Medicine and Health Sciences Commons^™

Isosorbide Mononitrate In Heart Failure With Preserved Ejection Fraction., Margaret M. Redfield, Kevin J. Anstrom, James A. Levine, Gabe A. Koepp, Barry A. Borlaug, Horng H. Chen, Martin M. Lewinter, Susan M. Joseph, Sanjiv J. Shah, Marc J. Semigran, G. Michael Felker, Robert T. Cole, Gordon R. Reeves, Ryan J. Tedford, W.H. Wilson Tang, Steven E. Mcnulty, Eric J. Velazquez, Monica R Shah, Eugene Braunwald

Division of Cardiology Faculty Papers

BACKGROUND: Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients.

METHODS: In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer …

Detection Of Sleep Disordered Breathing In Patients Hospitalized With Congestive Heart Failure, Sunil Sharma, Paul Mather

Department of Sleep Medicine Faculty Papers

OBJECTIVES: The purpose of this study was to evaluate the plethysmographic signal-derived oxygen desaturation index (ODI) as an inpatient screening strategy to identify sleep-disordered breathing (SDB) in patients with congestive heart failure (CHF).

BACKGROUND: SDB is highly prevalent among patients hospitalized with CHF but is widely underdiagnosed. We evaluated overnight photoplethysmography as a possible screening strategy for hospitalized patients with CHF.

METHODS: Consecutively admitted heart failure patients with high clinical suspicion of SDB and ODI ≥5 were offered outpatient polysomnography (PSG), which was completed within 4 weeks of discharge. PSG was considered positive if the apnea hypoxia index (AHI) was …

Loss Of Vglut3 Produces Circadian-Dependent Hyperdopaminergia And Ameliorates Motor Dysfunction And L-Dopa-Mediated Dyskinesias In A Model Of Parkinson's Disease., Christopher B. Divito, Kathy Steece-Collier, Daniel T. Case, Sean-Paul G. Williams, Jennifer A. Stancati, Lianteng Zhi, Maria E. Rubio, Caryl E. Sortwell, Timothy J. Collier, David Sulzer, Robert H. Edwards, Hui Zhang, Rebecca P. Seal

Department of Neuroscience Faculty Papers

UNLABELLED: The striatum is essential for many aspects of mammalian behavior, including motivation and movement, and is dysfunctional in motor disorders such as Parkinson's disease. The vesicular glutamate transporter 3 (VGLUT3) is expressed by striatal cholinergic interneurons (CINs) and is thus well positioned to regulate dopamine (DA) signaling and locomotor activity, a canonical measure of basal ganglia output. We now report that VGLUT3 knock-out (KO) mice show circadian-dependent hyperlocomotor activity that is restricted to the waking cycle and is due to an increase in striatal DA synthesis, packaging, and release. Using a conditional VGLUT3 KO mouse, we show that deletion …

Migrated Avalon Veno-Venous Extracorporeal Membrane Oxygenation Cannula: How To Adjust Without Interruption Of Flow., Daizo Tanaka, Harrsion T. Pitcher, Nicholas C. Cavarocchi, Hitoshi Hirose

Department of Surgery Faculty Papers

The Avalon dual lumen cannula is presently the cannula of choice for veno-venous extracorporeal membrane oxygenation (VV-ECMO) via right internal jugular cannulation. This cannula establishes VV-ECMO with a single cannulation; however, it requires appropriate positioning to gain adequate oxygenation. Malposition of this cannula can cause inadequate ECMO flow, hypoxia, and structural injury. We have experienced two cases of migration: one into the hepatic vein and the other into the right ventricle. The former was repositioned using echocardiographic guidance without using a guidewire. The latter was repositioned using a guidewire from the femoral vein under fluoroscopy, without antegrade wire placement into …

Saving Life And Brain With Extracorporeal Cardiopulmonary Resuscitation: A Single-Center Analysis Of In-Hospital Cardiac Arrests., Graham Peigh, Nicholas C. Cavarocchi, Hitoshi Hirose

Department of Surgery Faculty Papers

OBJECTIVE: Despite advances in medical care, survival to discharge and full neurologic recovery after cardiac arrest remains less than 20% after cardiopulmonary resuscitation. An alternate approach to traditional cardiopulmonary resuscitation is extracorporeal cardiopulmonary resuscitation, which places patients on extracorporeal membrane oxygenation during cardiopulmonary resuscitation and provides immediate cardiopulmonary support when traditional resuscitation has been unsuccessful. We report the results from extracorporeal cardiopulmonary resuscitation at the Thomas Jefferson University.

