Medicine and Health Sciences Commons^™

Single Cell-Transcriptomic Analysis Informs The Lncrna Landscape In Metastatic Castration Resistant Prostate Cancer, Debanjan Saha, Ha X Dang, Meng Zhang, David A Quigley, Felix Y Feng, Christopher A Maher

2020-Current year OA Pubs

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of prostate cancer. Although long-noncoding RNAs (lncRNAs) have been implicated in mCRPC, past studies have relied on bulk sequencing methods with low depth and lack of single-cell resolution. Hence, we performed a lncRNA-focused analysis of single-cell RNA-sequencing data (n = 14) from mCRPC biopsies followed by integration with bulk multi-omic datasets. This yielded 389 cell-enriched lncRNAs in prostate cancer cells and the tumor microenvironment (TME). These lncRNAs demonstrated enrichment with regulatory elements and exhibited alterations during prostate cancer progression. Prostate-lncRNAs were correlated with AR mutational status and response to treatment with …

Inhibiting Centrosome Clustering Reduces Cystogenesis And Improves Kidney Function In Autosomal Dominant Polycystic Kidney Disease, Tao Cheng, Aruljothi Mariappan, Ewa Langner, Kyuhwan Shim, Jay Gopalakrishnan, Moe R. Mahjoub

2020-Current year OA Pubs

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder accounting for approximately 5% of patients with renal failure, yet therapeutics for the treatment of ADPKD remain limited. ADPKD tissues display abnormalities in the biogenesis of the centrosome, a defect that can cause genome instability, aberrant ciliary signaling, and secretion of pro-inflammatory factors. Cystic cells form excess centrosomes via a process termed centrosome amplification (CA), which causes abnormal multipolar spindle configurations, mitotic catastrophe, and reduced cell viability. However, cells with CA can suppress multipolarity via "centrosome clustering," a key mechanism by which cells circumvent apoptosis. Here, we demonstrate that inhibiting …

Tubular Cpt1a Deletion Minimally Affects Aging And Chronic Kidney Injury, Safaa Hammoud, Yosuke Osaki, Steven Funk, Dongliang Lu, Benjamin D. Humphreys, Jeffrey Koenitzer, Justin Kern, Nidia Messias, Irfan J Lodhi, Leslie S. Gewin, Et Al.

2020-Current year OA Pubs

Kidney tubules use fatty acid oxidation (FAO) to support their high energetic requirements. Carnitine palmitoyltransferase 1A (CPT1A) is the rate-limiting enzyme for FAO, and it is necessary to transport long-chain fatty acids into mitochondria. To define the role of tubular CPT1A in aging and injury, we generated mice with tubule-specific deletion of Cpt1a (Cpt1aCKO mice), and the mice were either aged for 2 years or injured by aristolochic acid or unilateral ureteral obstruction. Surprisingly, Cpt1aCKO mice had no significant differences in kidney function or fibrosis compared with wild-type mice after aging or chronic injury. Primary tubule cells from aged Cpt1aCKO …

Effects Of Complete And Partial Loss Of The 24s-Hydroxycholesterol-Generating Enzyme, Hong-Jin Shu, Luke H Ziolkowski, Sofia V Salvatore, Ann M Benz, David F Wozniak, Carla M Yuede, Steven M Paul, Charles F Zorumski, Steven Mennerick

2020-Current year OA Pubs

Brain cholesterol metabolic products include neurosteroids and oxysterols, which play important roles in cellular physiology. In neurons, the cholesterol oxidation product, 24S-hydroxycholesterol (24S-HC), is a regulator of signaling and transcription. Here, we examined the behavioral effects of 24S-HC loss, using global and cell-selective genetic deletion of the synthetic enzyme CYP46A1. Mice that are globally deficient in CYP46A1 exhibited hypoactivity at young ages and unexpected increases in conditioned fear memory. Despite strong reductions in hippocampal 24S-HC in mice with selective loss of CYP46A1 in VGLUT1-positive cells, behavioral effects were not recapitulated in these conditional knockout mice. Global knockout produced strong, developmentally …

