Medical Specialties Commons^™

Targeting Il-11r/Ezh2 Signaling Axis As A Therapeutic Strategy For Osteosarcoma Lung Metastases, Eswaran Devarajan, R Eric Davis, Hannah C Beird, Wei-Lien Wang, V Behrana Jensen, Arumugam Jayakumar, Cheuk Hong Leung, Heather Y Lin, Chia-Chin Wu, Stephanie A Ihezie, Jen-Wei Tsai, P Andrew Futreal, Valerae O Lewis

Faculty, Staff and Student Publications

Lung metastases are the primary cause of death for osteosarcoma (OS) patients. We recently validated interleukin-11 receptor α (IL-11Rα) as a molecular target for the inhibition of OS lung metastases. Since there is no clinically approved antibody against this receptor, we sought to identify downstream targets that mediate the effects of IL-11Rα signaling. We used shRNA to deplete IL-11Rα from OS cells; as a complementary approach, we added IL-11 exogenously to OS cells. The resulting changes in gene expression identified EZH2 as a downstream candidate. This was confirmed by knockdown of IL-11Rα in OS cells, which led to increased expression …

Fate-Mapping And Functional Dissection Reveal Perilous Influence Of Type I Interferon Signaling In Mouse Brain Aging, Ethan R Roy, Sanming Li, Sepideh Saroukhani, Yanyu Wang, Wei Cao

Faculty, Staff and Student Publications

Background: Aging significantly elevates the risk of developing neurodegenerative diseases. Neuroinflammation is a universal hallmark of neurodegeneration as well as normal brain aging. Which branches of age-related neuroinflammation, and how they precondition the brain toward pathological progression, remain ill-understood. The presence of elevated type I interferon (IFN-I) has been documented in the aged brain, but its role in promoting degenerative processes, such as the loss of neurons in vulnerable regions, has not been studied in depth.

Methods: To comprehend the scope of IFN-I activity in the aging brain, we surveyed IFN-I-responsive reporter mice at multiple ages. We also examined 5- …

Neurogranin Modulates The Rate Of Association Between Calmodulin And Target Peptides, John A Putkey, Laurel Hoffman, Vladimir Berka, Xu Wang

Faculty, Staff and Student Publications

The best-known mode of action of calmodulin (CaM) is binding of Ca2+ to its N- and C-domains, followed by binding to target proteins. An underappreciated facet of this process is that CaM is typically bound to proteins at basal levels of free Ca2+, including the small, intrinsically disordered, neuronal IQ-motif proteins called PEP-19 and neurogranin (Ng). PEP-19 and Ng would not be effective competitive inhibitors of high-affinity Ca2+-dependent CaM targets at equilibrium because they bind to CaM with relatively low affinity, but they could influence the time course of CaM signaling by affecting the rate of association of CaM with …

Repeat Controlled Human Plasmodium Falciparum Infections Delay Bloodstream Patency And Reduce Symptoms, Patricia Ferrer, Andrea A Berry, Allison N Bucsan, Surendra K Prajapati, Karthik Krishnan, Michelle C Barbeau, David M Rickert, Sandra Mendoza Guerrero, Miho Usui, Yonas Abebe, Asha Patil, Sumana Chakravarty, Peter F Billingsley, Faith Pa'ahana-Brown, Kathy Strauss, Biraj Shrestha, Effie Nomicos, Gregory A Deye, B Kim Lee Sim, Stephen L Hoffman, Kim C Williamson, Kirsten E Lyke

Faculty, Staff and Student Publications

Resistance to clinical malaria takes years to develop even in hyperendemic regions and sterilizing immunity has rarely been observed. To evaluate the maturation of the host response against controlled repeat exposures to P. falciparum (Pf) NF54 strain-infected mosquitoes, we systematically monitored malaria-naïve participants through an initial exposure to uninfected mosquitoes and 4 subsequent homologous exposures to Pf-infected mosquitoes over 21 months (n = 8 males) (ClinicalTrials.gov# NCT03014258). The primary outcome was to determine whether protective immunity against parasite infection develops following repeat CHMI and the secondary outcomes were to track the clinical signs and symptoms of malaria and anti-Pf antibody …

