Digital Commons Network^™

Human Herpesvirus 8 Infects And Replicates In Langerhans Cells And Interstitial Dermal Dendritic Cells And Impairs Their Function., Giovanna Rappocciolo, Mariel Jais, Paolo A Piazza, Diana C Delucia, Frank J Jenkins, Charles R Rinaldo

Microbiology, Immunology, and Tropical Medicine Faculty Publications

The predominant types of dendritic cells (DC) in the skin and mucosa are Langerhans cells (LC) and interstitial dermal DC (iDDC). LC and iDDC process cutaneous antigens and migrate out of the skin and mucosa to the draining lymph nodes to present antigens to T and B cells. Because of the strategic location of LC and iDDC and the ability of these cells to capture and process pathogens, we hypothesized that they could be infected with human herpesvirus 8 (HHV-8) (Kaposi's sarcoma [KS]-associated herpesvirus) and have an important role in the development of KS. We have previously shown that HHV-8 …

Timing Of Pd-1 Blockade Is Critical To Effective Combination Immunotherapy With Anti-Ox40., David J Messenheimer, Shawn M. Jensen, Michael E Afentoulis, Keith W Wegman, Zipei Feng, David J Friedman, Michael J. Gough, Walter Urba, Bernard A Fox

Articles, Abstracts, and Reports

Purpose: Antibodies specific for inhibitory checkpoints PD-1 and CTLA-4 have shown impressive results against solid tumors. This has fueled interest in novel immunotherapy combinations to affect patients who remain refractory to checkpoint blockade monotherapy. However, how to optimally combine checkpoint blockade with agents targeting T-cell costimulatory receptors, such as OX40, remains a critical question.Experimental Design: We utilized an anti-PD-1-refractory, orthotopically transplanted MMTV-PyMT mammary cancer model to investigate the antitumor effect of an agonist anti-OX40 antibody combined with anti-PD-1. As PD-1 naturally aids in immune contraction after T-cell activation, we treated mice with concurrent combination treatment versus sequentially administering anti-OX40 …

No Difference In Myosin Kinetics And Spatial Distribution Of The Lever Arm In The Left And Right Ventricles Of Human Hearts, Divya Duggal, S. Requena, Janhavi Nagwekar, Sangram Raut, Ryan Rich, Hriday Das, Vipul Patel, Ignacy Gryczynski, Rafal Fudala, Zygmunt Gryczynski, Cheavar Blair, Kenneth S. Campbell, Julian Borejdo

Physiology Faculty Publications

The systemic circulation offers larger resistance to the blood flow than the pulmonary system. Consequently, the left ventricle (LV) must pump blood with more force than the right ventricle (RV). The question arises whether the stronger pumping action of the LV is due to a more efficient action of left ventricular myosin, or whether it is due to the morphological differences between ventricles. Such a question cannot be answered by studying the entire ventricles or myocytes because any observed differences would be wiped out by averaging the information obtained from trillions of myosin molecules present in a ventricle or myocyte. …

#Ilooklikeasurgeon: Embracing Diversity To Improve Patient Outcomes., Heather Logghe, Christian Jones, Alison Mccoubrey, Edward Fitzgerald

Department of Surgery Faculty Papers

No abstract provided.

Adversity And Academic Performance Among Adolescent Youth: A Community-Based Participatory Research Study, Sukhdip Purewal Boparai, Tiffani Marie, Eduardo Aguayo, Jordan Brooks, Estefany Juarez, Sheana Soriano, Alasia Waters, Jaquez Donaldson, Joseph Reagans, Gracee Anguiano, Allison Ipsen

Journal of Adolescent and Family Health

Researchers and youth stakeholders devised a survey on 27 adversities based on youth expertise, clinical practice, and adversity literature. The aim of the study was to understand the prevalence of individual and cumulative adversities, and association of adversities to age, gender, race/ethnicity and academic performance among a community sample of urban high school students. All participants experienced two or more adversities and experienced greater overall adversity than youth in population-based studies. Youth-proposed stressors were among the most prevalent, and females, older youth, and African American youth reported disproportionately greater number of adversities. Specific types of adversities were endorsed differentially based …

