Medical Immunology Commons^™

The Impact Of Human Myoblasts On Macrophage Polarization In A Coculture Model, Elisabeth Ann Stodola

Biomedical Engineering

Peripheral Artery Disease (PAD) is characterized by the buildup of atherosclerotic plaque in the lower extremities that occludes blood flow, and affects over 200 million people worldwide. Without effective treatment, PAD can lead to claudication, ischemia, ulcers, and gangrene. PAD causes more amputations in the United States than any other condition, and for severe cases that require revascularization, procedures benefit fewer than 50% of patients. This demonstrates a clear need for alternative therapies. Potential therapies for PAD target expansion of collateral blood vessels around the area of occlusion – a process called arteriogenesis to compensate for loss of blood flow …

Patient-Derived Ovarian Cancer Models Provide Insight Into Cancer Cell-Intrinsic And Immune Cell-Dependent Effects On Therapeutic Response, Parisa Nikeghbal

Biomedical Sciences ETDs

Ovarian cancer is the most lethal gynecologic malignancy, largely due to late diagnosis and resistance to chemotherapy. This dissertation applies patient-derived organoids (PDOs), xenograft-derived organoids (PDXOs), and humanized xenografts (huPDX) to investigate therapeutic responses and immune interactions. Organoids were shown to retain critical features of the original malignancy. Across platinum-sensitive, -resistant, and -refractory cases, both PDOs and PDXOs exhibited drug sensitivities that aligned with patients’ clinical classifications. Building on this foundation, a drug screen revealed novel strategies. Auranofin restored platinum sensitivity in Notch3-active models, afatinib broadly reduced viability, and adavosertib–gemcitabine and sorafenib–topotecan combinations produced synergy. Extending this work, immune interactions …

Identifying Novel Fibrotic Mechanisms Underlying Treatment-Resistant Lower Urinary Tract Dysfunction, Quentin Darcy

Graduate Doctoral Dissertations

ABSTRACT

IDENTIFYING NOVEL FIBROTIC MECHANISMS UNDERLYING TREATMENT-RESISTANT LOWER URINARY TRACT DYSFUNCTION

August 2025

Quentin D’Arcy, B.S., University of Massachusetts Amherst

Ph.D., University of Massachusetts Boston

Directed by Dr. Jill Macoska

Lower urinary tract dysfunction (LUTD) is a common, age-related disease that affects millions of men over the age of 50. Current treatment for this and other related prostate diseases concentrate on decreasing benign prostate growth and relaxing smooth muscle contractions to alleviate urinary voiding symptoms. However, up to 45% of patients with LUTD are treatment-resistant and require surgical intervention to resolve prostate issues. By focusing on the contribution of inflammation-derived …

Polymorphic Α-Glucans As Structural Scaffolds In Cryptococcus Cell Walls For Chitin, Capsule, And Melanin: Insights From 13c And 1h Solid-State Nmr, Ankur Ankur, Jayasubba Reddy Yarava, Isha Gautam, Faith J. Scott, Frederic Mentink-Vigier, Christine Chrissian, Li Xie, Dibakar Roy, Ruth E. Stark, Tamara L. Doering, Ping Wang, Tuo Wang

School of Graduate Studies Faculty Publications

Cryptococcus species are major fungal pathogens responsible for life-threatening infections in approximately a million individuals globally each year, with alarmingly high mortality rates. These fungi are distinguished by a distinctive cell wall architecture further reinforced by two virulence-associated layers, melanin and capsule, rendering them insensitive to antifungal agents targeting the cell wall, such as echinocandins. The molecular interplay between these three biomolecular layers remains poorly understood. Here we employ solid-state NMR spectroscopy to examine intact cells of both wild-type and capsule-deficient strains of C. neoformans, along with melanized cells. High-resolution 13C and 1H data revealed five distinct structural forms of …

Plasma Micrornas To Select Optimal Patients For Antibody Production From Anti-Addiction Vaccines, Thomas R Kosten, Amrit Koirala, David A Nielsen, Coreen B Domingo, Ynhi T Thomas, Preethi H Gunaratne, Cristian Coarfa

