Medical Genetics Commons^™

Epigenetic Mechanisms Influencing Therapeutic Response In Breast Cancer., Amaia Arruabarrena-Aristorena, Eneda Toska

Kimmel Cancer Center Faculty Papers

The majority of breast cancers are estrogen receptor (ER)+ and agents targeting the ER signaling pathway have markedly increased survival for women with breast cancer for decades. However, therapeutic resistance eventually emerges, especially in the metastatic setting. In the past decade disrupted epigenetic regulatory processes have emerged as major contributors to carcinogenesis in many cancer types. Aberrations in chromatin modifiers and transcription factors have also been recognized as mediators of breast cancer development and therapeutic outcome, and new epigenetic-based therapies in combination with targeted therapies have been proposed. Here we will discuss recent progress in our understanding of the chromatin-based …

Genomic Answers For Children: Dynamic Analyses Of >1000 Pediatric Rare Disease Genomes., Ana S A Cohen, Emily G. Farrow, Ahmed Abdelmoity, Joseph Alaimo, Shivarajan Manickavasagam Amudhavalli, John Anderson, Lalit R. Bansal, Lauren E. Bartik, Primo Baybayan, Bradley Belden, Courtney D. Berrios, Rebecca L. Biswell, Pawel Buczkowicz, Orion Buske, Shreyasee Chakraborty, Warren A. Cheung, Keith A. Coffman, Ashley M. Cooper, Laura A. Cross, Tom Curran, Thuy Tien T. Dang, Mary M. Elfrink, Kendra Engleman, Erin Day Fecske, Cynthia Fieser, Keely M. Fitzgerald, Emily Fleming, Randi N. Gadea, Jennifer L. Gannon, Rose N. Gelineau-Morel, Margaret Gibson, Jeffrey Goldstein, Elin Grundberg, Kelsee Halpin, Brian S. Harvey, Bryce Heese, Wendy Hein, Suzanne M. Herd, Susan Starling Hughes, Mohammed Ilyas, Jill Jacobson, Janda L. Jenkins, Shao Jiang, Jeffrey J. Johnston, Kathryn Keeler, Jonas Korlach, Jennifer Kussman, Christine Lambert, Caitlin E. Lawson, Jean-Baptist Lepichon, J Steven Leeder, Vicki C. Little, Daniel A. Louiselle, Michael Lypka, Brittany D. Mcdonald, Neil Miller, Ann Modrcin, Annapoorna Nair, Shelby H. Neal, Christopher M. Oermann, Donna M. Pacicca, Kailash Pawar, Nyshele L. Posey, Nigel Price, Laura M B Puckett, Julio Quezada, Nikita Raje, William J. Rowell, Eric T. Rush, Venkatesh Sampath, Carol J. Saunders, Caitlin Schwager, Richard M. Schwend, Elizabeth Shaffer, Craig Smail, Sarah E. Soden, Meghan Strenk, Bonnie Sullivan, Brooke Sweeney, Jade B. Tam-Williams, Adam Walter, Holly Welsh, Aaron M. Wenger, Laurel K. Willig, Yun Yan, Scott T. Younger, Dihong Zhou, Tricia N. Zion, Isabelle Thiffault, Tomi Pastinen

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program.

METHODS: Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes.

RESULTS: Diagnostic rates ranged from 11% in patients with prior negative …

Primary Cilia Of The Cardiac Neural Crest & Hedgehog-Mediated Mechanisms Of Congenital Heart Disease, Lindsey A. Fitzsimons

Electronic Theses and Dissertations

Elimination of primary cilia in cardiac neural crest cell (CNCC) progenitors is hypothesized to cause a variety of congenital heart defects (CHDs), including atrioventricular septal defects, and malformations of the developing cardiac outflow tract. We present an in vivo model of CHD resulting from the conditional elimination of primary cilia from CNCC using multiple, Wnt1:Cre-loxP, neural crest-specific systems, targeting two distinctive, but critical, primary cilia structural genes: Intraflagellar transport protein 88 (Ift88) or kinesin family member 3A (Kif3a). CNCC loss of primary cilia leads to widespread CHD, where homozygous mutant embryos (MUT) display a variety of outflow tract malformations, septation …

