aged 18 To 64 Years, Holly Yu, Tamuno Alfred, Jingying Zhou, Jennifer Judy, Margaret A. Olsen

2020-Current year OA Pubs

No abstract provided.

Malaria Parasites Require A Divergent Heme Oxygenase For Apicoplast Gene Expression And Biogenesis, Amanda Mixon Blackwell, Yasaman Jami-Alahmadi, Armiyaw S Nasamu, Shota Kudo, Akinobu Senoo, Celine Slam, Kouhei Tsumoto, James A Wohlschlegel, Jose Manuel Martinez Caaveiro, Daniel E Goldberg, Paul A Sigala

2020-Current year OA Pubs

Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection,

Effects Of Dietary Medium-Chain Triglyceride Supplementation On The Serum Metabolome Of Young Adult And Senior Canines, Yuanlong Pan, Miriam Sindelar, Ethan Stancliffe, Leah P Shriver, Rondo P Middleton, Gary J Patti

2020-Current year OA Pubs

In dogs, brain aging may lead to cognitive decline and cognitive dysfunction syndrome (CDS) [...].

Type I Ifn-Mediated Net Release Promotes Mycobacterium Tuberculosis Replication And Is Associated With Granuloma Caseation, Chanchal Sur Chowdhury, Rachel L Kinsella, Michael E Mcnehlan, Sumanta K Naik, Daniel S Lane, Priyanka Talukdar, Asya Smirnov, Neha Dubey, Ananda N Rankin, Samuel R Mckee, Reilly Woodson, Abigail Hii, Sthefany M Chavez, Darren Kreamalmeyer, Wandy Beatty, Joshua T Mattila, Christina L Stallings

2020-Current year OA Pubs

Neutrophils are the most abundant cell type in the airways of tuberculosis patients. Mycobacterium tuberculosis (Mtb) infection induces the release of neutrophil extracellular traps (NETs); however, the molecular regulation and impact of NET release on Mtb pathogenesis are unknown. We find that during Mtb infection in neutrophils, PAD4 citrullinates histones to decondense chromatin that gets released as NETs in a manner that can maintain neutrophil viability and promote Mtb replication. Type I interferon promotes the formation of chromatin-containing vesicles that allow NET release without compromising plasma membrane integrity. Analysis of nonhuman primate granulomas supports a model where neutrophils are exposed …

A Trivalent Mucosal Vaccine Encoding Phylogenetically Inferred Ancestral Rbd Sequences Confers Pan-Sarbecovirus Protection In Mice, James Brett Case, Shilpa Sanapala, Suzanne M Scheaffer, Déborah Carolina Carvalho Dos Anjos, Lucas J Adams, Nadia Soudani, Chieh-Yu Liang, Baoling Ying, Adrianus C M Boon, Daved H Fremont, Sean P J Whelan, Michael S Diamond, Et Al.

2020-Current year OA Pubs

The continued emergence of SARS-CoV-2 variants and the threat of future Sarbecovirus zoonoses have spurred the design of vaccines that can induce broad immunity against multiple coronaviruses. Here, we use computational methods to infer ancestral phylogenetic reconstructions of receptor binding domain (RBD) sequences across multiple Sarbecovirus clades and incorporate them into a multivalent adenoviral-vectored vaccine. Mice immunized with this pan-Sarbecovirus vaccine are protected in the upper and lower respiratory tracts against infection by historical and contemporary SARS-CoV-2 variants, SARS-CoV, and pre-emergent SHC014 and Pangolin/GD coronavirus strains. Using genetic and immunological approaches, we demonstrate that vaccine-induced protection unexpectedly is conferred principally …

Unraveling The Role Of Uils, A Urea-Induced Acyl-Homoserine Lactonase That Enhances Serratia Marcescens Fitness, Interbacterial Competition, And Urinary Tract Infection, Marisel R Tuttobene, Brayan S Arango Gil, Gisela Di Venanzio, Javier F Mariscotti, Rodrigo Sieira, Mario F Feldman, María Soledad Ramirez, Eleonora García Véscovi

2020-Current year OA Pubs

UNLABELLED:

IMPORTANCE: This work reveals the acyl-homoserine lactonase

Type I Interferon Signaling In Dendritic Cells Limits Direct Antigen Presentation And Cd8+ T Cell Responses Against An Arthritogenic Alphavirus, Christopher B Bullock, Leran Wang, Brian C Ware, Ngan Wagoner, Ray A Ohara, Tian-Tian Liu, Pritesh Desai, Bjoern Peters, Kenneth M Murphy, Scott A Handley, Thomas E Morrison, Michael S Diamond

