Medicine and Health Sciences Commons^™

Genetic Variations In A Cytochrome P450 Enzyme And The Effects On Clopidogrel Bioactivation And Metabolism, Maryanne Ventura, Lauren Desko, Kimberly Gathers, Ashley Overy, David Kisor

Pharmacy and Wellness Review

Clopidogrel, the top prescribed antiplatelet medication for individuals who have experienced a myocardial infarction or cerebral vascular accident or who have peripheral arterial disease, is administered orally as a prodrug. It relies on hepatic metabolism through cytochrome P450 enzymes for conversion to its active form. Current research shows that allelic variation m the gene coding for CYP2C19 is the main factor contributing to the variability of response associated with clopidogrel treatment. Through the promotion of genetic testing for variability in the CYP2C19 gene and competently interpreting test results, pharmacists have the opportunity to use these findings to significantly impact clopidogrel …

Pharmacogenomics: Your Medical Identity, Hilary Stewart, Lisa Berni, Tyler Bulcher, Joel Rittenhouse, Ryan W. Naseman, Jon E. Sprague

Pharmacy and Wellness Review

Pharmacogenomics, the fusion of pharmacology and genomics, shows strong potential to solve many of today's dosing problems. lnter-patient dosing requirements, mainly due to genetic variability between patients, represent significant challenges for prescribers. Certain receptors, drug-targeted proteins, drug-transport mechanisms and drug-metabolizing enzymes are genetically established. Hence, any defect, absence or abnormality in the gene could alter how an affected individual will respond to a given drug. Due to advancements in technology, health care professionals who utilize pharmacogenomics may assess a patient's genetic profile and determine a predicted response to specific medications. This may result in potentially optimal dosing at the onset …

Genetic Screening For Breast Cancer In The Primary Care Setting, Michael Nick Gomez

Doctor of Nursing Practice

The purpose of this project was to increase adherence to the U.S. Preventive Services Task Force and National Comprehensive Cancer Network guidelines for breast cancer screening and genetic testing. Screening for breast cancer risk factors including genetic testing helps reduce the incidence of breast cancer. A protocol was developed based on national clinical guidelines to increase screening and genetic testing for breast cancer. Provider responsibilities included screening all patients 18 years of age and older for risks factors of breast cancer, referring patients with a significant risk based on the screening for genetic testing and providing referrals for genetic counseling …

Msto1 Mutations Cause Mtdna Depletion, Manifesting As Muscular Dystrophy With Cerebellar Involvement., S Donkervoort, R Sabouny, P Yun, L Gauquelin, K R Chao, Y Hu, I Al Khatib, A Töpf, P Mohassel, B B Cummings, R Kaur, D Saade, S A Moore, L B Waddell, M A Farrar, J K Goodrich, P Uapinyoying, S H S Chan, A Javed, M E Leach, P Karachunski, J Dalton, L Medne, A Harper, C Thompson, Isabelle Thiffault, S Specht, R E Lamont, Carol J. Saunders, H Racher, F P Bernier, D Mowat, N Witting, J Vissing, R Hanson, Keith A. Coffman, Meagan K. Hainlen, J S Parboosingh, A Carnevale, G Yoon, R E Schnur, Care4rare Canada Consortium, K M Boycott, J K Mah, V Straub, A Reghan Foley, A M Innes, C G Bönnemann, T E Shutt

Manuscripts, Articles, Book Chapters and Other Papers

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA …

Identification And Molecular Analysis Of Dna In Exosomes, Jena Tavormina

Dissertations & Theses (Open Access)

Exosomes are heterogeneous nanoparticles 50-150nm in diameter. Exosomes contain many functional cargo components, such as protein, DNA, and RNA. While protein and RNA exosome content has been extensively studied, very little work has been done to characterize exosomal DNA. Here, we demonstrate that exosomal DNA is heterogeneous and its packaging into exosomes is dependent on the cell of origin. Furthermore, through a rigorous assessment of various isolation methods, we identify Size Exclusion Chromatography (SEC) as the best method for the isolation of exosomal DNA for downstream applications. Additionally, we evaluate the methylation status of exosomal DNA and demonstrate that exosomal …

