Immunology and Infectious Disease Commons^™

High-Grade Pleomorphic Sarcomas Treated With Immune Checkpoint Blockade: The Md Anderson Cancer Center Experience, Lewis F Nasr, Marianne Zoghbi, Rossana Lazcano, Michael Nakazawa, Andrew J Bishop, Ahsan Farooqi, Devarati Mitra, Beverly Ashleigh Guadagnolo, Robert Benjamin, Shreyaskumar Patel, Vinod Ravi, Dejka M Araujo, Andrew Livingston, Maria A Zarzour, Anthony P Conley, Ravin Ratan, Neeta Somaiah, Alexander J Lazar, Christina Roland, Emily Z Keung, Elise F Nassif Haddad

Faculty, Staff and Student Publications

BACKGROUND: Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas. Few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and other high-grade pleomorphic STS patients are available.

PURPOSE: The purpose of our study is to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution.

METHODS: This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023. Patients included in …

Neoadjuvant Chemoimmunotherapy For Nsclc: A Systematic Review And Meta-Analysis, Mark Sorin, Connor Prosty, Louis Ghaleb, Kathy Nie, Khaled Katergi, Muhammad H Shahzad, Laurie-Rose Dubé, Aline Atallah, Anikka Swaby, Matthew Dankner, Trafford Crump, Logan A Walsh, Pierre O Fiset, Boris Sepesi, Patrick M Forde, Tina Cascone, Mariano Provencio, Jonathan D Spicer

Faculty, Staff and Student Publications

IMPORTANCE: To date, no meta-analyses have comprehensively assessed the association of neoadjuvant chemoimmunotherapy with clinical outcomes in non-small cell lung cancer (NSCLC) in randomized and nonrandomized settings. In addition, there exists controversy concerning the efficacy of neoadjuvant chemoimmunotherapy for patients with NSCLC with programmed cell death 1 ligand 1 (PD-L1) levels less than 1%.

OBJECTIVE: To compare neoadjuvant chemoimmunotherapy with chemotherapy by adverse events and surgical, pathological, and efficacy outcomes using recently published randomized clinical trials and nonrandomized trials.

DATA SOURCES: MEDLINE and Embase were systematically searched from January 1, 2013, to October 25, 2023, for all clinical trials of …

Hierarchal Single-Cell Lineage Tracing Reveals Differential Fate Commitment Of Cd8 T-Cell Clones In Response To Acute Infection., Leena Abdullah

Dartmouth College Ph.D Dissertations

Generating balanced populations of CD8 effector and memory T cells is necessary for immediate and durable immunity to infections and cancer. Yet, a definitive understanding of CD8 differentiation remains unclear. Here we used CARLIN, a processive lineage recording mouse model with single-cell RNA-seq and TCR-seq to track endogenous antigen-specific CD8 T cells during acute viral infection.

Transcriptional profiling of antigen-specific T cells at the peak of the effector response to Vesicular stomatitis virus uncovered a diverse repertoire of expanded antigen-specific T-cell clones represented by seven transcriptional states. TCR enrichment analysis identified TCR clones with differential memory- or effector-fate biases during …

Antimicrobial Activity Of Cat Flea (Ctenocephalides Felis) Gut Proteins On Different Days After Blood Feeding, Dhruva K. Karnik

Honors College Theses

Cat fleas (Ctenocephalides felis) are a blood-feeding ectoparasitic insect and a common domestic pest found throughout the world. Because of their reliance on host blood, fleas are exposed to blood-borne pathogens; however, the flea gut lumen is a hostile environment for microbial colonization. For example, the gut epithelia differentially express immune genes in response to feeding. In the present study, we measured the antimicrobial activity of gut proteins from cat fleas at different days after feeding (2, 5, 7, and 14). Dissected flea guts were homogenized, passed through a syringe filter, and measured in a protein assay kit. …

Ectoparasites Of The Critically Endangered Green Sawfish Pristis Zijsron And Sympatric Elasmobranchs In Western Australia, Jack Ingelbrecht, Karissa O. Lear, Storm B. Martin, Alan J. Lymbery, Bradley M. Norman, Geoffrey A. Boxshall, David L. Morgan