Nrf2 Activation In Trp53;P16-Deficient Mice Drives Oral Squamous Cell Carcinoma, Samera H Hamad, Rani S Sellers, Nathan Wamsley, Paul Zolkind, Travis P Schrank, Michael B Major, Bernard E Weissman

2020-Current year OA Pubs

UNLABELLED: Aberrant activation of the NRF2/NFE2L2 transcription factor commonly occurs in head and neck squamous cell carcinomas (HNSCC). Mouse model studies have shown that NRF2 activation alone does not result in cancer. When combined with classic oncogenes and at the right dose, NRF2 activation promotes tumor initiation and progression. Here we deleted the tumor suppressor genes p16INK4A and p53 (referred to as CP mice), which are commonly lost in human HNSCC, in the presence of a constitutively active NRF2E79Q mutant (CPN mice). NRF2E79Q expression in CPN mice resulted in squamous cell hyperplasia or dysplasia with hyperkeratosis in the esophagus, oropharynx, …

Multi-Molecular Hyperspectral Prm-Srs Microscopy, Wenxu Zhang, Yajuan Li, Anthony A Fung, Zhi Li, Hongje Jang, Honghao Zha, Xiaoping Chen, Fangyuan Gao, Jane Y Wu, Huaxin Sheng, Junjie Yao, Dorota Skowronska-Krawczyk, Sanjay Jain, Lingyan Shi

2020-Current year OA Pubs

Lipids play crucial roles in many biological processes. Mapping spatial distributions and examining the metabolic dynamics of different lipid subtypes in cells and tissues are critical to better understanding their roles in aging and diseases. Commonly used imaging methods (such as mass spectrometry-based, fluorescence labeling, conventional optical imaging) can disrupt the native environment of cells/tissues, have limited spatial or spectral resolution, or cannot distinguish different lipid subtypes. Here we present a hyperspectral imaging platform that integrates a Penalized Reference Matching algorithm with Stimulated Raman Scattering (PRM-SRS) microscopy. Using this platform, we visualize and identify high density lipoprotein particles in human …

Implementation Of A Standardized Handoff Reference Tool From The Intensive Care Unit To The Operating Room, Sophia Agbomah, Stacie Summers

Doctor of Nursing Practice (DNP) Student Projects

Background and Review of Literature: This quality improvement (QI) intervention evaluated the effectiveness of a standardized handoff reference tool for patients transferring from the Surgical Intensive Care Unit (SICU) to the operating room (OR) in a large metropolitan level I trauma center. There was minimal data to assess the quality of this sequence of patient transfer as no systematic ICU-OR handoff content practices were currently employed at the hospital. This project aimed to help fill the practice-knowledge gap that could impact some of the most vulnerable patients during ICU-OR transfer. Methods: Pre- and post-implementation staff surveys, live observations, and chart …

Propofol Disposal In The Operating Room: Addressing The Practice Knowledge Gap, Samantha Trulove, Audreau Conley

Doctor of Nursing Practice (DNP) Student Projects

Background: There is an increasing incidence of propofol diversion and abuse amongst healthcare workers. Barnes Jewish Hospital (BJH) has implemented the Stericycle controlled substance disposal system (CsRx) in the operating rooms (ORs) to address this issue; however, propofol continued to be left unsecured.

Purpose: The QI initiative aimed to raise anesthesia clinician awareness of propofol’s abuse potential and of the Stericycle CsRx container, ultimately to reduce unsecured propofol.

Methods: An educational intervention was utilized to address the identified problem. Data on unsecured propofol was collected via an auditing process of pharmaceutical waste bin contents at the BJH North campus endoscopy …

Reducing Unsecured Medications In Anesthetizing Area, Christine Bergesch, Kate Manuel

Doctor of Nursing Practice (DNP) Student Projects

Background and Review of Literature: Anesthetic medications should be secured consistently to prevent adverse outcomes such as medication errors, drug diversion, and financial loss. Standardized practice for medication stewardship is not established by Washington University Department of Anesthesiology (WUDA). Anesthesia providers’ imprudent medication stewardship practices are a continuous challenge due to the controlled and time-sensitive drugs they provide. Purpose: The purpose of this quality improvement (QI) project was to decrease the number of medications left behind unsecured in anesthetizing areas, describe the most frequently encountered barriers and category of medications left behind unsecured, and improve knowledge and utilization of the …