2020-Current year OA Pubs

Ross River virus (RRV) and other alphaviruses cause chronic musculoskeletal syndromes that are associated with viral persistence, which suggests deficits in immune clearance mechanisms, including CD8

Whole-Blood Model Reveals Granulocytes As Key Sites Of Dengue Virus Propagation, Expanding Understanding Of Disease Pathogenesis, Hansa Praneechit, Somchai Thiemmeca, Dararat Prayongkul, Kessiri Kongmanas, Dumrong Mairiang, Nuntaya Punyadee, Adisak Songjaeng, Nattaya Tangthawornchaikul, Nasikarn Angkasekwinai, Kanokwan Sriruksa, Yupin Suputtamongkol, Wannee Limpitikul, John P Atkinson, Panisadee Avirutnan

2020-Current year OA Pubs

Dengue virus (DENV) infection poses a significant global health threat, yet our understanding of its immunopathogenesis remains incomplete due to limitations of existing models. Here, we establish an

Imlunestrant, An Oral Selective Estrogen Receptor Degrader, As Monotherapy And In Combination With Targeted Therapy In Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Phase Ia/Ib Ember Study, Komal L Jhaveri, Cynthia X Ma, Et Al.

2020-Current year OA Pubs

PURPOSE: Imlunestrant is a next-generation oral selective estrogen receptor (ER) degrader designed to deliver continuous ER target inhibition, including in

METHODS: An i3+3 dose-escalation design was used, followed by dose expansions of imlunestrant as monotherapy or in combination with abemaciclib with or without aromatase inhibitor (AI), everolimus, or alpelisib. Imlunestrant was administered orally once daily and with the combination partner per label.

RESULTS: Overall, 262 patients with ER+/HER2- ABC were treated (phase Ia, n = 74; phase Ib, n = 188). Among patients who received imlunestrant monotherapy (n = 114), no dose-limiting toxicities or discontinuations occurred. At the RP2D (400 …

Prenatal Social Disadvantage Is Associated With Alterations In Functional Networks At Birth, Ashley N Nielsen, Regina L Triplett, Lourdes M Bernardez, Ursula A Tooley, Max P Herzberg, Rachel E Lean, Sydney Kaplan, Dominique Meyer, Jeanette K Kenley, Dimitrios Alexopoulos, David Losielle, Aidan Latham, Tara A Smyser, Arpana Agrawal, Josh S Shimony, Joshua J Jackson, J Philip Miller, Marcus E Raichle, Barbara B Warner, Cynthia E Rogers, Chad M Sylvester, Deanna M Barch, Joan L Luby, Christopher D Smyser

2020-Current year OA Pubs

Childhood exposure to social disadvantage is a major risk factor for psychiatric disorders and poor developmental, educational, and occupational outcomes, presumably because adverse exposures alter the neurodevelopmental processes that contribute to risk trajectories. Yet, given the limited social mobility in the United States and other countries, childhood social disadvantage is frequently preceded by maternal social disadvantage during pregnancy, potentially altering fetal brain development during a period of high neuroplasticity through hormonal, microbiome, epigenetic, and immune factors that cross the placenta and fetal blood-brain barrier. The current study examines prenatal social disadvantage to determine whether these exposures in utero are associated …

Bio-Interventional Cyclodialysis And Allograft Scleral Reinforcement For Uveoscleral Outflow Enhancement In Open-Angle Glaucoma Patients: One-Year Clinical Outcomes, Tsontcho Ianchulev, Robert N Weinreb, Ernesto A Calvo, James Lewis, Gautam Kamthan, Arsham Sheybani, Douglas J Rhee, Iqbal K Ahmed

2020-Current year OA Pubs

BACKGROUND: To evaluate the one-year safety and effectiveness of bio-interventional cyclodialysis and scleral reinforcement in open-angle glaucoma (OAG) patients undergoing cataract surgery.

METHODS: An ab-interno approach was used to create a sectoral cyclodialysis in OAG patients who were prospectively followed in a consecutive case series. Subsequent visco-cycloplasty with scleral reinforcement using homologous minimally modified allograft scaffold was completed to maintain patency of the cyclodialysis reservoir and increase uveoscleral outflow. Outcomes were mean medicated IOP and mean number of IOP-lowering medications. Safety outcomes were adverse events (AEs) and best-corrected visual acuity (BCVA) changes.

