Medicine and Health Sciences Commons^™

Characterizing The Role Of Nucleosome Remodeling Factor (Nurf) In Tumorigenesis And Metastatic Progression Using Mouse Models Of Breast Cancer., Suehyb Alkhatib

Theses and Dissertations

Increasingly the role of epigenetic machinery as a bridge between underlying DNA sequence and cellular phenotype is being discovered. The establishment of a myriad of unique cellular types sharing identical gene sequences in a multicellular organism gives a broad sense for the inherent role of epigenetic influence on cell differentiation. Importantly, the epigenetic mechanisms involved in establishing cell identity unsurprisingly contribute to diseased states, including cancer. Recent research continues to elucidate contributory roles of epigenetic mechanisms, such as DNA methylation, histone modification, and microRNA regulation, in human cancers. Additionally, chromatin remodelers, such as the Nucleosome Remodeling Factor (NURF), have been …

Elucidating Genetic And Environmental Influences On Alcohol-Related Phenotypes, Jacquelyn Meyers

Theses and Dissertations

Decades of work has led researchers to believe that risk for complex behavioral phenotypes, such as alcohol use disorders, is likely influenced by multiple genes of small effect acting in conjunction with each other and the environment. Currently, the field of psychiatric genetics is developing methodologies for the identification of genetic risk variants that predispose individuals to the development of complex behavioral disorders. Several challenges related to the complex and polygenic nature of these phenotypes, must be considered. This dissertation study attempts to address these important challenges in the context of alcohol use disorders and related phenotypes. A rich twin …

Role Of The Pituitary-Adrenal Axis In G-Csf Therapy After Neonatal Hypoxia-Ischemia, Melissa Stephanie Charles

Loma Linda University Electronic Theses, Dissertations & Projects

Several reports indicate that the activity of the hypothalamic-pituitary-adrenal axis (HPA) as measured by the increased level of adrenocorticotropic hormone (ACTH), and corticosterone is increased after a brain insult. These hormones are the effectors secreted respectively by the pituitary and adrenal glands. It has been shown that the down-regulation of corticosterone levels can improve detrimental outcomes associated with ischemic brain injuries. Neonatal hypoxia-ischemia (HI) is a devastating perinatal event with a grim prognosis and limited therapeutic strategies. In recent studies, granulocyte-colony stimulating factor (G-CSF) has shown promise in neonatal HI investigations by improving neuromotor function and reducing apoptosis in the …

Metabolic Reconstruction For Metagenomic Data And Its Application To The Human Microbiome, Sahar Abubucker, Nicola Segata, Johannes Goll, Alyxandria M. Schubert, Jacques Izard, Brandi L. Cantarel, Beltran Rodriguez-Mueller, Jeremy Zucker, Mathangi Thiagarajan, Bernard Henrissat, Owen White, Scott T. Scott, Barbara Methé, Patrick D. Schloss, Dirk Gever, Makedonka Mitreva, Curtis Huttenhower

Department of Food Science and Technology: Faculty Publications

Microbial communities carry out the majority of the biochemical activity on the planet, and they play integral roles in processes including metabolism and immune homeostasis in the human microbiome. Shotgun sequencing of such communities’ metagenomes provides information complementary to organismal abundances from taxonomic markers, but the resulting data typically comprise short reads from hundreds of different organisms and are at best challenging to assemble comparably to single-organism genomes. Here, we describe an alternative approach to infer the functional and metabolic potential of a microbial community metagenome. We determined the gene families and pathways present or absent within a community, as …

Otx But Not Mitf Transcription Factors Are Required For Zebrafish Rpe Development, Brandon Lane

Theses and Dissertations

Mitf and Otx transcription factors have been identified as essential to the development of the retinal pigmented epithelium (RPE), but the relationship between these factors and their specific role in the RPE developmental pathway have not been clearly defined. The role of the two Mitf transcription factors (Mitfa and Mitfb) and two Otx transcription factors (Otx1a and Otx2) in zebrafish RPE development was explored in these experiments. The loss of Mitf activity in mitfa, mitfb, or double mitf null mutant fish lines had no effect on RPE pigmentation or development. The loss of Otx2 activity through morpholino knockdown produced a …

Cdo Patterns The Musculature Of The Esophagus And Is Required For Esophageal Motility In Mice, Anthony I. Romera, Jagmohan Singhb, Satish Rattan, Robert S. Krauss

Department of Medicine Faculty Papers

Introduction:

Cdo is a multifunctional cell surface co-receptor that promotes Hedgehog signaling during rostroventral midline development and cadherin-mediated signaling during skeletal myogenesis. We report here novel roles for Cdo in patterning of the murine esophageal musculature and esophageal motility disorders such as achalasia.