Genetic Origins Of Polycystic Ovarian Syndrome (Pcos): An Analysis Of The Genetic Correlation Between Pcos And Insulin Receptor Mutations, Lauren Henry

Undergraduate Theses

Polycystic Ovarian Syndrome (PCOS) remains an extremely common, yet understudied syndrome experienced by 6-12% of females of reproductive age. Not only does it cause painful side effects manifesting both physically and mentally, but it also poses a threat to the fertility of those affected. For this reason, a more in-depth analysis to better understand how to detect this condition early and prevent fertility complications later is certainly warranted. PCOS is suspected to be primarily genetic due to correlations among immediate female family members. Based on previous research, a good starting point for analysis is the INSR gene. Various mutations within …

The Use Of Embark In Teaching About Genetic Relatedness, Anna Bonvillain, Tori Trammel

Honors Theses

Because of the increasing importance of precision medicine, it is vital that future healthcare providers master concepts related to genetic variation taught during their undergraduate classes. However, studies have shown that physicians often lack an adequate understanding of genetics, which serves as a hindrance to effectively caring for their patients. To address this issue, we created a collaborative active-learning protocol to improve pre-health students' comprehension of key concepts such as genetic relatedness and the source of genetic variation between siblings. Our worksheet guides students to compare the genetic profiles of two canine siblings using the Embark DNA genotyping platform. Embark …

Script Concordance Testing In Genetic Counseling Training: A Pilot Study, Yakira Begun, Lila Rae Stange

Human Genetics Theses

Clinical decision-making has been successfully measured by script concordance testing in various healthcare training programs; it has never been used in genetic counseling education. The aim of this pilot study was to assess script concordance testing in the field of genetic counseling as an objective measure of clinical reasoning in trainees. The script concordance test was administered to 22 second year genetic counseling students in the Joan H. Marks Graduate Program in Human Genetics at Sarah Lawrence College. 12 genetic counselors served on a panel to provide expert judgment responses, and a scoring grid was developed using the Aggregate Scores …

Natural Killer Cells In Liver Transplantation: Can We Harness The Power Of The Immune Checkpoint To Promote Tolerance?, Jennifer Halma, Stephen Pierce, Rebecca Mclennan, Todd Bradley, Ryan T. Fischer

Manuscripts, Articles, Book Chapters and Other Papers

The roles that natural killer (NK) cells play in liver disease and transplantation remain ill-defined. Reports on the matter are often contradictory, and the mechanisms elucidated are complex and dependent on the context of the model tested. Moreover, NK cell attributes, such as receptor protein expression and function differ among species, make study of primate or rodent transplant models challenging. Recent insights into NK function and NK-mediated therapy in the context of cancer therapy may prove applicable to transplantation. Of specific interest are immune checkpoint molecules and the mechanisms by which they modulate NK cells in the tumor micro-environment. In …

Exploring Parental Attitudes On Autism Genetic Testing After Receiving Non-Pathogenic Results, Christina Szi

Human Genetics Theses

Whole exome sequencing (WES) is quickly moving toward becoming a first-tier test for autism spectrum disorder (ASD); however, the diagnostic yield of these tests can be quite low. Many parents will not receive a molecular diagnosis to explain the underlying cause of their child’s autism, so it is important to understand how these parents view genetic testing: both regarding satisfaction with genetic testing and if such results cause significant emotional distress. We surveyed 520 parents who enrolled their child with ASD in SPARK Research Match and received a null genetic finding through WES. We found that, despite not receiving a …

The Role Of High Throughput Functional Evidence In Reducing-Population Specific Differences In The Quality Of Variant Interpretation, Makenzie Fong, Taylor Silkey

Human Genetics Theses

Variants of uncertain significance (VUSs) in cancer pre-disposition genes are more frequent in non-White and/or Hispanic populations than non-Hispanic White (NHW), creating more ambiguity in cancer risk/management for these populations. High throughput functional evidence (HTFE) serves as a powerful classification tool for missense variants within the RING/BRCT domains of BRCA1. We sought to determine if HTFE provides preferential benefit in underrepresented racial and ethnic groups. Our cohort consisted of individuals who had BRCA1 testing and self-reported ancestry as Asian, Black, Hispanic, Middle Eastern, or NHW. For individuals with pathogenic, likely pathogenic, or VUS variants in the RING/BRCT domains, we evaluated …

