Pharmacy and Pharmaceutical Sciences Commons^™

Alopecia As An Early Clinical Marker For Azathioprine Induced Myelosuppression: A Case Report, Nilanjana Dutta , Final Year Mbbs, Dr. M Suresh Babu , Professor, Dr. Subramanian Ramaswamy , Professor, Dr. Mahabaleshwar Mamadapur , Assistant Professor

Digital Journal of Clinical Medicine

Azathioprine is a pro-drug and is metabolized by the TPMT enzyme in the body. In South Asians, Azathioprine is known to cause alopecia and bone marrow suppression in patients with TPMT enzyme deficiency. In India, the prevalence of TPMT mutation varies from 1.2- 10%. A new mutation was detected in 2014, NUDT15 whose incidence varies from 8.5-16%. Patients with mutation in both TPMT and NUDT15 develop myelosuppression faster. In our case, alopecia manifested as the first clinical feature of Azathioprine myelosuppression. Physicians need to recognize early clinical clues (alopecia) to avoid the impending development of myelosuppression and to look for …

Effects Of B4galnt1 Expression On Metastatic Phenotype And Response To Treatment In Osteosarcoma Cell Lines, Fatemeh Zareihajiabadi

Annual Research Symposium

No abstract provided.

Genetic And Pharmacogenetics Associations Of Cancer Disparities In Appalachia, Nan Lin

Theses and Dissertations--Pharmacy

Individuals residing in Appalachian regions have significant health disparities, including higher cancer incidence and mortality rates. Previous studies have addressed the impact of socioeconomic status and environmental risk factors on Appalachia cancer disparities, while few studies have evaluated genetic risk factors.

Germline whole exome sequencing samples from 7,078 individuals with cancer (759 Appalachians) were evaluated. Demographics and relatedness were assessed using KING. Ethnicity was verified by principal component analysis using TRACE, which included 6,034 individuals (85%) of European genetic ancestry. After QC filtering, 5,980 individuals were analyzed. To assess the overall predisposition of hereditary disease, gene level frequency of likely …

The Large And Small Of It: The Microbiome And Metagenomics, Austin Hopkins, Elaina Gollmar, Jessica Fernandez, Shawn Wolf, Austin Hilverding, Andrew M. Roecker

Pharmacy and Wellness Review

Metagenomics, the analysis of the microbial genome, permits scientists to understand the influences of external sources including diet, metabolism and antibiotics on the human microbiome. Research has revealed the possibility of a core symbiosis between humans and bacteria. The main role of the human microbiome is to aid in digestion, but identified ancillary roles include immunologic homeostasis and infection prevention. Quantifying the composition and variability of the microbiome will help lead to future treatments or preventive strategies against unhealthy change. A variety of methods may be used to define the microbiome, and 16S amplicon sequencing is primarily utilized today. Probiotics …

Characterization Of The Growth Factor Receptor Network Oncogenes In Lung Cancer, Ashley Duche

Pharmaceutical Sciences (MS) Theses

Lung cancer remains the leading cause of cancer related deaths worldwide, reportedly contributing to 1.8 million of the 10.0 million mortalities documented in the year 2020. Although advancements have been made in therapeutics and diagnostic methods, formulation of effective treatments and development of drug resistance continues to be a challenge. These challenges arise from our lack of understanding of intricate signaling pathways, such as the Growth Factor Receptor Network (GFRN), which contributes to complex lung tumor heterogeneity allowing for drug resistance development. In this study, gene expression signatures of six GFRN oncogenes overexpressed in human mammary epithelial cells (HMECs) were …

Comprehensive Analysis Of Nac Transcription Factor Family Uncovers Drought And Salinity Stress Response In Pearl Millet (Pennisetum Glaucum), Ambika Dudhate, Harshraj Shinde, Pei Yu, Daisuke Tsugama, Shashi Kumar Gupta, Shenkui Liu, Tetsuo Takano

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Pearl millet (Pennisetum glaucum) is a cereal crop that possesses the ability to withstand drought, salinity and high temperature stresses. The NAC [NAM (No Apical Meristem), ATAF1 (Arabidopsis thaliana Activation Factor 1), and CUC2 (Cup-shaped Cotyledon)] transcription factor family is one of the largest transcription factor families in plants. NAC family members are known to regulate plant growth and abiotic stress response. Currently, no reports are available on the functions of the NAC family in pearl millet.

