Now showing items 1-20 of 2013

    • The Effect of Unintended Pancreatic Duct Cannulation on Post-ERCP Pancreatitis

      Nguyen, Anita Hwei; Alizadeh, Madeline; Geisinger, Max; Halim, Ameer; Panagos, Katherine; Patel, Preet; Rodgers, Brandon; Thaker, Parth; Goldberg, Eric (2021-10)
    • Two Cases of Duodenal Perforation by IVC Filter

      Halim, Ameer; Chatila, Ahmed; Hudhud, Dania; Wellington, Jennifer; Patil, Seema A.; Goldberg, Eric (2021-10)
    • Frailty Rather Than Age is Associated With Infections and Surgeries in Inflammatory Bowel Disease

      Leopold, Andrew R.; Rodgers, Brandon; Chatila, Ahmed; Wong, Uni (2021-10)
    • Patient Perceptions of Pelvic Organ Prolapse Education Techniques

      Corley, Elizabeth; Paulosky, Kayla; Karsalia, Moli; Terse, Pranaya; Nemirovsky, Amy; Malik, Rena (2021-10)
    • Treatment of Lumbar Radiculitis in a Patient With a Lateral Ankle Sprain: A Case Report

      Feder, Ethan; Bowman, Peter; Pravdo, Alisa; Film, Roy (2021-10)
    • Does Delayed Closure of Both Bone Forearm Fractures Increase Infection Rates?

      Bridgham, Kelly; O'Hara, Nathan N.; O'Toole, Robert V.; Pensy, Raymond A. (2021)
    • Characterizing enhancer-driven transcriptional networks in schizophrenia

      Casella, Alex; Ament, Seth A. (2021)
      Genetic studies of schizophrenia have demonstrated that more than 90% of genetic risk is confined to non-coding portions of the genome. Advances in chromatin state prediction and chromatin accessibility assays have enabled us to better characterize the genomic features making up these regions and annotate genetic risk to these elements. The focus of this dissertation is to understand the role that tissue- and cell type- specific regulatory elements and the transcription factors that bind them play in risk for schizophrenia. I hypothesized that enhancer-based transcription factor-target networks that direct neuronal development are disrupted in schizophrenia. To test this hypothesis, I used high-quality chromatin state predictions in both the developing and the adult brain to develop a framework for testing enhancer properties for association with genetic risk. Any enhancer-level annotation can be used in this type of test, including transcription factor binding counts and chromosomal contact information. I first described and validated an atlas of transcription factor binding sites across multiple human tissue, including the brain. I then used this atlas to show that neurodevelopmental transcription factors and target genes are most associated with risk for developing schizophrenia.
    • Tubulin detyrosination induces apoptosis in breast epithelial cells that is overcome by induced oncogenic signaling

      Mathias, Trevor J.; Ju, Julia A.; Lee, Rachel M.; Thompson, Keyata N.; Mull, Makenzy L.; Chang, Katarina T.; Annis, David A.; Vitolo, Michele I.; Martin, Stuart S. (2021-09-22)
    • Tubulin-based microtentacles aid in heterotypic neutrophil-CTC clustering

      Ju, Julia A.; Thompson, Keyata N.; Mathias, Trevor J.; Lee, Rachel M.; Vitolo, Michele I.; Martin, Stuart S. (2021-09-22)
    • Protease Activated Receptor 1 elevation in circulating tumor cells increases migration, invasion, and clustering efficiency

      Thompson, Keyata N.; Ju, Julia A.; Martin, Stuart S.; Vitolo, Michele I. (2021-09-22)
    • Crossing the Chasm: A Pilot Study for Preparing PT’s for Telehealth through IPE and Simulation

      Gordes, Karen L.; Retener, Norman F.; Lee, Mei Ching W.; Horn, Linda B. (2021-10-23)
    • Genomic Medicine in Diabetes: Improving the Diagnostic Rate of Monogenic diabetes

