Medical Genetics Commons^™

Racial Disparities In Necrotizing Enterocolitis., Alain Cuna, Venkatesh Sampath, Minesh Khashu

Manuscripts, Articles, Book Chapters and Other Papers

Necrotizing enterocolitis (NEC) is a serious disease of the intestinal tract affecting 5-10% of pre-term infants with up to 50% mortality in those that require surgery. There is wide variation in the rates and outcomes of NEC by race and ethnicity, and the reasons for this disparity are poorly understood. In this article, we review the epidemiology and discuss possible explanations for racial and ethnic differences in NEC. Most of the current evidence investigating the role of race in NEC comes from North America and suggests that Hispanic ethnicity and non-Hispanic Black race are associated with higher risk of NEC …

Diverse And Converging Roles Of Erk1/2 And Erk5 Pathways On Mesenchymal To Epithelial Transition In Breast Cancer, Akshita B. Bhatt, Thomas D. Wright, Van Barnes, Suravi Chakrabarty, Margarite D. Matossian, Erin Lexner, Deniz A. Ucar, Lucio Miele, Patrick T. Flaherty, Matthew E. Burow, Jane E. Cavanaugh

School of Medicine Faculty Publications

The epithelial to mesenchymal transition (EMT) is characterized by a loss of cell polarity, a decrease in the epithelial cell marker E-cadherin, and an increase in mesenchymal markers including the zinc-finger E-box binding homeobox (ZEB1). The EMT is also associated with an increase in cell migration and anchorage-independent growth. Induction of a reversal of the EMT, a mesenchymal to epithelial transition (MET), is an emerging strategy being explored to attenuate the metastatic potential of aggressive cancer types, such as triple-negative breast cancers (TNBCs) and tamoxifen-resistant (TAMR) ER-positive breast cancers, which have a mesenchymal phenotype. Patients with these aggressive cancers have …

Long-Term Effects Of Very Low Dose Particle Radiation On Gene Expression In The Heart: Degenerative Disease Risks, Venkata Naga Srikanth Garikipati, Arsen Arakelyan, Eleanor A Blakely, Polly Y Chang, May M Truongcao, Maria Cimini, Vandana Malaredy, Anamika Bajpai, Sankar Addya, Malik Bisserier, Agnieszka Brojakowska, Abrisham Eskandari, Mary K Khlgatian, Lahouaria Hadri, Kenneth M Fish, Raj Kishore, David A Goukassian

Kimmel Cancer Center Faculty Papers

Compared to low doses of gamma irradiation (γ-IR), high-charge-and-energy (HZE) particle IR may have different biological response thresholds in cardiac tissue at lower doses, and these effects may be IR type and dose dependent. Three- to four-month-old female CB6F1/Hsd mice were exposed once to one of four different doses of the following types of radiation: γ-IR 137Cs (40-160 cGy, 0.662 MeV), 14Si-IR (4-32 cGy, 260 MeV/n), or 22Ti-IR (3-26 cGy, 1 GeV/n). At 16 months post-exposure, animals were sacrificed and hearts were harvested and archived as part of the NASA Space Radiation Tissue Sharing Forum. These heart tissue samples were …

Sequencing Of 53,831 Diverse Genomes From The Nhlbi Topmed Program, Daniel Taliun, Daniel N. Harris, Michael D. Kessler, Jedidiah Carlson, John Blangero, Joanne E. Curran, Michael C. Mahaney, Harald H. H. Goring, Ravindranath Duggirala, Juan M. Peralta

School of Medicine Publications and Presentations

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and …

Impaired Eif5a Function Causes A Mendelian Disorder That Is Partially Rescued In Model Systems By Spermidine., Víctor Faundes, Martin D. Jennings, Siobhan Crilly, Sarah Legraie, Sarah E. Withers, Sara Cuvertino, Sally J. Davies, Andrew G L Douglas, Andrew E. Fry, Victoria Harrison, Jeanne Amiel, Daphné Lehalle, William G. Newman, Patricia Newkirk, Judith Ranells, Miranda Splitt, Laura A. Cross, Carol J. Saunders, Bonnie Sullivan, Jorge L. Granadillo, Christopher T. Gordon, Paul R. Kasher, Graham D. Pavitt, Siddharth Banka