Improving Anesthesia Clinicians’ Knowledge And Confidence When Selecting Prophylactic Antimicrobials For Patients On Concomitant Antimicrobial Therapy, Garry Gregson, Emily Shands

Doctor of Nursing Practice (DNP) Student Projects

Anesthesia clinicians at Barnes Jewish Hospital (BJH) in Saint Louis, Missouri experienced uncertainty and discomfort when they selected preoperative antibiotics for patients who were already receiving concomitant therapeutic antimicrobials (CTA) unrelated to surgical prophylaxis. Various evidence-based interventions were proposed to address this issue. The first intervention was the addition of pathogens of concern to the surgical antimicrobial prophylaxis (SAP) protocol at BJH. The second intervention was the creation of a reference table that supplemented the revised protocol and allowed clinicians to efficiently determine the pathogens of concern for each surgery. This also included the CTAs efficacy for preventing surgical site …

Assessing Workflow In The Postanesthesia Care Unit, Laura Mcgrath, Emma Vierod

Doctor of Nursing Practice (DNP) Student Projects

The postanesthesia care unit (PACU) environment must function smoothly as a critical recovery area for monitoring of immediate postoperative patients. Timely responsiveness to complications is imperative to ensure patient safety. Following postanesthesia observation, a patient is discharged from the PACU to home or is admitted to the hospital. If this transition is delayed by excessive discharge times or poorly managed patient adverse events, it can cause major bottlenecks and issues with throughput for the perioperative setting. This project aims to study the present workflow in the PACU, identify gaps in the workflow and provide recommendations to perioperative leadership. Current PACU …

Impact Of Palliative Care Utilization Among Kidney Cancer Patients In Us Hospitals: A National-Scale Analysis, Rushin Patel, Mrunal Patel, Darshil Patel, Chieh Yang, Afoma Onyechi, Jessica Ohemeng-Dapaah, Zalak Patel, Safia Shaikh

2020-Current year OA Pubs

No abstract provided.

A Digital Intervention To Promote Self-Management Self-Efficacy Among Community-Dwelling Individuals With Stroke: Pilot Randomized Controlled Trial, Zhaoying Li, Yating Lei, Quoc Bui, Olivia Depaul, Ginger E Nicol, David C Mohr, Sunghoon I Lee, Mandy W M Fong, Christopher L Metts, Stephanie E Tomazin, Alex W K Wong

2020-Current year OA Pubs

BACKGROUND: Digital interventions provided through smartphones or the internet that are guided by a coach have been proposed as promising solutions to support the self-management of chronic conditions. However, digital intervention for poststroke self-management is limited; we developed the interactive Self-Management Augmented by Rehabilitation Technologies (iSMART) intervention to address this gap.

OBJECTIVE: This study aimed to examine the feasibility and initial effects of the iSMART intervention to improve self-management self-efficacy in people with stroke.

METHODS: A parallel, 2-arm, nonblinded, randomized controlled trial of 12-week duration was conducted. A total of 24 participants with mild-to-moderate chronic stroke were randomized to receive …

Genetic Drivers Of Heterogeneity In Type 2 Diabetes Pathophysiology, Ken Suzuki, Ping An, Adam E. Locke, Michael A. Province, Et Al.

2020-Current year OA Pubs

No abstract provided.

Description Of Cryptococcosis Following Sars-Cov-2 Infection: A Disease Survey Through The Mycosis Study Group Education And Research Consortium (Msg-19), Jeremey Walker, Andrej Spec, Adriana M Rauseo, Et Al.

2020-Current year OA Pubs

BACKGROUND: Invasive fungal infections have been described throughout the COVID-19 pandemic. Cryptococcal disease after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in several isolated case reports and 1 larger case series. We sought to describe cryptococcal infections following SARS-CoV-2 through establishing a database to investigate underlying risk factors, disease manifestations, and outcomes.