Sod1 Is A Synthetic-Lethal Target In Ppm1d-Mutant Leukemia Cells, Linda Zhang, Joanne I Hsu, Etienne D Braekeleer, Chun-Wei Chen, Tajhal D Patel, Alejandra G Martell, Anna G Guzman, Katharina Wohlan, Sarah M Waldvogel, Hidetaka Uryu, Ayala Tovy, Elsa Callen, Rebecca L Murdaugh, Rosemary Richard, Sandra Jansen, Lisenka Vissers, Bert B A De Vries, Andre Nussenzweig, Shixia Huang, Cristian Coarfa, Jamie Anastas, Koichi Takahashi, George Vassiliou, Margaret A Goodell

Faculty, Staff and Students Publications

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our …

Sod1 Is A Synthetic-Lethal Target In Ppm1d-Mutant Leukemia Cells, Linda Zhang, Joanne I Hsu, Etienne D Braekeleer, Chun-Wei Chen, Tajhal D Patel, Alejandra G Martell, Anna G Guzman, Katharina Wohlan, Sarah M Waldvogel, Hidetaka Uryu, Ayala Tovy, Elsa Callen, Rebecca L Murdaugh, Rosemary Richard, Sandra Jansen, Lisenka Vissers, Bert B A De Vries, Andre Nussenzweig, Shixia Huang, Cristian Coarfa, Jamie Anastas, Koichi Takahashi, George Vassiliou, Margaret A Goodell

Faculty, Staff and Students Publications

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our …

Maldi Imaging Mass Spectrometry Visualizes The Distribution Of Antidepressant Duloxetine And Its Major Metabolites In Mouse Brain, Liver, Kidney, And Spleen Tissues, Saleh M Khalil, Xuan Qin, John M Hakenjos, Jian Wang, Zhaoyong Hu, Xinli Liu, Jin Wang, Mirjana Maletic-Savatic, Kevin R Mackenzie, Martin M Matzuk, Feng Li

Faculty, Staff and Student Publications

Imaging mass spectrometry (IMS) is a powerful tool for mapping the spatial distribution of unlabeled drugs and metabolites that may find application in assessing drug delivery, explaining drug efficacy, and identifying potential toxicity. This study focuses on determining the spatial distribution of the antidepressant duloxetine, which is widely prescribed despite common adverse effects (liver injury, constant headaches) whose mechanisms are not fully understood. We used high-resolution IMS with matrix-assisted laser desorption/ionization to examine the distribution of duloxetine and its major metabolites in four mouse organs where it may contribute to efficacy or toxicity: brain, liver, kidney, and spleen. In none …

The Ifitm5 Mutation In Osteogenesis Imperfecta Type V Is Associated With An Erk/Sox9-Dependent Osteoprogenitor Differentiation Defect, Ronit Marom, I-Wen Song, Emily C Busse, Megan E Washington, Ava S Berrier, Vittoria C Rossi, Laura Ortinau, Youngjae Jeong, Ming-Ming Jiang, Brian C Dawson, Mary Adeyeye, Carolina Leynes, Caressa D Lietman, Bridget M Stroup, Dominyka Batkovskyte, Mahim Jain, Yuqing Chen, Racel Cela, Alexis Castellon, Alyssa A Tran, Isabel Lorenzo, D Nicole Meyers, Shixia Huang, Alicia Turner, Vinitha Shenava, Maegen Wallace, Eric Orwoll, Dongsu Park, Catherine G Ambrose, Sandesh Cs Nagamani, Jason D Heaney, Brendan H Lee

Faculty, Staff and Students Publications

Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes, in addition to the bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in interferon-induced transmembrane protein 5 (IFITM5). Here, we generated a conditional Rosa26-knockin mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with …

