Life Sciences Commons^™

Sequence Analysis Methods For The Design Of Cancer Vaccines That Target Tumor-Specific Mutant Antigens (Neoantigens), Jasreet Hundal

Arts & Sciences Electronic Theses and Dissertations

The human adaptive immune system is programmed to distinguish between self and non-self proteins and if trained to recognize markers unique to a cancer, it may be possible to stimulate the selective destruction of cancer cells. Therapeutic cancer vaccines aim to boost the immune system by selectively increasing the population of T cells specifically targeted to the tumor-unique antigens, thereby initiating cancer cell death.. In the past, this approach has primarily focused on targeted selection of ‘shared’ tumor antigens, found across many patients. The advent of massively parallel sequencing and specialized analytical approaches has enabled more efficient characterization of tumor-specific …

Grammar And Variation: Understanding How Cis-Regulatory Information Is Encoded In Mammalian Genomes, Dana Michele King

Arts & Sciences Electronic Theses and Dissertations

Understanding how genotype leads to phenotype is key to understand both the development and dysfunction of complex organisms. In the context of regulating the gene expression patterns that contribute to cell identity and function, the goal of my thesis research is to how changes in genome sequence may impact impact gene expression by determining how sequence features contribute to regulatory potential. To accomplish this goal, I first leveraged the key regulatory role of pluripotency transcription factors (TFs) in mouse embryonic stem cells (mESCs) and tested synthetically generated and genomic identified combinations of binding site for four TFs, OCT4, SOX2, KLF4, …

A Tail Of Two Pancancer Projects: Somatic Variant Identification And Driver Gene Discovery Using Tcga, Matthew Hawkins Bailey

Arts & Sciences Electronic Theses and Dissertations

The implementation of next-generation genomic sequencing has exploded over the past dozen years. Large consortia, such as The Cancer Genome Atlas (TCGA); the International Cancer Genetics Consortium (ICGC); and the Pediatric Cancer Genome Projects (PCGP), made great strides in democratizing big data for the scientific community. These data sets provide a rich resource to build tools for somatic variant discovery and exploratory analysis. Public repositories hold the answer to many novel biological and clinical revelations i.e., the discovery of complex indels, splice creating mutations, alternative super enhancer binding sites, machine learning models to predict mutation impact, and cancer subtype classification …

A Mechanism Of Antimicrobial Resistance And A Mitigation Strategy, Christopher Bulow

Arts & Sciences Electronic Theses and Dissertations

ABSTRACT OF THE DISSERTATION

A Mechanism of Antimicrobial Resistance and a Mitigation Strategy

by

Christopher Bulow

Doctor of Philosophy in Biology and Biomedical Sciences

Molecular Genetics and Genomics

Washington University in St. Louis, 2018

Professor Gautam Dantas, Chair

The ability to treat infections, perform surgery, and administer immunosuppressants and chemotherapy depends on effective antibiotics. The emergence and spread of antimicrobial resistance is far outpacing the development of new therapies1-3 threatening to thrust medicine into a post-antibiotic era4. Many mechanisms of antimicrobial action and of antimicrobial resistance remain poorly understood as drug development struggles to keep pace. As resistance develops, the …

The Mechanism Of Hyper Daptomycin Resistance In Corynebacterium Striatum And Daptomycinճ Mechanism Of Action, Nicholas Kevork Goldner

Arts & Sciences Electronic Theses and Dissertations

Daptomycin, a last line-of-defense antibiotic for treating Gram-positive infections, is experiencing clinical failure against important infectious agents, including Corynebacterium striatum. The recent transition of daptomycin to generic antibiotic status is projected to dramatically increase availability, use, and clinical failure. Despite daptomycinճ more than 30-year history as an important antibiotic, four major questions were left unanswered. 1) How do bacteria become hyper-resistant to daptomycin? 2) What is the in vivo membrane target of daptomycin? 3) How does daptomycin interact with the membrane? 4) What is daptomycinճ mechanism of killing? These four questions have plagued the daptomycin field, and even now conflicting …

Discerning Drivers Of Cancer: Computational Approaches To Somatic Exome Sequencing Data, Runjun Kumar

Arts & Sciences Electronic Theses and Dissertations

Paired tumor-normal sequencing of thousands of patient’s exomes has revealed millions of somatic mutations, but functional characterization and clinical decision making are stymied because biologically neutral ‘passenger’ mutations greatly outnumber pathogenic ‘driver’ mutations. Since most mutations will return negative results if tested, conventional resource-intensive experiments are reserved for mutations which are observed in multiple patients or rarer mutations found in well-established cancer genes. Most mutations are therefore never tested, diminishing the potential to discover new mechanisms of cancer development and treatment opportunities. Computational methods that reliably prioritize mutations for testing would greatly increase the translation of sequencing results to clinical …

Discovering Rare Hematopoietic Clones Harboring Leukemia-Associated Mutations Using Error-Corrected Sequencing, Andrew Lee Young

Arts & Sciences Electronic Theses and Dissertations

Cancer is a heterogeneous group of diseases that currently takes over half a million lives per year in the United States alone. Our understanding of cancer has improved dramatically over the last forty years, beginning with the discovery that cancer is a disease of the genome. Currently, the set of somatic mutations found in malignancy are largely known. The specific somatic mutations driving an individual’s disease can be readily assessed at clinical presentation. Additionally, the functional consequences for many of these mutations are known as well as their role in tumorigenesis. Despite this understanding, a cure for cancer remains elusive. …