METHODS: We created a crowdsourced call for cases solicited through the Mycoses Study Group Education and Research Consortium, the Centers for Disease Control and Prevention Emerging Infectious Diseases Network, and infectious diseases Twitter groups. Data were collected in a web-based and secure REDCap …

Virtual, Augmented, And Mixed Reality Applications For Surgical Rehearsal, Operative Execution, And Patient Education In Spine Surgery: A Scoping Review, Tim Bui, Miguel A Ruiz-Cardozo, Harsh S Dave, Karma Barot, Michael Ryan Kann, Karan Joseph, Sofia Lopez-Alviar, Gabriel Trevino, Samuel Brehm, Alexander T Yahanda, Camilo A Molina

2020-Current year OA Pubs

No abstract provided.

High Resolution Spatial Profiling Of Kidney Injury And Repair Using Rna Hybridization-Based In Situ Sequencing, Haojia Wu, Eryn E Dixon, Qiao Xuanyuan, Juanru Guo, Yasuhiro Yoshimura, Chitnis Debashish, Anezka Niesnerova, Hao Xu, Morgane Rouault, Benjamin D Humphreys

2020-Current year OA Pubs

Emerging spatially resolved transcriptomics technologies allow for the measurement of gene expression in situ at cellular resolution. We apply direct RNA hybridization-based in situ sequencing (dRNA HybISS, Cartana part of 10xGenomics) to compare male and female healthy mouse kidneys and the male kidney injury and repair timecourse. A pre-selected panel of 200 genes is used to identify cell state dynamics patterns during injury and repair. We develop a new computational pipeline, CellScopes, for the rapid analysis, multi-omic integration and visualization of spatially resolved transcriptomic datasets. The resulting dataset allows us to resolve 13 kidney cell types within distinct kidney niches, …

Androgen Exposure Impairs Neutrophil Maturation And Function Within The Infected Kidney, Teri N Hreha, Christina A Collins, Elisabeth B Cole, Rachel J Jin, David A Hunstad

2020-Current year OA Pubs

Urinary tract infections (UTIs) in men are uncommon yet carry an increased risk for severe pyelonephritis and other complications. In models of

Secretory Leukocyte Protease Inhibitor Protects Against Severe Urinary Tract Infection In Mice, Anne L Rosen, Michael A Lint, Dayne H Voelker, Nicole M Gilbert, Christopher P Tomera, Jesús Santiago-Borges, Meghan A Wallace, Thomas J Hannan, Carey-Ann D Burnham, Scott J Hultgren, Andrew L Kau

2020-Current year OA Pubs

Millions suffer from urinary tract infections (UTIs) worldwide every year with women accounting for the majority of cases. Uropathogenic

Yersiniabactin Is A Quorum-Sensing Autoinducer And Siderophore In Uropathogenic Escherichia Coli, James R Heffernan, John A Wildenthal, Hung Tran, George L Katumba, William H Mccoy, Jeffrey P Henderson

2020-Current year OA Pubs

Siderophores are secreted ferric ion chelators used to obtain iron in nutrient-limited environmental niches, including human hosts. While all

Lysosome-Related Organelles Contain An Expansion Compartment That Mediates Delivery Of Zinc Transporters To Promote Homeostasis, Adelita D Mendoza, Nicholas Dietrich, Chieh-Hsiang Tan, Daniel Herrera, Jennysue Kasiah, Zachary Payne, Ciro Cubillas, Daniel L Schneider, Kerry Kornfeld

2020-Current year OA Pubs

Zinc is an essential nutrient-it is stored during periods of excess to promote detoxification and released during periods of deficiency to sustain function. Lysosome-related organelles (LROs) are an evolutionarily conserved site of zinc storage, but mechanisms that control the directional zinc flow necessary for homeostasis are not well understood. In

Dna Hypomethylation Ameliorates Erosive Inflammatory Arthritis By Modulating Interferon Regulatory Factor-8, Gaurav Swarnkar, Nicholas P Semenkovich, Manoj Arra, Dorothy K Mims, Syeda Kanwal Naqvi, Timothy Peterson, Gabriel Mbalaviele, Chia-Lung Wu, Yousef Abu-Amer