RESULTS: Our genome-wide analysis found 151 NAC transcription factor genes (PgNACs) in the pearl millet genome. Thirty-eight …

Pharmacogenomics And Ssris Appropriateness In Older Community Dwelling African Americans, Wint War Phyo, Lana Sargent, Elvin T. Price

Graduate Research Posters

Background: Depressive and anxiety disorders are among the most common illnesses experienced by older adults (age > 60). The selective serotonin reuptake inhibitors (SSRIs) are preferred class of antidepressants for these disorders due to their high efficacy and safety profiles among older adults. However, SSRIs are metabolized by highly polymorphic cytochrome P450 enzymes, specifically CYP2D6 and CYP2C19. This can lead to variable dose-response outcomes, especially among older African American population.

Objective: Analyze the frequency of CYP2D6 and CYP2C19 polymorphisms in African American older adults who are taking SSRIs and identify potential inappropriate use of SSRIs in these older adults using the …

Multi-Generational Effects Of ∆9-Tetrahydrocannabinol Exposure On Gene Expression In Liver Tissue, Kayla Lovitt

Honors Theses

Cannabis is the most commonly used, cultivated, and trafficked illicit drug worldwide. Increased availability and acceptance of cannabis and cannabinoid-containing products provide the necessity for understanding how these substances influence aging. In this study, zebrafish (Danio rerio) were exposed to concentrations of Δ⁹-tetrahydrocannabinol (THC) (0.08, 0.4, 2 µM) during embryonic-larval development, the effects on aging were measured 30 months later and in the offspring of the exposed fish (F1 generation. We observed results indicating a biphasic and hormetic effect. Treatment with the lowest concentration of THC significantly increased egg production, while higher concentrations resulted in impaired …

Combination Of Investigational Cell-Based Therapy And Deep Brain Stimulation To Alter The Progression Of Parkinson’S Disease, Nader El Seblani

Theses and Dissertations--Pharmacy

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the motor symptoms are caused by progressive loss of midbrain dopamine neurons. There is no current treatment that can slow or reverse PD. Our current “DBS-Plus” clinical trial (NCT02369003) features the implantation in vivo of autologous Schwann cells (SCs) derived from a patient’s sural nerve into the substantia nigra pars compacta (SNpc) in combination with Deep Brain Stimulation (DBS) therapy for treating patients with advanced PD.

The central hypothesis of our research is that transdifferentiated SCs within conditioned nerve tissue will deliver pro-regenerative factors to enhance the survival of …

Ndrg1 And Myelin-Related Disease: Alcoholism And Chemotherapy-Induced Neuropathy, Guy Harris

Theses and Dissertations

Alcohol use disorder (AUD) is a prevalent neuropsychiatric disease with profound health, social, and economic consequences. With an estimated 50% heritability, identifying genes that engender risk and contribute to the underlying neurobiological mechanisms represents an important first step in developing effective treatments. Gene expression studies are an important source of candidate genes for studying AUD, providing windows into the molecular machinery engaged by the brain in response to ethanol. Our laboratory has implicated N-myc down-regulated gene 1 (Ndrg1) as a potential candidate gene that modulates ethanol-induced changes in myelin-related gene expression and acute sensitivity to ethanol. Analysis of …

Epigenetic Regulation Of Drug Metabolizing Enzymes In Normal Aging, Mohamad M. Kronfol