Efficacy And Safety Of Esmethadone (Rel-1017) In Patients With Major Depressive Disorder And Inadequate Response To Standard Antidepressants: A Phase 3 Randomized Controlled Trial, Maurizio Fava, Stephen M Stahl, Luca Pani, Sara De Martin, Andrew J Cutler, Vladimir Maletic, Charles W Gorodetzky, Frank J Vocci, Frank L Sapienza, Thomas R Kosten, Cornelia Kröger, Paggard Champasa, Cedric O'Gorman, Clotilde Guidetti, Andrea Alimonti, Stefano Comai, Andrea Mattarei, Franco Folli, David Bushnell, Sergio Traversa, Charles E Inturrisi, Paolo L Manfredi, Marco Pappagallo

Faculty, Staff and Students Publications

No abstract provided.

Sting Agonist 8803 Reprograms The Immune Microenvironment And Increases Survival In Preclinical Models Of Glioblastoma, Hinda Najem, Spencer T Lea, Shashwat Tripathi, Lisa Hurley, Chao-Hsien Chen, Ivana William, Moloud Sooreshjani, Michelle Bowie, Genevieve Hartley, Corey Dussold, Sebastian Pacheco, Crismita Dmello, Catalina Lee-Chang, Kathleen Mccortney, Alicia Steffens, Jordain Walshon, Martina Ott, Jun Wei, Anantha Marisetty, Irina Balyasnikova, Roger Stupp, Rimas V Lukas, Jian Hu, Charles David James, Craig M Horbinski, Maciej S Lesniak, David M Ashley, Waldemar Priebe, Leonidas C Platanias, Michael A Curran, Amy B Heimberger

Faculty, Staff and Student Publications

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 …

Developmental Milestones And Daily Living Skills In Individuals With Angelman Syndrome, Anjali Sadhwani, Sonya Powers, Anne Wheeler, Hillary Miller, Sarah Nelson Potter, Sarika U Peters, Carlos A Bacino, Steven A Skinner, Logan K Wink, Craig A Erickson, Lynne M Bird, Wen-Hann Tan

Faculty, Staff and Students Publications

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder associated with severe global developmental delay. However, the ages at which different developmental skills are achieved in these individuals remain unclear. We seek to determine the probability and the age of acquisition of specific developmental milestones and daily living skills in individuals with AS across the different molecular subtypes, viz. class I deletion, class II deletion, uniparental disomy, imprinting defect, and UBE3A variants.

METHODS: Caregivers participating in a longitudinal multicenter Angelman Syndrome Natural History Study completed a questionnaire regarding the age at which their children achieved specific developmental milestones and daily living …

Improving Patient Retention Of Medical Information: Lessons From The Contact Dermatitis Clinic, Jennifer Li-Wang, Rajani Katta

Faculty, Staff and Students Publications

Medical communication skills are widely recognized as important, especially for situations in which providers must present complex and detailed information. Although much research focuses on how providers can improve their delivery of medical information, an equally important part of communication is supporting patient retention of the information. We present several methods to improve patient retention of medical information that we have found successful in an allergic contact dermatitis clinic. Some recommendations address information transfer (follow effective structure, teach to different learning styles, provide written instructions, employ the teach-back method). Other methods are effective, focusing on the patient's emotional, social, and …

Deepcg: A Cell Graph Model For Predicting Prognosis In Lung Adenocarcinoma, Baoyi Zhang, Chenyang Li, Jia Wu, Jianjun Zhang, Chao Cheng

Faculty, Staff and Student Publications

Lung cancer is the first leading cause of cancer-related death in the United States, with lung adenocarcinoma as the major subtype accounting for 40% of all cases. To improve patient survival, image-based prognostic models were developed due to the ready availability of pathological images at diagnosis. However, the application of these models is hampered by two main challenges: the lack of publicly available image datasets with high-quality survival information and the poor interpretability of conventional convolutional neural network models. Here, we integrated matched transcriptomic and H&E staining data from TCGA (The Cancer Genome Atlas) to develop an image-based prognostic model, …