2020-Current year OA Pubs

Epigenetic regulation plays a crucial role in the pathogenesis of autoimmune diseases such as inflammatory arthritis. DNA hypomethylating agents, such as decitabine (DAC), have been shown to dampen inflammation and restore immune homeostasis. In the present study, we demonstrate that DAC elicits potent anti-inflammatory effects and attenuates disease symptoms in several animal models of arthritis. Transcriptomic and epigenomic profiling show that DAC-mediated hypomethylation regulates a wide range of cell types in arthritis, altering the differentiation trajectories of anti-inflammatory macrophage populations, regulatory T cells, and tissue-protective synovial fibroblasts (SFs). Mechanistically, DAC-mediated demethylation of intragenic 5'-Cytosine phosphate Guanine-3' (CpG) islands of the …

Outcomes Of Marginal Zone Lymphoma Treated With Ibrutinib In The First-Line Setting In The United States: A Real-World Analysis, Narendranath Epperla, Qiuhong Zhao, Tamara Moyo, Marcus P Watkins, Montreh Tavakkoli, Celeste Bello, Pallawi Torka, Nishitha Reddy, Colin Thomas, Kaitlin Annunzio, Beth Christian, Stefan K Barta, Geoffrey Shouse, Adam J Olszewski, Nancy L Bartlett

2020-Current year OA Pubs

No abstract provided.

A General Computational Design Strategy For Stabilizing Viral Class I Fusion Proteins, Karen J Gonzalez, Jiachen Huang, Miria F Criado, Avik Banerjee, Stephen M Tompkins, Jarrod J Mousa, Eva-Maria Strauch

2020-Current year OA Pubs

Many pathogenic viruses rely on class I fusion proteins to fuse their viral membrane with the host cell membrane. To drive the fusion process, class I fusion proteins undergo an irreversible conformational change from a metastable prefusion state to an energetically more stable postfusion state. Mounting evidence underscores that antibodies targeting the prefusion conformation are the most potent, making it a compelling vaccine candidate. Here, we establish a computational design protocol that stabilizes the prefusion state while destabilizing the postfusion conformation. With this protocol, we stabilize the fusion proteins of the RSV, hMPV, and SARS-CoV-2 viruses, testing fewer than a …

Inadequate Prophylaxis In Patients With Trauma: Anti-Xa-Guided Enoxaparin Dosing Management In Critically Ill Patients With Trauma, Grace Martin Niziolek, Lauren Mangan, Cassidi Weaver, Vanessa Prendergast, Raymond Lamore, Megan Zielke, Niels D Martin

2020-Current year OA Pubs

UNLABELLED: Venous thromboembolism (VTE) causes significant morbidity in patients with trauma despite advances in pharmacologic therapy. Prior literature suggests standard enoxaparin dosing may not achieve target prophylactic anti-Xa levels. We hypothesize that a new weight-based enoxaparin protocol with anti-Xa monitoring for dose titration in critically injured patients is safe and easily implemented.

METHODS: This prospective observational study included patients with trauma admitted to the trauma intensive care unit (ICU) from January 2021 to September 2022. Enoxaparin dosing was adjusted based on anti-Xa levels as standard of care via a performance improvement initiative. The primary outcome was the proportion of subtarget …

Dynamic Changes In The Mouse Hepatic Lipidome Following Warm Ischemia Reperfusion Injury, Kim H H Liss, Muhammad Mousa, Shria Bucha, Andrew Lutkewitte, Jeremy Allegood, L Ashley Cowart, Brian N Finck

2020-Current year OA Pubs

Liver failure secondary to metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common cause for liver transplantation in many parts of the world. Moreover, the prevalence of MASLD not only increases the demand for liver transplantation, but also limits the supply of suitable donor organs because steatosis predisposes grafts to ischemia-reperfusion injury (IRI). There are currently no pharmacological interventions to limit hepatic IRI because the mechanisms by which steatosis leads to increased injury are unclear. To identify potential novel mediators of IRI, we used liquid chromatography and mass spectrometry to assess temporal changes in the hepatic lipidome in …