Delayed Spinal Cord Infarction Following Anterior Cervical Surgical Decompression, Muhammad Faheem Khan, Rashid Jooma, Fauzan Alam Hashmi, Muhammad Faraz Raghib

Section of Neurosurgery

Anterior cervical discectomy and fusion (ACDF) for cord compression is a safe and effective procedure with good outcomes. However, worsening of myelopathy is the most feared adverse event of the surgery. We report the case of a 36-year-old male patient who presented with an acute non-traumatic C5-6 cervical disc herniation causing incomplete quadriparesis. He underwent an uncomplicated ACDF at C5-6, and after an initial period of improvement, he developed a delayed onset of an anterior cord syndrome on day 3, without any discerning cause. We have reviewed similar cases reported in the literature and believe that our patient's postsurgical course …

Role Of Microglial Amylin Receptors In Mediating Beta Amyloid (Aβ)-Induced Inflammation, Wen Fu, Vlatka Vukojevic, Aarti Patel, Rania Soudy, David Mactavish, David Westaway, Kamaljit Kaur, Valeri Goncharuk, Jack Jhamandas

Pharmacy Faculty Articles and Research

Background: Neuroinflammation in the brain consequent to activation of microglia is viewed as an important component of Alzheimer’s disease (AD) pathology. Amyloid beta (Aβ) protein is known to activate microglia and unleash an inflammatory cascade that eventually results in neuronal dysfunction and death. In this study, we sought to identify the presence of amylin receptors on human fetal and murine microglia and determine whether Aβ activation of the inflammasome complex and subsequent release of cytokines is mediated through these receptors.

Methods: The presence of dimeric components of the amylin receptor (calcitonin receptor and receptor activity modifying protein 3) …

Counseling Preferences Of Young Adults With Cancer., Jessica Taylor, Susan Kashubeck-West

Education Sciences and Professional Programs Faculty Works

This study examined preferences for counseling topics to discuss in individual, group, and family counseling among young adults with cancer, as well as their ranked preferences for attending individual, group, and family counseling. A sample of 320 young adults with cancer (18–39 years old) completed an online survey containing items relevant to young adults’ psychosocial needs. Participants rated anxiety, finances, sad feelings, sexual and intimacy concerns, and stress management as most helpful for individual counseling; finding social support and getting information about one’s medical situation as most helpful for group counseling; and no topics as most helpful for family counseling. …

Virus-Specific T Cells For The Immunocompromised Patient, A. Houghtelin, Catherine M. Bollard

Pediatrics Faculty Publications

While progress has been made in the treatment of both hematologic cancers and solid tumors, chemorefractory or relapsed disease often portends a dismal prognosis, and salvage chemotherapy or radiation expose patients to intolerable toxicities and may not be effective. Hematopoietic stem cell transplant offers the promise of cure for many patients, and while mismatched, unrelated or haploidentical donors are increasingly available, the recipients are at higher risk of severe immunosuppression and immune dysregulation due to graft versus host disease. Viral infections remain a primary cause of severe morbidity and mortality in this patient population. Again, many therapeutic options for viral …

Development Of A Unifying Target And Consensus Indicators For Global Surgical Systems Strengthening: Proposed By The Global Alliance For Surgery, Obstetric, Trauma, And Anaesthesia Care (The G4 Alliance), Adil H. Haider, John W. Scott, Colin D. Gause, Mira Meheš, Grace Hsiung, Albulena Prelvukaj, Dana Yanocha, Lauren M. Baumann, Faheem Ahmed, Asad Latif

Section of General Surgery

After decades on the margins of primary health care, surgical and anaesthesia care is gaining increasing priority within the global development arena. The 2015 publications of the Disease Control Priorities third edition on Essential Surgery and the Lancet Commission on Global Surgery created a compelling evidenced-based argument for the fundamental role of surgery and anaesthesia within cost-effective health systems strengthening global strategy. The launch of the Global Alliance for Surgical, Obstetric, Trauma, and Anaesthesia Care in 2015 has further coordinated efforts to build priority for surgical care and anaesthesia. These combined efforts culminated in the approval of a World Health …

Secondhand Smoke Exposure And Preclinical Markers Of Cardiovascular Risk In Toddlers, Judith A Groner, Hong Huang, Mandar S. Joshi, Nicholas Eastman, Lisa Nicholson, John Anthony Bauer

Pediatrics Faculty Publications

Objective: Links between secondhand smoke (SHS) exposure and cardiovascular disease in adults are well established but seldom reported during childhood. Although rates of smoking have decreased, young children from low-income backgrounds remain likely to be exposed to SHS. The purpose of this study was to investigate relationships between SHS exposure in young children and several preclinical markers of cardiovascular risk that have been established as relevant to adult populations.