RESULTS: Successful cyclodialysis and allograft bio-scaffold reinforcement was …

Domain-Specific Representation Of Social Inference By Neurons In The Human Amygdala And Hippocampus, Runnan Cao, Julien Dubois, Adam N Mamelak, Ralph Adolphs, Shuo Wang, Ueli Rutishauser

2020-Current year OA Pubs

Inferring the intentions and emotions of others from behavior is crucial for social cognition. While neuroimaging studies have identified brain regions involved in social inference, it remains unknown whether performing social inference is an abstract computation that generalizes across different stimulus categories or is specific to certain stimulus domain. We recorded single-neuron activity from the medial temporal lobe (MTL) and the medial frontal cortex (MFC) in neurosurgical patients performing different types of inferences from images of faces, hands, and natural scenes. Our findings indicate distinct neuron populations in both regions encoding inference type for social (faces, hands) and nonsocial (scenes) …

Sirtuins As Key Regulators In Pancreatic Cancer: Insights Into Signaling Mechanisms And Therapeutic Implications, Surbhi Chouhan, Anil Kumar, Naoshad Muhammad, Darksha Usmani, Tabish H Khan

2020-Current year OA Pubs

Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by rapid progression, pronounced chemoresistance, and a complex network of genetic and epigenetic dysregulation. Within this challenging context, sirtuins, NAD

Cellular Trafficking And Fate Mapping Of Cells Within The Nervous System After In Utero Hematopoietic Cell Transplantation, Matthew T Grant, Hemanth Ramesh Nelvagal, Maria Tecos, Amal Hamed, Kerry Swanson, Jonathan D Cooper, Jesse D Vrecenak

2020-Current year OA Pubs

In utero hematopoietic cell transplantation (IUHCT) utilizes fetal immune tolerance to achieve durable chimerism without conditioning or immunosuppression during a unique window in fetal development. Though donor cells have been observed within the nervous system following in utero injection, the timeline and distribution of cellular trafficking across the blood-brain barrier following IUHCT is not well understood. We injected 20 × 10

Alzheimer's Disease-Linked Risk Alleles Elevate Microglial Cgas-Associated Senescence And Neurodegeneration In A Tauopathy Model, Gillian K Carling, Xiaoying Chen, David M Holtzman, Et Al.

2020-Current year OA Pubs

The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2

X-Chromosome-Wide Association Study For Alzheimer's Disease, Julie Le Borgne, Carlos Cruchaga, John Morris, Et Al.

2020-Current year OA Pubs

No abstract provided.

Molecular Insights Into The Interaction Between A Disordered Protein And A Folded Rna, Rishav Mitra, Emery T Usher, Selin Dedeoğlu, Matthew J Crotteau, Olivia A Fraser, Neela H Yennawar, Varun V Gadkari, Brandon T Ruotolo, Alex S Holehouse, Loïc Salmon, Scott A Showalter, James C A Bardwell

2020-Current year OA Pubs

Intrinsically disordered protein regions (IDRs) are well established as contributors to intermolecular interactions and the formation of biomolecular condensates. In particular, RNA-binding proteins (RBPs) often harbor IDRs in addition to folded RNA-binding domains that contribute to RBP function. To understand the dynamic interactions of an IDR-RNA complex, we characterized the RNA-binding features of a small (68 residues), positively charged IDR-containing protein, Small ERDK-Rich Factor (SERF). At high concentrations, SERF and RNA undergo charge-driven associative phase separation to form a protein- and RNA-rich dense phase. A key advantage of this model system is that this threshold for demixing is sufficiently high …

Arousal Effects On Oscillatory Dynamics In The Non-Human Primate Brain, Shashank A Anand, Fatih Sogukpinar, Ilya E Monosov

2020-Current year OA Pubs

Arousal states are thought to influence many aspects of cognition and behavior by broadly modulating neural activity. Many studies have observed arousal-related modulations of alpha (~8 to 15 Hz) and gamma (~30 to 50 Hz) power and coherence in local field potentials across relatively small groups of brain regions. However, the global pattern of arousal-related oscillatory modulation in local field potentials is yet to be fully elucidated. We simultaneously recorded local field potentials in numerous cortical and subcortical regions in the primate brain and assessed oscillatory activity and inter-regional coherence associated with arousal state. In high arousal states, we found …

Phosphorylation Of Disordered Proteins Tunes Local And Global Intramolecular Interactions, Emery T Usher, Martin J Fossat, Alex S Holehouse