Novel Napi-Iic Mutations Causing Hhrh And Idiopathic Hypercalciuria In Several Unrelated Families: Long-Term Follow-Up In One Kindred., Y Yu, S R. Sanderson, M Reyes, A Sharma, N Dunbar, Tarak Srivastava, H Jüppner, C Bergwitz

Manuscripts, Articles, Book Chapters and Other Papers

Homozygous and compound heterozygous mutations in SLC34A3, the gene encoding the sodium-dependent co-transporter NaPi-IIc, cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate-wasting resulting in hypophosphatemia, elevated 1,25(OH)(2) vitamin D levels, hypercalciuria, rickets/osteomalacia, and frequently kidney stones or nephrocalcinosis. Similar albeit less severe biochemical changes are also observed in heterozygous carriers, which are furthermore indistinguishable from those encountered in idiopathic hypercalciuria (IH). We now searched for SLC34A3 mutations (exons and introns) in two previously not reported HHRH kindreds, which resulted in the identification of three novel mutations. The affected members of kindred A were compound heterozygous …

The Use Of Infliximab In Older Inflammatory Bowel Disease Patients, Stephanie M. Moleski, Christina C. Lindenmeyer, Patricia L. Kozuch

Department of Medicine Faculty Papers

Limited data suggest anti-tumor necrosis factor (TNF) antibodies have equal efficacy but higher morbidity and mortality in older compared to younger inflammatory bowel disease (IBD) patients(1).

Predictors Of Contralateral Breast Cancer In Brca Negative Women, Ann E. Simmons

Dissertations and Theses (Open Access)

Breast cancer is the most common cancer diagnosis and second leading cause of death in women. Risk factors associated with breast cancer include: increased age, alcohol consumption, cigarette smoking, white race, physical inactivity, benign breast conditions, reproductive and hormonal factors, dietary factors, and family history. Hereditary breast and ovarian cancer syndrome (HBOC) is caused by mutations in the BRCA1 and BRCA2 genes. Women carrying a mutation in these genes are at an increased risk to develop a second breast cancer. Contralateral breast cancer is the most common second primary cancer in patients treated for a first breast cancer. Other risk …

Evaluation Of Knowledge Regarding Diagnostic Strategies For Genetic Diseases In Select Residents, Samantha Penney

Dissertations and Theses (Open Access)

Genetics education for physicians has been a popular publication topic in the United States and in Europe for over 20 years. Decreasing numbers of medical genetics professionals and an increasing volume of genetic information has created a dire need for increased genetics training in medical school and in clinical practice. This study aimed to assess how well pediatrics-focused primary care physicians apply their general genetics knowledge to clinical genetic testing using scenario-based questions. We chose to specifically focus on knowledge of the diagnostic applicability of Chromosomal Microarray (CMA) technology in pediatrics because of its recent recommendation by the International Standard …

Tgf-Beta Receptors And Alcohol Sensitivity In Drosophila, Kristyn Sennett

Theses and Dissertations

Clic proteins influence ethanol-related behavior in flies and other species and also mediate TGF-β signaling. These findings suggest that Clics and the TGF-β signaling pathway might work together to modulate behavioral responses to ethanol. I used the Drosophila model to address the hypothesis that TGF-β signaling is important for ethanol sensitivity. Ethanol sensitivity was blunted by multiple transposon insertions in the TGF-β receptor gene thickveins. Collectively, however, I found no consistent correlation between expression of thickveins and altered ethanol sensitivity in flies harboring transposons. I therefore also assessed ethanol sensitivity in flies with loss of function point mutations in thickveins. …

Pharmacists And Pharmacogenomics: An Evaluation Of Knowledge, Beliefs, Attitudes And Practices, Laressa Bethishou, Angela Chen, Chrissie Chew, Richard Dang, Courtney Greenber, Rebecca Ashlee Klevens, Vlada Treynker, Andrew Warnock, Melissa Durham, Jeffery A. Goad, Edith Mirzaian

Pharmacy Faculty Articles and Research

"Pharmacogenomics is the term used to describe the rapidly advancing study on how genetic makeup can impact drug therapy. In specialized clinical situations, such as the use of irinotecan in colon cancer or abacavir in HIV infections, it is now possible to identify specific genotypes that correlate strongly with a patient's therapeutic outcome, with implications on both efficacy and side effects. On a broader scale, a systematic review published by the Journal of the American Medical Association on the top 27 adverse reaction-causing drugs found that a majority of the adverse effects have a genetic component, suggesting that an analysis …