      Zhang, Haichen; Pollin, Toni; 0000-0002-0615-2836 (2021)
      Monogenic diabetes is an uncommon type of diabetes caused by genetic defects in one of several genes, and it accounts for 1-2% of all diabetes. The primary subtypes are Maturity Onset Diabetes of the Young (MODY), neonatal diabetes, and syndromic diabetes. The correct treatment of each subtype of monogenic diabetes depends on the corresponding disease etiology that can only be confirmed by genetic testing. However, the diagnostic rate of monogenic diabetes is inadequate, mainly due to the overlapping phenotype of monogenic diabetes with type 1 diabetes and type 2 diabetes and lack of awareness among patients and physicians. To improve the diagnostic rate of monogenic diabetes, this project focuses on three aspects: 1) systematically screening of patients for genetic testing; 2) comprehensively re-analyzing next-generation sequencing (NGS) data from multiple diabetes cohorts; 3) assessing the ability of Direct-to-Consumer Genetic Testing (DTC-GT) raw data in detecting GCK-MODY variants. The Personalized Diabetes Medicine Program (PDMP) screened 2,522 patients with diabetes with a simple questionnaire, assigned patients to different algorithm criteria groups based on clinical features, and performed genetic testing on suspected patients. Overall, 38 of 313 patients suspected of monogenic diabetes were tested positive for causative variants. The group of patients diagnosed before age 30 who were not treated with insulin had the highest pick-up rate. The comprehensive re-analysis of NGS panel data in PDMP, including re-classification and updating variant calling algorithm, improved the diagnostic rate from 11.82% to 13.10%. Also, the comparison between exome sequencing (ES) and NGS panel or Sanger sequencing of the Progress for Diabetes Genetics in Youth samples showed ES failed to identify all MODY-causing variants, but re-analysis of ES unfiltered data discovered the missing variants. By analyzing the GCK variants in the 23andMe DTC-GT raw data from 3,044 anonymous volunteers and calculating the ancestry-specific allele frequency of GCK-MODY variants, some of the variants showed higher-than-expected minor allele frequency compared with the large population database. Such inconsistency suggests customers should not use DTC-GT as a supplementary method of clinical genetic testing for GCK-MODY. In a summary, these studies provide practical approaches to improve the diagnostic rate of monogenic diabetes.
    • Role of the Parabrachial Complex in Rodent Models of Pain

      Uddin, Olivia; Keller, Asaf; 0000-0001-7035-6836 (2021)
      The parabrachial complex (PB) is a midbrain structure that is vital to survival-related functions. This region receives and integrates incoming sensory information, communicating these signals to higher brain regions that are key in shaping behavior and affect. PB responds to painful somatosensory input, however, its most compelling role is in the development and maintenance of persistent pain. Pain persisting beyond the duration of a threat or tissue injury no longer serves a physiological purpose. Therefore, this type of maladaptive pain has a severe impact on health and quality of life. Current therapies for maladaptive pain are not optimal: it is necessary to better understand the neural circuitry underlying persistent pain so that we can design more effective therapies. The work presented here aims to outline PB’s role in four rodent models of pain. I approach this by combining anatomical tracing, electrophysiology, and behavioral studies. First, I show that in a model of orofacial neuropathic pain, PB neural activity is amplified. Next, I describe a novel and direct anatomical connection between the meninges and PB, via the trigeminal ganglion; this pathway is poised to underlie migraine headache-associated pain. Finally, I conduct behavioral studies aiming to hone rodent models of pain in the context of aging and amyloid accumulation, and pain during opioid withdrawal. These findings together confirm that PB is a crucial node in maladaptive pain processing and provide direction for further work clarifying PB’s role in new behavioral contexts.
    • Role of Adipose Lipolysis in Development of Alcoholic Liver Disease

      Mathur, Mallika; Yu, Liqing (2021)
      Alcoholic liver disease (ALD) pathologies include hepatic steatosis, inflammation and liver injury. The liver receives ~60% of fatty acids from adipose tissue. We examined the role of adipose lipolysis in ALD pathogenesis using adipose-specific CGI-58 knockout (FAT-KO) mice, a model of impaired adipose lipolysis. FAT-KO versus control mice were almost completely protected against ethanol-induced hepatic steatosis and lipid peroxidation when subjected to the 15-day NIAAA chronic-binge ethanol diet. This was unlikely from reduced lipid synthesis because ethanol feeding downregulated hepatic expression of lipogenic genes similarly in both genotypes. On a control diet, FAT-KO relative to control mice had increased hepatocyte injury, neutrophil infiltration, and activation of transcription factor STAT3 in the liver, none exacerbated by ethanol. This was associated with increased hepatic leptin receptor mRNA and adipose inflammatory cell infiltration. These findings identify a critical role for adipose lipolysis in hepatic steatosis and oxidative stress during ALD development.
    • Neuronal Intrinsic Apoptosis Mechanisms and Their Modulation by Sp1 Inhibition