Harold W. Manter Laboratory of Parasitology: Library Materials

This study reports the metazoan ectoparasite fauna of juvenile Critically Endangered green sawfish, Pristis zijsron, and sympatric elasmobranchs in Western Australia. Five parasite taxa were found on 76 screened P. zijsron: Caligus furcisetifer (Copepoda: Caligidae), Dermopristis pterophila (Monogenea: Microbothriidae), Branchellion plicobranchus and Stibarobdella macrothela (Hirudinea: Piscicolidae), and praniza larvae of an unidentified gnathiid isopod. Only C. furcisetifer and D. pterophila were common, exhibiting discrepant site-specificity, with C. furcisetifer occurring mostly on the head and rostrum, and D. pterophila around the pectoral and pelvic fins. Intensity of infection for C. furcisetifer and D. pterophila increased with host total length and …

Euhaplorchis Sp. A Effect On Social Behavior And Familiarity Of Gulf Killifish (Fundulus Grandis), Hannah Bauman

All HCAS Student Capstones, Theses, and Dissertations

Trophically transmitted parasites may manipulate their hosts’ phenotype (e.g., behavior, physiology, morphology) to increase the likelihood of transmission to the definitive host. In fishes, stable social groups develop familiarity over time through repeated interactions among individuals, and social preferences are often developed due to familiarity. Consequently, fishes often shoal with familiar fishes, a behavior that is likely to be protective against predation. Parasites may alter fish social dynamics in two ways: by decreasing association with familiar individuals, thereby isolating infected fish and making them more susceptible to predation by definitive hosts; and/or by incentivizing uninfected individuals to avoid infected fish …

Investigating Vital Neutrophil Extracellular Trap Pathogen Response In Neutropenic Individuals, Ryan Illig

Thinking Matters Symposium

Neutrophils, also called polymorphonuclear leukocytes (PMNs), constitute the majority of innate immune cells. These cells possess a complex arsenal of functions that allow them to detect and eliminate a broad spectrum of pathogens. Neutropenia is characterized by decreased levels of neutrophils in the bloodstream, typically falling below the normal range. Moderate to severe neutropenia can increase the risk of pathogenic infections and without treatment can be life-threatening. Although the concentration of neutrophils in neutropenic individuals is decreased, upon activation, neutrophils still release neutrophil extracellular traps (NETs). NETs are pivotal in combating a spectrum of pathogens through their non-selective nature. Overreactive …

Cultivating Excellence: A Literature Review On Harnessing The Power Of The Gut Microbiome For Athletic Performance, Maya Katharine Dean

Honors Projects

The interplay between our gut microbiome and health is immense. This literature review analyzes the current research assessing the interplay between gut microbiome and athletic performance. Knowing how to improve gut microbial diversity via nutrition and supplementation can take athletic performance to the next level; namely improvements in immune, mental, and physical health.

Regulation And Therapeutic Targeting Of Virus-Specific Resident Memory T Cells, Jordan Fredriksen Isaacs

Dartmouth College Ph.D Dissertations

CD8+ T cells are critical to the immune response to pathogens, as they kill infected cells and generate immunologic memory. Following infection, antigen-specific T cells expand approximately 10,000-fold and migrate to sites of inflammation in order to clear the pathogen. Once infection is resolved, a small pool of memory T cells persist in circulation and within tissues ready to respond rapidly upon re-exposure. Given the importance of CD8+ T cells, significant efforts have been made over the years to better understand how different memory T cell subsets are established, maintained, and regulated. The most recently identified subset, resident memory T …

An Exploration Of The Effectiveness Of Xanthorrhiza Simplicissima And Its Secondary Alkaloids As Antibiotics Against Staphylococcus Aureus With The Use Of Reserpine, Donald Bothe, Savita Chaurasia

Undergraduate Theses

Xanthorhiza simplicissima is a plant that is steeped in medical history. It has been used for hundreds of years by the Native Americans, and later by the Europeans, of Appalachia for its medicinal properties. One of the most useful medical applications of this plant are its antibiotic properties, as typified by its use as a tea that was consumed to treat mouth sores. These antibiotic properties can be attributed to some of its secondary alkaloids such as berberine, liriodenine, oxyacanthine, and magnoflorine. These compounds have been studied in other systems; however, oxyacanthine and magnoflorine have not been researched in tandem …

Heterogeneity And Plasticity Of The Naïve Cd4+ T Cell Compartment, Alia Sajani

Dartmouth College Ph.D Dissertations

Recent studies have illuminated unexpected heterogeneity in the naïve T cell compartment. Using single cell RNA sequencing of mouse naïve CD4⁺ T cells, we identified 5 unique transcriptional subsets within the naïve CD4⁺ T cell compartment. These include a quiescence cluster (T^Q) marked by Klf2, Klf6, Jun and Btg2, a memory-like cluster (T^MEM) marked by Ccr7, Il7r and Tcf7, a TCR reactive cluster (T^TCR) marked by Cd5, Cd6 and Nr4a1, an IFN responsive cluster (T^IFN) marked by Stat1, Irf7 and Ifit1 and …