Gucy2c Opposes Systemic Genotoxic Tumorigenesis By Regulating Akt-Dependent Intestinal Barrier Integrity, Jieru Egeria Lin, Adam Eugene Snook, Peng Li, Brian Arthur Stoecker, Gilbert Won Kim, Michael Sullivan Magee, Alex Vladimir Mejia Garcia, Michael Anthony Valentino, Terry Hyslop, Stephanie Schulz, Scott Arthur Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c^−/−) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated …

The Mechanical Behavior Of Mutant K14-R125p Keratin Bundles And Networks In Neb-1 Keratinocytes, Daniel R. Beriault, Oualid Haddad, John V. Mccuaig, Zachary J. Robinson, David Russell, E. Birgitte Lane, Douglas S. Fudge

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Epidermolysis bullosa simplex (EBS) is an inherited skin-blistering disease that is caused by dominant mutations in the genes for keratin K5 or K14 proteins. While the link between keratin mutations and keratinocyte fragility in EBS patients is clear, the exact biophysical mechanisms underlying cell fragility are not known. In this study, we tested the hypotheses that mutant K14-R125P filaments and/or networks in human keratinocytes are mechanically defective in their response to large-scale deformations. We found that mutant filaments and networks exhibit no obvious defects when subjected to large uniaxial strains and have no negative effects on the ability of human …

Quantitative Genetic Methods To Dissect Heterogeneity In Complex Traits, T. Bernard Bigdeli

Theses and Dissertations

Etiological models of complex disease are elusive[46, 33, 9], as are consistently replicable findings for major genetic susceptibility loci[54, 14, 15, 24]. Commonly-cited explanations invoke low-frequency genomic variation[41], allelic heterogeneity at susceptibility loci[33, 30], variable etiological trajectories[18, 17], and epistatic effects between multiple loci; these represent among the most methodologically-challenging issues in molecular genetic studies of complex traits. The response has been con- sistently reactionary—hypotheses regarding the relative contributions of known func- tional elements, or emphasizing a greater role of rare variation[46, 33] have undergone periodic revision, driving increasingly collaborative efforts to ascertain greater numbers of participants and which assay …

Down-Weighting Overlapping Genes Improves Gene Set Analysis, Adi Tarca, Sorin Draghici, Gaurav Bhatti, Roberto Romero

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

The identification of gene sets that are significantly impacted in a given condition based on microarray data is a crucial step in current life science research. Most gene set analysis methods treat genes equally, regardless how specific they are to a given gene set.

Results

In this work we propose a new gene set analysis method that computes a gene set score as the mean of absolute values of weighted moderated gene t-scores. The gene weights are designed to emphasize the genes appearing in few gene sets, versus genes that appear in many gene sets. We demonstrate the …

Genetic Variation In Glutathione S-Transferase Omega-1, Arsenic Methyltransferase And Methylene-Tetrahydrofolate Reductase, Arsenic Exposure And Bladder Cancer: A Case–Control Study, Jennifer L. Beebe-Dimmer, Priyanka T. Iyer, Jerome O. Nriagu, Greg R. Keele, Shilpin Mehta, Jaymie R. Meliker, Ethan M. Lange, Ann G. Schwartz, Kimberly A. Zuhlke, David Schottenfeld, Kathleen A. Cooney

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Ingestion of groundwater with high concentrations of inorganic arsenic has been linked to adverse health outcomes, including bladder cancer, however studies have not consistently observed any elevation in risk at lower concentrations. Genetic variability in the metabolism and clearance of arsenic is an important consideration in any investigation of its potential health risks. Therefore, we examined the association between genes thought to play a role in the metabolism of arsenic and bladder cancer.

Methods

Single nucleotide polymorphisms (SNPs) in GSTO-1, As3MT and MTHFR were genotyped using DNA from 219 bladder cancer cases and 273 controls participating in a …

Recent Updates On The Role Of Micrornas In Prostate Cancer, Oudai Hassan, Aamir Ahmad, Seema Sethi, Fazlul H. Sarkar

Wayne State University Associated BioMed Central Scholarship

Abstract

MicroRNAs (miRNAs) are short non-coding RNAs that are involved in several important biological processes through regulation of genes post-transcriptionally. Carcinogenesis is one of the key biological processes where miRNAs play important role in the regulation of genes. The miRNAs elicit their effects by binding to the 3' untranslated region (3'UTR) of their target mRNAs, leading to the inhibition of translation or the degradation of the mRNA, depending on the degree of complementary base pairing. To-date more than 1,000 miRNAs are postulated to exist, although the field is moving rapidly. Currently, miRNAs are becoming the center of interest in a …