Theses and Dissertations

Geriatric populations are at a higher risk for adverse drug reactions (ADRs). This may be partly due to changes in drug metabolism in old age, but the underlying mechanisms are poorly understood. Prior research in humans and mice has shown age-associated changes to the expression of several genes involved in drug metabolism. Furthermore, studies of human blood showed that epigenetic regulation of genes encoding drug metabolizing enzymes change with age. However, it is unknown if genes in the liver are similarly affected. Therefore, we hypothesize that genes encoding drug metabolizing enzymes may show differential epigenetic regulation in the liver with …

Cellular Localization Of Rad51d Mutant Proteins And The Application Of Art To Increase Scientific Literacy In America, Claire L. Chabot

Senior Theses

Ovarian cancers are the leading cause of death from cancer of the female reproductive system. Approximately 50% of ovarian cancers have defects in the homologous recombination (HR) DNA repair pathway that is required for the repair of DNA double-stranded breaks. The status of HR genes, such as BRCA1, BRCA2, and the RAD51 family, contributes to ovarian cancer development as well as treatment decisions regarding chemotherapy, radiation, and immunotherapy. The overarching goal of this project is to identify new insights into HR that can integrate with Precision Medicine Initiatives and align with the goals of the Cancer Moonshot 2020 Program. I …

Morphometric Characteristics And Time To Hatch As Efficacious Indicators For Potential Nanotoxicity Assay In Zebrafish, Seyed-Mohammadreza Samaee, Nafiseh Manteghi, Robert A. Yokel, Mohammad Reza Mohajeri-Tehrani

Pharmaceutical Sciences Faculty Publications

Although the effects of nano-sized titania (nTiO₂) on hatching events (change in hatching time and total hatching) in zebrafish have been reported, additional consequences of nTiO₂ exposure (i.e., the effects of nTiO₂-induced changes in hatching events and morphometric parameters on embryo-larvae development and survivability) have not been reported. To address this knowledge gap, embryos 4 h postfertilization were exposed to nTiO₂ (0, 0.01, 10, and 1000 μg/mL) for 220 h. Hatching rate (58, 82, and 106 h postexposure [hpe]), survival rate (8 times from 34 to 202 hpe), and 21 morphometric characteristics (8 times …

Gaw20: Methods And Strategies For The New Frontiers Of Epigenetics And Pharmacogenomics, Nathan L. Tintle, David W. Fardo, Marzia De Andrade, Stella Aslibekyan, Julia N. Bailey, Justo Lorenzo Bermejo, Rita M. Cantor, Saurabh Ghosh, Philip Melton, Xuexua Wang, Jean W. Maccluer, Laura Almasy

Biostatistics Faculty Publications

GAW20 provided a platform for developing and evaluating statistical methods to analyze human lipid-related phenotypes, DNA methylation, and single-nucleotide markers in a study involving a pharmaceutical intervention. In this article, we present an overview of the data sets and the contributions analyzing these data. The data, donated by the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) investigators, included data from 188 families (N = 1105) which included genome-wide DNA methylation data before and after a 3-week treatment with fenofibrate, single-nucleotide polymorphisms, metabolic syndrome components before and after treatment, and a variety of covariates. The contributions from individual …

Bioinformatic Analysis Of Endogenous And Exogenous Small Rnas On Lipoproteins, Ryan M. Allen, Shilin Zhao, Marisol A. Ramirez Solano, Wanying Zhu, Danielle L. Michell, Yuhuan Wang, Yu Shyr, Praveen Sethupathy, Macrae F. Linton, Gregory A. Graf, Quanhu Sheng, Kasey C. Vickers

Pharmaceutical Sciences Faculty Publications

To comprehensively study extracellular small RNAs (sRNA) by sequencing (sRNA-seq), we developed a novel pipeline to overcome current limitations in analysis entitled, “Tools for Integrative Genome analysis of Extracellular sRNAs (TIGER)”. To demonstrate the power of this tool, sRNA-seq was performed on mouse lipoproteins, bile, urine and livers. A key advance for the TIGER pipeline is the ability to analyse both host and non-host sRNAs at genomic, parent RNA and individual fragment levels. TIGER was able to identify approximately 60% of sRNAs on lipoproteins and >85% of sRNAs in liver, bile and urine, a significant advance compared to existing software. …

Polygenic Scores For Metabolic Traits And Related Drug Prescriptions In The Michigan Genomics Initiative, Samuel K. Handelman, Xiaomeng Du, Yanhua H. Chen, Elizabeth K. Speliotes

Biology and Medicine Through Mathematics Conference

No abstract provided.