A Systematic Comparison Of Lipopolymers For Sirna Delivery To Multiple Breast Cancer Cell Lines: In Vitro Studies, Hamidreza Montazeri Aliabadi, Remant Bahadur Kc, Emira Bousoik, Ashley Barbarino, Bindu Thapa, Melissa Coyle, Parvin Mahdipoor, Hasan Uludağ

Pharmacy Faculty Articles and Research

Small interfering RNA (siRNA) therapy is a promising approach for treatment of a wide range of cancers, including breast cancers that display variable phenotypic features. To explore the general utility of siRNA therapy to control aberrant expression of genes in breast cancer, we conducted a detailed analysis of siRNA delivery and silencing response in vitro in 6 separate breast cancer cell models (MDA-MB-231, MDA-MB-231-KRas-CRM, MCF-7, AU565, MDA-MB-435 and MDA-MB-468 cells). Using lipopolymers for siRNA complexation and delivery, we found a large variation in siRNA delivery efficiency depending on the specific lipopolymer used for siRNA complexation and delivery. Some lipopolymers were …

Nearly Complete Genome Sequences Of 17 Enterovirus D68 Strains From Kansas City, Missouri, 2018, Suman B. Pakala, Yi Tan, Ferdaus Hassan, Annie Mai, Robert H. Markowitz, Meghan H. Shilts, Seesandra V. Rajagopala, Rangaraj Selvarangan, Suman R. Das

Manuscripts, Articles, Book Chapters and Other Papers

Here, we report 17 nearly complete genome sequences of enterovirus D68 (EV-D68) isolated from Kansas City, MO, in 2018. Phylogenetic analysis suggests that these strains belong to subclade B3, similar to the ones that caused the 2016 epidemics in the United States but different from the 2014 outbreak B1 strains.

Acute Diagnosis Of Wilson’S Disease In A Teenage Patient, Sarah Irvin, Ryan Mccarthy

Marshall Journal of Medicine

Wilson’s Disease, a rare autosomal recessive genetic disease, is caused by a mutation in the ATP7B enzyme gene. Without this enzyme, copper builds up in the brain, liver, and cornea causing a multitude of symptoms. It is important to consider Wilson’s disease because the prognosis is dependent on timely diagnosis. This is an interesting case of a 19-year-old male who presented with suicidal thoughts and rapid weight loss. After many months and an extensive work-up, Wilson’s Disease was diagnosed. Due to his rapid decline, he was transferred to a larger university healthcare center where he is currently enrolled in clinical …

Genetic Predispositions To Opioid Addiction, Legislative Action And Implications To Pharmacy Practice, Adam N. Trimble, David N. Jones, Courtney L. Salvino, Michael M. Milks, David Kisor

Pharmacy and Wellness Review

Prescription pain-relievers can be powerfully effective agents in the treatment of moderate to severe pain; however, these drugs are also strongly associated with drug abuse and addiction. In the brain, opioid analgesics bind to various receptors in the mesocorticolimbic dopaminergic pathways, which play a multifaceted interaction of role in reward. Several specific single nucleotide polymorphisms (SNPs) have been identified as potential genetic factors that increase an individual's risk for addiction; however, confounding studies and lack of large trials prohibit definitive conclusions from being drawn. As a result of genetic testing, federal and state laws have been enacted to protect individuals …

Pharmacogenetics: Where Are We Now?, Brittany Dye, Megan Meyer, Vincent Wu, Michael D. Kaine

Pharmacy and Wellness Review

No abstract provided.

