Medical Pharmacology Commons^™

Pathologic Evaluation Of Tumor-Associated Macrophage Density And Vessel Inflammation In Invasive Breast Carcinomas, Yoshihiro Morita, Roy Zhang, Macall Leslie, Smita Adhikari, Nafis Hasan, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Tumor-associated macrophages (TAMs) are major constituents of the tumor microenvironment in solid tumors and have been implicated as mediators of tumor progression, invasion and metastasis. Correspondingly, accumulation of TAMs is associated with unfavorable clinical outcomes in numerous types of solid tumors. E-selectin is a hallmark of inflammation and a key adhesion molecule that accommodates the initial contact of circulating immune cells with the inflamed vessel surface. Currently, the association between E-selectin and TAMs is not fully elucidated; therefore, the present study investigated the association between vessel inflammation, TAM infiltration, and clinical outcome in breast cancer. A total of 53 procedure-naïve …

Brain Microvascular Injury And White Matter Disease Provoked By Diabetes-Associated Hyperamylinemia, Han Ly, Nirmal Verma, Fengen Wu, Miao Liu, Kathryn E. Saatman, Peter T. Nelson, John T. Slevin, Larry B. Goldstein, Geert Jan Biessels, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins.

METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses …

The Role Of Hif-1Α In Intestinal Epithelial Barrier Function In Alcoholic Liver Disease., Tuo Shao

Electronic Theses and Dissertations

Hypoxia inducible factor 1 α (HIF1α) is an oxygen-responsive subunit. HIF-1α plays a pivotal role in many pathophysiological processes. In addition to oxygen availability, HIF-1α can be regulated by multiple other factors in response to various pathophysiological processes. Previous studies showed that hepatic HIF-1α could be beneficial or harmful in experimental alcoholic liver disease (ALD). However, the role of intestinal HIF-1α in ALD has not yet been studied. Given the critical role of the gut-liver axis in ALD, it is important to elucidate the role of intestinal epithelial HIF-1α in ALD. In the first chapter, we used wide type (WT) …

Induction Of Mir-155 After Brain Injury Promotes Type 1 Interferon And Has A Neuroprotective Effect., Emily Harrison, Kathleen M. Emanuel, Benjamin G. Lamberty, Brenda M. Morsey, Min Li, Matthew L. Kelso, Sowmya V. Yelamanchili, Howard S. Fox

Journal Articles: Pharmacology & Experimental Neuroscience

Traumatic brain injury (TBI) produces profound and lasting neuroinflammation that has both beneficial and detrimental effects. Recent evidence has implicated microRNAs (miRNAs) in the regulation of inflammation both in the periphery and the CNS. We examined the expression of inflammation associated miRNAs in the context of TBI using a mouse controlled cortical impact (CCI) model and found increased levels of miR-21, miR-223 and miR-155 in the hippocampus after CCI. The expression of miR-155 was elevated 9-fold after CCI, an increase confirmed by in situ hybridization (ISH). Interestingly, expression of miR-155 was largely found in neuronal nuclei as evidenced by co-localization …

Examining The Influence And Role Of Pharmacogenetics Among Children With Autism Spectrum Disorder, Nuha Shaker

Masters Theses & Specialist Projects

Pharmacogenetics is the study of genomic-guided individualized drug prescription that plays an important role in preventing the severe adverse effects of drugs, decreasing the time and cost of therapeutic choices, and directing healthcare professionals to choose medications that are effective and safe. It is noteworthy that this approach becomes highly beneficial in patients suffering from chronic diseases or disorders, since these conditions may require multiple and long term pharmacological therapies, as in children with autism spectrum disorder (ASD). However, public acceptance is a major challenge when implementation of pharmacogenetics merges into clinical practice. The purpose of this study is a) …

Efficacy And Safety Of Sparsentan Compared With Irbesartan In Patients With Primary Focal Segmental Glomerulosclerosis: Randomized, Controlled Trial Design (Duet)., Radko Komers, Debbie S. Gipson, Peter Nelson, Sharon Adler, Tarak Srivastava, Vimal K. Derebail, Kevin E. Meyers, Pablo Pergola, Meghan E. Macnally, Jennifer L. Hunt, Alvin Shih, Howard Trachtman

Manuscripts, Articles, Book Chapters and Other Papers

Introduction: Primary focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease. There are no US Food and Drug Administration-approved therapies for FSGS, and treatment often fails to reduce proteinuria. Endothelin is an important factor in the pathophysiology of podocyte disorders, including FSGS. Sparsentan is a first-in-class, orally active, dual-acting angiotensin receptor blocker (ARB) and highly selective endothelin Type A receptor antagonist. This study is designed to evaluate whether sparsentan lowers proteinuria compared with an ARB alone and has a favorable safety profile in patients with FSGS.