The Role Of Obesity In Macrophage-Mediated Mechanisms Promoting Early-Onset Colon Cancer., Katharina Marietta Scheurlen

Electronic Theses and Dissertations

Early-onset colon cancer (EOCC) is a leading cause of cancer death among people younger than 50 years of age in the United States and is associated with metabolic dysfunction and obesity. Anti-inflammatory tumor-associated macrophages (TAM) and low Peroxisome Proliferator Activated Receptor Gamma (PPARγ) gene expression in colon cancer (CC) tissue promote tumor progression and decreased patient survival. Obesity-related hormones, such as leptin and adiponectin, have the potential to affect gene expression in TAM to promote CC progression and thereby link obesity and EOCC. The aim of this project was to identify target genes in human CC and to investigate the …

Enpp1 Variants In Patients With Gaci And Pxe Expand The Clinical And Genetic Heterogeneity Of Heritable Disorders Of Ectopic Calcification., Douglas Ralph, Yvonne Nitschke, Michael A Levine, Matthew Caffet, Tamara Wurst, Amir Hossein Saeidian, Leila Youssefian, Hassan Vahidnezhad, Sharon F Terry, Frank Rutsch, Jouni Uitto, Qiaoli Li

Department of Medicine Faculty Papers

Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1, the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively. All patients were found to carry biallelic variants in ENPP1. Among ten ENPP1 variants, one homozygous variant demonstrated uniparental disomy …

A Patient-Derived Ipsc Model To Study Glutamate Deficiency By Shank-3 Mutation In Autism Spectrum Disorder, Tiffany Berry, Courtney Caccia

Biology Student Scholarship

Tiffany Berry ’22, Majors: Biology and Psychology

Courtney Caccia ’22, Majors: Biology and Psychology

Faculty Mentor: Dr. Charles Toth, Biology

The use of human stem cell lines derived from persons with Autism Spectrum Disorder (ASD) provides a unique opportunity to model brain growth and potential to regain brain activity for treatment. Our lab has previously used stem cells to derive 3D cardiomyocytes to examine cardiovascular disease as well as kidney organoids and macrophages to study kidney disease. Using techniques our lab has learned using these stem cell models have prepared us to examine cell communication in mutated neurons. We will …

Epigenetic Pathogenesis Of Neurological Disorders In Utero And Considerations For Genetic Counseling, Lauren Juga

Senior Honors Theses

Epigenetic modifications are a major focus of study in the pathogenesis of many disorders regarding metabolism, aging, neurodevelopment, and neurodegeneration. Epigenetic mechanisms are present throughout life but are especially vital to guiding fetal development. The precise timing of gene activation and deactivation guides stem cell differentiation through each embryonic stage. After exposure to environmental stimuli, gene expression can be altered by transcription factors, resulting in observable phenotypes and even pathology. Here, the epigenetic mechanisms responsible for the pathogenesis of neurodevelopmental and neuropsychiatric disorders are explored in response to environmental perturbations in utero. The present goal is to identify correlations between …

The Experiences And Needs Of Individuals With A Variant Of Uncertain Significance (Vus) On Genetic Tests For Hereditary Cancer Syndromes: A Grounded Theory Study, Danielle Gould

Doctoral Dissertations

Background: The use of multigene panel testing for identifying individuals with hereditary cancer susceptibility has expanded in recent years. The number of individuals who have a variant of unknown significance (VUS) result is increasing. However, little is known about the experiences and needs of this group. This study’s purpose was to describe the experiences and needs of individuals with a VUS result by focusing on their experiences in communicating with healthcare providers and family members. Methods: A constructivist grounded theory approach was used. Recruitment took place from January–July 2021 through social media: the Prospective Registry of Multiplex Testing (PROMPT), and …

Landscape Of Molecular Crosstalk Perturbation Between Lung Cancer And Covid-19, Aditi Kuchi, Jiande Wu, Jyotsna Fuloria, Chindo Hicks

