Medical Sciences Commons^™

Analysis Of Clock-Regulated Genes In Neurospora Reveals Widespread Posttranscriptional Control Of Metabolic Potential, Jennifer M. M. Hurley, Arko Dasgupta, Jillian M. Emerson, Xiaoying Zhou, Carol S. Ringelberg, Nicole Knabe

Dartmouth Scholarship

Neurospora crassa has been for decades a principal model for filamentous fungal genetics and physiology as well as for understanding the mechanism of circadian clocks. Eukaryotic fungal and animal clocks comprise transcription-translation-based feedback loops that control rhythmic transcription of a substantial fraction of these transcriptomes, yielding the changes in protein abundance that mediate circadian regulation of physiology and metabolism: Understanding circadian control of gene expression is key to understanding eukaryotic, including fungal, physiology. Indeed, the isolation of clock-controlled genes (ccgs) was pioneered in Neurospora where circadian output begins with binding of the core circadian transcription factor WCC to a subset …

E2f4 Regulatory Program Predicts Patient Survival Prognosis In Breast Cancer, Sari S. Khaleel, Erik H. Andrews, Matthew Ung, James Direnzo, Chao Chung

Dartmouth Scholarship

Genetic and molecular signatures have been incorporated into cancer prognosis prediction and treatment decisions with good success over the past decade. Clinically, these signatures are usually used in early-stage cancers to evaluate whether they require adjuvant therapy following surgical resection. A molecular signature that is prognostic across more clinical contexts would be a useful addition to current signatures. We defined a signature for the ubiquitous tissue factor, E2F4, based on its shared target genes in multiple tissues. These target genes were identified by chromatin immunoprecipitation sequencing (ChIP-seq) experiments using a probabilistic method. We then computationally calculated the regulatory activity score …

Downregulation Of Prdm16 Is Critical For Hoxb4-Mediated Benign Hsc Expansion In Vivo, Hui Yu

Theses and Dissertations (ETD)

Overexpression of HOXB4 in hematopoietic stem cells (HSCs) leads to increased self-renewal without causing hematopoietic malignancies in transplanted mice. The molecular basis of HOXB4-mediated benign HSC expansion in vivo is not well understood. To gain further insight into the molecular events underlying HOXB4-mediated HSC expansion, we analyzed gene expression changes at multiple time points in Lin-Sca1+c-kit+ (LSK) cells from mice transplanted with bone marrow (BM) cells transduced with a MSCV-HOXB4-ires-YFP vector. A distinct HOXB4 transcriptional program was reproducibly induced and stabilized by 12 weeks after transplant. Dynamic expression changes were observed in genes critical for HSC self- renewal as well …

Effect Of Nedd4 Haploinsufficiency On Insulin Sensitivity, Adiposity And Neuronal Behaviors, Jingjing Li

Theses and Dissertations (ETD)

The neural precursor cell expressed developmentally down-regulated gene 4 (NEDD4) is a HECT-type E3 ubiquitin ligase that has received broad attention in recent years. Many of its reported substrates are active players in metabolism, implying a potential role of NEDD4 itself in metabolic regulation. Since homozygous Nedd4 deletion leads to embryonic or perinatal lethality, we investigated the function of NEDD4 in metabolic regulation in vivo, using Nedd4- haploinsufficient mice in a high fat diet-induced obesity (HFDIO) model.

Our studies show that Nedd4-haploinsufficient mice fed a normal diet (ND) exhibited decreased body weight in both genders and proportionally reduced tissue mass …

The Role Of Mcl-1 In The Heart: Gateway From Life To Death, Xi Wang

Theses and Dissertations (ETD)

MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we have demonstrated that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy preceded by loss of myofibrils and cardiac contractility, abnormal mitochondria ultrastructure, defective mitochondrial respiration, and impaired autophagy. Genetic ablation of both pro-apoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, Mcl-1-, Bax-, and Bak-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration, and are hypersensitive to chronic …

Autoimmune Susceptibility Imposed By Public Tcrβ Chains, Yunqian Zhao

Theses and Dissertations (ETD)