Manuscripts, Articles, Book Chapters and Other Papers

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles …

Investigating The Role Of Znf384 Rearrangements In Acute Leukemia, Kirsten Dickerson

Theses and Dissertations (ETD)

Chromosomal rearrangements involving ZNF384 are the defining lesion in 5% of pediatric and adult B-cell acute lymphoblastic leukemia and tumors are characterized by aberrant myeloid marker expression. Additionally, ZNF384 rearrangements are the defining lesion in nearly half of pediatric B/myeloid mixed phenotype acute leukemia. These fusions juxtapose full-length ZNF384 to the N terminal portion of a diverse range of partners, most often, transcription factors or epigenetic modifiers. It has been shown that ZNF384-rearranged tumors have a distinct gene expression profile that is consistent between disease groups and N terminal partners. Genomic analyses of patient tumors has shown that ZNF384 fusions …

Molecular Mechanisms Of Epithelial To Mesenchymal Transition Regulated By Erk5 Signaling, Akshita B. Bhatt, Saloni Patel, Margarite D. Matossian, Deniz A. Ucar, Lucio Miele, Matthew E. Burow, Patrick T. Flaherty, Jane E. Cavanaugh

School of Medicine Faculty Publications

Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-β (TGF-β), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription …

Epigenetic States Regulate Tumor Aggressiveness And Response To Targeted Therapies In Lung Adenocarcinoma, Fan Chen

Theses and Dissertations--Toxicology and Cancer Biology

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, 85% of which are lung adenocarcinomas (LUAD). Although molecular studies of NSCLC identified targetable mutations of some oncogenes including BRAF, EGFR and ALK, no targeted therapies exist for most cases. Cancer epigenetics is the study of epigenetic modifications, including histone modifications, that control gene expression in cancer. Recent advances have revealed numerous epigenetic abnormalities in human cancers, and targeting epigenetic regulators could be effective at reversing dysregulated epigenetic programs or driving sensitivity to other targeted therapies.

Inhibitors of the histone methyltransferase EZH2 have recently been approved as …

The Role Of Ms-818 In Altering Age-Related Characteristics Of An In Vitro Model Of Senescence In Neural Stem Cells, Sandeep Sreerama

Honors Undergraduate Theses

Aging of the brain is the leading risk factor for neurodegenerative diseases and brain cancers and has deleterious effects on brain functions. It follows that attempts to reverse the aging process may be therapeutically valuable. Neural stem cells (NSC) have been shown to play a critical role in maintaining brain functions, and their number is severely decreased with age. The development of senescence-like characteristics and declining functions in NSCs have been proposed to be responsible for brain aging and tumorigenesis. MS-818 is a pyrrolopyrimidine that has been shown to increase the NSC population and reverse the decline of behavioral function …

The Role Of Vascular Endothelial Growth Factor In Leukemia Trafficking, Shaw Powell

Theses and Dissertations--Medical Sciences

Vascular endothelial growth factor (VEGF) is a signaling protein involved in inducing and regulating endothelial cell proliferation and function (Duffy et al 2000). VEGF is also involved in cancer progression, as it induces vascular permeability and promotes angiogenesis to tumor laden areas, giving cancer cells critical oxygen and nutrients (Hoeppner et al.,2012. Studies indicate VEGF prevents lymphoblast apoptosis, which may contribute to leukemia formation and enable the proliferation of leukemic cells (Duffy et al 2000). Ongoing research seeks to further examine VEGF in leukemia, using a rag2:GFP-Myc expressing transgenic zebrafish as the animal model of T-cell Acute Lymphoblastic Leukemia (T-ALL). …

Genomic Education – Bench To Bedside: A Novel Approach To Teaching Genetic Diagnosis, J. Keith Williams, Michael M. Segal, Lynn K. Feldman