Methods: DUET is a phase 2, randomized, active-control, …

Clinical Pharmacogenetics Implementation Consortium Guideline (Cpic) For Cyp2d6 And Cyp2c19 Genotypes And Dosing Of Tricyclic Antidepressants: 2016 Update., J K. Hicks, K Sangkuhl, J J. Swen, V L. Ellingrod, D J. Müller, K Shimoda, J R. Bishop, E D. Kharasch, T C. Skaar, Andrea Gaedigk, H M. Dunnenberger, T E. Klein, K E. Caudle, J C. Stingl

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Alternative Splicing Promotes Tumour Aggressiveness And Drug Resistance In African American Prostate Cancer., Bi-Dar Wang, Kristin Ceniccola, Sujin Hwang, Ramez Andrawis, Anelia Horvath, Jennifer A Freedman, Jacqueline Olender, Stefan Knapp, Travers Ching, Lana Garmire, Vyomesh Patel, Mariano A Garcia-Blanco, Steven R Patierno, Norman H Lee

Pharmacology and Physiology Faculty Publications

linical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, PIK3CD-S, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative …

Hypersensitivity Of Vagal Pulmonary Afferents Induced By Tumor Necrosis Factor Alpha In Mice, Ruei-Lung Lin, Qihai Gu, Lu-Yuan Lee

Physiology Faculty Publications

Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, plays a significant role in the pathogenesis of allergic asthma. Inhalation of TNFα also induces airway hyperresponsiveness in healthy human subjects, and the underlying mechanism is not fully understood. A recent study reported that TNFα caused airway inflammation and a sustained elevation of pulmonary chemoreflex responses in mice, suggesting a possible involvement of heightened sensitivity of vagal pulmonary C-fibers. To investigate this possibility, the present study aimed to investigate the effect of a pretreatment with TNFα on the sensitivity of vagal pulmonary afferents in anesthetized mice. After TNFα (10 μg/ml, 0.03 ml) …

Nfatc2 Modulates Microglial Activation In The Aβpp/Ps1 Mouse Model Of Alzheimer's Disease, Gunjan D. Manocha, Atreyi Ghatak, Kendra L. Puig, Susan D. Kraner, Christopher M. Norris, Colin K. Combs

Pharmacology and Nutritional Sciences Faculty Publications

Alzheimer’s disease (AD) brains are characterized by fibrillar amyloid-β (Aβ) peptide containing plaques and associated reactive microglia. The proinflammatory phenotype of the microglia suggests that they may negatively affect disease course and contribute to behavioral decline. This hypothesis predicts that attenuating microglial activation may provide benefit against disease. Prior work from our laboratory and others has characterized a role for the transcription factor, nuclear factor of activated T cells (NFAT), in regulating microglial phenotype in response to different stimuli, including Aβ peptide. We observed that the NFATc2 isoform was the most highly expressed in murine microglia cultures, and inhibition or …

Signalling Via The Osteopontin And High Mobility Group Box-1 Axis Drives The Fibrogenic Response To Liver Injury, Elena Arriazu, Xiaodong Ge, Tung-Ming Leung, Fernando Magdaleno, Aritz Lopategi, Yongke Lu, Naoto Kitamura, Raquel Urtasun, Neil Theise, Daniel J. Antoine, Natalia Nieto

Pharmacology, Physiology and Toxicology

Objective: Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression. Design and results: Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas …

Targeting Ledgf/P75 To Sensitize Chemoresistant Prostate Cancer Cells To Taxanes, Leslimar Rios-Colón

Loma Linda University Electronic Theses, Dissertations & Projects

Prostate cancer (PCa) is the second most diagnosed cancer in males. This disease disproportionately affects African American men, with a higher incidence and mortality compared to other ethnic/racial groups. An aging male population and the complexity of addressing the health disparities associated with this disease puts PCa into the spotlight due to its serious public health implications and the imminent fiscal challenge over the next decades. Chronic prostate inflammation resulting in activation of stress and prosurvival pathways contribute to disease progression and the development of chemoresistance. Lens epithelium-derived growth factor p75 (LEDGF/p75) is a stressresponse protein that promotes cellular survival …

Bioactivity Of Oral Linaclotide In Human Colorectum For Cancer Chemoprevention., David S. Weinberg, Jieru E. Lin, Nathan R. Foster, Gary Della'zanna, Asad Umar, Drew Seisler, Walter K. Kraft, David M. Kastenberg, Leo C. Katz, Paul J. Limburg, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Guanylate cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of its luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Linaclotide is an FDA-approved oral GUCY2C agonist formulated for gastric release, inducing fluid secretion into the small bowel to treat chronic idiopathic constipation. The ability of oral linaclotide to induce a pharmacodynamic response in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of 0.87 mg of oral linaclotide daily for 7 days to healthy …