Methods: 139 children, 2–5 years of age, were enrolled in a cross-sectional study. SHS exposure was objectively determined by hair nicotine level; a comprehensive panel of clinical markers (AM blood pressure, …

Report Of The Ishlt Working Group On Primary Lung Graft Dysfunction Part Iii: Mechanisms: A 2016 Consensus Group Statement Of The International Society For Heart And Lung Transplantation, Andrew E. Gelman, Andrew J. Fisher, Howard J. Huang, Maher A. Baz, Ciara M. Shaver, Thomas M. Egan, Micheal S. Mulligan

Surgery Faculty Publications

No abstract provided.

Acute Treatment With Doxorubicin Affects Glutamate Neurotransmission In The Mouse Frontal Cortex And Hippocampus, Theresa Currier Thomas, Joshua A. Beitchman, Francois Pomerleau, Teresa Noel, Paiboon Jungsuwadee, D. Allan Butterfield, Daret K. St. Clair, Mary Vore, Greg A. Gerhardt

Spinal Cord and Brain Injury Research Center Faculty Publications

Doxorubicin (DOX) is a potent chemotherapeutic agent known to cause acute and long-term cognitive impairments in cancer patients. Cognitive function is presumed to be primarily mediated by neuronal circuitry in the frontal cortex (FC) and hippocampus, where glutamate is the primary excitatory neurotransmitter. Mice treated with DOX (25 mg/kg i.p.) were subjected to in vivo recordings under urethane anesthesia at 24h post-DOX injection or 5 consecutive days of cognitive testing (Morris Water Maze; MWM). Using novel glutamate-selective microelectrode arrays, amperometric recordings measured parameters of extracellular glutamate clearance and potassium-evoked release of glutamate within the medial FC and dentate gyrus (DG) …

The Write Stuff - Autumn 2017 (Vol. 14, No. 4), Research Medical Library

Write Stuff 2017

• ICMJE member journals to begin requiring data sharing statements
• Online tools for researchers
• Changes to NIH forms for studies involving human subjects
• Unusual terms used in scientific writing and publishing: Text recycling

The Dual Role Of Group V Secretory Phospholipase A2 In Pancreatic Β-Cells, Preetha Shridas, Victoria P. Noffsinger, Andrea C. Trumbauer, Nancy R. Webb

Saha Cardiovascular Research Center Faculty Publications

Purpose

Group X (GX) and group V (GV) secretory phospholipase A₂ (sPLA₂) potently release arachidonic acid (AA) from the plasma membrane of intact cells. We previously demonstrated that GX sPLA₂ negatively regulates glucose-stimulated insulin secretion (GSIS) by a prostaglandin E2 (PGE2)-dependent mechanism. In this study we investigated whether GV sPLA₂ similarly regulates GSIS.

Methods

GSIS and pancreatic islet-size were assessed in wild-type (WT) and GV sPLA₂-knock out (GV KO) mice. GSIS was also assessed ex vivo in isolated islets and in vitro using MIN6 pancreatic beta cell lines with or without GV sPLA …

Community Perception Of The Hiv Vaccine In Western Kenya: Acceptability, Potential Behavior Changes, And Views On Compulsory Vaccination, Deborah Keen

Independent Study Project (ISP) Collection

Human Immunodeficiency Virus (HIV) suppresses the immune system by attacking T cells, leading to the development of acquired immunodeficiency syndrome (AIDS). HIV affects over 30 million people around the world and 1.6 million people in Kenya. On August 18, 1987, the FDA sanctioned the first human testing of a candidate vaccine for HIV. Currently, multiple HIV vaccines—projected to be on the market in five to ten years—are being tested for efficacy and safety. The goal of this study was to explore opinions related to the HIV vaccine so that there is a guide for future policy development in Western Kenya. …

