Digital Commons Network^™

Outcomes In Patients With Poor-Risk Cytogenetics With Or Without Tp53 Mutations Treated With Venetoclax And Azacitidine, Daniel A Pollyea, Keith W Pratz, Andrew H Wei, Vinod Pullarkat, Brian A Jonas, Christian Recher, Sunil Babu, Andre C Schuh, Monique Dail, Yan Sun, Jalaja Potluri, Brenda Chyla, Courtney D Dinardo

Faculty, Staff and Student Publications

PURPOSE: To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt.

PATIENTS AND METHODS: We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1-28) + azacitidine (75 mg/m2 days 1-7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally.

RESULTS: Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared …

3d Imaging Analysis On An Organoid-Based Platform Guides Personalized Treatment In Pancreatic Ductal Adenocarcinoma, Ya'an Kang, Jenying Deng, Jianhua Ling, Xinqun Li, Yi-Ju Chiang, Eugene J Koay, Huamin Wang, Jared K Burks, Paul J Chiao, Mark W Hurd, Manoop S Bhutani, Jeffrey H Lee, Brian R Weston, Anirban Maitra, Naruhiko Ikoma, Ching-Wei D Tzeng, Jeffrey E Lee, Ronald A Depinho, Robert A Wolff, Shubham Pant, Florencia Mcallister, Matthew Hg Katz, Jason B Fleming, Michael P Kim

Faculty, Staff and Student Publications

BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with unpredictable responses to chemotherapy. Approaches to assay patient tumors before treatment and identify effective treatment regimens based on tumor sensitivities are lacking. We developed an organoid-based platform (OBP) to visually quantify patient-derived organoid (PDO) responses to drug treatments and associated tumor-stroma modulation for personalized PDAC therapy.METHODSWe retrospectively quantified apoptotic responses and tumor-stroma cell proportions in PDOs via 3D immunofluorescence imaging through annexin A5, α-smooth muscle actin (α-SMA), and cytokeratin 19 (CK-19) levels. Simultaneously, an ex vivo organoid drug sensitivity assay (ODSA) was used to measure responses to standard-of-care …

Pavement Ants (Tetramorium Immigrans Santschi), Ryan S. Davis, Lori R. Spears, Austin Taylor

All Current Publications

This fact sheet describes pavement ants. It covers identification, biology and habits, and management.

Japanese Beetle (Popillia Japonica Newman), Lori R. Spears, Diane G. Alston, Joey Caputo, Erin Hodgson, Cory Stanley, Kristopher Watson

All Current Publications

This fact sheet describes Japanese beetles and reviews damage symptoms, life cycle, monitoring, and management.

Invasive Species Handbook: A Resource For Educators - Grades 3-8, Natalie D'Souza, Marion Murray, Lori R. Spears

All Current Publications

This handbook includes six chapters that discuss invasive species and their environmental, economic, and health impacts. It also reviews pathways of invasive species spread and prevention, monitoring, and control. The handbook is a resource for educators teaching children in grades 3 through 8. Learning objectives, activities, and vocabulary are also included.

Systems Level Analysis Of Organelle Biogenesis In Saccharomyces Cerevisiae, Kiandokht Panjtan Amiri

Arts & Sciences Graduate Student Theses and Dissertations

Eukaryotic cells contain hundreds of subcellular structures that serve different functions to maintain cellular homeostasis. A hallmark of Eukaryotic cells is its compartmentalization into membrane-bound organelles. One of the grand challenges in quantitative cell biology is understanding the precision with which cells assemble and maintain subcellular organelles. Despite identification of numerous molecular factors that regulate organelle sizes we lack insight into the quantitative principles underlying organelle size control. We examine organelle sizes from Saccharomyces cerevisiae and human iPS cells with mathematical theory to show that cells can robustly control average fluctuations in organelle size. By demonstrating that organelle sizes obey …

Analysis Of Regulatory Element Variation In Autism Spectrum Disorder, Evin Mitchel Padhi

Arts & Sciences Graduate Student Theses and Dissertations

Autism Spectrum Disorder (ASD) is a highly prevalent neurodevelopmental disorder that affects over 2% of the population. Studies of this disorder have demonstrated that genetics plays a strong role in the underlying etiology and over the past decade, substantial progress has been made in elucidating the genetic architecture. Large-scale studies have now been conducted to identify the genes involved in the genetic architecture by analyzing data from over 40,000 probands. However, the identification and characterization of regulatory elements involved have remained non-trivial for many reasons. Generally, studies that have analyzed whole genome sequencing (WGS) have demonstrated enrichment of de novo …