The major histocompatibility complex (MHC) is the strongest genetic risk factor for autoimmunity. It acts together with a corresponding TCR repertoire, yet, considering the extent of the repertoire's diversity, how this imposes disease susceptibility on a population is not well understood. We address the hypothesis that shared or public TCR, those present in most individuals, modulate autoimmune risk. High resolution analyses of autoimmune encephalomyelitis-associated T-cell receptor β chain (TCRβ) showed preferential utilization of public TCR sequences, implicating them in pathogenesis. Disease-associated public TCRβ, when transgenically expressed in association with endogenously rearranged T-cell receptor α chain (TCRα), could further endow unprimed …

An Integrated Transcriptome And Expressed Variant Analysis Of Sepsis Survival And Death., Ephraim L. Tsalik, Raymond J. Langley, Darrell L. Dinwiddie, Neil A. Miller, Byunggil Yoo, Jennifer C. Van Velkinburgh, Laurie D. Smith, Isabella Thiffault, Anja K. Jaehne, Ashlee M. Valente, Ricardo Henao, Xin Yuan, Seth W. Glickman, Brandon J. Rice, Micah T. Mcclain, Lawrence Carin, G Ralph Corey, Geoffrey S S. Ginsburg, Charles B. Cairns, Ronny M. Otero, Vance G. Fowler, Emanuel P. Rivers, Christopher W. Woods, Stephen F. Kingsmore

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality.

METHODS: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene …

Xk Aprosencephaly And Anencephaly In Sibs, Phillip Townes, Karen Reuter, E. Rosquete, B. Magee

B. Dale Magee

Recent studies have suggested a causal and pathogenetic relationship between holoprosencephaly and anencephaly. In support of the proposed relationship we report a sibship that includes anencephalic male twins and a female infant with a severe form of alobar holoprosencephaly, radial aplasia, and oligodactyly. The upper limb and brain malformations are considered to represent aprosencephaly syndrome. The coexistence of anencephaly and aprosencephaly within a sibship suggests that XK aprosencephaly syndrome may be an autosomal recessive disorder.

The Influence Of Gene Environment Interaction On The Risk Of Cognitive Impairment: Reducing Sexual Risk Behaviors And Alcohol Use In Hiv-Infected Adults, Karina Villalba Phd

FIU Electronic Theses and Dissertations

Memory deficits and executive dysfunction are highly prevalent among HIV-infected adults. These conditions can affect their quality of life, antiretroviral adherence, and HIV risk behaviors. Several factors have been suggested including the role of genetics in relation to HIV disease progression. This dissertation aimed to determine whether genetic differences in HIV-infected individuals were correlated with impaired memory, cognitive flexibility and executive function and whether cognitive decline moderated alcohol use and sexual transmission risk behaviors among HIV-infected alcohol abusers participating in an NIH-funded clinical trial comparing the efficacy of the adapted Holistic Health Recovery Program (HHRP-A) intervention to a Health Promotion …

Role Of A Genetic Variant On The 15q25.1 Lung Cancer Susceptibility Locus In Smoking-Associated Nasopharyngeal Carcinoma, Xuemei Ji, Weidong Zhang, Jiang Gui, Xia Fan, Weiwei Zhang, Yafang Li, Guangyu An, Dakai Zhu, Qiang Hu

Dartmouth Scholarship

Background: The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC).

Methods: In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and …

Analysis Of Candida Albicans Mutants Defective In The Cdk8 Module Of Mediator Reveal Links Between Metabolism And Biofilm Formation, Allia K. Lindsay, Diana K. Morales, Zhongle Liu, Nora Grahl, Anda Zhang, Sven D. Willger, Lawrence C. Myers, Deborah A. Hogan

Dartmouth Scholarship

Candida albicans biofilm formation is a key virulence trait that involves hyphal growth and adhesin expression. Pyocyanin (PYO), a phenazine secreted by Pseudomonas aeruginosa, inhibits both C. albicans biofilm formation and development of wrinkled colonies. Using a genetic screen, we identified two mutants, ssn3Δ/Δ and ssn8Δ/Δ, which continued to wrinkle in the presence of PYO. Ssn8 is a cyclin-like protein and Ssn3 is similar to cyclin-dependent kinases; both proteins are part of the heterotetrameric Cdk8 module that forms a complex with the transcriptional co-regulator, Mediator. Ssn3 kinase activity was also required for PYO sensitivity as a kinase dead mutant maintained …

Analysis Of Differential Mrna And Mirna Expression In An Alzheimer’S Disease Mouse Model, Amanda Hazy, Matthew Dalton

Other Undergraduate Scholarship

Research has shown that changes in gene expression play a critical role in the development of Alzheimer’s Disease (AD). Our project will evaluate genome-wide RNA expression patterns from brain and blood in an AD mouse model. This analysis will provide insight regarding the mechanisms of AD pathology as well as determine a possible diagnostic tool utilizing RNA expression patterns found in the blood as biomarkers for AD.