Reduced Sensitivity To Future Consequences Underlies Gambling Decision In Cerebellar Ataxia, Ruo-Yah Lai, Eli Levy, Christian J Amlang, Ihika Rampalli, Rory Mahabir, Ming-Kai Pan, Chi-Ying R Lin, Sheng-Han Kuo

Faculty, Staff and Students Publications

Introduction: Previous research has identified that people with cerebellar ataxia (CA) showed impaired reward-related decision-making in the Iowa Gambling Task (IGT). To investigate the mechanisms underlying this impairment, we examined CA participants' combination of performance in the IGT, which predominantly tests reward seeking, and the modified IGT (mIGT), which mainly assesses punishment avoidance.

Methods: Fifty participants with CA and one hundred controls completed the IGT and mIGT. Task performance in each of the five twenty-trial blocks was compared between groups and the learning rates were assessed with simple linear regressions. Each participant's IGT score and mIGT score were compared.

Results: …

Spatial Modulation Of Primate Inferotemporal Responses By Eye Position, Kievershen Nargan, Joel N Glasgow, Sajid Nadeem, Threnesan Naidoo, Gordon Wells, Robert L Hunter, Anneka Hutton, Kapongo Lumamba, Mpumelelo Msimang, Paul V Benson, Adrie J C Steyn

Faculty, Staff and Student Publications

BACKGROUND: The ability to detect evidence of Mycobacterium tuberculosis (Mtb) infection within human tissues is critical to the study of Mtb physiology, tropism, and spatial distribution within TB lesions. The capacity of the widely-used Ziehl-Neelsen (ZN) staining method for identifying Mtb acid-fast bacilli (AFB) in tissue is highly variable, which can limit detection of Mtb bacilli for research and diagnostic purposes. Here, we sought to circumvent these limitations via detection of Mtb mRNA and secreted antigens in human tuberculous tissue.

METHODS: We adapted RNAscope, an RNA in situ hybridisation (RISH) technique, to detect Mtb mRNA in ante- and postmortem human …

Association Between Helicobacter Pylori Infection, Mismatch Repair, Her2 And Tumor-Infiltrating Lymphocytes In Gastric Cancer, Carlos A Castaneda, Miluska Castillo, Luis A Bernabe, Joselyn Sanchez, Matteo Fassan, Katherine Tello, Ignacio Ivan Wistuba, Ivan Chavez Passiuri, Eloy Ruiz, Juvenal Sanchez, Fernando Barreda, Daniel Valdivia, Yaqueline Bazan, Milagros Abad-Licham, Claudio Mengoa, Hugo Fuentes, Paola Montenegro, Ebert Poquioma, Raul Alatrista, Claudio J Flores, Luis Taxa

Faculty, Staff and Student Publications

BACKGROUND: The influence of Helicobacter-pylori (H. pylori) infection and the characteristics of gastric cancer (GC) on tumor-infiltrating lymphocyte (TIL) levels has not been extensively studied. Analysis of infiltrating-immune-cell subtypes as well as survival is necessary to obtain comprehensive information.

AIM: To determine the rates of deficient mismatch-repair (dMMR), HER2-status and H. pylori infection and their association with TIL levels in GC.

METHODS: Samples from 503 resected GC tumors were included and TIL levels were evaluated following the international-TILs-working-group recommendations with assessment of the intratumoral (IT), stromal (ST) and invasive-border (IB) compartments. The density of CD3, CD8 and CD163 …

In-Silico Analysis Of Tmem2 As A Pancreatic Adenocarcinoma And Cancer-Associated Fibroblast Biomarker, And Functional Characterization Of Nsc777201, For Targeted Drug Development, Prateeti Srivastava, Vijesh Kumar Yadav, Tzu-Hao Chang, Emily Chia-Yu Su, Bashir Lawal, Alexander Th Wu, Hsu-Shan Huang