      Makarevich, Oleg; Stoica, Bogdan A.; 0000-0003-2061-2285 (2021)
      Drug-induced DNA damage, reactive oxygen species (ROS), inflammatory mediators and central neurotoxicity have all been shown to play a role in cognitive impairments after chemotherapy, after CNS injury or in neurodegenerative diseases. Intrinsic apoptosis is a regulated cell death pathway implicated in many of these conditions. This pathway proceeds sequentially through DNA damage responses, including phosphorylation of ATM, H2AX and Tumor Protein 53 (p53), transcriptional activation of pro-apoptotic BH3-only proteins, and mitochondrial outer membrane permeabilization (MOMP), activating caspase-dependent and caspase-independent apoptosis. Previous work has indicated that Sp1 may regulate p53’s transcriptional profile and ability to promote apoptosis after DNA damage. To examine the role of Sp1 in DNA-damage-induced apoptosis, my work has utilized Mithramycin, a drug that binds G-C rich DNA to compete with Sp1 chromatin binding. Our hypothesis is that Mithramycin competes with Sp1 chromatin binding and thus protects neurons from DNA damage-induced, p53-dependent intrinsic apoptosis. However, it is vital to recognize that neurons increase their resistance to cytotoxic stimuli as they mature, leading to decreased levels of apoptosis. Thus, we additionally characterized the changes in the intrinsic apoptosis pathway upon neuronal maturation. Despite significant attenuation of the intrinsic apoptosis pathway in mature neurons, we found evidence that Mithramycin can still attenuate DNA-damage dependent intrinsic apoptosis in this paradigm to the extent that it is induced by neurons. Additional experiments showed that mature animal cortices or hippocampi do not demonstrate evidence of end-stage apoptosis (caspase activity) in response to DNA damage, unlike those in immature animals. However, in vivo administration of Mithramycin was able to attenuate cortical expression of p53-dependent genes. Thus, our studies provide evidence that: 1) Mithramycin attenuates activation of the DNA damage-dependent intrinsic apoptosis pathway via indirect inhibition of p53-dependent transcription and 2) Mature neurons restrict intrinsic apoptosis pathway activation in response to DNA damage. Therefore, Sp1 is likely to play a significant role in DNA damage-dependent neuronal intrinsic apoptosis, and Mithramycin treatment is protective when this pathway is activated. However, mature neurons significantly downregulate this pathway, thus limiting the potential therapeutic effects of Mithramycin in adult animals.
    • Modulation of Inflammation and Stromal Remodeling Processes in Autoimmune Arthritis by Microbial Indole Derivatives

      Langan, David; Moudgil, Kamal; 0000-0002-4525-9767 (2021)
      Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial tissue that can lead to joint damage and deformities. Inflammation, new blood vessel formation (angiogenesis), and bone resorption (osteoclastogenesis) are three key processes of the pathophysiology of RA. ‘Dysbiosis’ of the gut microbiota is implicated in RA pathogenesis because it can cause an imbalance in the microbial metabolites that regulate host health and disease. However, there is little information about the impact of two such indole derivatives, indole-3-aldehyde (IAld) and indole-3-acetic acid (I3AA), on arthritis-related processes. Using established cell-based models and the adjuvant-induced arthritis animal model, we conducted a comparative analysis of IAld and I3AA to understand how these metabolites might impact RA pathogenesis. To our surprise, despite their structural similarities, the bioactivities of these two metabolites were profoundly different. IAld, but not I3AA, altered the expression of genes encoding arthritis-associated cytokines (IL-1β, IL-6, VEGF) in RAW 264.7 (murine macrophage) cells stimulated with heat-killed M. tuberculosis. Further investigation of this anti-inflammatory activity of IAld suggested that inhibition of the MyD88-dependent activation of NF-κB and MAPK pathways was unlikely to be involved. IAld also exhibited pro-osteoclastogenic and pro-angiogenic activity. In contrast, I3AA exhibited only anti-angiogenic activity. Both IAld and I3AA are proposed agonists of the aryl hydrocarbon receptor (AhR). However, AhR inhibitor CH-223191 suppressed the anti-angiogenic activity of I3AA, but failed to mitigate any of the effects of IAld. There is a cross-talk between the AhR and Nrf2 pathways, and some plant-derived phytochemicals are multifunctional ligands of both pathways. Our findings show that IAld, unlike I3AA, can suppress the Nrf2-dependent antioxidant response of macrophages to an Nrf2 agonist, but that IAld also potentially reduces intracellular ROS levels during osteoclast differentiation. Furthermore, oral administration of IAld to rats resulted in the reduction of arthritis severity compared to the arthritic control group. Taken together, our findings suggest that the relative bioavailability of these microbial indole derivatives has the potential to influence their immunomodulatory effects in healthy individuals as well as patients with RA.
    • Monomeric IL-12p40 binds partner proteins to modulate immune cell function