Community Cancer Services, Clinical Trials, And Quality Initiatives—Year 1 Ncccp At Lehigh Valley Health Network, Gregory R. Harper Md, Phd, Ada M. Rivera Ba, Eliot L. Friedman Md, Kathleen A. Leies Rn, Ocn, Nadesda Mack Rn, Bsn, Mba, Ocn, Lenore Mcgonigle Med, Suresh G. Nair Md, Tara Namey Ms, Cgc, Debbie Salas-Lopez Md, Mph, Facp, Ronald W. Swinfard Md, Facp

Debbie Salas-Lopez MD, MPH, FACP

No abstract provided.

Activation Of C-Myc And Cyclin D1 By Jcv T-Antigen And Β-Catenin In Colon Cancer, Michael J. Ripple, Amanda Parker Struckhoff, Jimena Trillo-Tinoco, Li Li, David A. Margolin, Robin Mcgoey, Luis Del Valle

School of Medicine Faculty Publications

During the last decade, mounting evidence has implicated the human neurotropic virus JC virus in the pathology of colon cancer. However, the mechanisms of JC virus-mediated oncogenesis are still not fully determined. One candidate to mediate these effects is the viral early transcriptional product T-Antigen, which has the ability to inactivate cell cycle regulatory proteins such as p53. In medulloblastomas, T-Antigen has been shown to bind the Wnt signaling pathway protein β-catenin; however, the effects of this interaction on downstream cell cycle regulatory proteins remain unknown. In light of these observations, we investigated the association of T-Antigen and nuclear β-catenin …

Disrupted Human–Pathogen Co-Evolution: A Model For Disease, Nuri Kodaman, Rafal S. Sobota, Robertino Mera, Barbara G. Schneider, Scott M. Williams

Dartmouth Scholarship

A major goal in infectious disease research is to identify the human and pathogenic genetic variants that explain differences in microbial pathogenesis. However, neither pathogenic strain nor human genetic variation in isolation has proven adequate to explain the heterogeneity of disease pathology. We suggest that disrupted co-evolution between a pathogen and its human host can explain variation in disease outcomes, and that genome-by-genome interactions should therefore be incorporated into genetic models of disease caused by infectious agents. Genetic epidemiological studies that fail to take both the pathogen and host into account can lead to false and misleading conclusions about disease …

Co-Infection With Hpv Types From The Same Species Provides Natural Cross-Protection From Progression To Cervical Cancer, Rafal S. Sobota, Doreen Ramogola-Masire, Scott M. Williams, Nicola M. Zetola

Dartmouth Scholarship

The worldwide administration of bivalent and quadrivalent HPV vaccines has resulted in cross-protection against non-vaccine HPV types. Infection with multiple HPV types may offer similar cross-protection in the natural setting. We hypothesized that infections with two or more HPV types from the same species, and independently, infections with two or more HPV types from different species, associate with protection from high-grade lesions.

Dissecting The Roles Of Trim24 In Regulation Of Hepatic Lipid Metabolism And Inflammation, Lindsey C. Minter

Dissertations & Theses (Open Access)

DISSECTING THE ROLES OF TRIM24 IN REGULATION OF HEPATIC LIPID

METABOLISM AND INFLAMMATION

Lindsey Cauthen Minter, B.S., B.A.

Advisory Professor: Michelle C. Barton, Ph.D.

In this dissertation, I report the characterization of a new mouse model that recapitulates development of hepatocellular carcinoma (HCC) following spontaneous hepatic lipid accumulation, inflammation, and damage of liver tissue, due to complete loss of Trim24 expression. In human HCC and other cancers, TRIM24 expression is aberrantly high, while deletion of TRIM24 in the mouse has been shown to act as a liver specific tumor suppressor. The hypothesis tested here was that TRIM24, the E3 ubiquitin …

Characterization Of Primary Care Clinicians’ Use Of Genomic And Pharmacogenomic Testing, Brian Stello Md, Heather Bittner-Fagan Md, Mph, Christopher V. Chambers Md, Melanie B. Johnson Mpa, Geoffrey Mills Md, Phd, Michael P. Rosenthal Md, Kyle Shaak Bs

Department of Family Medicine

No abstract provided.