A Cardiopulmonary Bypass Based Blood Management Strategy In Adult Cardiac Surgery, A Budak, Kevin Mccusker, S Gunaydin

NYMC Faculty Publications

BACKGROUND: Despite the recent introduction of a number of technical and pharmacologic blood conservation measures, bleeding and allogeneic transfusion remain persistent problems in open-heart surgical procedures. Efforts should be made to decrease or completely avoid transfusions to avoid these negative reactions. METHODS: Our coronary artery bypass grafting database was reviewed retrospectively and a total of 243 patients who underwent cardiac surgery with cardiopulmonary bypass (CPB) were studied in a 12-month period (January-December 2016) after the implementation of the new program, and compared with 275 patients of the previous 12-month period.All the staff involved in the care of the patients were …

Development And Validation Of A Hybrid Virtual/Physical Nuss Procedure Surgical Trainer, Mohammad F. Obeid

Computational Modeling & Simulation Engineering Theses & Dissertations

With continuous advancements and adoption of minimally invasive surgery, proficiency with nontrivial surgical skills involved is becoming a greater concern. Consequently, the use of surgical simulation has been increasingly embraced by many for training and skill transfer purposes. Some systems utilize haptic feedback within a high-fidelity anatomically-correct virtual environment whereas others use manikins, synthetic components, or box trainers to mimic primary components of a corresponding procedure.

Surgical simulation development for some minimally invasive procedures is still, however, suboptimal or otherwise embryonic. This is true for the Nuss procedure, which is a minimally invasive surgery for correcting pectus excavatum (PE) – …

Nucleotide-Dependent Preferential Localization Of Ras In Model Membranes With Lipid Raft Nanodomains, Anna Shishina

Dissertations (1934 -)

Membrane proteins constitute a third of all proteins in the cell and more than 50% of drug targets. However, the analysis of membrane proteins has many challenges owing to their partially hydrophobic surfaces, flexibility and lack of stability. One example of an essential membrane protein is Ras superfamily. Ras is a small monomeric GTPase involved in regulation of cell growth, proliferation and differentiation. Therefore, Ras and its effectors are among the most important targets for cancer therapy. A detailed knowledge of the processes occurring during signal propagation via Ras might help to elucidate the mechanisms of the involved signal cascades. …

Efficacy Of Daclizumab Beta Versus Intramuscular Interferon Beta-1a On Disability Progression Across Patient Demographic And Disease Activity Subgroups In Decide., Stanley Cohan, Ludwig Kappos, Gavin Giovannoni, Heinz Wiendl, Krzysztof Selmaj, Eva Kubala Havrdová, John Rose, Steven Greenberg, Glenn Phillips, Wei Ma, Ping Wang, Gabriel Lima, Guido Sabatella

Articles, Abstracts, and Reports

BACKGROUND: Demonstration of clinical benefits on disability progression measures is an important attribute of effective multiple sclerosis (MS) treatments.

OBJECTIVE: Examine efficacy of daclizumab beta versus intramuscular (IM) interferon beta-1a on measures of disability progression in patient subgroups from DECIDE.

METHODS: Twenty-four-week confirmed disability progression (CDP), 24-week sustained worsening on a modified Multiple Sclerosis Functional Composite (MSFCS) where 3-Second Paced Auditory Serial Addition Test was replaced by Symbol Digit Modalities Test, and proportion of patients with clinically meaningful worsening in 29-Item Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS) score from baseline to week 96 were examined in the …

An Investigation Of Human Beta-Defensins And Cathelicidin Expression In Patients With Pterygium., Remzi Karadag, Nurettin Bayram, Serpil Oguztuzun, Huseyin Bayramlar, Busra Bozer, Gulcin Simsek, Christopher J Rapuano

Wills Eye Hospital Papers

PURPOSE: To investigate human beta-defensins (HBDs) and cathelicidin LL-37 (LL-37) expressions in patients with pterygium.

METHODS: In this retrospective consecutive case series, 26 pterygium specimens and 15 normal conjunctival specimens of 15 control subjects were in vestigated. Expressions of HBD-1, HBD-2, HBD-3, and LL-37 were assessed using immuno histochemical staining. A brown color in the cytoplasm and/or nuclei of epithelial cells indicated positive staining for HBDs and LL-37. For each antibody, the intensity of the reaction (negative [-], weak [1+], moderate [2+], or strong [3+]) was determined to describe the immunoreactions.