Genetic Variants In Hsd17b3, Smad3, And Ipo11 Impact Circulating Lipids In Response To Fenofibrate In Individuals With Type 2 Diabetes, Daniel M. Rotroff, Sonja S. Pijut, Skylar W. Marvel, John R. Jack, Tammy M. Havener, Aurora Pujol, Agatha Schluter, Gregory A. Graf, Henry N. Ginsberg, Hetal S. Shah, He Gao, Mario-Luca Morieri, Alessandro Doria, Josyf C. Mychaleckyi, Howard L. Mcleod, John B. Buse, Michael J. Wagner, Alison A. Motsinger-Reif, Accord/Accordion Investigators

Pharmaceutical Sciences Faculty Publications

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin‐treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed‐up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10^‐6). Rare variant and gene expression changes …

Spontaneous Dna Damage To The Nuclear Genome Promotes Senescence, T Redox Imbalance And Aging, Andria R. Robinson, Matthew J. Yousefzadeh, Tania A. Rozgaja, Jin Wang, Xuesen Li, Jeremy S. Tilstra, Chelsea H. Feldman, Siobhan Q. Gregg, Caroline H. Johnson, Erin M. Skoda, Marie-Celine Frantz, Harris Bell-Temin, Hannah Pope-Varsalona, Aditi U. Gurkar, Luigi A. Nasto, Rena A.S. Robinson, Heike Fuhrmann-Stroissnigg, Jolanta Czerwinska, Sara J. Mcgowan, Nadiezhda Cantu-Madellin, Jamie B. Harris, Salony Maniar, Mark A. Ross, Christy E. Trussoni, Nicholas F. Larusso, Eugenia Cifuentes-Pagano, Patrick J. Pagano, Barbara Tudek, Nam V. Vo, Lora H. Rigatti, Patricia L. Opresko, Donna B. Stolz, Simon C. Watkins, Christin E. Burd, Claudette M. St, Croix, Gary Siuzdak, Nathan A. Yates, Paul D. Robbins, Yinsheng Wang, Peter Wipf, Eric E. Kelley, Laura J. Neidernhofer

Faculty & Staff Scholarship

Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1-/Δ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/Δ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1-/Δ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1-/Δ mice never exceeded that …

Macrophage Sensing Of Single- Walled Carbon Nanotubes Via Toll- Like Receptors, Sourav P. Mukherjee, Olesja Bondarenko, Pekka Kohonen, Fernando T. Andon, Tana Brzicova, Isabel Gessner, Sanjay Mathur, Massimo Bottini, Paolo Calligari, Lorenzo Stella, Elena Kisin, Anna Shvedova, Reija Autio, Heli Salminen-Mankonen, Ritta Lahesmaa, Bengt Fadeel

Faculty & Staff Scholarship

Carbon-based nanomaterials including carbon nanotubes (CNTs) have been shown to trigger

inflammation. However, how these materials are ‘sensed’ by immune cells is not known. Here we compared the effects of two carbon-based nanomaterials, single-walled CNTs (SWCNTs) and graphene oxide (GO), on primary human monocyte-derived macrophages. Genome-wide transcriptomics assessment was performed at sub-cytotoxic doses. Pathway analysis of the microarray data revealed pronounced effects on chemokine-encoding genes in macrophages exposed to SWCNTs, but not in response to GO, and these results were validated by multiplex array-based cytokine and chemokine profiling. Conditioned medium from SWCNT-exposed cells acted as a chemoattractant for dendritic cells. …

