Preclinical and Toxicology Assessment of ALW-II-41-27, an Inhibitor of the Eph Receptor A2 (EphA2).

Background And Objective: The EphA2 receptor inhibitor ALW-II-41-27 has proven to be an effective in vitro antagonist of Pneumocystis β-glucan-induced proinflammatory signaling. This suggests its potential as a candidate for initial anti-inflammatory drug testing in the rodent model of Pneumocystis pneumonia (PCP).

Methods: Initially, single-dose intraperitoneal (IP) injections of ALW-II-41-27 were administered at concentrations of 0, 10, 15, 20, and 30 mg/kg over a 24-h treatment period.

Metabolic modulation: phosphoglucomutase is a target influencing host recognition.

Herein, this manuscript explores the significance of the phosphoglucomutase (PGM) enzyme in spp., focusing on its role in fungal surface mannoprotein formation. Through expression of the in a strain, we demonstrate restoration of binding to the mannose receptor (MR) and macrophages to wildtype yeast levels in this complemented strain.

The intestinal commensal fungus Wallemia mellicola enhances asthma in mice through Dectin-2.

Overgrowth of the fungus Wallemia mellicola in the intestines of mice enhances the severity of asthma. Wallemia mellicola interacts with the immune system through Dectin-2 expressed on the surface of myeloid and intestinal epithelial cells. Using Dectin-2-deficient mice, we show that the interaction of W.

Characterization of the and phosphoglucomutases (Pgm2s): a potential target for therapy.

cyst life forms contain abundant β-glucan carbohydrates, synthesized using β-1,3 and β-1,6 glucan synthase enzymes and the donor uridine diphosphate (UDP)-glucose. In yeast, phosphoglucomutase (PGM) plays a crucial role in carbohydrate metabolism by interconverting glucose 1-phosphate and glucose 6-phosphate, a vital step in UDP pools for β-glucan cell wall formation. This pathway has not yet been defined in .

Targeting host tyrosine kinase receptor EphA2 signaling via small-molecule ALW-II-41-27 inhibits macrophage pro-inflammatory signaling responses to β-glucans.

the fungus that causes pneumonia (PJP), is a leading cause of morbidity and mortality in immunocompromised individuals. We have previously shown that lung epithelial cells can bind spp. β-glucans via the EphA2 receptor, resulting in activation and release of proinflammatory cytokines.

Idiopathic pulmonary fibrosis in the United States: time to diagnosis and treatment.

Objective: Create a timeline of diagnosis and treatment for IPF in the US.

Design, Setting, And Participants: A retrospective analysis was performed in collaboration with the OptumLabs Data Warehouse using an administrative claims database of Medicare Fee for Service beneficiaries. Adults 50 and over with IPF were included (2014 to 2019).

Lung Epithelial Cell Line Immune Responses to .

sp. are fungal pathogens and members of the Ascomycota phylum. Immunocompetent individuals can readily eliminate the fungus, whereas immunocompromised individuals can develop pneumonia (PJP).

Targeting Pulmonary Fibrosis by SLC1A5-Dependent Glutamine Transport Blockade.

The neutral amino acid glutamine plays a central role in TGF-β (transforming growth factor-β)-induced myofibroblast activation and differentiation. Cells take up glutamine mainly through a transporter expressed on the cell surface known as solute carrier SLC1A5 (solute carrier transporter 1A5). In the present work, we demonstrated that profibrotic actions of TGF-β are mediated, at least in part, through a metabolic maladaptation of SLC1A5 and that targeting SLC1A5 abrogates multiple facets of fibroblast activation.

CLEC4A and CLEC12B C-type lectin receptors mediate interactions with cell wall components.

C-type lectin receptors (CLRs) are prominently expressed on myeloid cells where they perform multiple functions including serving as pattern recognition receptors (PRRs) to drive innate as well as adaptive immunity to pathogens. Depending on the presence of a tyrosine-based signalling motif, CLR-microbial pathogen engagement may result in either anti- or pro-inflammatory signalling. In this manuscript, we report our laboratory study of two novel CLRs that recognize cell wall homogenates (CWH) and a purified cell wall fraction (CWF).