      Gerber, Allison; Singh, Nevil; 0000-0001-9442-3255 (2021)
      Cytokines are critical mediators used by immune cells to communicate as well as protect. The IL-12 family of cytokines are made up of  and  subunits typically assembled within one cell and secreted as a heterodimer. IL-12p40 is the shared β-subunit for both IL-12 (paring with IL-12p35) and IL-23 (with IL-23p19). However, the IL-12p40 monomer is often secreted in excess during infections, but its biological role was not known. In this thesis we investigated the function of secreted IL-12p40 monomer in vivo with the central hypothesis that the monomer combines with multiple α-subunits in vivo to generate IL-12 as well as other heterodimeric cytokines. Consistent with this hypothesis, in chimeric mice containing mixtures of cells that can only express either IL-12p40 or IL-12p35, but not both together, we found that functionally active IL-12 was generated. This alternate two-cell pathway requires IL-12p40 from hematopoietic cells to extracellularly associate with IL-12p35 from radiation-resistant cells. The two-cell mechanism was sufficient to influence local T cell differentiation in sites distal to the initial infection and helped control systemic dissemination of a pathogen although not parasite burden at the site of infection. Broadly, this suggests that early secretion of IL-12p40 monomers by sentinel cells at the infection site may help prepare distal host tissues for potential pathogen arrival. In addition to this role in generating IL-12 through two-cell assembly, we found that IL-12p40 has a novel partner protein, CD5L. This novel heterodimer was present in the serum of uninfected mice, with differences in the basal levels between B6 and Balb/c animals, with Balb/c having higher amounts of p40-CD5L. Functionally, we found that treatment with p40-CD5L leads to IL-4 and IL-10 production by T cells. Taken together, this thesis offers at least two major fundamental advances in cytokine biology – one the concept of a two-cell assembled cytokine and second the identity of a novel TH2-promoting heterodimeric cytokine. The first has significance in immunotherapy and understanding immunity to tissue-specific modulation of immune responses. The second is expected to drive significant research on allergy, responses to parasites and immune deviation.
    • The Molecular Basis of IL-1 Family Signaling: Strategies to Modulate Inflammation

      Fields, James; Sundberg, Eric J.; 0000-0001-5923-108X (2021)
      Interleukin-1 (IL-1) family cytokines are potent signaling molecules that influence both innate and adaptive immune systems. The IL-1 family, composed of 11 cytokines and 10 receptors, mediate inflammation to a wide array of stimuli and act on myriad cell types for diverse immunological outcomes. Altogether, IL-1 family signaling is integral to a multitude of inflammatory responses and occurs in distinct steps. First, an agonist cytokine binds its cognate receptor at high affinity. Next, this cytokine-receptor complex recruits an often-shared co-receptor. As this cytokine/receptor/co-receptor complex forms, Toll/IL-1 Receptor (TIR) domains, residing cytoplasmically, oligomerize, initiating a potent signaling cascade that results in prototypical NF-κB signal transduction. Due to the strong nature of IL-1 family signaling, multiple physiological mechanisms exist to stem this inflammatory signal, including antagonist cytokines and decoy receptors. Within the IL-1 family, the cytokines and receptors can be further divided into four subfamilies dependent on their secondary receptors. The IL-1 subfamily contains IL-1, IL-33, and IL-36 as they all share IL-1RAcP as their secondary receptor; the IL-18 subfamily is distinct as it utilizes IL-18Rβ as its secondary receptor. Here, we describe how structural biology has guided our understanding of IL-1 family signaling and how that knowledge can be leveraged for the design of therapeutics to stem aberrant cytokine signaling. In our first study, we demonstrate the feasibility of targeting a shared co-receptor, IL-1RAcP, for selective cytokine inhibition. Indeed, dependent on the specific epitope targeted on IL-1RAcP, differential cytokine signaling inhibition can be achieved. In addition, we developed our own IL-33 therapeutics by leveraging the high affinity IL-33 has for its primary receptor, the stability imparted by the secondary receptor, and the extended half-life gained through an Fc-fused receptor. Two of these molecules inhibit IL-33 signaling better than the natural antagonist sST2. Altogether, structural biology has informed our understanding of IL-1 family signaling, generated approaches to improve existing therapeutics, namely antibody epitope targeting, and led to the creation of additional IL-33 target therapeutics in the form of our “cytokine traps.”