The Molecular Basis Of Talin2'S High Affinity Toward Β1-Integrin, Yaxia Yuan, Liqing Li, Yanyan Zhu, Lei Qi, Latifeh Azizi, Vesa P. Hytönen, Chang-Guo Zhan, Cai Huang

Molecular Modeling and Biopharmaceutical Center Faculty Publications

Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β–integrin tails. Also, substitution of talin1 C336 with Ser enhanced the affinity of talin1, whereas substitution of talin2 S339 with …

Living With Fragile X Syndrome: Occupations As An Outcome Measure In A Clinical Trial, Kaylee E. Gothelf, Ty Duong, Ana Baldinger, Theresa Chase

Student Research Posters

The purpose of this study was to evaluate the use of semi-structured interviews as an outcome measure in a clinical trial for children with fragile X syndrome (FXS) ages 2-6. This qualitative approach was used to analyze twenty-five interviews of parents with children in a double-blind medication trial - sertraline or placebo. The aim was to assess occupational improvements in their child that may not have been detected with the use quantitative outcome measures alone. Results showed greater improvements in the sertraline group in areas of behavior, social participation, sensory-related behaviors, receptive language, education, family impact and therapeutic strategies. Our …

Hiv Vaccines: Progress, Limitations And A Crispr/Cas9 Vaccine, Omar A. Garcia Martinez

Biology: Student Scholarship & Creative Works

ABSTRACT: The HIV-1 pandemic continues to thrive due to ineffective HIV-1 vaccines. Historically, the world’s most infectious diseases, such as polio and smallpox, have been eradicated or have come close to eradication due to the advent of effective vaccines. Highly active antiretroviral therapy is able to delay the onset of AIDS but can neither rid the body of HIV-1 proviral DNA nor prevent further transmission. A prophylactic vaccine that prevents the various mechanisms HIV-1 has to evade and attack our immune system is needed to end the HIV-1 pandemic. Recent advances in engineered nuclease systems, like the CRISPR/Cas9 system, have …

Engineering A Mutation In The Heparin Binding Pocket Of The Human Fibroblast Growth Factor, Roshni Patel

Chemistry & Biochemistry Undergraduate Honors Theses

Fibroblast growth factors (FGFs) are family of proteins that belong to a group of growth factors that are found in mammals and play an important role in angiogenesis, differentiation, organogenesis, and tissue repair. In summary, their main functionality is involved in cell division and proliferation. Because FGFs plays such a vital role in cell proliferation, they are mainly involved in the process of wound healing and injuries. FGF binds to its ligand, heparin—a heavily sulfated glycosaminoglycan. The binding of heparin to FGF occurs through electrostatic interactions, specifically between the negatively charged sulfate groups on heparin and positively charged residues such …

Nucleosome Distortion As A Possible Mechanism Of Transcription Activation Domain Function, Tamara Y. Erkina, Alexandre M. Erkine

Scholarship and Professional Work – COPHS

After more than three decades since the discovery of transcription activation domains (ADs) in gene-specific activators, the mechanism of their function remains enigmatic. The widely accepted model of direct recruitment by ADs of co-activators and basal transcriptional machinery components, however, is not always compatible with the short size yet very high degree of sequence randomness and intrinsic structural disorder of natural and synthetic ADs. In this review, we formulate the basis for an alternative and complementary model, whereby sequence randomness and intrinsic structural disorder of ADs are necessary for transient distorting interactions with promoter nucleosomes, triggering promoter nucleosome translocation and …

Target-Directed Biosynthetic Evolution: Redirecting Plant Evolution To Genomically Optimize A Plant’S Pharmacological Profile, Dustin Paul Brown