2020-Current year OA Pubs

Protein post-translational modifications, such as phosphorylation, are important regulatory signals for diverse cellular functions. In particular, intrinsically disordered protein regions (IDRs) are subject to phosphorylation as a means to modulate their interactions and functions. Toward understanding the relationship between phosphorylation in IDRs and specific functional outcomes, we must consider how phosphorylation affects the IDR conformational ensemble. Various experimental techniques are suited to interrogate the features of IDR ensembles; molecular simulations can provide complementary insights and even illuminate ensemble features that may be experimentally inaccessible. Therefore, we sought to expand the tools available to study phosphorylated IDRs by all-atom Monte Carlo …

A Preoperative Window-Of-Opportunity Study Of Oral Serd, Imlunestrant, In Newly Diagnosed Er-Positive, Her2-Negative Early Breast Cancer: Results From The Ember-2 Study, Patrick Neven, Rebecca Aft, Et Al.

2020-Current year OA Pubs

PURPOSE: Imlunestrant is an oral selective estrogen receptor degrader with favorable safety and preliminary efficacy in patients with advanced breast cancer. Pharmacodynamic (PD) biomarker data can optimize drug dosing; in this study, we present PD data from the EMBER-2 study.

PATIENTS AND METHODS: Postmenopausal women with untreated, operable estrogen receptor (ER)-positive, HER2-negative early breast cancer were randomized to 400 versus 800 mg of imlunestrant daily for ∼2 weeks before surgery. A single arm study tested a daily dose of 200 mg. PD biomarker changes (ER, progesterone receptor, Ki-67 by IHC, and mRNA expression of ER-related genes) were evaluated in paired …

Redesigning The Hospital Environment To Improve Restfulness, Caellagh D Catley, Kayla Paynter, Kendall Jackson, Ashley Huggins, Jenny Ji, Sai Anusha Sanka, Michelle Simkins, Thomas M Maddox, Patrick G Lyons

2020-Current year OA Pubs

IMPORTANCE: Hospital wards are often not conducive to patient sleep, negatively affecting patient health and experience.

OBJECTIVES: To assess determinants of in-hospital restfulness and to design and test rest-promoting interventions on the wards in partnership with clinicians, staff, and patients.

DESIGN, SETTING, AND PARTICIPANTS: This rapid-sequential mixed-methods quality improvement study was performed at a large urban academic hospital in St Louis, Missouri, from May 1, 2021, to December 31, 2022, with follow-up through hospitalization. Mixed-methods activities involved purposively selected hospitalized adults on the wards, nurses, hospitalists, and hospital staff. Interventions included all adult hospitalizations on the study wards.

INTERVENTIONS: Sequential …

Secure Messaging Use And Wrong-Patient Ordering Errors Among Inpatient Clinicians, Sunny S Lou, Daphne Lew, Linlin Xia, Laura Baratta, Elise Eiden, Thomas Kannampallil

2020-Current year OA Pubs

IMPORTANCE: Use of secure messaging for clinician-to-clinician communication has increased exponentially over the past decade, but its association with clinician work is poorly understood.

OBJECTIVE: To investigate the association between secure messaging use and wrong-patient ordering errors.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included inpatient attending physicians, trainee physicians, and advanced practice practitioners (APPs) from 14 academic and community hospitals. Secure messaging volume was assessed over a 3-month period (February 1 to April 30, 2023).

EXPOSURE: Secure messaging volume per clinician-day, measured as the count of secure messages sent and received by a clinician on a given clinician-day.

MAIN …

Medical And Surgical Episodes Among Hospital Participants In The Bundled Payments For Care Improvement-Advanced Program, Keenan J Robbins, Jie Zheng, R J Waken, E John Orav, Arnold M Epstein, Karen E Joynt Maddox

2020-Current year OA Pubs

IMPORTANCE: Hospital participation in the Bundled Payments for Care Improvement-Advanced (BPCI-A) initiative has been associated with modest savings and stable clinical outcomes overall, but it is unknown whether the program performs differently for medical and surgical or procedural (henceforth, surgical) episodes.

OBJECTIVE: To assess the association of BPCI-A participation with Medicare spending and clinical outcomes for medical and surgical episodes.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective difference-in-differences cohort study utilized 100% Medicare fee-for-service inpatient claims for episodes initiated between January 1, 2017, and September 30, 2019, and included 90 days of follow-up. The setting was hospitals participating in BPCI-A and …