Internet Journal of Allied Health Sciences and Practice

Problem: Teaching genetic diagnosis is required in all medical schools and physician assistant programs. However, with thousands of relevant findings and thousands more rare diseases, lectures and narrative resources are inadequate for the task. Whatever information that is taught is easily forgotten and does not carry over into the clinic. Many rare disease patients suffer through “diagnostic odysseys” (3 to 30 years to correct diagnosis). Approach: We used a commercially available diagnostic decision support system (DDSS) that encompasses all Mendelian disorders with known genes, together with other conditions in their differential diagnosis, and a case-based educational approach to teach diagnostic …

Refinement Of Saliva Microrna Biomarkers For Sports-Related Concussion, Steven D. Hicks, Cayce Onks, Raymond Y. Kim, Kevin J. Kim, Kevin J. Zhen, Jayson Loeffert, Andrea C. Loeffert, Robert P. Olympia, Gregory Fedorchak, Samantha Devita, Zofia Gagnon, Callan Mcloughlin, Miguel M. Madeira, Scott L. Zuckerman, Timothy Lee, Matthew Heller, Chuck Monteith, Thomas R. Campbell, Christopher Neville, Elise Fengler, Michael N. Dretsch

Rehabilitation Sciences Faculty Publications

Purpose

Recognizing sport-related concussion (SRC) is challenging and relies heavily on subjective symptom reports. An objective, biological marker could improve recognition and understanding of SRC. There is emerging evidence that salivary micro-ribonucleic acids (miRNAs) may serve as biomarkers of concussion; however, it remains unclear whether concussion-related miRNAs are impacted by exercise. We sought to determine whether 40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports. Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.

Methods

This case-control study harmonized …

Developing A Targeted Ultrasound-Responsive Nanobubble-Based Gene Delivery System For Osteoporosis Treatment, Angela Shar

Honors Undergraduate Theses

The overall goal of this project was to develop, optimize, and test an ultrasound-responsive targeted nanobubble for delivering osteoporosis-related silencing genes such as Cathepsin K small interfering RNA (CTSK siRNA) for osteoporosis treatment. The nanobubbles were synthesized using an in situ sonochemical method. The nanobubble (NB) is composed of a gas core made from perfluorocarbon, stabilized with albumin, encapsulated with CTSK siRNA, and embedded with alendronate (AL) for bone targeting (CTSK siRNA-NB-AL). Following its development, the responsiveness of CTSK siRNA-NB-AL to a therapeutic ultrasound probe was examined. The results of biocompatibility tests with human bone marrow-derived mesenchymal stem cells proved …

Monopolar Gene Electrotransfer Enhances Plasmid Dna Delivery To Skin, Anna Bulysheva, Loree Heller, Michael Francis, Frency Varghese, Carly Boye, Richard Heller

Electrical & Computer Engineering Faculty Publications

A novel monopolar electroporation system and methodologies were developed for in vivo electroporation intended for potential clinical applications such as gene therapy. We hypothesized that an asymmetric anode/cathode electrode applicator geometry could produce favorable electric fields for electroporation, without the typical drawback associated with traditional needle and parallel plate geometries. Three monopolar electrode applicator prototypes were built and tested for gene delivery of reporter genes to the skin in a guinea pig model. Gene expression was evaluated in terms of kinetics over time and expression distribution within the treatment site. Different pulsing parameters, including pulse amplitude, pulse duration, and pulse …

Evaluation Of Growth In Clinical Genetics Competency Among Pcps Participating In The Uvmhn Genomic Dna Testing Program, Christina Hansen

Family Medicine Clerkship Student Projects

Recently UVM Health Network Family Medicine practices have implemented “The Genomic DNA Test” pilot program to begin a concerted effort toward offering genetically informed primary care to all patients. The program aims to increase the number of participating primary care providers stepwise over time. However, some providers may find integration of genomic testing and discussion of clinical genetics issues with patients to be challenging given the relatively recent change toward emphasis on these topics in medical training curricula. The aim of this project was to develop a pilot survey to gather information from current participating providers about how participation in …

Cornelia De Lange Syndrome Research From 1953 To 2020: A Bibliometric Analysis, Dr. Mirza Muhammad Naseer, Dr. Abu Waris

Library Philosophy and Practice (e-journal)