School of Medicine Faculty Publications

Background: Lung cancer patients have the worst outcomes when affected by coronavirus disease 2019 (COVID-19). The molecular mechanisms underlying the association between lung cancer and COVID-19 remain unknown. The objective of this investigation was to determine whether there is crosstalk in molecular perturbation between COVID-19 and lung cancer, and to identify a molecular signature, molecular networks and signaling pathways shared by the two diseases. Methods: We analyzed publicly available gene expression data from 52 severely affected COVID-19 human lung samples, 594 lung tumor samples and 54 normal disease-free lung samples. We performed network and pathways analysis to identify molecular networks …

Differential Microrna Expression In Glioblastoma As A Therapeutic Target Or Potential Biomarker, Drew Hines, Levi Marcum, Aubrey Strong, Ryan Wade

Channels: Where Disciplines Meet

MicroRNA (miRNA) is an epigenetic factor that plays an important role in the post-transcriptional regulation of gene and protein expression. Recent research has shown that in many types of cancer, differentially expressed levels of certain types of miRNA are significantly correlated with the transformation of and ongoing issues caused by cancer cells. Specifically, in Glioblastoma, one of the most lethal and aggressive human cancers, differential levels of miRNAs contribute to the cell’s lack of pro-apoptotic gene presence and its high resistance to current treatments. Results from current studies could provide information about which microRNAs are differentially expressed in glioblastoma when …

Molecular Diagnoses Of X-Linked And Other Genetic Hypophosphatemias: Results From A Sponsored Genetic Testing Program., Eric T. Rush, Britt Johnson, Swaroop Aradhya, Daniel Beltran, Sara L. Bristow, Scott Eisenbeis, Norma E. Guerra, Stan Krolczyk, Nicole Miller, Ana Morales, Prameela Ramesan, Soodabeh Sarafrazi, Rebecca Truty, Kathryn Dahir

Manuscripts, Articles, Book Chapters and Other Papers

X-linked hypophosphatemia (XLH), a dominant disorder caused by pathogenic variants in the PHEX gene, affects both sexes of all ages and results in elevated serum fibroblast growth factor 23 (FGF23) and below-normal serum phosphate. In XLH, rickets, osteomalacia, short stature, and lower limb deformity may be present with muscle pain and/or weakness/fatigue, bone pain, joint pain/stiffness, hearing difficulty, enthesopathy, osteoarthritis, and dental abscesses. Invitae and Ultragenyx collaborated to provide a no-charge sponsored testing program using a 13-gene next-generation sequencing panel to confirm clinical XLH or aid diagnosis of suspected XLH/other genetic hypophosphatemia. Individuals aged ≥6 months with clinical XLH or …

Using Crispr Gene Editing To Prevent Accumulation Of Lipids In Hepatocytes, Erin Young, Cem Kuscu, Christine Watkins, Murat Dogan

Longitudinal Scholar's Project

CRISPR gene editing is a molecular technology that can be used to silence gene expression. In this experiment, genes that are known to play a role in lipid accumulation in hepatocytes were targeted. Specifically, levels of fatty acid transport proteins 2 and 5 (FATP2 & 5) have been shown to be elevated in cases of non-alcoholic fatty liver disease. The goal of this experiment was to reduce expression of these genes by using a dead Cas9 (dCas9) protein with an attached inhibitory domain (KRAB) that acts on the promotor region. When measuring the mRNA expression, it was determined that the …

Extracellular Mechanotransduction, Stephen J. Haller, Andrew T. Dudley

Journal Articles: Genetics, Cell Biology & Anatomy

We highlight the force-sensing function of extracellular matrix and present a complementary mechanotransduction paradigm.

Mintruls: Prediction Of Mirna-Mrna Target Site Interactions Using Regularized Least Square Method, Sushil Kumar Shakyawar, Siddesh Southekal, Chittibabu Guda

Journal Articles: Genetics, Cell Biology & Anatomy

Identification of miRNA-mRNA interactions is critical to understand the new paradigms in gene regulation. Existing methods show suboptimal performance owing to inappropriate feature selection and limited integration of intuitive biological features of both miRNAs and mRNAs. The present regularized least square-based method, mintRULS, employs features of miRNAs and their target sites using pairwise similarity metrics based on free energy, sequence and repeat identities, and target site accessibility to predict miRNA-target site interactions. We hypothesized that miRNAs sharing similar structural and functional features are more likely to target the same mRNA, and conversely, mRNAs with similar features can be targeted by …