Draft Genome Sequence For Pseudomonas Aeruginosa Strain Pao579, A Mucoid Derivative Of Pao381, T. Ryan Withers, Shannon L. Johnson, Hongwei D. Yu

Hongwei Yu

Pseudomonas aeruginosa is an opportunistic pathogen that establishes a chronic lung infection in individuals afflicted with cystic fibrosis. Here, we announce the draft genome of P. aeruginosa strain PAO579, an alginate-overproducing derivative of strain PAO381.

Primary Care Clinicians Use Of Genomics And Pharmacogenomic Testing, Heather Bittner-Fagan Md, Mph, Brian Stello Md, Christopher V. Chambers Md, Geoffrey Mills Md, Phd, Beth Careyva Md, Melanie B. Johnson Mpa, Dierdre B. Axell-House Ba, Michael P. Rosenthal Md

Department of Family Medicine

No abstract provided.

Dr. Kingsmore, Dr. Goggin Honored With Endowed Chairs, Children's Mercy Hospital

Our Story Continues

No abstract provided.

Genomics Into Healthcare: The 5th Pan Arab Human Genetics Conference And 2013 Golden Helix Symposium., Paolo Fortina, Najib Al Khaja, Mahmoud Taleb Al Ali, Abdul Rezzak Hamzeh, Pratibha Nair, Federico Innocenti, George P. Patrinos, Larry J. Kricka

Department of Cancer Biology Faculty Papers

The joint 5th Pan Arab Human Genetics conference and 2013 Golden Helix Symposium, "Genomics into Healthcare" was coorganized by the Center for Arab Genomic Studies (http://www.cags.org.ae) in collaboration with the Golden Helix Foundation (http://www.goldenhelix.org) in Dubai, United Arab Emirates from 17 to 19 November, 2013. The meeting was attended by over 900 participants, doctors and biomedical students from over 50 countries and was organized into a series of nine themed sessions that covered cancer genomics and epigenetics, genomic and epigenetic studies, genomics of blood and metabolic disorders, cytogenetic diagnosis and molecular profiling, next-generation sequencing, consanguinity and hereditary diseases, clinical genomics, …

Availability Of Dental Anomaly Phenotype In Individuals With Familial Adenomatous Polyposis, Andrea M. Lewis

Dissertations & Theses (Open Access)

Background: Mutations in the APC gene cause familial adenomatous polyposis (FAP), an autosomal dominant colorectal cancer predisposition associated with the development of hundreds to thousands of adenomatous colorectal polyps beginning in childhood or adolescence. Both malignant and non-malignant extracolonic manifestations are associated with APC gene mutations, including approximately 17% of individuals with various dental anomalies. The availability of dental anomaly information in the medical record remains to be evaluated.

Methods: Medical records were reviewed for documentation of dental anomalies. Dental questionnaires were mailed to 271 individuals with FAP at The University of Texas M. D. Anderson Cancer Center (UTMDACC) to …

Latinas And The Traditional Genetic Counseling Model: A Qualitative Study, Stephanie Thompson

Dissertations & Theses (Open Access)

The traditional genetic counseling model reflects an individualized counseling session that includes the presentation of information about genes, chromosomes, personalized risk assessment, and genetic testing and screening options. Counselors are challenged to balance providing educational information with discussion of implications of this information in an allotted amount of time. The aim of this study was to explore the perceptions of pregnant Latinas on the benefits and limitations of the traditional prenatal genetic counseling model and to determine the specific preferences for receiving prenatal genetic counseling. Data were collected through focus groups and one-on-one, semi-structured interviews of twenty-five Spanish speaking Latinas …

Evaluation Of Current Clinical Criteria For Li-Fraumeni Syndrome In A Diverse Sample Of Tp53 Mutation Carriers, Emily A. Parham

Dissertations & Theses (Open Access)

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by heterozyogous germline mutations in the TP53 gene and characterized by an excess of early-onset cancers, high lifetime risk of cancer, and a wide range of tumor types. Recent studies suggesting a benefit in comprehensive screening protocols for both children and adults make the timely identification of individuals with LFS increasingly important.