Faculty, Staff and Student Publications

Pancreatic adenocarcinoma (PAAD), known as one of the deadliest cancers, is characterized by a complex tumor microenvironment, primarily comprised of cancer-associated fibroblasts (CAFs) in the extracellular matrix. These CAFs significantly alter the matrix by interacting with hyaluronic acid (HA) and the enzyme hyaluronidase, which degrades HA - an essential process for cancer progression and spread. Despite the critical role of this interaction, the specific functions of CAFs and hyaluronidase in PAAD development are not fully understood. Our study investigates this interaction and assesses NSC777201, a new anti-cancer compound targeting hyaluronidase. This research utilized computational methods to analyze gene expression data …

Variance-Components Tests For Genetic Association With Multiple Interval-Censored Outcomes, Jaihee Choi, Zhichao Xu, Ryan Sun

Faculty, Staff and Student Publications

Massive genetic compendiums such as the UK Biobank have become an invaluable resource for identifying genetic variants that are associated with complex diseases. Due to the difficulties of massive data collection, a common practice of these compendiums is to collect interval-censored data. One challenge in analyzing such data is the lack of methodology available for genetic association studies with interval-censored data. Genetic effects are difficult to detect because of their rare and weak nature, and often the time-to-event outcomes are transformed to binary phenotypes for access to more powerful signal detection approaches. However transforming the data to binary outcomes can …

Modificaciones Realizadas En Cirugías Y En Cuidados De Pacientes En Ecuador, Addison Wolfe

NEXUS: The Liberty Journal of Interdisciplinary Studies

No abstract provided.

Cardiac Magnetic Resonance In The Assessment Of The Anomalous Right Coronary Artery Originating From The Left Sinus Of Valsalva, Alberto Cipriani, Mauro Lo Rito, Silvia Pica, Monica De Gaspari, Ilaria Rigato, Martina Perazzolo Marra, Giorgio De Conti, Simone Corradin, Raffaella Motta, Valeria Pergola, Francesco Secchi, Massimo Lombardi, Barbara Bauce, Alessandro Zorzi, Gaetano Thiene, Cristina Basso, Silvana Molossi, Massimo Antonio Padalino, Domenico Corrado

Faculty, Staff and Students Publications

No abstract provided.

Contrast-Enhanced Magnetic Resonance Imaging Based T1 Mapping And Extracellular Volume Fractions Are Associated With Peripheral Artery Disease, Asem I Fitian, Michael C Shieh, Olga A Gimnich, Tatiana Belousova, Addison A Taylor, Christie M Ballantyne, Jean Bismuth, Dipan J Shah, Gerd Brunner

Faculty, Staff and Students Publications

BACKGROUND: Extracellular volume fraction (ECV), measured with contrast-enhanced magnetic resonance imaging (CE-MRI), has been utilized to study myocardial fibrosis, but its role in peripheral artery disease (PAD) remains unknown. We hypothesized that T1 mapping and ECV differ between PAD patients and matched controls.

METHODS AND RESULTS: A total of 37 individuals (18 PAD patients and 19 matched controls) underwent 3.0T CE-MRI. Skeletal calf muscle T1 mapping was performed before and after gadolinium contrast with a motion-corrected modified look-locker inversion recovery (MOLLI) pulse sequence. T1 values were calculated with a three-parameter Levenberg-Marquardt curve fitting algorithm. ECV and T1 maps were quantified …

Assessing The Impact Of Storage Conditions On Rna From Human Saliva And Its Application To The Identification Of Mrna Biomarkers For Asthma, Poorna Manasa Bhamidimarri, David Fuentes, Laila Salameh, Bassam Mahboub, Rifat Hamoudi

Faculty, Staff and Student Publications

Introduction: Human saliva was used to develop non-invasive liquid biopsy biomarkers to establish saliva as an alternate to blood and plasma in translational research. The present study focused on understanding the impact of sample storage conditions on the extraction of RNA from saliva and the RNA yield, to be applied in clinical diagnosis. In this study, genes related to asthma were used to test the method developed.