The Effects Of Nmda Antagonism On Neuronal Activity And Neurovascular Coupling In Non-Human Primate Cortex, Benjamin Thomas Acland

Arts & Sciences Graduate Student Theses and Dissertations

The N-methyl-D-aspartate receptor (NMDAR) plays a variety of important roles in the development and function of primate central nervous systems. This thesis describes three nonhuman primate studies that, together, demonstrate that pharmacologically reducing NMDAR activity not only causes dramatic changes in neural activity in cortex, but also changes the relationship between that activity and a key signal often used as its proxy in human studies, the blood-oxygen-level-dependent (BOLD) signal. The first study reveals that NMDA antagonism is sufficient to induce powerful low-frequency modulation of spiking activity and extracellular local field potential (LFP) and discusses the implications of this finding for …

Testing Of A Novel Combined Eating-Disorder And Weight-Loss Online Guided-Self Help Intervention For Young Adults With A Binge-Type Eating Disorder And Overweight Or Obesity, Grace Elise Monterubio

Arts & Sciences Graduate Student Theses and Dissertations

Binge-type eating disorders (EDs) and obesity-related health concerns are two serious medical issues, though study of their treatment has largely remained separate. This study implemented an online, guided self-help ED intervention that concurrently offered Cognitive Behavioral Therapy (CBT)-based tools to improve ED symptoms, while also teaching energy-density food principles of behavioral weight loss (BWL), for individuals with clinical/sub-clinical binge-type EDs with comorbid overweight/obesity. The study aimed to examine change in weight, change in ED symptoms, and program engagement between a combined intervention (CBT + BWL) and an ED-only intervention. Participants in the combined intervention group received weekly session content pertaining …

Behavioral, Neural, And Psychiatric Correlates Of Responses To Social Feedback, Brent Rappaport

Arts & Sciences Graduate Student Theses and Dissertations

Problems responding to peer feedback and disrupted interpersonal relationships arise in numerous psychiatric disorders; yet heterogeneity and homogeneity across disorders suggests both common and unique mechanisms of impaired social function. Identifying brain correlates of these disruptions could help explain diagnostic comorbidities as well as unique pathways, thus informing more individualized treatments. However, studies seeking to understand the link between psychological and neural mechanisms often have to rely on reverse inference assumptions to match psychological processes to brain activity. One hypothesis is that social feedback is processed similar to other forms of feedback (e.g., monetary). Thus, we aimed to test such …

Canonical And Noncanonical Mechanisms Of Resistance To Arginine Starvation In Cancer, Leonard Christopher Rogers

Arts & Sciences Graduate Student Theses and Dissertations

The enzyme argininosuccinate synthetase 1 (ASS1) catalyzes the condensation of citrulline and aspartate into argininosuccinate as part of the urea cycle and citrulline-nitric oxide cycle. This reaction is essential for mammals to synthesize the amino acid arginine, which is required for all cells. Nearly all human tissues express at least some ASS1, but they import most of their arginine from the extracellular space after it is produced and released by the kidneys. Most solid tumors lack a functional level of ASS1, including over 85% of sarcomas, which are cancers of connective tissues. Published evidence suggests that this provides a proliferation …

Analyzing The Interconnectedness Of The Human Genome, Nicholas Jacobs

Arts & Sciences Graduate Student Theses and Dissertations

The human genome is much more interconnected than many people realize. In this thesis, I will outline two efforts to portray this idea. First, I will seek to display that cell fitness is an omniphenotype. That is to say, cell fitness can be used to determine whether an unknown factor interacts with a known factor for any phenotype. The human genome is sufficiently interconnected that if two factors interact with one another then that can be reflected by a multiplicative change in cell fitness. This change in fitness can be used to determine if a new factor of interest is …

Functionalized Plasmonic Nanostructures For Ultrasensitive Single Cell Analysis, Priya Rathi

Arts & Sciences Graduate Student Theses and Dissertations

Ultrasensitive detection and quantification of soluble, secreted and cell surface-bound proteins is critical for advancing our understanding of cellular systems, enabling effective drug development, novel therapies, and bio-diagnostics. However, exiting technologies are largely limited by their sensitivity, making the detection and quantification of low-abundant proteins extremely challenging. This forms a major barrier in various fields of biology and biomedical sciences. In this work, we introduce novel cellular analysis methodologies based on plasmon-enhanced fluorescence for analyzing cell structure and probing surface and secreted proteins from cells. In the first part, we introduce plasmon-enhanced expansion microscopy and demonstrate the effectiveness of employing …