Manipulating Fate: Medical Innovations, Ethical Implications, Theatrical Illuminations, Karen H. Rothenberg, Lynn W. Bush

Faculty Scholarship

Transformative innovations in medicine and their ethical complexities create frequent confusion and misinterpretation that color the imagination. Placed in historical context, theatre provides a framework to reflect upon how the ethical, legal, and social implications of emerging technologies evolve over time and how attempts to control fate through medical science have shaped -- and been shaped by -- personal and professional relationships. The drama of these human interactions is powerful and has the potential to generate fear, create hope, transform identity, and inspire empathy -- a vivid source to observe the complex implications of translating research into clinical practice through …

Erlin2 Promotes Breast Cancer Cell Survival By Modulating Endoplasmic Reticulum Stress Pathways, Guohui Wang, Gang Liu, Xiaogang Wang, Seema Sethi, Rouba Ali-Fehmi, Judith Abrams, Ze Zheng, Kezhong Zhang, Stephen Ethier, Zeng-Quan Yang

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Amplification of the 8p11-12 region has been found in approximately 15% of human breast cancer and is associated with poor prognosis. Previous genomic analysis has led us to identify the endoplasmic reticulum (ER) lipid raft-associated 2 (ERLIN2) gene as one of the candidate oncogenes within the 8p11-12 amplicon in human breast cancer, particularly in the luminal subtype. ERLIN2, an ER membrane protein, has recently been identified as a novel mediator of ER-associated degradation. Yet, the biological roles of ERLIN2 and molecular mechanisms by which ERLIN2 coordinates ER pathways in breast carcinogenesis remain unclear.

Methods

We established the MCF10A-ERLIN2 …

Limitations Of The Rhesus Macaque Draft Genome Assembly And Annotation, Xiongfei Zhang, Joel Goodsell, Robert B. Norgren

Journal Articles: Genetics, Cell Biology & Anatomy

Finished genome sequences and assemblies are available for only a few vertebrates. Thus, investigators studying many species must rely on draft genomes. Using the rhesus macaque as an example, we document the effects of sequencing errors, gaps in sequence and misassemblies on one automated gene model pipeline, Gnomon. The combination of draft genome with automated gene finding software can result in spurious sequences. We estimate that approximately 50% of the rhesus gene models are missing, incomplete or incorrect. The problems identified in this work likely apply to all draft vertebrate genomes annotated with any automated gene model pipeline and thus …

Bsa Nanoparticles For Sirna Delivery: Coating Effects On Nanoparticle Properties, Plasma Protein Adsorption, And In Vitro Sirna Delivery, Haran Yogasundaram, Markian Stephan Bahniuk, Harsh-Deep Singh, Hamidreza Montazeri Aliabadi, Hasan Uludag, Larry David Unsworth

Pharmacy Faculty Articles and Research

Developing vehicles for the delivery of therapeutic molecules, like siRNA, is an area of active research. Nanoparticles composed of bovine serum albumin, stabilized via the adsorption of poly-L-lysine (PLL), have been shown to be potentially inert drug-delivery vehicles. With the primary goal of reducing nonspecific protein adsorption, the effect of using comb-type structures of poly(ethylene glycol) (1 kDa, PEG) units conjugated to PLL (4.2 and 24 kDa) on BSA-NP properties, apparent siRNA release rate, cell viability, and cell uptake were evaluated. PEGylated PLL coatings resulted in NPs with ζ-potentials close to neutral. Incubation with platelet-poor plasma showed the composition of …

Effects Of Apoptotic Cell Accumulation Caused By Mer Deficiency On Germinal Center B Cells And Helper T Cells, Tahsin N. Khan, Eric B. Wong, Ziaur S.M. Rahman

Department of Microbiology and Immunology Faculty Papers

Mer (MerTK), a member of the Tyro-3/Axl/Mer subfamily receptor tyrosine kinases, expression on phagocytes facilitates their clearance of apoptotic cells (ACs). Mer expression in germinal centers (GCs) occurs predominantly on tingible body macrophages. B and T cells do not express Mer. Mer deficiency (Mer-/-) results in the accumulation of ACs in GCs and augmented antibody-forming cell (AFC), GC and IgG2 Ab responses against T-dependent (TD) Ag. Here, we show that AC accumulation in GCs and elevated AFC, GC and IgG2 Ab responses in Mer-/- mice lasted for at least 80 days after immunization with NP-OVA. Enhanced responses and AC accumulation …