Faculty, Staff and Students Publications

Background: Cocaine and illicit amphetamines (disguised as “Adderall”) are being laced with fentanyl and producing accidental and intentional fatal overdoses. Vaccines can prevent these overdoses, but 33% of humans generate insufficient anti-drug antibody (AB) levels. Plasma microRNAs (miRs) can be used to predict non-responders. We have plasma stored from 152 cocaine vaccine trial participants following three vaccinations over 9 weeks and examined miRs as potential response biomarkers. Methods: We compared 2517 miRs before anti-cocaine vaccination in participants with the highest (n = 25) to the lowest (n = 23) antibody levels. False Discovery Rates (FDRs) were applied to identify differentially …

Resilience And Reality: Exploring The Lived Experiences Of People Living With Hiv In Texas During The Covid-19 Pandemic – A Qualitative Study., Ahmed F. Alanazi

Social Work Dissertations - Archive

This study investigated the lived experiences of individuals living with HIV (PLWH) in the Dallas-Fort Worth (DFW) area of Texas during the COVID-19 pandemic, using an Interpretative Phenomenological Analysis (IPA) framework. The research examined the intersection of health, social dynamics, and psychological resilience among PLWH, who faced compounded vulnerabilities due to systemic inequities and the dual public health crises of HIV and COVID-19. Through semi-structured interviews with ten participants from diverse backgrounds, the study captured the profound impacts of disrupted healthcare systems, heightened stigma, and social isolation on this marginalized population. The findings reveal that the pandemic exacerbated existing inequities …

Creb-Binding Protein/P300 Bromodomain Inhibition Reduces Neutrophil Accumulation And Activates Antitumor Immunity In Triple-Negative Breast Cancer, Xueying Yuan, Xiaoxin Hao, Hilda L Chan, Na Zhao, Diego A Pedroza, Fengshuo Liu, Kang Le, Alex J Smith, Sebastian J Calderon, Nadia Lieu, Michael J Soth, Philip Jones, Xiang Hf Zhang, Jeffrey M Rosen

Faculty, Staff and Students Publications

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB-binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing …

Exploring New Frontiers In Space Medicine: Unprecedented Detailed Mapping Of Human Biology During Spaceflight, Laura Ioana Patras, Nadia Houerbi, Jankeun Kim

FRONTIERS UNBOUND: Exploring Extreme Environments

No abstract provided.

Targeting Ribosome Biogenesis Is A Novel Approach For The Management Of Pancreatic Cancer, Mudassier Ahmad, Haider Ahsan, Carlos Perez, Muhammad Bangash, Andrew Massey, Emmanuel Anning, Manish Tripathi, Dae Kim, Subhash C. Chauhan, Bilal Bin Hafeez

Research Colloquium

Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related deaths in the United States with limited therapeutic options available. Gemcitabine, a deoxycytidine nucleoside analog is currently considered the most effective therapy for PanCa. However, it shows only a marginal survival benefit of six months. Aberrant ribosome biogenesis occurs in most tumor types. We observed that PanCa cells are addicted to ribosome biogenesis, which supports their highly aggressive metastatic phenotypes. Thus, strategically targeting ribosome biogenesis process could be one of the ideal strategies for the prevention and treatment of PanCa. In this study, we elucidated the molecular mechanisms of POLR1A …

Role Of Poly(A)-Binding Protein Cytoplasmic 1, A Trna-Derived Rna Fragment-Bound Protein, In Respiratory Syncytial Virus Infection, Devin V Davis, Eun-Jin Choi, Deena Ismail, Miranda L Hernandez, Jong Min Choi, Ke Zhang, Kashish Khatkar, Sung Yun Jung, Wenzhe Wu, Xiaoyong Bao

Faculty, Staff and Students Publications

Respiratory Syncytial Virus (RSV) is a significant cause of lower respiratory tract infections (LRTI) across all demographics, with increasing mortality and morbidity among high-risk groups such as infants under two years old, the elderly, and immunocompromised individuals. Although newly approved vaccines and treatments have substantially reduced RSV hospitalizations, accessibility remains limited, and response to treatment varies. This underscores the importance of comprehensive studies on host-RSV interactions. tRNA-derived RNA fragments (tRFs) are recently discovered non-coding RNAs, notable for their regulatory roles in diseases, including viral infections. Our prior work demonstrated that RSV infection induces tRFs, primarily derived from the 5'-end of …