A Novel Lentiviral Vector-Based Approach To Generate Chimeric Antigen Receptor T Cells Targeting, Pappanaicken R Kumaresan, Sebastian Wurster, Karishma Bavisi, Thiago Aparecido Da Silva, Paul Hauser, Jordan Kinnitt, Nathaniel D Albert, Uddalak Bharadwaj, Sattva Neelapu, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Invasive aspergillosis (IA) is a common and deadly mold infection in immunocompromised patients. As morbidity and mortality of IA are primarily driven by poor immune defense, adjunct immunotherapies, such as chimeric antigen receptor (CAR) T cells, are direly needed. Here, we propose a novel approach to generate Aspergillus fumigatus (AF)-CAR T cells using the single-chain variable fragment domain of monoclonal antibody AF-269-5 and a lentiviral vector system. These cells successfully targeted mature hyphal filaments of representative clinical and reference AF isolates and elicited a potent release of cytotoxic effectors and type 1 T cell cytokines. Furthermore, AF-CAR T cells generated …

The Conceptual Foundations Of Innate Immunity: Taking Stock 30 Years Later, Thomas Pradeu, Bart P.H.J. Thomma, Stephen E. Girardin, Bruno Lemaitre

Presidential Fellows Articles and Research

While largely neglected over decades during which adaptive immunity captured most of the attention, innate immune mechanisms have now become central to our understanding of immunology. Innate immunity provides the first barrier to infection in vertebrates, and it is the sole mechanism of host defense in invertebrates and plants. Innate immunity also plays a critical role in maintaining homeostasis, shaping the microbiota, and in disease contexts such as cancer, neurodegeneration, metabolic syndromes, and aging. The emergence of the field of innate immunity has led to an expanded view of the immune system, which is no longer restricted to vertebrates and …

Gut Microbial Dysbiosis Differs In Two Distinct Cachectic Tumor-Bearing Models Consuming The Same Diet, Lauri O. Byerley, Brittany Lorenzen, Hsiao Man Chang, William G. Hartman, Michael J. Keenan, Ryan Page, Meng Luo, Scot E. Dowd, Christopher M. Taylor

School of Medicine Faculty Publications

The impact of cancer cachexia on the colonic microbiota is poorly characterized. This study assessed the effect of two cachectic-producing tumor types on the gut microbiota to determine if a similar dysbiosis could be found. In addition, it was determined if a diet containing an immunonutrient-rich food (walnuts) known to promote the growth of probiotic bacteria in the colon could alter the dysbiosis and slow cachexia. Male Fisher 344 rats were randomly assigned to a semi-purified diet with or without walnuts. Then, within each diet group, rats were further assigned randomly to a treatment group: tumor-bearing ad libitum fed (TB), …

Monophosphoryl Lipid A-Based Adjuvant To Promote The Immunogenicity Of Multivalent Meningococcal Polysaccharide Conjugate Vaccines, Kishore Alugupalli

Department of Microbiology and Immunology Faculty Papers

Activation of the adaptive immune system requires the engagement of costimulatory pathways in addition to B and T cell Ag receptor signaling, and adjuvants play a central role in this process. Many Gram-negative bacterial polysaccharide vaccines, including the tetravalent meningococcal conjugate vaccines (MCV4) and typhoid Vi polysaccharide vaccines, do not incorporate adjuvants. The immunogenicity of typhoid vaccines is due to the presence of associated TLR4 ligands in these vaccines. Because the immunogenicity of MCV4 is poor and requires boosters, I hypothesized that TLR4 ligands are absent in MCV4 and that incorporation of a TLR4 ligand-based adjuvant would improve their immunogenicity. …

Post-Vaccination Sars-Cov-2 Igg Spike Antibody Responses Among Clinical And Non-Clinical Healthcare Workers At A Tertiary Facility In Kenya, Lucy Wangari, Geoffrey Omuse, Rodney Adam, George Ongete, Cyrus Matheka, Patrick Mugaine, Shahin Sayed, Daniel Maina

Pathology, East Africa

Introduction: Following the coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, vaccination became the main strategy against disease severity and even death. Healthcare workers were considered high-risk for infection and, thus, were prioritised for vaccination.

