Informatics and Artificial Intelligence-Guided Assessment of the Regulatory and Translational Research Landscape of First-in-Class Oncology Drugs in the United States, 2018-2022.

Purpose: Cancer drug development remains a critical but challenging process that affects millions of patients and their families. Using biomedical informatics and artificial intelligence (AI) approaches, we assessed the regulatory and translational research landscape defining successful first-in-class drugs for patients with cancer.

Methods: This is a retrospective observational study of all novel first-in-class drugs approved by the US Food and Drug Administration (FDA) from 2018 to 2022, stratified by cancer versus noncancer drugs.

The PAX LC Trial: A Decentralized, Phase 2, Randomized, Double-Blind Study of Nirmatrelvir/Ritonavir Compared with Placebo/Ritonavir for Long COVID.

Background: Individuals with long COVID lack evidence-based treatments and have difficulty participating in traditional site-based trials. Our digital, decentralized trial investigates the efficacy and safety of nirmatrelvir/ritonavir, targeting viral persistence as a potential cause of long COVID.

Methods: The PAX LC trial (NCT05668091) is a Phase 2, 1:1 randomized, double-blind, superiority, placebo-controlled trial in 100 community-dwelling, highly symptomatic adult participants with long COVID residing in the 48 contiguous US states to determine the efficacy, safety, and tolerability of 15 days of nirmatrelvir/ritonavir compared with placebo/ritonavir.

Pathobiology of Candida auris infection analyzed by multiplexed imaging and single cell analysis.

Fungal organisms contribute to significant human morbidity and mortality and Candida auris (C. auris) infections are of utmost concern due to multi-drug resistant strains and persistence in critical care and hospital settings. Pathogenesis and pathology of C.

Depletion of the Microbiota Has a Modest but Important Impact on the Fungal Burden of the Heart and Lungs during Early Systemic Infection in Neutropenic Mice.

The progression and systemic pathobiology of in the absence of a microbiota have not been described. Here, we describe the influence of the microbiota during the first 5 days of infection in germ-free or antibiotic-depleted mice. Depletion of the bacterial microbiota in both germ-free and antibiotic-depleted models results in a modest but important increase in the early stages of infection.

Inclusive Science: Inspiring 8th Graders from Underrepresented Groups to Embrace STEM with Microbiology and Immunology.

Inclusivity in STEM requires practices that include transforming the culture in a classroom. This can be done not only by placing value on diversity but also by providing an engaging student experience, instilling a sense of belonging, and encouraging students at all levels to use a critical lens to solve problems. As a way to develop an inclusive science curriculum for students in a community that is among the poorest in New York state, local STEM organization Rise High Inc.

Impact of Candida auris Infection in a Neutropenic Murine Model.

has become a global public health threat due to its multidrug resistance and persistence. Currently, there are limited murine models to study infection. Those models use a combination of cyclophosphamide and cortisone acetate, suppressing both innate and adaptive immunity.

Dectin-2-mediated signaling triggered by the cell wall polysaccharides of Cryptococcus neoformans.

Cryptococcus neoformans is rich in polysaccharides of the cell wall and capsule. Dectin-2 recognizes high-mannose polysaccharides and plays a central role in the immune response to fungal pathogens. Previously, we demonstrated Dectin-2 was involved in the activation of dendritic cells upon stimulation with C.

Polydopamine Coating of Glucan Particles Increases Uptake into Peyer's Patches.

Glucan particles (GPs) are hollow, porous 3-4 μm microspheres derived from the cell walls of Baker's yeast (). The β-1,3-D glucan outer shell of GPs provides for receptor-mediated uptake by phagocytic cells expressing β-glucan receptors. GPs have been used for efficient encapsulation of different types of payloads (DNA, siRNA, proteins, antigens, small molecules), and these payloads have been delivered in vivo by a variety of routes including oral delivery.

RNA isolation from Peyer's patch lymphocytes and mononuclear phagocytes to determine gene expression profiles using NanoString technology.