Methods: Salivary RNA was extracted from three subjects using the Qiazol® based method and quantified by both spectrophotometric (NanoDrop) and fluorometric (Qubit®) methods. RNA integrity was measured using a bioanalyzer. Quantitative PCR was …

Scanless Two-Photon Voltage Imaging, Ruth R Sims, Imane Bendifallah, Christiane Grimm, Aysha S Mohamed Lafirdeen, Soledad Domínguez, Chung Yuen Chan, Xiaoyu Lu, Benoît C Forget, François St-Pierre, Eirini Papagiakoumou, Valentina Emiliani

Faculty, Staff and Students Publications

Two-photon voltage imaging has long been heralded as a transformative approach capable of answering many long-standing questions in modern neuroscience. However, exploiting its full potential requires the development of novel imaging approaches well suited to the photophysical properties of genetically encoded voltage indicators. We demonstrate that parallel excitation approaches developed for scanless two-photon photostimulation enable high-SNR two-photon voltage imaging. We use whole-cell patch-clamp electrophysiology to perform a thorough characterization of scanless two-photon voltage imaging using three parallel illumination approaches and lasers with different repetition rates and wavelengths. We demonstrate voltage recordings of high-frequency spike trains and sub-threshold depolarizations from neurons …

Viral And Host Factors Are Associated With Mortality In Hospitalized Patients With Covid-19, Neil R Aggarwal, Jacquie Nordwall, Dominique L Braun, Lucy Chung, Jordan Coslet, Tatyana Der, Nnakelu Eriobu, Adit A Ginde, Awori J Hayanga, Helene Highbarger, Mark Holodniy, Juan P Horcajada, Mamta K Jain, Kami Kim, Sylvain Laverdure, Jens Lundgren, Ven Natarajan, Hien H Nguyen, Sarah L Pett, Andrew Phillips, Garyphallia Poulakou, David A Price, Philip Robinson, Angela J Rogers, Uriel Sandkovsky, Katy Shaw-Saliba, Jeffrey M Sturek, Barbara W Trautner, Michael Waters, Cavan Reilly

Faculty, Staff and Students Publications

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials.

METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid …

Persistent Gram-Negative Bloodstream Infection Increases The Risk Of Recurrent Bloodstream Infection With The Same Species, Paa Kwesi Ankrah, Andrew Bock, Felicia Ruffin, Blake M Hanson, Cesar A Arias, Stacey A Maskarinec, Joshua Parsons, Vance G Fowler, Joshua T Thaden

Faculty, Staff and Student Publications

The association between persistent gram-negative bloodstream infection (GN-BSI), or ongoing positive cultures, and recurrent GN-BSI has not been investigated. Among 992 adults, persistent GN-BSI was associated with increased recurrent GN-BSI with the same bacterial species and strain (6% vs 2%; P = .04). Persistent GN-BSI may be a marker of complicated infection.

Immunotherapy In Locally Advanced Cervical Cancer: Integrating Keynote-A18 Into Management Strategies, Jeffrey A How, Amir A Jazaeri

Faculty, Staff and Student Publications

In locally advanced cervical cancer (LACC), the benefit of PD-1 blockade was unknown. In KEYNOTE-A18, Lorusso et al.1 compared the efficacy and safety of adding pembrolizumab to chemoradiation in LACC and demonstrated favorable outcomes. Given multiple approved indications of pembrolizumab in cervical cancer, strategies for optimal integration into management will be needed to maximize overall survival.