RESULTS: The median age was 52 years in both …

High Trait Shame Undermines The Protective Effects Of Prevalence Knowledge On State Shame Following Hpv/Cin Diagnosis In Women, Sarah Mcqueary Flynn, Tory A. Eisenlohr-Moul, Suzanne C. Segerstrom, Christen T. Logue, Jamie L. Studts

Psychology Faculty Publications

Human papillomavirus (HPV), and the related, cervical intraepithelial neoplasia (CIN), are common yet poorly understood physical conditions. The diagnosis of HPV often elicits shame and guilt, which in turn may undermine psychological and physical health. The current study compared shame and guilt responses to diagnosis among two groups: women diagnosed with HPV/CIN and women diagnosed with Epstein–Barr Virus (EBV/IM). Eighty women recently diagnosed with HPV/CIN or EBV/IM completed measures of shame- and guilt-proneness, shame and guilt following diagnosis, and disease knowledge including prevalence estimates (HPV and EBV, respectively). HPV/CIN (vs. EBV/IM) predicted more diagnosis-related shame and guilt. Estimates of high …

Angptl4 Promotes The Progression Of Cutaneous Melanoma To Brain Metastasis., Sivan Izraely, Shlomit Ben-Menachem, Orit Sagi-Assif, Tsipi Meshel, Diego M Marzese, Shuichi Ohe, Inna Zubrilov, Metsada Pasmanik-Chor, Dave S B Hoon, Isaac P Witz

Articles, Abstracts, and Reports

In an ongoing effort to identify molecular determinants regulating melanoma brain metastasis, we previously identified Angiopoietin-like 4 (ANGPTL4) as a component of the molecular signature of such metastases. The aim of this study was to determine the functional significance of ANGPTL4 in the shaping of melanoma malignancy phenotype, especially in the establishment of brain metastasis. We confirmed that ANGPTL4 expression is significantly higher in cells metastasizing to the brain than in cells from the cutaneous (local) tumor from the same melanoma in a nude mouse xenograft model, and also in paired clinical specimens of melanoma metastases than in primary melanomas …

The Influence Of A Kdt501, A Novel Isohumulone, On Adipocyte Function In Humans, Brian S. Finlin, Beibei Zhu, Bernard P. Kok, Cristina Godio, Philip M. Westgate, Neile Grayson, Robert Sims, Jeffrey S. Bland, Enrique Saez, Philip A. Kern

Internal Medicine Faculty Publications

Objective: In a phase II clinical trial in nine obese, insulin-resistant humans, we observed that treatment with KDT501, a novel isohumulone drug, increased total and high-molecular weight (HMW) adiponectin in plasma. The objective was to determine whether KDT501 increased adiponectin secretion from subcutaneous white adipose tissue (SC WAT) and the underlying mechanism(s).

Methods: Nine obese participants with either prediabetes or with normal glucose tolerance plus three features of metabolic syndrome were part of the study. SC WAT biopsies were performed before and after 28 days of KDT501 treatment in a clinical research setting. In addition, a cold stimulus was used …

Patient Centered Family Planning Care, Lauren Thaxton

Biomedical Sciences ETDs

The Institute of Medicine defines six important domains of health care quality: safety, efficacy, timeliness, efficiency, equitable delivery and patient-centeredness. Quality family planning care aims to provide individuals with the tools needed to engage in healthy and satisfying sex lives while planning and spacing pregnancies to achieve desired family size. The field of family planning strongly relies on the domain of patient-centeredness as individual values and preferences guide clinical care. Yet large gaps in knowledge exist in understanding how to improve patients’ clinical experience. This hybrid thesis posits avenues for improving the quality and patient-centeredness of clinical care.