A number of criteria have been proposed to identify patients with LFS. The National Comprehensive Cancer Network (NCCN) combines several in its Clinical Practice Guidelines for TP53 genetic testing. Prior studies have shown that the cumulative sensitivity of …

Role Of Membrane Fusion Protein Ykt6 In Regulating Epithelial Cell-Cell And Cell-Matrix Adhesions., Supriya Joshi

Theses and Dissertations

Intercellular junctions and cell-matrix adhesions play important roles in the maintenance of epithelial integrity. Assembly and remodeling of the plasma membrane complexes are regulated by membrane trafficking and fusion. This thesis is aimed to elucidate the roles of an important membrane fusion protein, Ykt6, in the regulation of epithelial cell adhesion and migration. For the first time, we show that Ykt6 is essential for assembly of adherens junctions and tight junctions in human prostate epithelial cells. We also observed that Ykt6 negatively regulates both collective epithelial cell migration and cell invasion into Matrigel. The effects of YKT6 on epithelial junctions …

Differential Regulation Of Iress In The Aurora A Mrna By Bfgf Through The Mtor Complex Torc2 Modulates Aurora A Kinase Expression, Roy L. Voice Iii

Dissertations & Theses (Open Access)

Identifying the mechanisms that contribute to tumorigenesis is a major area of focus in our fight against cancer. Epithelial malignant tumors, such as breast, colon, ovarian and pancreatic cancers have been shown to overexpress proteins that control cell mitosis, growth, and proliferation. One of those proteins is the Aurora A kinase. Aurora A kinase is a member of a small family of kinases that contribute to mitotic events such as centrosome duplication, separation, and maturation. Aurora A overexpression leads to genomic instability, which can contribute to tumorigenesis, on the other hand, inhibiting Aurora A expression leads to apoptosis, making it …

Modulated Functions Of The Fanconi Anemia Core Complex, Yaling Huang

Dissertations & Theses (Open Access)

Cells derived from Fanconi anemia (FA) patients are characterized by hypersensitivity to DNA interstrand crosslinks (ICLs), suggesting that FA genes play a role in ICL repair. Fanconi anemia core complex (including A, B, C, E, F, G, L, FAAP20, and FAAP100) activates the Fanconi pathway by providing the essential E3 ligase activity for FANCD2 mono-ubiquitination. Previous studies suggested the existence of three protein-protein interaction groups. However, the functions of most FA core complex protein are still limited to their presence in the complex. How the spatially-defined FANCD2 ubiquitination is accomplished by the core complex remains unknown.

To elucidate the roles …

Cancers Associated With Brca1 And Brca2 Mutations Other Than Breast And Ovarian, Jacqueline Mersch

Dissertations & Theses (Open Access)

Mutations in BRCA1 and BRCA2 cause tumor development in Hereditary Breast and Ovarian Cancer syndrome (HBOC) through accumulation of unrepaired DNA damage. Extensive research of BRCA1 and BRCA2 mutations has led to well-defined breast and ovarian cancer risks in individuals with HBOC. Previous studies have reported additional cancers associated with BRCA mutations; however, the type of cancer, magnitude of risk, and differences between sexes remains to be clarified. Ultimately, a consensus of additional cancer risks can aid in better recommendations for genetic testing and more effective screening and prevention guidelines.

A retrospective chart review of MD Anderson Cancer Center patients …

Predicting Targeted Drug Combinations Based On Pareto Optimal Patterns Of Coexpression Network Connectivity, Nadia M. Penrod, Casey S. Greene, Jason H. Moore

Dartmouth Scholarship

Molecularly targeted drugs promise a safer and more effective treatment modality than conventional chemotherapy for cancer patients. However, tumors are dynamic systems that readily adapt to these agents activating alternative survival pathways as they evolve resistant phenotypes. Combination therapies can overcome resistance but finding the optimal combinations efficiently presents a formidable challenge. Here we introduce a new paradigm for the design of combination therapy treatment strategies that exploits the tumor adaptive process to identify context-dependent essential genes as druggable targets. We have developed a framework to mine high-throughput transcriptomic data, based on differential coexpression and Pareto optimization, to investigate drug-induced …