Development Of Biochemical And Cellular Probes To Study Ripk1 Target Engagement, Xin Yu, Hanfeng Lin, Feng Li, Jin Wang, Dong Lu

Faculty, Staff and Students Publications

RIPK1 inhibitors have emerged as promising candidates for treating diverse diseases, including inflammatory diseases, autoimmune disorders, Alzheimer’s disease, and cancer. However, the previously reported binding assays have limited sensitivity and stability, impeding high-throughput screening and robust characterization of the RIPK1 inhibitors. To address this challenge, we introduced two probes, T2-BDP-FL and T3-BDP-FL, derived from distinct RIPK1 inhibitors with different binding modes to establish time-resolved fluorescence resonance energy transfer (TR-FRET) displacement assays. Employing our TR-FRET displacement assays, we quantified the biochemical binding affinities of a series of RIPK1 inhibitors with diverse structural and binding modes for human RIPK1. Consistent results were …

Frequency Of Pharmacogenomic Variation And Medication Exposures Among All Of Us Participants, Andrew Haddad, Aparna Radhakrishnan, Sean Mcgee, Joshua D Smith, Jason H Karnes, Eric Venner, Marsha M Wheeler, Karynne Patterson, Kimberly Walker, Divya Kalra, Sara E Kalla, Qiaoyan Wang, Richard A Gibbs, Gail P Jarvik, Janeth Sanchez, Anjene Musick, Andrea H Ramirez, Joshua C Denny, Philip E Empey

Faculty, Staff and Students Publications

Pharmacogenomics promises improved outcomes through individualized prescribing. However, the lack of diversity in studies impedes clinical translation and equitable application of precision medicine. We evaluated the frequencies of PGx variants, predicted phenotypes, and medication exposures using whole genome sequencing and EHR data from nearly 100k diverse All of Us Research Program participants. We report 100% of participants carried at least one pharmacogenomics variant and nearly all (99.13%) had a predicted phenotype with prescribing recommendations. Clinical impact was high with over 20% having both an actionable phenotype and a prior exposure to an impacted medication with pharmacogenomic prescribing guidance. Importantly, we …

Protocol For Improving Care By Faster Risk-Stratification Through Use Of High Sensitivity Point-Of-Care Troponin In Patients Presenting With Possible Acute Coronary Syndrome In The Emergency Department (Icare-Faster): A Stepped-Wedge Cluster Randomised Quality Improvement Initiative, John W Pickering, Gerard Devlin, Richard Body, Sally Aldous, Allan S Jaffe, Fred S Apple, Nicholas Mills, Richard W Troughton, Peter Kavsak, W Frank Peacock, Louise Cullen, Sarah J Lord, Christian Müller, Laura Joyce, Chris Frampton, Cameron James Lacey, Arthur M Richards, Suzanne Pitama, Martin Than

Faculty, Staff and Students Publications

Introduction: Clinical assessment in emergency departments (EDs) for possible acute myocardial infarction (AMI) requires at least one cardiac troponin (cTn) blood test. The turn-around time from blood draw to posting results in the clinical portal for central laboratory analysers is ~1-2 hours. New generation, high-sensitivity, point-of-care cardiac troponin I (POC-cTnI) assays use whole blood on a bedside (or near bedside) analyser that provides a rapid (8 min) result. This may expedite clinical decision-making and reduce length of stay. Our purpose is to determine if utilisation of a POC-cTnI testing reduces ED length of stay. We also aim to establish an …

Chagas Disease In Immunocompromised Patients, Eva H Clark, Louisa A Messenger, Jeffrey D Whitman, Caryn Bern

Faculty, Staff and Students Publications

As Chagas disease remains prevalent in the Americas, it is important that healthcare professionals and researchers are aware of the screening, diagnosis, monitoring, and treatment recommendations for the populations of patients they care for and study. Management of Trypanosoma cruzi infection in immunocompromised hosts is challenging, particularly because, regardless of antitrypanosomal treatment status, immunocompromised patients with Chagas disease are at risk for T. cruzi reactivation, which can be lethal. Evidence-based practices to prevent and manage T. cruzi reactivation vary depending on the type of immunocompromise. Here, we review available data describing Chagas disease epidemiology, testing, and management practices for various …