Neuroangiogenesis: A Vascular Basis For Alzheimer's Disease And Cognitive Decline During Aging, Charles T. Ambrose

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Angiogenesis directs development of the brain's microcirculation during antenatal and postnatal development, but its role later in life is less well recognized. I contend that during senescence a reduced cerebral capillary density accounts in part for the vascular cognitive impairment observed in many older persons and possibly for some forms of Alzheimer's disease. I propose that neuroangiogenesis is essential throughout adult life for maintaining the microcirculation of the cerebral cortex and elsewhere in the brain and that it commonly declines with old age. To support this hypothesis I have examined the neurological literature for relevant studies on cerebral capillary density …

Copy Number Variation Signature To Predict Human Ancestry, Melissa Pronold, Marzieh Vali, Roger Pique-Regi, Shahab Asgharzadeh

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Copy number variations (CNVs) are genomic structural variants that are found in healthy populations and have been observed to be associated with disease susceptibility. Existing methods for CNV detection are often performed on a sample-by-sample basis, which is not ideal for large datasets where common CNVs must be estimated by comparing the frequency of CNVs in the individual samples. Here we describe a simple and novel approach to locate genome-wide CNVs common to a specific population, using human ancestry as the phenotype.

Results

We utilized our previously published Genome Alteration Detection Analysis (GADA) algorithm to identify common ancestry …

Genetic Studies Of Complex Human Diseases: Characterizing Snp-Disease Associations Using Bayesian Networks, Bing Han, Xue-Wen Chen, Zohreh Talebizadeh, Hua Xu

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Detecting epistatic interactions plays a significant role in improving pathogenesis, prevention, diagnosis, and treatment of complex human diseases. Applying machine learning or statistical methods to epistatic interaction detection will encounter some common problems, e.g., very limited number of samples, an extremely high search space, a large number of false positives, and ways to measure the association between disease markers and the phenotype.

Results

To address the problems of computational methods in epistatic interaction detection, we propose a score-based Bayesian network structure learning method, EpiBN, to detect epistatic interactions. We apply the proposed method to both simulated datasets and …

Genetics And Cancer, Sachin Puri

A with Honors Projects

Genes' effect in body and relationship with cancer. Role in cell cycle and angiogenesis.

Genetically Modified T-Cells Expressing Chimeric Antigen Receptors In The Treatment Of Cancer, Efrat Bruck

The Science Journal of the Lander College of Arts and Sciences

Dr. Carl June and his colleagues at the University of Pennsylvania have succeeded in treating patients with Chronic Lymphocytic Leukemia using gene therapy. Two of the three patients treated sustained a complete remission and one a partial remission. The procedure involved transducing the patients’ T cells to express chimeric antigen receptors which target a particular protein found on both healthy and cancerous B cells. Following infusion of the newly transduced T cells, each patient developed clinical symptoms associated with an intense immune response. Shortly thereafter, tumors were completely eliminated in two of the patients and partially eliminated in the third. …

Structural Properties Of Thermoresponsive Poly(N-Isopropylacrylamide)-Poly(Ethyleneglycol) Microgels, J. Clara-Rahola, A. Fernandez-Nieves, B. Sierra-Martin, A. B. South, L. Andrew Lyon, J. Kohlbrecher, A. F. Barbero

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The application of RNA interference to treat disease is an important yet challenging concept in modern medicine. In particular, small interfering RNA (siRNA) have shown tremendous promise in the treatment of cancer. However, siRNA show poor pharmacological properties, which presents a major hurdle for effective disease treatment especially through intravenous delivery routes. In response to these shortcomings, a variety of nanoparticle carriers have emerged, which are designed to encapsulate, protect, and transport siRNA into diseased cells. To be effective as carrier vehicles, nanoparticles must overcome a series of biological hurdles throughout the course of delivery. As a result, one promising …

Regulation Of Hepatic Gene Expression During Liver Development And Disease, Hui Ren

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

My first project was to investigate the role of Hepatocyte Nuclear Factor 1 (HNF1) and Nuclear Factor I (NFI) on alpha-fetoprotein (AFP) promoter activity during liver development. AFP is highly expressed in the fetal liver, silenced at birth, and remains at very low levels in the adult liver. A GA substitution located at -119 of the human AFP promoter is associated with hereditary persistence of AFP (HPAFP) expression in the adult liver (Hum Molec Genet, 1993, 2:379). The -120 region harbors overlapping binding sites for HNF1 and NFI. While it has been shown that the GA substitution increases HNF1 binding, …