Theses and Dissertations--Neuroscience

The dissertation describes a novel method for plant drug discovery based on mutation and selection of plant cells. Despite the industry focus on chemical synthesis, plants remain a source of potent and complex bioactive metabolites. Many of these have evolved as defensive compounds targeted on key proteins in the CNS of herbivorous insects, for example the insect dopamine transporter (DAT). Because of homology with the human DAT protein some of these metabolites have high abuse potential, but others may be valuable in treating drug dependence. This dissertation redirects the evolution of a native Lobelia species toward metabolites with greater activity …

Identification And Characterization Of Cysteine Protease Genes In Tobacco For Use In Recombinant Protein Production, Kishor Duwadi

Electronic Thesis and Dissertation Repository

Plants are an attractive host system for pharmaceutical protein production. Many therapeutic proteins have been produced and scaled up in plants at a low cost compared to the conventional microbial and animal based systems. The main technical challenge during this process is to produce sufficient level of proteins in plants. Low yield is generally caused by proteolytic degradation during expression and downstream processing of recombinant proteins. The yield of a human therapeutic protein interleukin (IL) -10 produced in transgenic tobacco leaves was found to be below the critical level, and is potentially due to degradation by tobacco cysteine proteases (CysPs). …

Childhood Obesity And Familial Hypercholesterolemia: Genetic Diseases That Contribute To Cardiovascular Disease, Alyssa Caudle

Senior Honors Theses

Childhood obesity occurs as the result of an imbalance between caloric intake and energy expenditure. Genetic risk factors for obesity have become an area of research due to its permanency. Mutated genes such as Fat Mass and Obesity Associated (FTO), Leptin (LEP), Leptin Receptor (LEPR), Melanocortin 4 Receptor (MC4R), Adiponectin C1Q and Collagen Domain Containing (ADIPOQ), Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1), and Peroxisome Proliferator-Activated Receptor Gamma (PPARG) all contribute to the development of childhood obesity. In the presence of high cholesterol caused by obesity, the genetic condition known as familial hypercholesterolemia is exacerbated. Familial hypercholesterolemia is caused by a …

Development Of Tools To Assess The Effects Of Lunasin On Normal Development And Tumor Progression In Drosophila Melanogaster, Gillian E. Jones

Masters Theses & Specialist Projects

Soy contains many bioactive molecules known to elicit anti-cancer effects. One such peptide, Lunasin, has been shown to selectively act on newly transformed cells while having no cytotoxic effect on non-tumorigenic or established cancer cell lines. In this study we attempt to understand the developmental effects of Lunasin overexpression in vivo and create reagents that will help us understand Lunasin’s anti tumorigenic effects in an intact organism. cDNA encoding lunasin and EGFP-lunasin were cloned into pUAST and microinjected into Drosophila embryos. Tissue-specific overexpression of EGFP-Lun in the resulting transgenic lines was accomplished by crossing transgenics to various GAL4 driver lines. …

Functional Interplay Between Chromatin Remodeling Complexes Rsc, Swi/Snf And Iswi In Regulation Of Yeast Heat Shock Genes, Tamara Y. Erkina, Y. Zou, S. Freeling, V. I. Vorobyev, Alexander M. Erkine

Scholarship and Professional Work – COPHS

Chromatin remodeling is an essential part of transcription initiation. We show that at heat shock gene promoters functional interactions between individual ATP-dependent chromatin remodeling complexes play critical role in both nucleosome displacement and Pol II recruitment. Using HSP12, HSP82 and SSA4 gene promoters as reporters, we demonstrated that while inactivation of SNF2, a critical ATPase of the SWI/SNF complex, primarily affects the HSP12 promoter, depletion of STH1- a SNF2 homolog from the RSC complex reduces histone displacement and abolishes the Pol II recruitment at all three promoters. From these results, we conclude that redundancy between SWI/SNF and RSC complexes …

Ppar Agonists Down-Regulate The Expression Of Atp10c Mrna During Adipogenesis, A Peretich, Maria Cekanova Ms, Rndr, Phd, S Hurst, Sj Baek, Madhu Dahr

Faculty Publications and Other Works -- Biochemistry, Cellular and Molecular Biology

No abstract provided.