The Significance Of Cell-Surface Α2,3-Linked Sialic Acid In Osteoclasts, Christopher S. Harding

EWU Masters Thesis Collection

Osteoclasts are giant, multinucleated cells that, alongside osteoblasts, are central to maintaining physiologically healthy bone. The functions of osteoclasts and osteoblasts-degrading and depositing bone matrix, respectively-are paired in healthy bone tissue, thereby yielding no net bone loss or deposition. When these functions become imbalanced, it results in net bone loss or gain, depending on which cell type is being outcompeted. Osteoporosis is one of the most common pathologies stemming from such an imbalance, and predominantly affects postmenopausal women, as the ablation of circulating estrogen-a pro-death signal for osteoclasts-causes a prolongation of osteoclast lifespan and consequent lengthening of their resorptive activity. …

Familial Hypercholesterolemia And Treatments, Alexis Steer

Williams Honors College, Honors Research Projects

My project will be a literature review regarding the genetic mutations associated with

familial hypercholesterolemia and the current available treatments.

Anthracyclines Attenuate The Nrf1-Mediated Bounce-Back Response, Bader Albalawi

Theses and Dissertations

Proteasome inhibitors, such as carfilzomib, are FDA-approved to treat multiple myeloma and mantle cell lymphoma. Unfortunately, proteasome inhibitors have only produced clinically significant results in patients with hematologic cancers, despite their predicted pan-cancer utility, and even hematologic cancer types frequently show intrinsic and acquired resistance.

One proposed mechanism responsible for the proteasome inhibitors' shortcomings is the NRF1-mediated bounce-back response. Identification of drugs that can potentiate the action of proteasome inhibitors could overcome resistance in patients with hematologic cancers and expand proteasome inhibitors' use to treat solid tumors. Our previous studies have identified anthracyclines as potential compounds that interfere with the …

Robust Meta-Analysis For Large-Scale Genomic Experiments Based On An Empirical Approach, Sinjini Sikdar

Mathematics & Statistics Faculty Publications

BACKGROUND: Recent high-throughput technologies have opened avenues for simultaneous analyses of thousands of genes. With the availability of a multitude of public databases, one can easily access multiple genomic study results where each study comprises of significance testing results of thousands of genes. Researchers currently tend to combine this genomic information from these multiple studies in the form of a meta-analysis. As the number of genes involved is very large, the classical meta-analysis approaches need to be updated to acknowledge this large-scale aspect of the data.

METHODS: In this article, we discuss how application of standard theoretical null distributional assumptions …

Plasmonic-Based Biosensor For The Early Diagnosis Of Prostate Cancer, Thakshila Liyanage, Bayan Alharbi, Linh Quan, Aurora Esquela-Kerscher, Gymama Slaughter

Bioelectrics Publications

A tapered optical fiber (TOF) plasmonic biosensor was fabricated and used for the sensitive detection of a panel of microRNAs (miRNAs) in human serum obtained from noncancer and prostate cancer (PCa) patients. Oncogenic and tumor suppressor miRNAs let7a, let-7c, miR-200b, miR-141, and miR-21 were tested as predictive cancer biomarkers since multianalyte detection minimizes false-positive and false-negative rates and establishes a strong foundation for early PCa diagnosis. The biosensing platform integrates metallic gold triangular nanoprisms (AuTNPs) laminated on the TOF to excite surface plasmon waves in the supporting metallic layer and enhance the evanescent mode of the fiber surface. …

Reduction Of Plasmid Vector Backbone Length Enhances Reporter Gene Expression, Carly Boye, Sezgi Arpag, Michael Francis, Scott Declemente, Aislin West, Richard Heller, Anna Bulysheva

Electrical & Computer Engineering Faculty Publications

Gene therapy has a wide range of applications for various types of pathologies. Viral methods of gene delivery provide high levels of gene expression but have various safety concerns. Non-viral methods are largely known to provide lower levels of expression. We aim to address this issue by using plasmid DNA with smaller backbones to increase gene expression levels when delivered using non-viral methods. In this study we compare gene expression levels between two vectors with firefly luciferase encoding gene insert using liposome complexes and gene electrotransfer as delivery methods. A 2-fold reduction in plasmid vector backbone size, disproportionately enhanced gene …