Methods: A follow-up to a SARS-CoV-2 seroprevalence study among clinical and non-clinical HCWs at the Aga Khan University Hospital, Nairobi, we assessed how vaccination influenced SARS-CoV-2 anti-spike IgG antibody responses and kinetics. Blood samples were drawn at two points spanning 6 to 18 months post-vaccination, and SARS-CoV-2 spike antibody levels were determined by enzyme-linked immunosorbent assay.

Results: Almost all participants, …

Large-Scale Phenotyping Of Patients With Long Covid Post-Hospitalization Reveals Mechanistic Subtypes Of Disease, Felicity Liew, Claudia Efstathiou, Sara Fontanella, Matthew Richardson, Ruth Saunders, Dawid Swieboda, Jasmin K Sidhu, Stephanie Ascough, Shona C Moore, Noura Mohamed, Jose Nunag, Clara King, Olivia C Leavy, Omer Elneima, Hamish J C Mcauley, Aarti Shikotra, Amisha Singapuri, Marco Sereno, Victoria C Harris, Linzy Houchen-Wolloff, Neil J Greening, Nazir I Lone, Matthew Thorpe, A A Roger Thompson, Sarah L Rowland-Jones, Annemarie B Docherty, James D Chalmers, Ling-Pei Ho, Alexander Horsley, Betty Raman, Krisnah Poinasamy, Michael Marks, Onn Min Kon, Luke S Howard, Daniel G Wootton, Jennifer K Quint, Thushan I De Silva, Antonia Ho, Christopher Chiu, Ewen M Harrison, William Greenhalf, J Kenneth Baillie, Malcolm G Semple, Lance Turtle, Rachael A Evans, Louise V Wain, Christopher Brightling, Ryan S Thwaites, Peter J M Openshaw, Phosp-Covid Collaborative Group, Isaric Investigators

Faculty, Staff and Student Publications

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers …

Role Of Toll-Like Receptor 2 In Macrophage Recognition And Response To Borrelia Burgdorferi, Yukiye A. Koide

Master's Theses

Lyme disease is the most common vector-borne disease in the US and will experience an uptick as the insect host, the ixodid tick, gains habitat with climate change. The causative agent of Lyme disease, Borrelia burgdorferi, is recognized by Toll-like receptor 2 (TLR2), which initiates the innate immune response. Here, I used ELISA and SEAP detection assays to determine that knocking out TLR2 in THP-1 macrophages reduces the amount of NFkB activation, as well as IL-10 and IL-1β secretion. Then, I used fluorescence microscopy and Incucyte assays to quantify the amount of phagocytosis performed by wild-type and knock-out THP-1 cells. …

Decreasing The Antibiotic Survival Of Multi-Drug Resistant Gram-Positive Organisms, Areej Malik

Biomedical Sciences Theses & Dissertations

Biofilm production plays a crucial role in bacterial antibiotic tolerance and novel approaches are needed to combat it. The stringent response (SR), activated by nucleotide alarmones (pp)pGpp, is crucial for bacterial transcriptional reprogramming. In Clostridioides difficile, the SR is implicated in antibiotic survival, contributing to infection recurrence. Despite its known roles in sporulation and biofilm production in other bacterial species, the broader influence of the SR on C. difficile physiology remains undiscovered. This study deletes the C. difficile SR gene relQ, revealing the pivotal role of RelQ in regulating SR-dependent phenotypes in this organism. The absence of RelQ …

Randomized Phase 2 Trial Of Tremelimumab And Durvalumab In Combination Versus Sequentially In Recurrent Platinum-Resistant Ovarian Cancer, Emily M Hinchcliff, Anne Knisely, Naomi Adjei, Bryan Fellman, Ying Yuan, Ami Patel, Cai Xu, Shannon N Westin, Anil K Sood, Pamela T Soliman, Aaron Shafer, Nicole D Fleming, David M Gershenson, Raghunandan Vikram, Tharakeswara Bathala, David Vining, Dhakshina M Ganeshan, Karen H Lu, Charlotte C Sun, Larissa A Meyer, Amir A Jazaeri

Faculty, Staff and Student Publications

BACKGROUND: Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%-40% of patients achieve stable disease. The primary objective was to estimate progression-free survival (PFS) after sequential versus combination cytotoxic T-lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum-resistant high-grade serous ovarian cancer (HGSOC).

METHODS: Patients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end …