Antidepressant Dosing In Major Depression: A Pharmacogenomic Approach, Morgan Homan, Haval Norman, Victoria Cho, Yousif Rojeab

Pharmacy and Wellness Review

Major depressive disorder (MDD) is the most predominant mental disorder in the United States, with serious and costly health risks if not successfully managed. Pharmacotherapy is a standard option for MDD treatment, but patients often require extensive therapy adjustments to find a suitable regimen. Pharmacogenomics may enable greater precision in antidepressant therapy. Genotypic variations in CYP2D6 and CYP2C19 metabolic enzymes are reliable predictors of serum drug concentration, but the complex dose-response relationship of antidepressants prevents such variations from predicting therapy success. Additionally, ABCBl has been examined for its role in P-glycoprotein efflux of antidepressants in the brain, yet it is …

The Effect Of Cyp3a5 Polymorphism On Kidney Transplant Recipients Given Tacrolimus, Samia Alam, Sunitha Johns, Haval Norman, Brian Heilbronner, Yousif Rojeab

Pharmacy and Wellness Review

Tacrolimus, an immunosuppressant agent indicated for organ transplants, is commonly administered to reduce the risk of renal graft rejection in patients with chronic kidney disease (CKD) and end stage renal disease (ESRD). Due to its narrow therapeutic index and high inter-patient variability, studies have suggested that CYP3A5-based dosing provides specialized regimens which may significantly improve the chances of achieving therapeutic concentrations. According to the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations, extensive (CYP3A5*1/*1) and intermediate metabolizers (CYP3A5*1/*3) require a higher initial dose while poor metabolizers (CYP3A5*3/*3) require a lower initial dose in order to achieve target tacrolimus concentrations. Studies concluded that …

Programmed Death Pathway Inhibition: Emerging Therapeutic Options For Treatment Of Advanced Or Refractory Cancers, Katherine Elsass, Morgan Homan, Jana Randolph, Brendan Rasor, David Kinder

Pharmacy and Wellness Review

The programmed death-1 (PD-1) pathway has a significant role in the promotion of immune tolerance. The PD-1 receptor ligands are normally expressed on various inactive immune cells. When cancer cells express these ligands, they are able to interact with active T and B lymphocytes to induce this tolerance. Nivolumab and pembrolizumab are two recently approved agents that act to disrupt this binding and facilitate an immune response against cancer cells. Numerous trials, including KEYNOTE-002 and CheckMate 063, have demonstrated the superior safety and efficacy of these drugs in patients with advanced or refractory cancers. Initially approved for the treatment of …

Pharmacogenetics: Cyps, Nat2 And 5-Htt Related To Antidepressants, Molly Kulp, Armond Cosiano, Kevin Krivanek, Amanda Lanker, Taylor Roberson, David F. Kisor

Pharmacy and Wellness Review

Pharmacogenetics (PGt), the study of a gene's influence on patient response to a drug, shows strong potential for explaining issues with efficacy related to antidepressant medications. Each year, antidepressants are one of the most commonly prescribed medications due to the millions of Americans affected by depression. Importantly, it is recognized that there is wide interpatient variability in drug response to antidepressants caused by genetic mutations, which can alter the pharmacodynamic (PD) and pharmacokinetic (PK) properties of various drugs used to treat depression. Proteins that are mainly involved in how patients respond to medications include receptors, drug-targeted proteins, drug transport proteins …

Phenoconversion: Drug-Drug-Gene Interactions, Molly Kulp, Emily Limberg, Brooke Marlowe, Taylor Roberson, David F. Kisor

Pharmacy and Wellness Review

Based on the extensive, poor, intermediate and ultrarapid phenotypes of patients, inferences may be made relative to drug metabolism, ultimately leading to changes in therapeutic drug choice or dosing. Phenoconversion is a phenomenon that occurs when an individual's drug metabolizing capacity is altered due to the combination of a drug-drug interaction and a drug-gene interaction. Phenoconversion can affect pharmacokinetics as well as pharmacodynamics. Some examples of phenoconversions include amiodarone-warfarin, duloxetine-codeine, rifampin-clopidogrel, and rifampinwarfarin. Pharmacists must consider phenoconversion in cases of multi-drug therapy.