METHODS: Between 2010 and June 2014, 107 adult extracorporeal membrane oxygenation procedures were performed at the Thomas Jefferson University. Patient demographics, survival to discharge, and neurologic recovery of patients who underwent extracorporeal …

Repression Of Esophageal Neoplasia And Inflammatory Signaling By Anti-Mir-31 Delivery In Vivo., Cristian Taccioli, Michela Garofalo, Hongping Chen, Yubao Jiang, Guidantonio Malagoli Tagliazucchi, Gianpiero Di Leva, Hansjuerg Alder, Paolo Fadda, Justin Middleton, Karl J. Smalley, Tommaso Selmi, Srivatsava Naidu, John L. Farber, Carlo M. Croce, Louise Fong

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined.

METHODS: To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks. miR-31 expression was determined by northern blotting, quantitative polymerase chain reaction, and in situ hybridization. Physiological miR-31 targets were identified by microarray analysis and verified by luciferase reporter …

Right Ventricular Dysfunction After Resuscitation Predicts Poor Outcomes In Cardiac Arrest Patients Independent Of Left Ventricular Function., Vimal Ramjee, Anne V. Grossestreuer, Yuan Yao, Sarah M. Perman, Marion Leary, James N. Kirkpatrick, Paul R. Forfia, Daniel M. Kolansky, Benjamin S. Abella, David F. Gaieski

Department of Emergency Medicine Faculty Papers

OBJECTIVE: Determination of clinical outcomes following resuscitation from cardiac arrest remains elusive in the immediate post-arrest period. Echocardiographic assessment shortly after resuscitation has largely focused on left ventricular (LV) function. We aimed to determine whether post-arrest right ventricular (RV) dysfunction predicts worse survival and poor neurologic outcome in cardiac arrest patients, independent of LV dysfunction.

METHODS: A single-center, retrospective cohort study at a tertiary care university hospital participating in the Penn Alliance for Therapeutic Hypothermia (PATH) Registry between 2000 and 2012.

PATIENTS: 291 in- and out-of-hospital adult cardiac arrest patients at the University of Pennsylvania who had return of spontaneous …

Dna-Repair Defects And Olaparib In Metastatic Prostate Cancer., Joaquin Mateo, Suzanne Carreira, Shahneen Sandhu, Susana Miranda, Helen Mossop, Raquel Perez-Lopez, Daniel Nava Rodrigues, Dan Robinson, Aurelius Omlin, Nina Tunariu, Gunther Boysen, Nuria Porta, Penny Flohr, Alexa Gillman, Ines Figueiredo, Claire Paulding, George Seed, Suneil Jain, Christy Ralph, Andrew Protheroe, Syed Hussain, Robert Jones, Tony Elliott, Ursula Mcgovern, Diletta Bianchini, Jane Goodall, Zafeiris Zafeiriou, Chris T Williamson, Roberta Ferraldeschi, Ruth Riisnaes, Bernardette Ebbs, Gemma Fowler, Desamparados Roda, Wei Yuan, Yi-Mi Wu, Xuhong Cao, Rachel Brough, Helen Pemberton, Roger A'Hern, Amanda Swain, Lakshmi P Kunju, Rosalind Eeles, Gerhardt Attard, Christopher J Lord, Alan Ashworth, Mark A Rubin, Karen E Knudsen, Felix Y Feng, Arul M Chinnaiyan, Emma Hall, Johann S De Bono

Department of Medicine Faculty Papers

BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.

METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the …

Effect Of Mycophenolate Mofetil On The White Blood Cell Count And The Frequency Of Infection In Systemic Lupus Erythematosus., Ananta Subedi, Laurence S. Magder, Michelle Petri

Department of Medicine Faculty Papers

Leukopenia is a common manifestation of SLE. Addition of immunosuppressive therapy in a SLE patient who is already leukopenic is a clinical concern. It could worsen leukopenia, increase the risk of infection, or both. The aim of this study was to analyze the immediate effect of mycophenolate mofetil on the white blood cell count and the rate of infection in SLE patients. Two hundred and forty-four patients within the Hopkins Lupus Cohort who were newly started on mycophenolate mofetil were included in the study. The white blood cell count and interval infection history on the day mycophenolate mofetil was started …

Racial Disparities In Intravenous Recombinant Tissue Plasminogen Activator Use Persist At Primary Stroke Centers., Hugo J. Aparicio, Brendan G. Carr, Scott E. Kasner, Michael J. Kallan, Karen C. Albright, Dawn O. Kleindorfer, Michael T. Mullen

Department of Emergency Medicine Faculty Papers

BACKGROUND: Primary stroke centers (PSCs) utilize more recombinant tissue plasminogen activator (rt-PA) than non-PSCs. The impact of PSCs on racial disparities in rt-PA use is unknown.

METHODS AND RESULTS: We used data from the Nationwide Inpatient Sample from 2004 to 2010, limited to states that publicly reported hospital identity and race. Hospitals certified as PSCs by The Joint Commission were identified. Adults with a diagnosis of ischemic stroke were analyzed. Rt-PA use was defined by the International Classification of Diseases, 9th Revision procedure code 99.10. Discharges (304 152 patients) from 26 states met eligibility criteria, and of these 71.5% were …

Characterization Of 1577 Primary Prostate Cancers Reveals Novel Biological And Clinicopathologic Insights Into Molecular Subtypes., Scott A. Tomlins, Mohammed Alshalalfa, Elai Davicioni, Nicholas Erho, Kasra Yousefi, Shuang Zhao, Zaid Haddad, Robert B. Den, Adam P. Dicker, Bruce J. Trock, Angelo M. Demarzo, Ashley E. Ross, Edward M. Schaeffer, Eric A. Klein, Cristina Magi-Galluzzi, R. Jeffrey Karnes, Robert B. Jenkins, Felix Y. Feng

Department of Radiation Oncology Faculty Papers

BACKGROUND: Prostate cancer (PCa) molecular subtypes have been defined by essentially mutually exclusive events, including ETS gene fusions (most commonly involving ERG) and SPINK1 overexpression. Clinical assessment may aid in disease stratification, complementing available prognostic tests.

OBJECTIVE: To determine the analytical validity and clinicopatholgic associations of microarray-based molecular subtyping.

DESIGN, SETTING, AND PARTICIPANTS: We analyzed Affymetrix GeneChip expression profiles for 1577 patients from eight radical prostatectomy cohorts, including 1351 cases assessed using the Decipher prognostic assay (GenomeDx Biosciences, San Diego, CA, USA) performed in a laboratory with Clinical Laboratory Improvements Amendment certification. A microarray-based (m-) random forest ERG classification model …

A Phase 3 Trial Of 2 Years Of Androgen Suppression And Radiation Therapy With Or Without Adjuvant Chemotherapy For High-Risk Prostate Cancer: Final Results Of Radiation Therapy Oncology Group Phase 3 Randomized Trial Nrg Oncology Rtog 9902., Seth A. Rosenthal, Daniel Hunt, A. Oliver Sartor, Kenneth J. Pienta, Leonard G. Gomella, David Grignon, Raghu Rajan, Kevin J. Kerlin, Christopher U. Jones, Michael Dobelbower, William U Shipley, Kenneth Zeitzer, Daniel A. Hamstra, Viroon Donavanik, Marvin Rotman, Alan C. Hartford, Jeffrey Michalski, Michael Seider, Harold Kim, Deborah A. Kuban, Jennifer Moughan, Howard Sandler

Department of Urology Faculty Papers

PURPOSE: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS).

METHODS AND MATERIALS: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was …

The Evolution Of Epilepsy Surgery Between 1991 And 2011 In Nine Major Epilepsy Centers Across The United States, Germany, And Australia., Lara Jehi, Daniel Friedman, Chad Carlson, Gregory Cascino, Sandra Dewar, Christian Elger, Jerome Engel, Robert Knowlton, Ruben Kuzniecky, Anne Mcintosh, Terence J O'Brien, Dennis Spencer, Michael R. Sperling, Gregory Worrell, Bill Bingaman, Jorge Gonzalez-Martinez, Werner Doyle, Jacqueline French

Department of Neurology Faculty Papers

OBJECTIVE: Epilepsy surgery is the most effective treatment for select patients with drug-resistant epilepsy. In this article, we aim to provide an accurate understanding of the current epidemiologic characteristics of this intervention, as this knowledge is critical for guiding educational, academic, and resource priorities.