Herpes Vegetans In A Patient With Acquired Immunodeficiency Syndrome (Aids) In The Setting Of Immune Reconstitution Inflammatory Syndrome, Angelique Ruml, Ibeth Caceres, Anna Catinis, Theodore Rosen

Faculty, Staff and Students Publications

Herpes simplex virus (HSV) infections classically present as a vesicular eruption on an erythematous base; however, viral infections may present much differently in the setting of immune deficiency. Herpes vegetans is an atypical presentation of HSV that occurs in immunocompromised patients, typically those with human immunodeficiency virus infection and acquired immunodeficiency syndrome (AIDS). Herpes vegetans is characterized by hyperkeratotic, exophytic, and, sometimes, ulcerated nodules, often with a chronic and persistent course. Herein, we present an interesting example of biopsy-confirmed anogenital herpes vegetans in a 61-year-old male with AIDS in the setting of immune reconstitution inflammatory syndrome, an association that is …

Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation In Melanoma: Impact Of Antibiotic Preconditioning On Microbiome And Immunity, Isabella C Glitza, Yongwoo David Seo, Christine N Spencer, Jennifer R Wortman, Elizabeth M Burton, Farah A Alayli, Christopher P Loo, Shikha Gautam, Ashish Damania, Julie Densmore, Justin Fairchild, Christopher R Cabanski, Matthew C Wong, Christine B Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher Mcchalicher, Emily Walsh, Michael T Tetzlaff, Omid Hamid, Patrick A Ott, Genevieve M Boland, Ryan J Sullivan, Kenneth F Grossmann, Nadim J Ajami, Theresa Lavallee, Matthew R Henn, Hussein A Tawbi, Jennifer A Wargo

Faculty, Staff and Student Publications

Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate …

Viral Reprogramming Of Host Transcription Initiation, Nathan A. Ungerleider, Claire Roberts, Tina M. O’Grady, Trang T. Nguyen, Melody Baddoo, Jia Wang, Eman Ishaq, Monica Concha, Meggie Lam, Jordan Bass, Truong D. Nguyen, Nick Van Otterloo, Nadeeshika Wickramarachchige-Dona, Dorota Wyczechowska, Maria Morales, Tianfang Ma, Yan Dong, Erik K. Flemington

School of Medicine Faculty Publications

Viruses are master remodelers of the host cell environment in support of infection and virus production. For example, viruses typically regulate cell gene expression through modulating canonical cell promoter activity. Here, we show that Epstein Barr virus (EBV) replication causes ‘de novo’ transcription initiation at 29674 new transcription start sites throughout the cell genome. De novo transcription initiation is facilitated in part by the unique properties of the viral pre-initiation complex (vPIC) that binds a TATT[T/A]AA, TATA box-like sequence and activates transcription with minimal support by additional transcription factors. Other de novo promoters are driven by the viral transcription factors, …

Kras Allelic Variants In Biliary Tract Cancers, Gordon Taylor Moffat, Zishuo Ian Hu, Funda Meric-Bernstam, Elisabeth Kathleen Kong, Dean Pavlick, Jeffrey S Ross, Karthikeyan Murugesan, Lawrence Kwong, Anaemy Danner De Armas, Anil Korkut, Milind Javle, Jennifer J Knox

Faculty, Staff and Student Publications

IMPORTANCE: Biliary tract cancers (BTCs) contain several actionable molecular alterations, including FGFR2, IDH1, ERBB2 (formerly HER2), and KRAS. KRAS allelic variants are found in 20% to 30% of BTCs, and multiple KRAS inhibitors are currently under clinical investigation.