Genetic And Transcriptomic Aspects Of Major Depressive Disorder: In Vivo Functional Assays Of Risk-Associated Variation, Candidate Disease Cell Types, And Their Pharmacologic And Sex Interactions, Bernard Mulvey

Arts & Sciences Graduate Student Theses and Dissertations

Major depressive disorder (MDD) is a debilitating illness that affects hundreds of millions globally, with substantial personal, medical, economic, and societal consequences. While depression occurs more commonly in females, the biology of the brain and sex underlying this skewed prevalence remains unclarified. This body of work explores two aspects of how biological sex may influence the brain at the level of gene expression: through intrinsic sex differences and through sex-mediated effects of depression risk genetics.The monoamine hypothesis of depression suggests that modulatory neurotransmitters including serotonin and norepinephrine constitute a key axis in development of MDD. Large-scale studies of MDD treatment …

Dysregulation Of Gene Expression In Non-Photosensitive Trichothiodystrophy, Brittany Townley

Arts & Sciences Graduate Student Theses and Dissertations

The pre-mRNA life cycle requires intron processing; yet, how intron processing defects influence splicing and gene expression is unclear. Here, we find TTDN1, which is frequently mutated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to the spliceosome. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, while its N-terminal intrinsically disordered region (IDR) binds the intron binding complex (IBC). The IDR forms condensates in vitro and is needed for IBC interaction. TTDN1 loss causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. Ttdn1∆/∆ mice recapitulate …

Tracking Reducing Equivalents Between Cellular Compartments To Understand The Metabolic Demands Of Proliferation, Yahui Wang

Arts & Sciences Graduate Student Theses and Dissertations

Proliferating cancer cells compartmentalize metabolic reactions, many of which require reducing equivalents. This compartmentalization is functionally important, but it is challenging to study with current technologies. As a consequence, our understanding of proliferating metabolism has been limited. Here, I developed an approach to track reducing equivalents between cellular compartments. By applying this method to a panel of different cell lines under various conditions, I investigated a dysregulated metabolic phenotype in proliferating cells known as “aerobic glycolysis”. Aerobic glycolysis is characterized by an elevated rate of glucose fermentation to lactate irrespective of oxygen availability. Using the NCI-60 cell lines, I first …

Bioinformatics And Cancer Genomics Approaches To Advance Precision Medicine And Elucidate Tumor Mutational Landscapes, Kelsy Cotto

Arts & Sciences Graduate Student Theses and Dissertations

Next-generation sequencing of DNA and RNA continues to be integrated into pre-clinical and clinical research. However, challenges still remain that impede the translation of findings into an improved understanding of human diseases or clinically actionable alterations. The projects described in this dissertation start with compiling efforts from experts who have identified druggable genes within the human genome, followed by in-depth analyses which characterize the pan-cancer landscape of splice-associated mutations and noncoding, regulatory mutations across multiple subtypes of breast cancer. In Chapters 2 and 3, substantial efforts were made to update the content and the user experience for the drug-gene interaction …

The Impact Of Nucleolar Stress On Thymocyte Development And T Cell Acute Lymphoblastic Leukemia Transformation, Joseph Ryan Krambs

Arts & Sciences Graduate Student Theses and Dissertations

Increased Notch signaling is thought to be central to T-ALL pathogenesis, with activatingmutations of NOTCH1 in 60% of cases, and Notch pathway activation due to mutations in FBXW7 in an additional 15% of cases. Increased Notch signaling results in markedly increased ribosome biogenesis, inducing a negative feedback loop called the nucleolar stress pathway. This is an evolutionarily conserved homeostatic pathway that is triggered by excessive ribosome biogenesis that serves to limit rRNA synthesis, protein translation, and ultimately cell growth. CDKN2A, encoding both ARF and INK4A, plays a key role in the nucleolar stress pathway. Activation of ARF and INK4A inhibits …

Sik3 & Wnk Signals Through Fray To Regulate Glial K+ Buffering And Seizure Susceptibility In Drosophila Models Of Hyperexcitability, Lorenzo Laronn Lones

