Medicine and Health Sciences Commons^™

The Anti-Cancer Effect Of Retinoic Acid Signaling In Crc Occurs Via Decreased Growth Of Aldh+ Colon Cancer Stem Cells And Increased Differentiation Of Stem Cells, Shirin R. Modarai, Anindita Gupta, Lynn M. Opdenaker, Ryan Kowash, Gabriel Masters, Vignesh Viswanathan, Tao Zhang, Jeremy Z. Fields, Bruce M. Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Background: Tumorigenesis is driven by stem cell (SC) overpopulation. BecauseALDH is both a marker for SCs in many tissues and a key enzyme in retinoid acid (RA)signaling, we studied RA signaling in normal and malignant colonic SCs.Hypothesis: RA signaling regulates growth and differentiation of ALDH+ colonicSCs dysregulation of RA signaling contributes to SC overpopulation and colorectalcancer (CRC) development.Methods: We analyzed normal and malignant colonic tissues and CRC cell linesto see if retinoid receptors (RXR &RAR) are exclusively expressed in ALDH+ SCs,and if RA signaling changes during CRC development. We determined whether RAsignaling regulates cancer SC (CSC) proliferation, differentiation, sphere formation,and …

Listeria Monocytogenes As A Vector For Cancer Immunotherapy: Current Understanding And Progress, John C. Flickinger, Ulrich Rodeck, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Listeria monocytogenes, a Gram-positive facultative anaerobic bacterium, is becoming a popular vector for cancer immunotherapy. Indeed, multiple vaccines have been developed utilizing modified Listeria as a tool for generating immune responses against a variety of cancers. Moreover, over a dozen clinical trials testing Listeria cancer vaccines are currently underway, which will help to understand the utility of Listeria vaccines in cancer immunotherapy. This review aims to summarize current views on how Listeria-based vaccines induce potent antitumor immunity and the current state of Listeria-based cancer vaccines in clinical trials. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.

The Guanylate Cyclase C-Cgmp Signaling Axis Opposes Intestinal Epithelial Injury And Neoplasia., Jeffrey A. Rappaport, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Guanylate cyclase C (GUCY2C) is a transmembrane receptor expressed on the luminal aspect of the intestinal epithelium. Its ligands include bacterial heat-stable enterotoxins responsible for traveler's diarrhea, the endogenous peptide hormones uroguanylin and guanylin, and the synthetic agents, linaclotide, plecanatide, and dolcanatide. Ligand-activated GUCY2C catalyzes the synthesis of intracellular cyclic GMP (cGMP), initiating signaling cascades underlying homeostasis of the intestinal epithelium. Mouse models of GUCY2C ablation, and recently, human populations harboring GUCY2C mutations, have revealed the diverse contributions of this signaling axis to epithelial health, including regulating fluid secretion, microbiome composition, intestinal barrier integrity, epithelial renewal, cell cycle progression, responses …

Visual Field Changes In Professional Wind Versus Non-Wind Musical Instrument Players In The Philadelphia Orchestra, Shuai‑Chun Lin, Cindy X. Zheng, Michael Waisbourd, Jeanne Molineaux, Lichuan Zeng, Tingting Zhan, Kamran Rahmatnejad, Arthur Resende, Anand V. Mantravadi, Lisa A. Hark, Marlene R. Moster, Joseph I. Markoff, George L. Spaeth, L. Jay Katz

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Purpose: We compare the prevalence of glaucoma in professional wind versus non‑wind instrument players in the Philadelphia Orchestra. Visual field changes in individuals with glaucoma and glaucoma suspects were evaluated, and the results were correlated with cumulative practice time. Methods: In this cross‑sectional, observational study, fifty‑one Philadelphia Orchestra musicians were enrolled and categorized as wind or non‑wind instrument players. All study participants underwent screening fundus photography. Participants with optic discs suspicious for glaucoma underwent further evaluation, including standard automated visual field perimetry and a comprehensive eye examination by a glaucoma specialist. Results: Of the 51 musicians enrolled, 9 of …

Evaluating Comfort Measures For Commonly Performed Painful Procedures In Pediatric Patients., Sana Dastgheyb, Keith Fishlock, Constantine Daskalakis, Jami Kessel, Paul Rosen

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Introduction: Management of pediatric pain from medical procedures is of great importance for improving both patient care and experience. In this study, we investigated methods of managing acute pain in infants and children by studying the correlation between the number of attempts to complete painful procedures, given different comfort measures.

Methods: The study is a retrospective review of 74,276 procedures performed at two pediatric hospitals in an integrated academic children's health system between 2013 and 2016. We compared three comfort measures most frequently offered: positions of comfort (POC), distraction (DIST), and pharmacological (PHARM). These methods were compared in the setting …

Human Gucy2c-Targeted Chimeric Antigen Receptor (Car)-Expressing T Cells Eliminate Colorectal Cancer Metastases., Michael S. Magee, Tara S. Abraham, Trevor R. Baybutt, John C. Flickinger, Natalie A. Ridge, Glen P Marszalowicz, Priyanka Prajapati, Adam R. Hersperger, Scott A. Waldman, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting …

Buprenorphine In Neonatal Abstinence Syndrome., Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Infants exposed in utero to opioids will demonstrate a withdrawal syndrome known as neonatal abstinence syndrome (NAS). Buprenorphine is a long-acting opioid with therapeutic use in medication-assisted treatment of opioid dependency in adults and adolescents. Emerging data from clinical trials and treatment cohorts demonstrate the efficacy and safety of sublingual buprenorphine for those infants with NAS who require pharmacologic treatment. Pharmacometric modeling will assist in defining the exposure-response relationships and facilitate dose optimization.

Process Improvement For Maximized Therapeutic Innovation Outcome., Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Deconvoluting key biological mechanisms forms the framework for therapeutic discovery. Strategies that enable effective translation of those insights along the development and regulatory path ultimately drive validated clinical application in patients and populations. Accordingly, parity in What vs. How we transform novel mechanistic insights into therapeutic paradigms is essential in achieving success. Aligning molecular discovery with innovations in structures and processes along the discovery-development-regulation-utilization continuum maximizes the return on public and private investments for next-generation solutions in managing health and disease.

Neonatal Safety Information Reported To The Fda During Drug Development Studies., Debbie Avant, Gerri Baer, Jason N. Moore, Panli Zheng, Alfred Sorbello, Ron Ariagno, Lynne Yao, Gilbert J. Burckart, Jian Wang

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: Relatively few neonatal drug development studies have been conducted, but an increase is expected with the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA). Understanding the safety of drugs studied in neonates is complicated by the unique nature of the population and the level of illness. The objective of this study was to examine neonatal safety data submitted to the FDA in studies pursuant to the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) between 1998 and 2015.

METHODS: FDA databases were searched for BPCA and/or PREA studies that enrolled …