Airway tryptase levels inform the lack of clinical efficacy of the tryptase inhibitor MTPS9579A in asthma.

Background: Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract.

Methods: Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks.

ImmCellTyper facilitates systematic mass cytometry data analysis for deep immune profiling.

Mass cytometry is a cutting-edge high-dimensional technology for profiling marker expression at the single-cell level, advancing clinical research in immune monitoring. Nevertheless, the vast data generated by cytometry by time-of-flight (CyTOF) poses a significant analytical challenge. To address this, we describe ImmCellTyper (https://github.

The effects of inhaled corticosteroids on healthy airways.

Background: The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined.

Objectives: To delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS responsiveness.

Methods: Randomized open-label bronchoscopy study of high-dose ICS therapy in 30 healthy adult volunteers randomized 2:1 to (i) fluticasone propionate 500 mcg bd daily or (ii) no treatment, for 4 weeks.

Aqueous humour protein dysregulation in Asian eyes with primary open angle glaucoma.

The pathophysiology of Primary Open Angle Glaucoma (POAG) remains poorly understood. Through proteomic analysis of aqueous humour (AH) from POAG patients, we aim to identify changes in protein composition of these samples compared to control samples. High resolution mass spectrometry-based TMT6plex quantitative proteomics analysis is performed on AH samples collected from POAG patients, and compared against a control group of patients with cataracts.

Alternative Splicing Is a Major Factor Shaping Transcriptome Diversity in Mild and Severe Chronic Obstructive Pulmonary Disease.

The role of alternative splicing in chronic obstructive pulmonary disease (COPD) is still largely unknown. We aimed to investigate the differences in alternatively splicing events between patients with mild-to-moderate and severe COPD compared with non-COPD control subjects and to identify splicing factors associated with aberrant alternative splicing in COPD. For this purpose, we performed genome-wide RNA-sequencing analysis of bronchial brushings from 23 patients with mild-to-moderate COPD, 121 with severe COPD, and 23 non-COPD control subjects.

Pre-treatment with systemic agents for advanced NSCLC elicits changes in the phenotype of autologous T cell therapy products.

The antitumor activity of adoptive T cell therapies (ACT) is highly dependent on the expansion, persistence, and continued activity of adoptively transferred cells. Clinical studies using ACTs have revealed that products that possess and maintain less differentiated phenotypes, including memory and precursor T cells, show increased antitumor efficacy and superior patient outcomes owing to their increased expansion, persistence, and ability to differentiate into effector progeny that elicit antitumor responses. Strategies that drive the differentiation into memory or precursor-type T cell subsets with high potential for persistence and self-renewal will enhance adoptively transferred T cell maintenance and promote durable antitumor efficacy.

Combining experiment and energy landscapes to explore anaerobic heme breakdown in multifunctional hemoproteins.

To survive, many pathogens extract heme from their host organism and break down the porphyrin scaffold to sequester the Fe ion a heme oxygenase. Recent studies have revealed that certain pathogens can anaerobically degrade heme. Our own research has shown that one such pathway proceeds NADH-dependent heme degradation, which has been identified in a family of hemoproteins from a range of bacteria.

A bronchial gene signature specific for severe COPD that is retained in the nose.

Introduction: A subset of COPD patients develops advanced disease with severe airflow obstruction, hyperinflation and extensive emphysema. We propose that the pathogenesis in these patients differs from mild-moderate COPD and is reflected by bronchial gene expression. The aim of the present study was to identify a unique bronchial epithelial gene signature for severe COPD patients.

LYVE-1 macrophages form a collaborative CCR5-dependent perivascular niche that influences chemotherapy responses in murine breast cancer.

Tumor-associated macrophages (TAMs) are a heterogeneous population of cells that facilitate cancer progression. However, our knowledge of the niches of individual TAM subsets and their development and function remain incomplete. Here, we describe a population of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1)-expressing TAMs, which form coordinated multi-cellular "nest" structures that are heterogeneously distributed proximal to vasculature in tumors of a spontaneous murine model of breast cancer.

Blood transcriptomic signature in type-2 biomarker-low severe asthma and asthma control.

Background: Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids.

Objectives: We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker-high/-low patients with severe asthma to relate transcriptomic signatures to T2 biomarkers and asthma symptom scores.

Methods: Bulk RNA-seq data were generated for blood samples (baseline, week 24, week 48) from 301 participants recruited to a randomized clinical trial of corticosteroid optimization in severe asthma.

Early plasma angiopoietin-2 is prognostic for ARDS and mortality among critically ill patients with sepsis.

Angiopoietin-2 (Ang-2) is associated with vascular endothelial injury and permeability in the acute respiratory distress syndrome (ARDS) and sepsis. Elevated circulating Ang-2 levels may identify critically ill patients with distinct pathobiology amenable to targeted therapy. We hypothesized that plasma Ang-2 measured shortly after hospitalization among patients with sepsis would be associated with the development of ARDS and poor clinical outcomes.