OBJECTIVES: To describe the genomic landscape, co-sequence variations, immunophenotype, genomic ancestry, and survival outcomes of KRAS-mutated BTCs and to calculate the median overall survival (mOS) for the most common allelic variants.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective, multicenter, pooled cohort study obtained clinical and next-generation sequencing data from multiple databases between January 1, 2017, and December 31, 2022. These databases included Princess …

Cord Blood-Derived Invariant Natural Killer T Cells As A Platform For Allogeneic Chimeric Antigen Receptor Cell Therapy, Maison Grefe

Dissertations and Theses (Open Access)

Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematopoietic malignancies achieving >50% complete response rates in numerous refractory/relapsed B cell malignancies. However, there are challenges that hinder CAR-T efficacy and bar the broader use of this therapy in patients. One approach to address these challenges is to create a safe allogeneic CAR cell product by using cells that do not cause graft versus host disease (GvHD). Invariant natural killer T (iNKT) cells are an ideal candidate as they are restricted to the monomorphic CD1d protein in contrast to HLA restricted αβ-T cells and therefore are safe in …

Lncrna Impact On Regorafenib Resistance In Colorectal Cancer, Ricardo Pequeno Bracho, Kyle Doxtater, Dennis Kwabiah, Yamile Abuchard Anaya, Sophia Leslie, Mohammad Shabir Hussain, Manish Tripathi

Research Symposium

Cancer metastasis is one of the deadliest aspects of the disease, with about 90% of all cancer-related deaths due to its development at different sites within the body. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the United States, with 40-50% of all patients developing metastasis at some point during their fight with the disease. With the approval of Regorafenib for treating metastatic colorectal cancer, steps have been taken to combat metastasis in colorectal cancer. A vital aspect of the development of metastasis is the development of resistance to first-line chemotherapy. Regorafenib is an oral small-molecule …

Dendritic Cells Overcome Cre/Lox Induced Gene Deficiency By Siphoning Cytosolic Material From Surrounding Cells, Christopher H. Herbst, Aurélie Bouteau, Evelin J. Menykő, Zhen Qin, Ervin Gyenge, Qingtai Su, Vincent Cooper, Neil A. Mabbott, Botond Z. Igyártó

Department of Microbiology and Immunology Faculty Papers

In a previous report, keratinocytes were shown to share their gene expression profile with surrounding Langerhans cells (LCs), influencing LC biology. Here, we investigated whether transferred material could substitute for lost gene products in cells subjected to Cre/Lox conditional gene deletion. We found that in human Langerin-Cre mice, epidermal LCs and CD11b+CD103+ mesenteric DCs overcome gene deletion if the deleted gene was expressed by neighboring cells. The mechanism of material transfer differed from traditional antigen uptake routes, relying on calcium and PI3K, being susceptible to polyguanylic acid inhibition, and remaining unaffected by inflammation. Termed intracellular monitoring, this process was specific …

The Curious Case Of A Painful Leg Ulcer, Jay R Patel, Rubi Montejano, Christina Hopkins, Hanna Siatecka, Theodore Rosen

Faculty, Staff and Students Publications

Sickle cell disease is a condition that can involve numerous organ systems secondary to vascular occlusion. Herein, we present a case of a 21-year-old male with sickle cell disease requiring long-term hydroxyurea therapy. Upon migrating to the United States from Yemen, the patient developed a rapidly progressive, exquisitely painful ulcer on his right lower extremity. Given his country of origin, a broad differential, including select infectious diseases, was essential. Moreover, establishing the unequivocally correct diagnosis was crucial to determine proper and safe therapy. Ultimately, a lesional biopsy demonstrated numerous sickled red blood cells occluding blood vessels, leading to the diagnosis …

Tim/Tam Receptors: A Potential Biomarker For Predicting Sensitivity To Zika Virus-Induced Oncolysis In Non-Small Cell Lung Cancers, Shankari Somasekar

Honors Undergraduate Theses

Non-small cell lung cancers (NSCLC) constitute 80-85% of lung cancers and are the leading cause of cancer-related deaths globally. The most common cause is prolonged smoking. Current treatment options for NSCLC include surgery, radiation, chemotherapy, targeted drug therapy, and immunotherapy. Although these medications are effective in the short term, patients often face issues of drug resistance and debilitating side effects with prolonged use. Currently, the use of Zika virus (ZIKV) is being researched as a possible alternative treatment for cancer, which minimizes side effects and the risk of drug resistance. TIM/TAM proteins are identified as the putative ZIKV receptors on …