The present study was conducted to explore various aspects of Cornelia de Lange Syndrome (CdLS) research publications including annual scientific productivity, top contributing authors and their impact, top contributing countries and organizations, most relevant sources of publication, highly cited documents, and most frequently used words. Bibliometric methods were used to investigate these aspects of CdLS research publications. Results of the study disclosed that the annual scientific productivity of CdLS literature is increasing gradually with the passage of time. A. Selicorni contributed the highest number of publications (45) to CdLS literature while I. D. Krantz had the highest impact in the …

Goblet Cell Carcinoma Of The Appendix: A Case Report On Goblet Cell Carcinoid, Sheliza Kabani, Aubtin Saedi, Austin Lehr, Lina O'Brien

HCA Healthcare Journal of Medicine

Goblet cell carcinoid of the appendix is a rare neoplasm with histological features of both neuroendocrine and adenocarcinomas. The combination of its aggressive behavior, infrequent occurrence, and variable clinical presentation convolutes the management of this tumor. We report the case of a 75-year-old female presenting with acute appendicitis. A laparoscopic appendectomy was performed. The pathology report showed goblet cell carcinoid at the base of the appendix with involvement of the proximal surgical margins. At her postoperative visit, the patient’s pathology report and options for management were reviewed, and the patient agreed to proceed with a right hemicolectomy 8-10 weeks after …

A Case Of Simpson-Golabi-Behmel Syndrome Presenting With Cutaneous Findings, Tessa Mullins, Abigail Russell, Chad Johnston

HCA Healthcare Journal of Medicine

Simpson-Golabi-Behmel syndrome is a rare, X-linked recessive syndrome associated with mutations in the genes encoding glypican 3 (GPC3). The majority of cases have been described in pediatric males, with those affected showing manifestations of overgrowth, congenital heart defects, and increased incidence of neoplasia. Due to the X-linked nature of this disorder, penetrance is not well understood in female cases. Very few cases of female presentations of Simpson-Golabi-Behmel syndrome have been described, and this case highlights that there may be an association between mutated GPC3 carrier status and other cancers. We present a case of GPC3 gene mutation suggestive …

Tumor Necrosis Factor Alpha Snp Variant In Promoter Region G308a, Cause Preeclampsia During Pregnancy In Pakistani Women, A Case Control Study, Azizah Ziauddin, Sadia Ahmad, Asad Iqbal, Abdul Majid Khan, Shahid Mahmood Baig

Journal of Bioresource Management

Preeclampsia (PE) is a very common critical condition during pregnancy. As PE is a high-risk condition during pregnancy, occurring in 25% of all pregnancies, worldwide. In women with PE there is an increase in hypertension and albuminuria. Elevated blood pressure can be life-threatening after 20^th week of pregnancy. Single nucleotide variation in gene sequence can be disease causing, among these pathogenic SNPs, a variant in TNF-α, G308A is analyzed in many studies as a causative variant to cause preeclampsia. In this case control study fifty patients and fifty healthy individuals were enrolled for analysis of TNF-α promoter region …

Modulation Of Aub-Tdrd Interactions Elucidates Pirna Amplification And Germplasm Formation., Nicholas Vrettos, Manolis Maragkakis, Panagiotis Alexiou, Paraskevi Sgourdou, Fadia Ibrahim, Daniel Palmieri, Yohei Kirino, Phd, Zissimos Mourelatos

Computational Medicine Center Faculty Papers

Aub guided by piRNAs ensures genome integrity by cleaving retrotransposons, and genome propagation by trapping mRNAs to form the germplasm that instructs germ cell formation. Arginines at the N-terminus of Aub (Aub-NTRs) interact with Tudor and other Tudor domain-containing proteins (TDRDs). Aub-TDRD interactions suppress active retrotransposons via piRNA amplification and form germplasm via generation of Aub-Tudor ribonucleoproteins. Here, we show that Aub-NTRs are dispensable for primary piRNA biogenesis but essential for piRNA amplification and that their symmetric dimethylation is required for germplasm formation and germ cell specification but largely redundant for piRNA amplification.