Overview Of Kalydeco® (Ivacaftor) For Treatment Of Cystic Fibrosis, Andrew Skouby, Kayti Kintner, Kimberly Loughlin, Emily Blum, Michael Rush

Pharmacy and Wellness Review

Cystic fibrosis (CF) is a genetic disease associated with specific gene mutations that presents with pulmonary inflammation and frequent lung infections, exocrine pancreatic insufficiency, altered sweat composition and declining lung function. Ivacaftor (Kalydeco®) was approved for treatment of cystic fibrosis in patients 6 years of age and older with a G551D mutation on the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a CFTR potentiator and does not work in patients with a mutation of the F508del. Efficacy has been demonstrated in several trials with a primary outcome of improved FEV1, improvements in pulmonary exacerbations, patient-reported decrease in respiratory …

Ado-Trastuzumab Emtansine For Her2 Positive Breast Cancer, Kimberly Baucher, Taylor Beale, Maria Laikos, Eric Stack, Mary Ellen Hethcox

Pharmacy and Wellness Review

No abstract provided.

Use Of Pharmacogenomics In Mtm Services, Molly Kulp, Halle Orlinski, Zachary R. Jones, Zachary Crawford, David Kisor

Pharmacy and Wellness Review

Incorporation of pharmacogenomic data into Medication Therapy Management (MTM) allows pharmacists to optimize treatment regimens for patients leading to better overall outcomes. Utilizing pharmacogenomics makes it easier for health care professionals to initiate medication regimens with reduced adverse reactions, improves outcomes due to specialized dosing and therapies and allows the treatment process to be as cost-effective as possible for the patient. Pharmacists have an opportunity to educate the rest of the health care team on issues such as: which ethnicities possess higher odds of carrying certain genetic variants, the most common or most relevant medications that can have variable effects …

The Impact Of Pharmacogenomics On Chemotherapeutic Drug Development And Use, Lara Long, Amy Pasternak, Ellen Hazelet, David Kisor

Pharmacy and Wellness Review

Cancer therapy is largely dependent on general treatment guidelines, and patients undergoing chemotherapy often experience treatment failure with standard drugs. The development of individualized drug therapy through pharmacogenomics has the potential to enhance chemotherapy regimen selection and improve patient outcomes. Antineoplastic agents such as cetuximab and trastuzumab are effective in treating cancers possessing specific genetic biomarker characteristics. Patients need to undergo genetic testing before these agents are administered to ensure appropriate use. Cetuximab has been shown to improve outcomes in metastatic colorectal cancers and head and neck squamous cell carcinomas positive for EGFR. Trastuzumab has shown benefit in human epidermal …

The Pharmacogenetics Of Opioid Pain Management, Maryanne Ventura, Lauren Desko, Kimberly Gathers, Ashley Overy, David Kisor

Pharmacy and Wellness Review

High rates of interpatient variability in drug metabolism and drug response for nearly all medications lead to the hypothesis that assessment of an individual patient's genotype with respect to their ability metabolize certain drugs can be a useful tool in predicting a patient's responsiveness to certain medications. Evaluating patients using pharmacogenomics as a basis for assessment could allow pharmacists to decide which treatment options would be most efficacious in a given patient and, thereby, have significant impact in the clinical setting. This holds true especially in the case of prodrugs, which require in vivo activation to an active or more …

Preparing For The Genomic Age: Thiopurine S-Methytransferase Polymorphism, Hilary Stewart, Lisa Berni, Tyler Bulcher, Joel Rittenhouse, Ryan W. Naseman