Targeting interleukin-33 and thymic stromal lymphopoietin pathways for novel pulmonary therapeutics in asthma and COPD.

Interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) are alarmins that are released upon airway epithelial injury from insults such as viruses and cigarette smoke, and play critical roles in the activation of immune cell populations such as mast cells, eosinophils and group 2 innate lymphoid cells. Both cytokines were previously understood to primarily drive type 2 (T2) inflammation, but there is emerging evidence for a role for these alarmins to additionally mediate non-T2 inflammation, with recent clinical trial data in asthma and COPD cohorts with non-T2 inflammation providing support. Currently available treatments for both COPD and asthma provide symptomatic relief with disease control, improving lung function and reducing exacerbation rates; however, there still remains an unmet need for further improving lung function and reducing exacerbations, particularly for those not responsive to currently available treatments.

A Randomized Trial of a Composite T2-Biomarker Strategy Adjusting Corticosteroid Treatment in Severe Asthma: A Post Hoc Analysis by Sex.

Background: Approximately 5% to 10% of patients with asthma have severe disease, with a consistent preponderance in females. Current asthma guidelines recommend stepwise treatment to achieve symptom control with no differential treatment considerations for either sex.

Objective: To examine whether patient sex affects outcomes when using a composite T2-biomarker score to adjust corticosteroid (CS) treatment in patients with severe asthma compared with standard care.

A genome-wide association study of chronic spontaneous urticaria risk and heterogeneity.

Background: Chronic spontaneous urticaria (CSU) is a dermatologic condition characterized by spontaneous, pruritic hives and/or angioedema that persists for 6 weeks or longer with no identifiable trigger. Antihistamines and second-line therapies such as omalizumab are effective for some CSU patients, but others remain symptomatic, with significant impact on quality of life. This variable response to treatment and autoantibody levels across patients highlight clinically heterogeneous subgroups.

The Use of a Suprascapular Nerve Block to Facilitate the Reduction of an Anterior Shoulder Dislocation: An Alternative for Elderly and Patients With Cardiopulmonary Comorbidities?

Background: Anterior shoulder dislocation is a common presentation to the emergency department (ED). Dislocations are spontaneous or traumatic. Generally, a reduction is performed under procedural sedation and analgesia (PSA).

Phase 2 randomized clinical trial of astegolimab in patients with moderate to severe atopic dermatitis.

Background: The binding of IL-33 to its receptor ST2 (alias of IL1RL1) leads to the release of inflammatory mediators and may play a role in the pathogenesis of atopic dermatitis. Astegolimab is a fully human, IgG mAb that binds to ST2 and inhibits IL-33 signaling.

Objectives: This study sought to assess the efficacy, safety, and pharmacokinetics of astegolimab in patients with atopic dermatitis.

Integrated systems modeling of severe asthma: Exploration of IL-33/ST2 antagonism.

Asthma is a complex, heterogeneous disease with a high unmet medical need, despite therapies targeting a multitude of pathways. The ability to quantitatively integrate preclinical and clinical data on these pathways could aid in the development and testing of novel targets and therapeutics. In this work, we develop a computational model of asthma biology, including key cell types and mediators, and create a virtual population capturing clinical heterogeneity.

Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation.

Background: Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations.

Aim: To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation.

Airway remodelling rather than cellular infiltration characterizes both type2 cytokine biomarker-high and -low severe asthma.

Background: The most recognizable phenotype of severe asthma comprises people who are blood eosinophil and FeNO-high, driven by type 2 (T2) cytokine biology, which responds to targeted biological therapies. However, in many people with severe asthma, these T2 biomarkers are suppressed but poorly controlled asthma persists. The mechanisms driving asthma in the absence of T2 biology are poorly understood.

Exacerbation Profile and Risk Factors in a Type-2-Low Enriched Severe Asthma Cohort: A Clinical Trial to Assess Asthma Exacerbation Phenotypes.

The past 25 years have seen huge progress in understanding of the pathobiology of type-2 (T2) asthma, identification of measurable biomarkers, and the emergence of novel monoclonal antibody treatments. Although present in a minority of patients with severe asthma, very little is known about the mechanisms underlying T2-low asthma, making it a significant unmet need in asthma research. The objective of this study was to explore the differences between study exacerbators and nonexacerbators, to describe physiological changes at exacerbation in those who are T2 and T2 at the time of exacerbation, and to evaluate the stability of inflammatory phenotypes when stable and at exacerbation.

Genome-wide association study identifies kallikrein 5 in type 2 inflammation-low asthma.

Background: Clinical studies of type 2 (T2) cytokine-related neutralizing antibodies in asthma have identified a substantial subset of patients with low levels of T2 inflammation who do not benefit from T2 cytokine neutralizing antibody treatment. Non-T2 mechanisms are poorly understood in asthma but represent a redefined unmet medical need.

Objective: We sought to gain a better understanding of genetic contributions to T2-low asthma.