Blinatumomab Consolidation Post-Autologous Stem Cell Transplantation In Patients With Diffuse Large B-Cell Lymphoma, Armin Ghobadi, Nicole C Foley, Jared Cohen, Michael P Rettig, Amanda F Cashen, Leah Gehrs, Stephanie Christ, Emily Street, Nicholas Wallace, Julie Ritchey, Neha Mehta-Shah, Peter Westervelt, Todd A Fehniger, Brad Kahl, Nancy L Bartlett, John F Dipersio

2020-Current year OA Pubs

Outcomes in patients with relapsed diffuse large B-cell lymphoma (DLBCL) who undergo autologous stem cell transplant (auto-SCT) are poor. Blinatumomab is a CD3/CD19 bispecific T-cell engager that directs cytotoxic T cells to CD19+ cells. Here, we performed a pilot study of blinatumomab consolidation after auto-SCT for 14 patients with DLBCL or transformed follicular lymphoma. All patients underwent standard-of-care auto-SCT with carmustine, etoposide, cytarabine, and melphalan (BEAM) conditioning followed by 1 cycle (4 weeks continuous infusion) of blinatumomab consolidation starting at day 42 after auto-SCT. All 14 patients treated on study completed BEAM auto-SCT and 1 cycle of posttransplant blinatumomab. Five …

Connexin43 In Mesenchymal Lineage Cells Regulates Body Adiposity And Energy Metabolism In Mice, Seung-Yon Lee, Francesca Fontana, Toshifumi Sugatani, Ignacio Portales Castillo, Giulia Leanza, Ariella Coler-Reilly, Roberto Civitelli

2020-Current year OA Pubs

Connexin43 (Cx43) is the most abundant gap junction protein present in the mesenchymal lineage. In mature adipocytes, Cx43 mediates white adipose tissue (WAT) beiging in response to cold exposure and maintains the mitochondrial integrity of brown adipose tissue (BAT). We found that genetic deletion of Gja1 (Cx43 gene) in cells that give rise to chondro-osteogenic and adipogenic precursors driven by the Dermo1/Twist2 promoter led to lower body adiposity and partial protection against the weight gain and metabolic syndrome induced by a high-fat diet (HFD) in both sexes. These protective effects were related to increased locomotion, fuel utilization, energy expenditure, nonshivering …

Circuit-Based Intervention Corrects Excessive Dentate Gyrus Output In The Fragile X Mouse Model, Pan-Yue Deng, Ajeet Kumar, Valeria Cavalli, Vitaly A Klyachko

2020-Current year OA Pubs

Abnormal cellular and circuit excitability is believed to drive many core phenotypes in fragile X syndrome (FXS). The dentate gyrus is a brain area performing critical computations essential for learning and memory. However, little is known about dentate circuit defects and their mechanisms in FXS. Understanding dentate circuit dysfunction in FXS has been complicated by the presence of two types of excitatory neurons, the granule cells and mossy cells. Here we report that loss of FMRP markedly decreased excitability of dentate mossy cells, a change opposite to all other known excitability defects in excitatory neurons in FXS. This mossy cell …

Predicting Proximal Tubule Failed Repair Drivers Through Regularized Regression Analysis Of Single Cell Multiomic Sequencing, Nicolas Ledru, Parker C Wilson, Yoshiharu Muto, Yasuhiro Yoshimura, Haojia Wu, Dian Li, Amish Asthana, Stefan G Tullius, Sushrut S Waikar, Giuseppe Orlando, Benjamin D Humphreys

2020-Current year OA Pubs

Renal proximal tubule epithelial cells have considerable intrinsic repair capacity following injury. However, a fraction of injured proximal tubule cells fails to undergo normal repair and assumes a proinflammatory and profibrotic phenotype that may promote fibrosis and chronic kidney disease. The healthy to failed repair change is marked by cell state-specific transcriptomic and epigenomic changes. Single nucleus joint RNA- and ATAC-seq sequencing offers an opportunity to study the gene regulatory networks underpinning these changes in order to identify key regulatory drivers. We develop a regularized regression approach to construct genome-wide parametric gene regulatory networks using multiomic datasets. We generate a …