Pharmacy and Wellness Review

Interpatient variability among medication doses has been a long-standing obstacle for many prescribers. Some medications result in increased morbidity and mortality in a small percentage of the population. For many years, the cause of such toxicities was unknown. This mystery has been resolved by the discovery that the abscence or abnormality of specific genes that code for receptros, drug-treated proteins, drug transport mechanisms, and drug metabolizing enzymes could alter how an affected individual will respond to a given drug. One such incidence is the genetic polymorphism in thiopurine s-methytransferase (TPMT). In comprehending the mechanism of this polymorphism, it is important …

Eugenics In The 21st Century, Jessica Linn Chin

Dissertations, Theses, and Capstone Projects

Eugenics is the science of enhancing the human population through the management of breeding and hereditary traits. This thesis explores the history of eugenics and shows how eugenic practices continue in the 21^st century with advancements in technology and positive eugenic goals that can result in adverse effects on the human body and society. When Sir Francis Galton coined the term eugenics in 1883, he intended to improve British society with the use of positive eugenics. Galton used positive eugenics to encourage people with good mental and physical qualities to produce more children. He avoided negative eugenics, which involved …

Screening And Diagnosing Spinal Muscular Atrophy By Use Of Buccal Swabs: A Validation Study Using Ddpcr, Anna Mackay

Honors Scholar Theses

Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder characterized by progressive muscle weakness due to the degeneration of motor neurons. SMA is caused by a homozygous deletion, mutation or rearrangement in the Survival Motor Neuron 1 (SMN1) gene. Survival Motor Neuron 2 (SMN2) is located tandem to SMN1 and is identical to SMN1 except for a single nucleotide substitution in exon 7. SMA diagnosis and carrier status can be determined by droplet digital PCR (ddPCR). This study sought to validate Bio-Rad’s ddPCR SMN1and SMN2 gene determination copy number assay for SMA diagnosis and screening using buccal swabs specimens. Buccal …

Predicting Premature Birth Risk With Cfrna, Jason Lin, Jonathan Marin, John Santerre

SMU Data Science Review

Identifying which genes are early indicators for preterm births using cell-free ribonucleic acid (cfRNA) from non-invasive blood tests provided by pregnant women can improve prenatal care. Currently, there are no medical tests for early detection of preterm birth risk in routine checkups for pregnant women. Recent studies have shown potential genes that can predict preterm birth. Machine learning techniques are utilized to see if the Area Under the Curve (AUC) can be improved upon when evaluating the prediction accuracy for chosen genes sequences and concentrations. Using cell-free RNA data from non-invasive blood tests in conjunction with machine learning, we improve …

Rheumatoid Arthritis-Relevant Dna Methylation Changes Identified In Acpa-Positive Asymptomatic Individuals Using Methylome Capture Sequencing., Xiaojian Shao, Marie Hudson, Ines Colmegna, Celia M T Greenwood, Marvin J. Fritzler, Philip Awadalla, T Pastinen, Sasha Bernatsky

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk.

METHODS: With banked serum from a random subset (N = 3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. …

New Insights Into Dna Methylation Signatures: Smarca2 Variants In Nicolaides-Baraitser Syndrome., Eric Chater-Diehl, Resham Ejaz, Cheryl Cytrynbaum, Michelle T. Siu, Andrei Turinsky, Sanaa Choufani, Sarah J. Goodman, Omar Abdul-Rahman, Melanie Bedford, Naghmeh Dorrani, Kendra Engleman, Josue Flores-Daboub, David Genevieve, Roberto Mendoza-Londono, Wendy Meschino, Laurence Perrin, Nicole Safina, Sharron Townshend, Stephen W. Scherer, Evdokia Anagnostou, Amelie Piton, Matthew Deardorff, Michael Brudno, David Chitayat, Rosanna Weksberg

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a neurodevelopmental disorder caused by pathogenic sequence variants in SMARCA2 which encodes the catalytic component of the chromatin remodeling BAF complex. Pathogenic variants in genes that encode epigenetic regulators have been associated with genome-wide changes in DNA methylation (DNAm) in affected individuals termed DNAm signatures.