Quality care …

Chronic Hypobaric Hypoxia Modulates Primary Cilia Differently In Adult And Fetal Ovine Kidneys, Kiumars Shamloo, Juan Chen, Jasmine Sardar, Rinzhin T. Sherpa, Rajasekharreddy Pala, Kimberly F. Atkinson, William J. Pearce, Lubo Zhang, Surya M. Nauli

Pharmacy Faculty Articles and Research

Hypoxic environments at high altitude have significant effects on kidney injury. Following injury, renal primary cilia display length alterations. Primary cilia are mechanosensory organelles that regulate tubular architecture. The effect of hypoxia on cilia length is still controversial in cultured cells, and no corresponding in vivo study exists. Using fetal and adult sheep, we here study the effect of chronic hypobaric hypoxia on the renal injury, intracellular calcium signaling and the relationship between cilia length and cilia function. Our results show that although long-term hypoxia induces renal fibrosis in both fetal and adult kidneys, fetal kidneys are more susceptible to …

Predictors Of Responses To Immune Checkpoint Blockade In Advanced Melanoma., N Jacquelot, M P Roberti, D P Enot, S Rusakiewicz, N Ternès, S Jegou, D M Woods, A L Sodré, M Hansen, Y Meirow, M Sade-Feldman, A Burra, S S Kwek, C Flament, M Messaoudene, C P M Duong, L Chen, B S Kwon, A C Anderson, V K Kuchroo, B Weide, F Aubin, C Borg, S Dalle, O Beatrix, M Ayyoub, B Balme, G Tomasic, A M Di Giacomo, M Maio, D Schadendorf, I Melero, B Dréno, A Khammari, R Dummer, M Levesque, Yoshinobu Koguchi, L Fong, M Lotem, M Baniyash, H Schmidt, I M Svane, G Kroemer, A Marabelle, S Michiels, A Cavalcanti, M J Smyth, J S Weber, A M Eggermont, L Zitvogel

Articles, Abstracts, and Reports

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, …

Stress Exposure And Physical, Mental, And Behavioral Health Among American Indian Adults With Type 2 Diabetes, Melissa L. Walls, Kelley J. Sittner, Benjamin D. Aronson, Angie K. Forsberg, Les B. Whitbeck, Mustafa Al'absi

Pharmacy Faculty Scholarship

American Indian (AI) communities experience disproportionate exposure to stressors and health inequities including type 2 diabetes. Yet, we know little about the role of psychosocial stressors for AI diabetes-related health outcomes. We investigated associations between a range of stressors and psychological, behavioral, and physical health for AIs with diabetes. This community-based participatory research with 5 AI tribes includes 192 AI adult type 2 diabetes patients recruited from clinical records at tribal clinics. Data are from computer-assisted interviews and medical charts. We found consistent bivariate relationships between chronic to discrete stressors and mental and behavioral health outcomes; several remained even after …

Neurosyphilis Increases Human Immunodeficiency Virus (Hiv)-Associated Central Nervous System Inflammation But Does Not Explain Cognitive Impairment In Hiv-Infected Individuals With Syphilis., Emily L Ho, Clare L Maxwell, Shelia B Dunaway, Sharon K Sahi, Lauren C Tantalo, Sheila A Lukehart, Christina M Marra

Articles, Abstracts, and Reports

Background: Individuals infected with human immunodeficiency virus (HIV) who have previously had syphilis may have cognitive impairment. We tested the hypothesis that neurosyphilis causes cognitive impairment in HIV by amplifying HIV-related central nervous system (CNS) inflammation.

Methods: HIV-infected participants enrolled in a study of cerebrospinal fluid (CSF) abnormalities in syphilis underwent the mental alternation test (MAT), venipuncture, and lumbar puncture. CSF concentrations of chemokine (C-X-C motif) ligand 10 (CXCL10), chemokine (C-C motif) ligand 2 (CCL2), and neurofilament light (NFL) were determined by commercial assays. The proportion of peripheral blood mononuclear cells (PBMCs) and of CSF white blood cells (WBCs) that …

Posttranscriptional Regulation Of Parg Mrna By Hur Facilitates Dna Repair And Resistance To Parp Inhibitors, Saswati N. Chand, Mahsa Zarei, M. J. Schiewer, Akshay R. Sanan, Carmella Romeo, Shruti Lal, Joseph A. Cozzitorto, Avinoam Nevler, Laura Scolaro, Eric R. Londin, Wei Jiang, Nicole Meisner-Kober, Michael J. Pishvaian, Karen E. Knudsen, Charles Yeo, John M Pascal, Jordan M. Winter, Jonathan R. Brody

Department of Surgery Faculty Papers

The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9–mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3⁰ untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to …