METHODS: We profile the practice of epilepsy surgery between 1991 and 2011 in nine major epilepsy surgery centers in the United States, Germany, and Australia. Clinical, imaging, surgical, and histopathologic data were derived from the surgical databases at various centers.

RESULTS: Although five of the centers performed their highest number of surgeries for mesial temporal sclerosis …

Simple New Risk Score Model For Adult Cardiac Extracorporeal Membrane Oxygenation: Simple Cardiac Ecmo Score., Graham Peigh, Nicholas Cavarocchi, Scott W. Keith, Hitoshi Hirose

Department of Surgery Faculty Papers

BACKGROUND: Although the use of cardiac extracorporeal membrane oxygenation (ECMO) is increasing in adult patients, the field lacks understanding of associated risk factors. While standard intensive care unit risk scores such as SAPS II (simplified acute physiology score II), SOFA (sequential organ failure assessment), and APACHE II (acute physiology and chronic health evaluation II), or disease-specific scores such as MELD (model for end-stage liver disease) and RIFLE (kidney risk, injury, failure, loss of function, ESRD) exist, they may not apply to adult cardiac ECMO patients as their risk factors differ from variables used in these scores.

METHODS: Between 2010 and …

Caffeine And Progression Of Parkinson Disease: A Deleterious Interaction With Creatine., David K. Simon, Cai Wu, Barbara C. Tilley, Anne-Marie Wills, Michael J. Aminoff, Jacquelyn Bainbridge, Robert A. Hauser, Jay S. Schneider, Saloni Sharma, Carlos Singer, Caroline M. Tanner, Daniel Truong, Pei Shieen Wong

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

OBJECTIVE: Increased caffeine intake is associated with a lower risk of Parkinson disease (PD) and is neuroprotective in mouse models of PD. However, in a previous study, an exploratory analysis suggested that, in patients taking creatine, caffeine intake was associated with a faster rate of progression. In the current study, we investigated the association of caffeine with the rate of progression of PD and the interaction of this association with creatine intake.

METHODS: Data were analyzed from a large phase 3 placebo-controlled clinical study of creatine as a potentially disease-modifying agent in PD. Subjects were recruited for this study from …

Computerized Adaptive Tests Detect Change Following Orthopaedic Surgery In Youth With Cerebral Palsy., M J Mulcahey, Mary D Slavin, Pengsheng Ni, Lawrence C Vogel, Scott H Kozin, Stephen M Haley, Alan M Jette

Department of Occupational Therapy Faculty Papers

BACKGROUND: The Cerebral Palsy Computerized Adaptive Test (CP-CAT) is a parent-reported outcomes instrument for measuring lower and upper-extremity function, activity, and global health across impairment levels and a broad age range of children with cerebral palsy (CP). This study was performed to examine whether the Lower Extremity/Mobility (LE) CP-CAT detects change in mobility following orthopaedic surgery in children with CP.

METHODS: This multicenter, longitudinal study involved administration of the LE CP-CAT, the Pediatric Outcomes Data Collection Instrument (PODCI) Transfer/Mobility and Sports/Physical Functioning domains, and the Timed "Up & Go" test (TUG) before and after elective orthopaedic surgery in a convenience …

The Fate Of Spacers In The Treatment Of Periprosthetic Joint Infection., Miguel M Gomez, Timothy L Tan, Jorge Manrique, Gregory K Deirmengian, Javad Parvizi Md

Rothman Institute Faculty Papers

BACKGROUND: Two-stage exchange arthroplasty remains the preferred method to treat periprosthetic joint infection. The aim of this study was to investigate the clinical course of periprosthetic joint infection following resection arthroplasty and insertion of a spacer.

METHODS: Our institutional database was used to identify 504 cases of periprosthetic joint infection (326 knees and 178 hips) treated with resection arthroplasty and spacer insertion as part of a two-stage exchange arthroplasty. A review of the patient charts was performed to extract information relevant to the objectives of this study that included the details of the clinical course following resection arthroplasty.