Spatial Transcriptomics Resolve An Emphysema-Specific Lymphoid Follicle B Cell Signature In Chronic Obstructive Pulmonary Disease, Joselyn Rojas-Quintero, Scott A Ochsner, Felicia New, Prajan Divakar, Chen Xi Yang, Tianshi David Wu, Jerid Robinson, Darshan Shimoga Chandrashekar, Nicholas E Banovich, Ivan O Rosas, Maor Sauler, Farrah Kheradmand, Amit Gaggar, Camilla Margaroli, Raul San Jose Estepar, Neil J Mckenna, Francesca Polverino

Faculty, Staff and Students Publications

Rationale

Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component.

Objectives

To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema.

Methods

Lung sections from 40 patients with COPD and ever-smokers were used for LF proteomic and transcriptomic spatial profiling. Formalin- and O.C.T.-fixed lung samples obtained from biopsies or lung explants were assessed for LF presence. Emphysema measurements were obtained from clinical chest computed tomographic scans. High-confidence transcriptional target intersection analyses were conducted to resolve emphysema-induced transcriptional networks. …

Detection Of Invasive Bartonella Infections With Next-Generation Sequencing Of Microbial Cell-Free Dna, Fernando H Centeno, Ahmed M Hamdi, Todd M Lasco, Mayar Al Mohajer

Faculty, Staff and Students Publications

We report 9 patients with invasive Bartonella infections, including 5 with endocarditis, who were diagnosed with microbial cell-free DNA next-generation sequencing and Bartonella serology studies. Diagnosis with plasma mcfDNA NGS enabled a faster clinical and laboratory diagnosis in 8 patients. Prompt diagnosis impacted antibiotic management in all 9 patients.

Pdgfra And B Copositive Fibroblasts Drive Fibrosis In Mouse Salivary Glands Through Tgfβ Signaling, Renae Williams Atkinson

Electronic Theses & Dissertations (2024 - present)

Fibrosis is of significant concern to the medical community as numerous disease processes are characterized by progressive fibrosis leading to organ damage. We begin the process of examining the mechanism of fibrosis to salivary gland hypofunction and briefly consider Sjögren’s Disease (SjD). Method: We employed single-cell RNA sequencing data from a reversible mouse salivary gland injury model and from NOD/ShiLtJ mice, a model of secondary SjD. We performed treatment comparisons with the help of Seurat dotplots and UMAPS. Using differential gene expression analysis and the publicly available R packages: clusterProfiler, WikiPathways and Cytoscape, we identified the processes and pathways …

Formate Supplementation Enhances Antitumor Cd8+ T-Cell Fitness And Efficacy Of Pd-1 Blockade, Jared H Rowe, Ilaria Elia, Osmaan Shahid, Emily F Gaudiano, Natalia E Sifnugel, Sheila Johnson, Amy G Reynolds, Megan E Fung, Shakchhi Joshi, Martin W Lafleur, Joon Seok Park, Kristen E Pauken, Joshua D Rabinowitz, Gordon J Freeman, Marcia C Haigis, Arlene H Sharpe

Faculty, Staff and Student Publications

UNLABELLED: The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for …

Enhanced Cd19 Activity In B Cells Contributes To Immunodeficiency In Mice Deficient In The Icf Syndrome Gene Zbtb24, Zhengzhou Ying, Swanand Hardikar, Joshua B Plummer, Tewfik Hamidi, Bin Liu, Yueping Chen, Jianjun Shen, Yunxiang Mu, Kevin M Mcbride, Taiping Chen

Faculty, Staff and Student Publications

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency. It is caused by mutations in DNMT3B, ZBTB24, CDCA7, or HELLS. While progress has been made in elucidating the roles of these genes in regulating DNA methylation, little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype. Here, we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels …

Respons Inflamasi Pada Kasus Bedah, Yefta Moenadjat

Department of Surgery Teaching Materials and Monographs

Buku ini mengulas aspek seluler dan molekuler respons inflamasi pada beberapa kasus bedah, baik akut maupun kronis yang kerap dihadapkan pada masalah di klinik. Beberapa topik diulas antara lain kasus dengan respons inflamasi akut seperti trauma berat, luka bakar, cedera kepala dan respons inflamasi pada pediatrik serta beberapa kasus kronik seperti respons inflamasi pada diabetes mellitus dan lanjut usia

Penyembuhan Luka: Aspek Seluler Dan Biomolekuler, Yefta Moenadjat

Department of Surgery Teaching Materials and Monographs

Mengulas aspek seluler dan molekuler penyembuhan luka di setiap fase, dimulai dari hemostasis, inflamasi dan resolusi inflamasi, proliferasi, dan maturasi. Pada bagian terakhir dulas pula gangguan proses penyembuhan luka (luka kronik, non–healing wound) yang kerap dijumpai di klinik.

Smarcb1 Regulates The Hypoxic Stress Response In Sickle Cell Trait, Melinda Soeung, Luigi Perelli, Ziheng Chen, Eleonora Dondossola, I-Lin Ho, Federica Carbone, Li Zhang, Hania Khan, Courtney N Le, Cihui Zhu, Michael D Peoples, Ningping Feng, Shan Jiang, Niki Millward Zacharias, Rosalba Minelli, Daniel D Shapiro, Angela K Deem, Sisi Gao, Emily H Cheng, Donatella Lucchetti, Cheryl L Walker, Alessandro Carugo, Virginia Giuliani, Timothy P Heffernan, Andrea Viale, Nizar M Tannir, Giulio F Draetta, Pavlos Msaouel, Giannicola Genovese

Faculty, Staff and Student Publications

Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels …

Development Of Combination Therapy Strategies To Treat Cancer Using Dihydroorotate Dehydrogenase Inhibitors, Nicholas Mullen

Theses & Dissertations

Cancer cells require supraphysiologic levels of nucleotide triphosphates to fuel their malignant behaviors, including uncontrolled proliferation, immune evasion, metastasis, and therapy resistance. This requirement is met by hyperactive flux through the de novo pyrimidine and de novo purine pathways. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine pathway that can be targeted by FDA approved and experimental drug compounds. A robust body of preclinical evidence, encompassing hundreds of independent studies over several decades, demonstrates impressive activity of DHODH inhibitors in animal models of cancer. Paradoxically, however, all clinical trials to date have failed to demonstrate efficacy …

Barriers To Care In Juvenile Localized And Systemic Scleroderma: An Exploratory Survey Study Of Caregivers’ Perspectives, Leigh A Stubbs, Andrew M Ferry, Danielle Guffey, Christina Loccke, Erin Moriarty Wade, Pamela Pour, Kaveh Ardalan, Peter Chira, Ingrid M Ganske, Daniel Glaser, Gloria Higgins, Nadia Luca, Katharine F Moore, Vidya Sivaraman, Katie Stewart, Natalia Vasquez-Canizares, Raegan D Hunt, Renata S Maricevich, Kathryn S Torok, Suzanne C Li, Childhood Arthritis, Rheumatology Research Alliance (Carra) Scleroderma Workgroup

Faculty, Staff and Students Publications

BACKGROUND: Juvenile localized scleroderma (LS) and systemic sclerosis (SSc) are rare pediatric conditions often associated with severe morbidities. Delays in diagnosis are common, increasing the risk for permanent damage and worse outcomes. This study explored caregiver perspectives on barriers they encountered while navigating diagnosis and care for their child's scleroderma.

METHODS: In this cross-sectional study, caregivers of juvenile LS or SSc patients were recruited from a virtual family scleroderma educational conference and a juvenile scleroderma online interest group. The survey queried respondents about their child's condition and factors affecting diagnosis and treatment.

RESULTS: The response rate was 61% (73/120), with …

Pyroptosis In Neutrophils: Multimodal Integration Of Inflammasome And Regulated Cell Death Signaling Pathways, George R Dubyak, Brandon A Miller, Eric Pearlman

Faculty, Staff and Student Publications

Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which …