Sampling and immune surveillance within gut-associated lymphoid tissues such as the intestinal Peyer's patch (PP) occurs by an elegantly orchestrated effort that involves the epithelial barrier, B and T lymphocytes, and an extensive network of mononuclear phagocytes. Although we now understand more about the dynamics of antigen and microbial sampling within PPs, the gene expression changes that occur in individual cell subsets during sampling are not well characterized. This protocol describes the isolation of high-quality RNA from sorted PP, B and T-lymphocytes, and CD11c phagocytes for use with nCounter-NanoString technology.

Candida albicans Elicits Pro-Inflammatory Differential Gene Expression in Intestinal Peyer's Patches.

The details of how gut-associated lymphoid tissues such as Peyer's patches (PPs) in the small intestine play a role in immune surveillance, microbial differentiation and the mucosal barrier protection in response to fungal organisms such as Candida albicans are still unclear. We particularly focus on PPs as they are the immune sensors and inductive sites of the gut that influence inflammation and tolerance. We have previously demonstrated that CD11c phagocytes that include dendritic cells and macrophages are located in the sub-epithelial dome within PPs sample C.

Assessment of environmental and occupational exposure while working with multidrug resistant (MDR) fungus in an animal facility.

In less than a decade since its identification in 2009, the emerging fungal pathogen has become a major public health threat due to its multidrug resistant (MDR) phenotype, high transmissibility, and high mortality. Unlike other species, has acquired high levels of resistance to an already limited arsenal of antifungals. As an emerging pathogen, there are currently a limited number of documented murine models of infection.

Enhanced gut barrier integrity sensitizes colon cancer to immune therapy.

Oral IL-10 suppressed tumor growth in the APC mouse/ colon cancer model while a similar formulation of IL-12 exacerbated disease. In contrast, combined treatment with IL-10 and IL-12 resulted in near-complete tumor eradication and a significant extension of survival. The cytokines mediated distinct immunological effects in the gut, i.

Green Fluorescent Protein Expression in Pseudogymnoascus destructans to Study Its Abiotic and Biotic Lifestyles.

Pseudogymnoascus destructans (Pd) is the etiologic agent of bat White-nose syndrome, a disease that has caused the unprecedented reduction in the hibernating bat populations across eastern North America. The Pd pathogenesis appears to be a complex adaptation of fungus in its abiotic (caves and mines) and biotic (bats) environments. There is a general lack of experimental tools for the study of Pd biology.

Intravaginal Administration of Interleukin 12 during Genital Gonococcal Infection in Mice Induces Immunity to Heterologous Strains of .

It has previously been shown that genital tract infection with in mice does not induce a state of protective immunity against reinfection but instead suppresses the development of adaptive immune responses against dependent on transforming growth factor beta (TGF-β) and interleukin 10 (IL-10). Intravaginal administration during gonococcal infection of IL-12 encapsulated in biodegradable microspheres (IL-12/ms) reverses the immunosuppression and promotes the production of gamma interferon (IFN-γ) and of specific antibodies in serum and genital secretions and accelerates clearance of the infection. In this study, microspheres were shown to remain largely within the genital tract lumen and to release IL-12 over the course of 4 days.

Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenicCD4 T-cells and induction of antitumor CD8 T-cell activity.

An oral sustained-release formulation of Interleukin-10 suppressed tumor growth and enhanced survival in the APC/ spontaneous colon cancer model. Therapeutic benefit was associated with a 5-fold reduction in CD4RORγtFoxp3IL-17 T-helper cell, CD4RORγtFoxp3IL-17 pathogenic T-regulatory cell and CD4RORγtFoxp3IL-17 conventional T-regulatory cell numbers and a concurrent 2-fold enhancement in CD8 T-cell activity in the colon. Selective subset depletion and functional blockade studies demonstrated that at steady-state CD4RORγtIL-17 T-cell subsets and CD4Foxp3 cTreg supported tumorigenesis, whereas CD8 cytotoxic T-lymphocytes impeded tumor progression following IL-10 therapy.

Role of Maternal Dietary Peanut Exposure in Development of Food Allergy and Oral Tolerance.

Background: The impact of maternal ingestion of peanut during pregnancy and lactation on an offspring's risk for peanut allergy is under debate.

Objective: To investigate the influence of maternal dietary peanut exposure and breast milk on an offspring's allergy risk.

Methods: Preconceptionally peanut-exposed C3H/HeJ females were either fed or not fed peanut during pregnancy and lactation.