RESULTS: The …

Thromboembolism After Intramedullary Nailing For Metastatic Bone Lesions., Brandon Shallop, Alexandria Starks, Simon Greenbaum, David S Geller, Alan Lee, John Ready, Geno J Merli, Mitchell Maltenfort, Phd, John A Abraham

Rothman Institute Faculty Papers

BACKGROUND: The risk of venous thromboembolism (VTE) in patients undergoing intramedullary nailing for skeletal metastatic disease is currently undefined. The purpose of our study was to determine the risk of thromboembolic events, to define the risk factors for VTE, and to define the rate of wound complications in this population.

METHODS: A retrospective review of surgical databases at three National Cancer Institute (NCI)-designated cancer centers identified 287 patients with a total of 336 impending or pathologic long-bone fractures that were stabilized with intramedullary nailing between February 2001 and April 2013. Statistical analysis was performed utilizing multivariable logistic regression and Fisher …

Gm1 Ganglioside In Parkinson's Disease: Pilot Study Of Effects On Dopamine Transporter Binding., Jay S. Schneider, Franca Cambi, Stephen M. Gollomp, Hiroto Kuwabara, James R. Brašić, Benjamin E. Leiby, Stephanie Sendek, Dean F. Wong

Department of Pharmacology and Experimental Therapeutics Faculty Papers

OBJECTIVE: GM1 ganglioside has been suggested as a treatment for Parkinson's disease (PD), potentially having symptomatic and disease modifying effects. The current pilot imaging study was performed to examine effects of GM1 on dopamine transporter binding, as a surrogate measure of disease progression, studied longitudinally.

METHODS: Positron emission tomography (PET) imaging data were obtained from a subset of subjects enrolled in a delayed start clinical trial of GM1 in PD [1]: 15 Early-start (ES) subjects, 14 Delayed-start (DS) subjects, and 11 Comparison (standard-of-care) subjects. Treatment subjects were studied over a 2.5 year period while Comparison subjects were studied over 2 …

Pkcε Is An Essential Mediator Of Prostate Cancer Bone Metastasis., Alvaro Gutierrez-Uzquiza, Cynthia Lopez-Haber University Of Pennsylvania, Danielle L. Jernigan, Alessandro Fatatis, Marcelo G. Kazanietz

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

UNLABELLED: The bone is a preferred site for metastatic homing of prostate cancer cells. Once prostate cancer patients develop skeletal metastases, they eventually succumb to the disease; therefore, it is imperative to identify key molecular drivers of this process. This study examines the involvement of protein kinase C epsilon (PKCε), an oncogenic protein that is abnormally overexpressed in human tumor specimens and cell lines, on prostate cancer cell bone metastasis. PC3-ML cells, a highly invasive prostate cancer PC3 derivative with bone metastatic colonization properties, failed to induce skeletal metastatic foci upon inoculation into nude mice when PKCε expression was silenced …

Type Of Preoperative Aura May Predict Postsurgical Outcome In Patients With Temporal Lobe Epilepsy And Mesial Temporal Sclerosis., Ali Akbar Asadi-Pooya, Maromi Nei, Ashwini Sharan, Michael R. Sperling

Department of Neurology Faculty Papers

PURPOSE: As the initial symptoms of epileptic seizures, many types of auras have significant localizing or lateralizing value. In this study, we hypothesized that the type of aura may predict postsurgical outcome in patients with medically refractory temporal lobe epilepsy (TLE) and mesial temporal sclerosis (MTS).

METHODS: In this retrospective study, all patients with a clinical diagnosis of medically refractory TLE due to unilateral mesial temporal sclerosis who underwent epilepsy surgery at the Jefferson Comprehensive Epilepsy Center were recruited. Patients were prospectively registered in a database from 1986 through 2014. Postsurgical outcome was classified into two groups: seizure freedom or …

Expression Of The Il-11 Gene In Metastatic Cells Is Supported By Runx2-Smad And Runx2-Cjun Complexes Induced By Tgfβ1., Xuhui Zhang, Hai Wu, Jason R. Dobson, Gillian Browne, Deli Hong, Jacqueline Akech, Lucia R. Languino, Gary S. Stein, Jane B. Lian