Arts & Sciences Graduate Student Theses and Dissertations

K+ homeostasis is important for maintaining healthy, physiological levels of neuronal activity. Glial cells play a central role in maintaining homeostatic ion gradients. In previous work from our lab, we unravel a glial K+ buffering program that is centered on a key kinase, salt-inducible kinase 3 (SIK3). SIK3-HDAC4 signaling in glial regulates the transcription of channels and transporters involved in water and ion transport. Defects in this pathway lead to peripheral nerve edema, neuronal hyperactivity, and seizure sensitivity. In an hyperexcitability mutant, eag Shaker, we show this pathway is downregulated and genetic activation suppresses seizure behavior. In this thesis, I …

Contributions Of Specific Retinal Circuits And Their Respective Projections To Visual Behaviors, Jenna Mackenzie Krizan

Arts & Sciences Graduate Student Theses and Dissertations

The survival of a species is inextricably linked to its ability to successfully navigate and interact with its surroundings, whether to seek safety from predators or gain sustenance from prey. Both functions are performed by mice, guided by vision, and rely on intricate processing in the retina and subcortical targets in the brain. This dissertation addresses how specific features of the visual environment and specific retinal ganglion cell circuits that sample a particular space in the visual environment are used to guide efficient predation in mice.Recent studies have begun to link the ability to detect, track, and ultimately capture prey …

Generation, Characterization, And Treatment Of Functional Zebrafish Models For Musculoskeletal Disorders, Julia Nicole Whittle

Arts & Sciences Graduate Student Theses and Dissertations

Musculoskeletal disorders in humans present with a broad range of phenotypes that vary in severity, onset, and genetic cause. The musculoskeletal system is comprised of complex and diverse tissues that make up the majority of total body mass. Thus, mutations in many different genes with differing structure and function can produce phenotypically similar developmental and morphological defects in the muscle and skeleton. In addition, the muscular and skeletal systems develop non-autonomously, wherein development and function of each will affect development of the other. Thus, mutations in genes responsible for development of this complex system have the potential to influence morphogenesis …

Synthesis And Application Of Functional Unimolecular [N]Catenanes In Novel Polymeric Materials, Mark Andrew Nosiglia

Arts & Sciences Graduate Student Theses and Dissertations

Mechanically interlocked molecules (MIMs) possess unique architectures and non-traditional degrees of freedom that arise from well-defined topologies that are achieved through precise mechanical bonding. Incorporation of MIMs into materials can thus provide an avenue to discover new and emergent macroscale properties. Here, the synthesis of a phenanthroline-based [2]catenane crosslinker and its incorporation into polyacrylate organogels is described. Specifically, Cu(I) metalation and de-metalation was used as a post-gelation strategy to tune the mechanical properties of a gel by controlling the conformational motions of integrated MIMs. The organogels were prepared via thermally initiated free radical polymerization, and Cu(I) metal was added in …

Understanding Individual Cells In Zebrafish Caudal Fin Regeneration (从单细胞视角理解斑马鱼尾鳍再生历程), Yiran Hou

Arts & Sciences Graduate Student Theses and Dissertations

Humans are incapable of complex body structure regeneration. Understanding how other species retain the ability to regenerate can help us to find solutions for improving our regenerative capacities. The zebrafish is an organism that is capable of regenerating multiple organs in its body. Using zebrafish as a model organism, previous studies have identified key processes and illustrated the crucial cell types and genes for regeneration. In caudal fin specifically, blastema formation is a key predictor of successful regeneration. However, a comprehensive molecular understanding of cell type-specific contributions to this process is lacking. In this dissertation, I present our efforts toward …

Fructose Promotes The Growth Of Tumors Through Metabolite Exchange With Non-Malignant Tissues, Ronald Joseph Fowle-Grider

Arts & Sciences Graduate Student Theses and Dissertations

The amount of dietary fructose consumed in the United States has increased considerably over the past five decades, largely due to the widespread use of high fructose corn syrup as a sweetener. The potential link between this elevated fructose intake and the development of cancer remains incompletely understood. Here we show that, even though cervical cancer cells themselves cannot directly utilize fructose carbon, diets high in fructose enhance the growth of cervical tumors by nearly threefold in mice. We demonstrate that efficient utilization of fructose carbon requires ketohexokinase-C, which was not expressed in ~100 cervical tumors that we examined from …

Characterizing Complex Affective Processing Across Age And In Relation To Social Anxiety Symptoms, M. Catalina Camacho