Sampling of Candida albicans and Candida tropicalis by Langerin-positive dendritic cells in mouse Peyer's patches.

Members of the Candida genus, including C. albicans and C. tropicalis are opportunistic fungal pathogens that are increasingly associated with gastrointestinal infections and inflammatory bowel diseases.

Rapid effects of a protective O-polysaccharide-specific monoclonal IgA on Vibrio cholerae agglutination, motility, and surface morphology.

2D6 is a dimeric monoclonal immunoglobulin A (IgA) specific for the nonreducing terminal residue of Ogawa O-polysaccharide (OPS) of Vibrio cholerae. It was previously demonstrated that 2D6 IgA is sufficient to passively protect suckling mice from oral challenge with virulent V. cholerae O395.

Oral interleukin-10 alleviates polyposis via neutralization of pathogenic T-regulatory cells.

Immune dysregulation drives the pathogenesis of chronic inflammatory, autoimmune, and dysplastic disorders. While often intended to address localized pathology, most immune modulatory therapies are administered systemically and carry inherent risk of multiorgan toxicities. Here, we demonstrate, in a murine model of spontaneous gastrointestinal polyposis, that site-specific uptake of orally administered IL10 microparticles ameliorates local and systemic disease to enhance survival.

A population of Langerin-positive dendritic cells in murine Peyer's patches involved in sampling β-glucan microparticles.

Glucan particles (GPs) are 2-4 μm hollow, porous shells composed of 1,3-β-D-glucan that have been effectively used for oral targeted-delivery of a wide range of payloads, including small molecules, siRNA, DNA, and protein antigens. While it has been demonstrated that the transepithelial transport of GPs is mediated by Peyer's patch M cells, the fate of the GPs once within gut-associated lymphoid tissue (GALT) is not known. Here we report that fluorescently labeled GPs administered to mice by gavage accumulate in CD11c+ DCs situated in Peyer's patch sub-epithelial dome (SED) regions.

Three-dimensional reconstruction of murine Peyer's patches from immunostained cryosections.

Peyer's patches, macroscopic aggregates of lymphoid follicles present throughout the small intestines of humans and other mammals, are considered the gateway through which luminal dietary antigens and microbes are sampled by the mucosal immune system. The cellular make-up of Peyer's patch lymphoid follicles is not only complex, but highly dynamic, as there are at least four major cell types that are known to migrate in response to antigenic stimulation. In an effort to capture the complexity and dynamic nature of this specialized tissue, here we report the three-dimensional (3D) reconstruction of immunofluorescent-labeled mouse Peyer's patch cryosections.

Isolating and immunostaining lymphocytes and dendritic cells from murine Peyer's patches.

Peyer's patches (PPs) are integral components of the gut-associated lymphoid tissues (GALT) and play a central role in intestinal immunosurveillance and homeostasis. Particulate antigens and microbes in the intestinal lumen are continuously sampled by PP M cells in the follicle-associated epithelium (FAE) and transported to an underlying network of dendritic cells (DCs), macrophages, and lymphocytes. In this article, we describe protocols in which murine PPs are (i) dissociated into single cell suspensions and subjected to flow cytometry and (ii) prepared for cryosectioning and immunostaining.

Macrophage autophagy in immunity to Cryptococcus neoformans and Candida albicans.

Autophagy is used by eukaryotes in bulk cellular material recycling and in immunity to intracellular pathogens. We evaluated the role of macrophage autophagy in the response to Cryptococcus neoformans and Candida albicans, two important opportunistic fungal pathogens. The autophagosome marker LC3 (microtubule-associated protein 1 light chain 3 alpha) was present in most macrophage vacuoles containing C.

Glucuronoxylomannan, galactoxylomannan, and mannoprotein occupy spatially separate and discrete regions in the capsule of Cryptococcus neoformans.

The capsular polysaccharides of Cryptococcus neoformans have historically been divided into three components namely, glucuronoxylomannan (GXM), galactoxylomannan (GalXM), and mannoprotein (MP) but their relative spatial-geographical relationship in the capsule is unknown.  To explore this problem would require the capacity for visualizing these components in the capsule.  Prior studies have reported serological reagents to GXM and GalXM but no antibodies are available against MPs.