Department of Cancer Biology Faculty Papers

In tumor cells, two factors are abnormally increased that contribute to metastatic bone disease: Runx2, a transcription factor that promotes expression of metastasis related and osteolytic genes; and IL-11, a secreted osteolytic cytokine. Here, we addressed a compelling question: Does Runx2 regulate IL-11 gene expression? We find a positive correlation between Runx2, IL-11 and TGFβ1, a driver of the vicious cycle of metastatic bone disease, in prostate cancer (PC) cell lines representing early (LNCaP) and late (PC3) stage disease. Further, like Runx2 knockdown, IL-11 knockdown significantly reduced expression of several osteolytic factors. Modulation of Runx2 expression results in corresponding changes …

Locomotor Adaptation Is Influenced By The Interaction Between Perturbation And Baseline Asymmetry After Stroke., Christine M. Tyrell, Erin Helm, Darcy S. Reisman

Department of Physical Therapy Faculty Papers

Stroke survivors without cerebellar involvement retain the ability to adapt to the split-belt treadmill; however it has been suggested that their rate of adaptation may be slowed compared to those who are neurologically intact. Depending on limb placement, the split-belt treadmill can be configured to either exaggerate baseline asymmetry, or reduce it, which may affect the behavior of adaptation or de-adaptation. The objectives of this study were to characterize the rate and magnitude of locomotor (de)adaptation in chronic stroke survivors compared to healthy matched subjects, and to evaluate whether exaggeration or reduction of baseline asymmetry impact the responses. Seventeen stroke …

Mechanisms Of Activation Of Nucleus Accumbens Neurons By Cocaine Via Sigma-1 Receptor-Inositol 1,4,5-Trisphosphate-Transient Receptor Potential Canonical Channel Pathways., Jeffrey L. Barr, Elena Deliu, Gabriela Cristina Brailoiu, Pingwei Zhao, Guang Yan, Mary E. Abood, Ellen M. Unterwald, Eugen Brailoiu

College of Pharmacy Faculty Papers

Cocaine promotes addictive behavior primarily by blocking the dopamine transporter, thus increasing dopamine transmission in the nucleus accumbens (nAcc); however, additional mechanisms are continually emerging. Sigma-1 receptors (σ1Rs) are known targets for cocaine, yet the mechanisms underlying σ1R-mediated effects of cocaine are incompletely understood. The present study examined direct effects of cocaine on dissociated nAcc neurons expressing phosphatidylinositol-linked D1 receptors. Endoplasmic reticulum-located σ1Rs and inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) were targeted using intracellular microinjection. IP3 microinjection robustly elevated intracellular Ca(2+) concentration, [Ca(2+)]i. While cocaine alone was devoid of an effect, the IP3-induced response was σ1R-dependently enhanced by cocaine co-injection. Likewise, …

Adiporon, The First Orally Active Adiponectin Receptor Activator, Attenuates Postischemic Myocardial Apoptosis Through Both Ampk-Mediated And Ampk-Independent Signalings., Yanqing Zhang, Jianli Zhao, Rui Li, Wayne Bond Lau, Yue-Xing Yuan, Bin Liang, Rong Li, Er-He Gao, Walter J. Koch, Xin-Liang Ma, Ya-Jing Wang

Department of Emergency Medicine Faculty Papers

Adiponectin (APN) is a cardioprotective molecule. Its reduction in diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury. Although APN administration in animals attenuates MI/R injury, multiple factors limit its clinical application. The current study investigated whether AdipoRon, the first orally active molecule that binds APN receptors, may protect the heart against MI/R injury, and if so, to delineate the involved mechanisms. Wild-type (WT), APN knockout (APN-KO), and cardiomyocyte specific-AMPK dominant negative (AMPK-DN) mice were treated with vehicle or AdipoRon (50 mg/kg, 10 min prior to MI) and subjected to MI/R (30 min/3-24 h). Compared with vehicle, oral administration of AdipoRon to WT …

Structure-Based Screen Identifies A Potent Small Molecule Inhibitor Of Stat5a/B With Therapeutic Potential For Prostate Cancer And Chronic Myeloid Leukemia., Zhiyong Liao, Lei Gu, Jenny Vergalli, Samanta A. Mariani, Marco De Dominici, Ravi K. Lokareddy, Ayush Dagvadorj, Puranik Purushottamachar, Peter A. Mccue, Edouard J. Trabulsi, Costas D. Lallas, Shilpa Gupta, Elyse Ellsworth, Shauna Blackmon, Adam Ertel, Paolo Fortina, Benjamin E. Leiby, Guanjun Xia, Hallgeir Rui, David T. Hoang, Leonard G Gomella, Gino Cingolani, Vincent Njar, Nagarajan Pattabiraman, Bruno Calabretta, Marja T. Nevalainen