A Novel Micro Cold Atmospheric Plasma Device For Glioblastoma Both In Vitro And In Vivo., Zhitong Chen, Hayk Simonyan, Xiaoqian Cheng, Eda Gjika, Li Lin, Jerome Canady, Jonathan H Sherman, Colin Young, Michael Keidar

Pharmacology and Physiology Faculty Publications

: Cold atmospheric plasma (CAP) treatment is a rapidly expanding and emerging technology for cancer treatment. Direct CAP jet irradiation is limited to the skin and it can also be invoked as a supplement therapy during surgery as it only causes cell death in the upper three to five cell layers. However, the current cannulas from which the plasma emanates are too large for intracranial applications. To enhance efficiency and expand the applicability of the CAP method for brain tumors and reduce the gas flow rate and size of the plasma jet, a novel micro-sized CAP device (µCAP) was developed …

Tumor Necrosis Factor Inhibitors In Psoriatic Arthritis., Santhi Mantravadi, Alexis Ogdie, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

INTRODUCTION: Psoriatic arthritis (PsA) is a chronic inflammatory disease that can result in significant disability. With the emergence of tumor necrosis factor inhibitors (TNFi), therapeutic outcomes in PsA have improved substantially. The clinical efficacy and the inhibition of radiographic progression demonstrated by TNFi have transformed the management of PsA. However, there is still an unmet need for a subset of patients who do not respond adequately to TNFi. Areas covered: This review provides an overview of the pharmacokinetics of TNFi, the efficacy of TNFi in PsA, and the role of immunogenicity of TNFi in the treatment of PsA. In addition, …

Pediatric Leukemia: Diagnosis To Treatment–A Review, Samantha C. Bernard, Ehab H. Abdelsamad, Paisley A. Johnson, Daniel L. Chapman, Madhukiran Parvathaneni

Faculty Works

Leukemia is cancer of the blood and bone marrow, it is the most common cancer found in children and is found to be more than one fourth of pediatric cancers. It causes white blood cells to become abnormal and the body to become weak. This deficiency in the immune system reduces the body's ability to fight infection or simple airborne illnesses, causing extensive treatment of common pathogens and cancer treatment. The present review covers all topics, from diagnosis to treatment of pediatric leukemia, as well as the stages of growth and physiological changes throughout the process. As leukemia has a …

Method For Alleviating Side Effects Of Retinoic Acid Therapy And/Or Improving Efficacy Without Interfering With Efficacy, Elaine L. Jacobson, Myron K. Jacobson, Russell Coyle, Hyuntae Kim, Donna L. Coyle

Pharmacology and Nutritional Sciences Faculty Patents

The invention relates to the use of nicotinic acid alkyl esters, especially myristyl nicotinate, to inhibit side effects associated with retinoic acid therapy. Also a part of the invention is a method for improving skin cell differentiation by administering the nicotinic acid alkyl ester in an amount sufficient to increase expression of caspase 14 and filaggrin. Deficiencies in expression of these molecules can be treated in this way as well.

The Nephrotoxicity Of Vancomycin., Edward J. Filippone, Walter K. Kraft, John L. Farber

Department of Medicine Faculty Papers

No abstract provided.

Comparing Nebivolol And Spironolactone In The Treatment Of Heart Failure With A Preserved Ejection Fraction, Caroline Joseph, Alison Fenter

Physician Assistant Capstones, 2016 to 2019

Objective: To assess the efficacy of improving diastolic dysfunction with the use of nebivolol, a selective beta-1 adrenergic receptor antagonist, as compared to spironolactone, a mineralocorticoid receptor antagonist, in the treatment of diastolic heart failure. To assess whether or not these medications have a favorable outcome in terms of improving exercise capacity in patients with Heart Failure with Preserved Ejection Fraction (HFpEF). Design: Systematic Literature Review. Methods: Searches in PubMed and the JMU online library database using mesh terms that included “diastolic heart failure”, “nebivolol”, and “spironolactone”. In order to narrow down relevant articles, filter terms included “humans”, …

Guanylate Cyclase C As A Target For Prevention, Detection, And Therapy In Colorectal Cancer., Allison A. Aka, Jeff A. Rappaport, Amanda M. Pattison, Takami Sato, Adam E. Snook, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

INTRODUCTION: Colorectal cancer remains the second leading cause of cancer death in the United States, and new strategies to prevent, detect, and treat the disease are needed. The receptor, guanylate cyclase C (GUCY2C), a tumor suppressor expressed by the intestinal epithelium, has emerged as a promising target. Areas covered: This review outlines the role of GUCY2C in tumorigenesis, and steps to translate GUCY2C-targeting schemes to the clinic. Endogenous GUCY2C-activating ligands disappear early in tumorigenesis, silencing its signaling axis and enabling transformation. Pre-clinical models support GUCY2C ligand supplementation as a novel disease prevention paradigm. With the recent FDA approval of the …