Dysbiosis of the intestinal fungal microbiota increases lung resident group 2 innate lymphoid cells and is associated with enhanced asthma severity in mice and humans.

Background: The gut-lung axis is the concept that alterations of gut microbiota communities can influence immune function in the lungs. While studies have explored the relationship between intestinal bacterial dysbiosis and asthma development, less is understood about the impact of commensal intestinal fungi on asthma severity and control and underlying mechanisms by which this occurs.

Methods: Wild-type mice were treated with Cefoperazone to deplete gut bacteria and administered Candida albicans or water through gavage.

Prognostic Significance of Early Declines in Pulmonary Function After Allogeneic Hematopoietic Stem Cell Transplantation.

Background: Pulmonary function test (PFT) impairments are common after allogeneic hematopoietic stem cell transplantation. The prognostic significance of these declines on outcomes is not well understood.The objectives were to determine the frequency of declines in pulmonary function (FVC, FEV, and diffusing capacity for carbon monoxide [D]) in the early post-transplantation period; and to determine the prognostic significance of these declines on mortality or development of bronchiolitis obliterans syndrome.

Risk factors and outcomes of Pneumocystis pneumonia in solid organ transplant recipients: Impact of posttransplant lymphoproliferative disorder.

Background: Pneumocystis jirovecii pneumonia (PJP) is a potentially fatal infection afflicting the immunocompromised population, including solid organ transplant (SOT) recipients. Several risk factors have been described; however, little is known regarding the risk of PJP in SOT recipients with posttransplant lymphoproliferative disorder (PTLD).

Methods: We performed a nested case-control study of SOT recipients diagnosed with PJP from 2000 to 2020.

Biomarkers of cellular senescence in idiopathic pulmonary fibrosis.

Background: Cellular senescence is a cell fate in response to diverse forms of age-related damage and stress that has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The associations between circulating levels of candidate senescence biomarkers and disease outcomes have not been specifically studied in IPF. In this study we assessed the circulating levels of candidate senescence biomarkers in individuals affected by IPF and controls and evaluated their ability to predict disease outcomes.

Screening for idiopathic pulmonary fibrosis using comorbidity signatures in electronic health records.

Idiopathic pulmonary fibrosis (IPF) is a lethal fibrosing interstitial lung disease with a mean survival time of less than 5 years. Nonspecific presentation, a lack of effective early screening tools, unclear pathobiology of early-stage IPF and the need for invasive and expensive procedures for diagnostic confirmation hinder early diagnosis. In this study, we introduce a new screening tool for IPF in primary care settings that requires no new laboratory tests and does not require recognition of early symptoms.

Post-Transplant and In-Hospital Risk Factors for ARDS After Hematopoietic Stem Cell Transplantation.

Background: ARDS is a serious complication of hematopoietic stem cell transplant (HSCT). Pre-transplant risk factors for developing ARDS after HSCT have been recently identified. The objective of this study was to better understand post-transplant risk factors for developing ARDS after HSCT.

A Learning Health System Approach to Hospital Quality Performance Benchmarking: The Composite Hospital Quality Index.

US hospital quality rankings and ratings use disparate methodologies and are weakly correlated. This causes confusion for patients and hospital quality staff. At the authors' institution, a Composite Hospital Quality Index (CHQI) was developed to combine hospital quality ratings.

Preclinical and Toxicology Studies of BRD5529, a Selective Inhibitor of CARD9.

Background: The caspase recruitment domain-containing protein 9 (CARD9) inhibitor BRD5529 has been shown to be an effective in vitro inhibitor of Pneumocystis β-glucan-induced proinflammatory signaling, suggesting its viability as a candidate for preliminary anti-Pneumocystis drug testing in the rodent Pneumocystis pneumonia (PCP) model.

Methods: Mice were injected intraperitoneally (IP) daily with either vehicle or BRD5529 at 0.1 or 1.