Arts & Sciences Graduate Student Theses and Dissertations

Humans require a shared understanding of others’ emotions for adaptive social functioning. For instance, if someone tells a joke and another person laughs, we assume the laughing person was happy because we have a shared concept for such positive interactions. Children develop and refine these concepts as they grow up, but the underlying neural processing that supports this development is unknown. Identifying the neurodevelopment underlying emotion processing could provide important insight to emotional disorders. For example, social anxiety is associated differences in the detection and interpretation of negative or neutral emotional cues, but the underlying neurodevelopment of this behavior is …

Circadian Circuitry And Glioblastoma: Interactions With Behavior, Carcinogenesis, And Clinical Practice., Anna R. Damato

Arts & Sciences Graduate Student Theses and Dissertations

Glioblastoma (GBM) is the most common primary adult brain tumor diagnosed, with a 15-month prognosis using current standard of care treatment which includes chemotherapy with temozolomide (Temodar, TMZ). Chronotherapy, the practice of considering time of day in treating a disease, has been shown to improve outcome in several cancers, but had not been applied to GBM. Previous work in the lab on a cultured murine mesenchymal GBM cell line showed a time-of-day dependent maximum in sensitivity to TMZ corresponding with the daily peak of Bmal1 and trough of Per2 expression, two core clock genes. Based on this finding, we sought …

Functional Analysis Of Recurrent Non-Coding Variants In Human Melanoma, Paula Maria Godoy

Arts & Sciences Graduate Student Theses and Dissertations

Worldwide incidence rates of cutaneous melanoma are increasing, and while survival rates for early stages of melanoma are high, rates drop precipitously for metastatic melanomas or those that are unable to be targeted by currently available treatments. As melanomas have a propensity to quickly metastasize, understanding the contributions of melanoma initiation remains critical for early intervention. Onset of melanoma is characterized most by mutations that stimulate mitogen-activated protein kinase (MAPK) signaling, disrupt DNA damage checkpoints, and trigger mechanisms to bypass senescence through elongation of telomeres. Additionally, in zebrafish melanoma models, the earliest cluster of melanoma-initiating cells activate expression of a …

Development Of Redox-Responsive Phenazine-Based Foldamers. Acylative Kinetic Resolution Of Hydroxamic Acids, Jingwei Yin

Arts & Sciences Graduate Student Theses and Dissertations

Two different research directions have been presented in this thesis. The first project is about phenazine-based foldamers as molecular actuators. Researchers have been interested in the design and synthesis of foldamers and molecular actuators for years. We began our exploration by demonstrating that phenazine-1,6-dicarboxamides can function as redox-responsive molecular switches. We then designed and synthesized two generations of phenazine-based interleafed foldamers and studied their stability and redox behaviors under chemical and electrochemical conditions. In the second project, we have developed the first acylative kinetic resolution on hydroxamic acids. Although chiral hydroxamic acids have extensive applications, synthetic methods towards them are …

Reassessing The History Of The Poverty Point Phenomenon: A Case Study From The Jaketown Site, Mississippi, Usa, Seth Bradley Grooms

Arts & Sciences Graduate Student Theses and Dissertations

Towards the end of the Late Archaic period (ca. 4800-3000 cal BP), between 3,600 and 3,300 years ago, Native Americans engineered a colossal earthwork complex that covers approximately 200 hectares in northeast Louisiana. Today, it is a UNESCO World Heritage site known as Poverty Point and the namesake for a material culture pattern documented to varying degrees at sites throughout the Lower Mississippi Valley (LMV). However, the nature of interactions between these sites and the type site is poorly understood. The people who constructed the Poverty Point site lived on wild food resources. They hunted, fished, and gathered food from …

Mechanisms For High Light Tolerance In A Fast-Growing Cyanobacterium, Patricia Walker

Arts & Sciences Graduate Student Theses and Dissertations

Through oxygenic photosynthesis, cyanobacteria, algae, and plants convert light into chemical energy. However, highly energetic light often damages the photosynthetic apparatus, which can lead to the decline of photosynthetic activity (photoinhibition), and prolonged photoinhibition can lead to cell death. Cyanobacteria enact various protective mechanisms to mitigate photodamage, many of which have been conserved in plants. Repair of PSII reaction centers, decreased light absorption, quenching of excess absorbed energy, and biosynthesis of antioxidants all work to mitigate damage during high light. Due to the adjustments to photosynthesis, acclimation to high light requires remodeling of cellular metabolism and physiology. Therefore, phototrophs have …