METHODS: Genome-wide DNAm was assessed in whole-blood samples from the individuals with pathogenic SMARCA2 variants and NCBRS diagnosis (n = 8) compared to neurotypical controls (n = 23) using the Illumina MethylationEPIC array. Differential methylated CpGs between groups (DNAm signature) were identified and used to generate a model enabling classification …

Integrative Analysis Of Vascular Endothelial Cell Genomic Features Identifies Aida As A Coronary Artery Disease Candidate Gene., Simon Lalonde, Valérie-Anne Codina-Fauteux, Sébastian Méric De Bellefon, Francis Leblanc, Mélissa Beaudoin, Marie-Michelle Simon, Rola Dali, Tony Kwan, Ken Sin Lo, T Pastinen, Guillaume Lettre

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD) and blood pressure (BP) or hypertension. Many of these loci are not linked to traditional risk factors, nor do they include obvious candidate genes, complicating their functional characterization. We hypothesize that many GWAS loci associated with vascular diseases modulate endothelial functions. Endothelial cells play critical roles in regulating vascular homeostasis, such as roles in forming a selective barrier, inflammation, hemostasis, and vascular tone, and endothelial dysfunction is a hallmark of atherosclerosis and hypertension. To test this hypothesis, we generate an integrated map of gene …

Updated Genes, Lifestyles, And Their Interactions For Human Longevity, Brenda Bin Su, Alexis Villafranca, Chunxiang Mao, Stephanie Hernandez, Stephanie Lozano, Masoud M. Zarei, Kesheng Wang, Saraswathy Nair, Chun Xu

Health & Biomedical Sciences Faculty Publications and Presentations

Healthy aging is the prolonging of optimal wellbeing during the progressive decline in physiological functions that are necessary for survival. Two important components of aging include an individual’s genetic makeup and lifestyle choices such as diet and exercise. Genetic factors are responsible for the functional physiology of the body including cell maintenance, metabolism and apoptosis. The individual effects of genes and lifestyle choices on aging are reported mainly in Caucasian populations, with very limited studies in minority populations. In this review, we included the effects of genes and environment and the interaction between them on aging in Hispanic population in …

Autoimmune Polyglandular Syndrome Type 1: A Case Report And Brief Review., Ifeanyi Nwosu, Oreoluwa Oladiran, Chinyere Ogbonna-Nwosu, Anulika Anyata

Reading Hospital Internal Medicine Residency

Autoimmune polyglandular syndrome (APS) type 1 is a rare autoimmune disorder inherited in an autosomal recessive pattern due to loss of function of the AIRE gene and defective removal of self-reactive T-lymphocytes during the process of thymic T cell maturation. Its manifestation starts early in life with the cardinal clinical disorders being one of muco-cutaneous candidiasis, Addison's disease, and hypoparathyroidism. Recognizing the syndromic nature of one autoimmune disease will facilitate an active search for other conditions which would allow early detection, management, follow-up, and most importantly patient education and counselling to avoid potential complications. We present the case of a …

Cyclin C Regulated Oxidative Stress Responsive Transcriptome In Mus Musculus Embryonic Fibroblasts, David C Stieg, Kai-Ti Chang, Katrina F Cooper, Randy Strich

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The transcriptional changes that occur in response to oxidative stress help direct the decision to maintain cell viability or enter a cell death pathway. Cyclin C-Cdk8 is a conserved kinase that associates with the RNA polymerase II Mediator complex that stimulates or represses transcription depending on the locus. In response to oxidative stress, cyclin C, but not Cdk8, displays partial translocation into the cytoplasm. These findings open the possibility that cyclin C relocalization is a regulatory mechanism governing oxidative stress-induced transcriptional changes. In the present study, the cyclin C-dependent transcriptome was determined and compared to transcriptional changes occurring in oxidatively …