Department of Cancer Biology Faculty Papers

Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic …

Age At Onset In Patients With Medically Refractory Temporal Lobe Epilepsy And Mesial Temporal Sclerosis: Impact On Clinical Manifestations And Postsurgical Outcome., Ali Akbar Asadi-Pooya, Michael R. Sperling

Department of Neurology Faculty Papers

PURPOSE: To evaluate the demographic and clinical manifestations and postsurgical outcome of childhood-onset mesial temporal sclerosis and temporal lobe epilepsy (MTS-TLE) and establishing the potential differences as compared to the patients with adult-onset MTS-TLE.

METHOD: In this retrospective study all patients with a clinical diagnosis of medically refractory TLE due to mesial temporal sclerosis, who underwent epilepsy surgery at Jefferson comprehensive epilepsy center, were recruited. Patients were prospectively registered in a database from 1986 through 2014. Postsurgical outcome was classified into two groups; seizure-free or relapsed. Clinical manifestations and outcome were compared between patients with childhood-onset MTS-TLE (i.e., age at …

Sex And Race And/Or Ethnicity Differences In Patients Undergoing Radiofrequency Ablation For Barrett's Esophagus: Results From The U.S. Rfa Registry., Sarina Pasricha, Nan Li, William J. Bulsiewicz, Richard I. Rothstein, Anthony Infantolino, Atilla Ertan, Daniel S. Camara, Evan S. Dellon, George Triadafilopoulos, Charles J. Lightdale, Ryan D. Madanick, William D. Lyday, Raman V. Muthusamy, Bergein F. Overholt, Nicholas J. Shaheen

Department of Medicine Faculty Papers

BACKGROUND: Little is known about differences in Barrett's esophagus (BE) characteristics by sex and race and/or ethnicity or these differences in response to radiofrequency ablation (RFA).

OBJECTIVE: We compared disease-specific characteristics, treatment efficacy, and safety outcomes by sex and race and/or ethnicity in patients treated with RFA for BE.

DESIGN: The U.S. RFA patient registry is a multicenter collaboration reporting processes and outcomes of care for patients treated with RFA for BE.

PATIENTS: Patients enrolled with BE.

INTERVENTIONS: RFA.

MAIN OUTCOME MEASUREMENTS: We assessed safety (stricture, bleeding, perforation, hospitalization), efficacy (complete eradication of intestinal metaplasia [CEIM]), complete eradication of dysplasia, …

Dna-Pkcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression And Metastasis., Jonathan F Goodwin, Vishal Kothari, Justin M Drake, Shuang Zhao, Emanuela Dylgjeri, Jeffry L. Dean, Matthew J. Schiewer, Christopher Mcnair, Jennifer K. Jones, Alvaro Aytes, Michael S. Magee, Adam E. Snook, Ziqi Zhu, Robert Den, Ruth C. Birbe, Leonard G. Gomella, Nicholas A. Graham, Ajay A. Vashisht, James A. Wohlschlegel, Thomas G. Graeber, R. Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, Scott A. Tomlins, Cory Abate-Shen, Nima Sharifi, Owen N. Witte, Felix Y. Feng, Karen E. Knudsen

Department of Cancer Biology Faculty Papers

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver …

Ketamine For The Treatment Of Depression In Patients Receiving Hospice Care: A Retrospective Medical Record Review Of Thirty-One Cases., Alana Iglewicz, Katherine Morrison, Richard A. Nelesen, Tingting Zhan, Boris Iglewicz, Nathan Fairman, Jeremy M. Hirst, Scott A. Irwin

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: Depression is prevalent in patients receiving hospice care. Standard antidepressant medications do not work rapidly enough in this setting. Evidence suggests that ketamine rapidly treats treatment refractory depression in the general population. Ketamine׳s role for treating depression in the hospice population warrants further study.

METHODS: A retrospective medical record review of 31 inpatients receiving hospice care who received ketamine for depression on a clinical basis was conducted. The primary outcome measure was the Clinical Global Impression Scale, which was used retrospectively to rate subjects׳ therapeutic improvement, global improvement, and side effects from ketamine over 21 days. Additionally, time to …