Two-fold proton coupled electron transfer of a Ta(V) aniline complex mediated by a redox active NNN pincer ligand.

We report the proton-coupled electron transfer (PCET) reactivity of an octahedral Ta(V) aniline complex supported by an acridane-derived redox active NNN pincer ligand. The reversible binding of aniline to a Ta(V) dichloride induces significant coordination-induced bond weakening (CIBW) of the aniline N-H bonds. This enables a rare two-fold hydrogen atom abstraction, resulting in a terminal imido complex and a two-electron oxidation of the NNN pincer ligand, all while maintaining the metal's oxidation state.

Development of Direct Electron Transfer-Type Extended Gate Field Effect Transistor Enzymatic Sensors for Metabolite Detection.

In this work, direct electron transfer (DET)-type extended gate field effect transistor (EGFET) enzymatic sensors were developed by employing DET-type or quasi-DET-type enzymes to detect glucose or lactate in both 100 mM potassium phosphate buffer and artificial sweat. The system employed either a DET-type glucose dehydrogenase or a quasi-DET-type lactate oxidase, the latter of which was a mutant enzyme with suppressed oxidase activity and modified with amine-reactive phenazine ethosulfate. These enzymes were immobilized on the extended gate electrodes.

Development of a glycated albumin sensor employing dual aptamer-based extended gate field effect transistors.

Glycated albumin (GA), defined as the percentage of serum albumin glycation, is a mid-term glycemic control marker for diabetes. The concentrations of both glycated human serum albumin (GHSA) and total human serum albumin (HSA) are required to calculate GA. Here, we report the development of a GA sensor employing two albumin aptamers: anti-GHSA aptamer which is specific to GHSA and anti-HSA aptamer which recognizes both glycated and non-glycated HSA.

TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase.

Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn.

Th2 high and mast cell gene signatures are associated with corticosteroid sensitivity in COPD.

Rationale: Severe asthma and chronic obstructive pulmonary disease (COPD) share common pathophysiological traits such as relative corticosteroid insensitivity. We recently published three transcriptome-associated clusters (TACs) using hierarchical analysis of the sputum transcriptome in asthmatics from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort comprising one Th2-high inflammatory signature (TAC1) and two Th2-low signatures (TAC2 and TAC3).

Objective: We examined whether gene expression signatures obtained in asthma can be used to identify the subgroup of patients with COPD with steroid sensitivity.

Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma.

Background: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma.

Pathways linked to unresolved inflammation and airway remodelling characterize the transcriptome in two independent severe asthma cohorts.

Background And Objective: Severe asthma (SA) is a heterogeneous disease. Transcriptomic analysis contributes to the understanding of pathogenesis necessary for developing new therapies. We sought to identify and validate mechanistic pathways of SA across two independent cohorts.

Clinical and transcriptomic features of persistent exacerbation-prone severe asthma in U-BIOPRED cohort.

Background: Exacerbation-prone asthma is a feature of severe disease. However, the basis for its persistency remains unclear.

Objectives: To determine the clinical and transcriptomic features of frequent exacerbators (FEs) and persistent FEs (PFEs) in the U-BIOPRED cohort.

Mapping atopic dermatitis and anti-IL-22 response signatures to type 2-low severe neutrophilic asthma.

Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.

Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma.

Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies.

Instability of sputum molecular phenotypes in U-BIOPRED severe asthma.

https://bit.ly/35aj489

Sputum macrophage diversity and activation in asthma: Role of severity and inflammatory phenotype.

Background: Macrophages control innate and acquired immunity, but their role in severe asthma remains ill-defined. We investigated gene signatures of macrophage subtypes in the sputum of 104 asthmatics and 16 healthy volunteers from the U-BIOPRED cohort.

Methods: Forty-nine gene signatures (modules) for differentially stimulated macrophages, one to assess lung tissue-resident cells (TR-Mφ) and two for their polarization (classically and alternatively activated macrophages: M1 and M2, respectively) were studied using gene set variation analysis.

Front-line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control.

Background: Approximately 3%-5% of lung adenocarcinoma is driven by anaplastic lymphoma kinase (ALK) fusion oncogene, whose activity can be suppressed by multiple ALK inhibitors. Crizotinib and ceritinib have demonstrated superior efficacy to platinum-based chemotherapy as front-line treatment for patients with ALK-positive advanced non-small cell lung cancer (NSCLC). However, the direct comparison between them in the front-line setting remains lacking.

PlatformTM, a standards-based data custodianship platform for translational medicine research.

Biomedical informatics has traditionally adopted a linear view of the informatics process (collect, store and analyse) in translational medicine (TM) studies; focusing primarily on the challenges in data integration and analysis. However, a data management challenge presents itself with the new lifecycle view of data emphasized by the recent calls for data re-use, long term data preservation, and data sharing. There is currently a lack of dedicated infrastructure focused on the 'manageability' of the data lifecycle in TM research between data collection and analysis.

Prior EGFR-TKI Treatment in EGFR-Mutated NSCLC Affects the Allele Frequency Fraction of Acquired T790M and the Subsequent Efficacy of Osimertinib.

Background: The first (1G) and second (2G) generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show differential inhibitory capacities towards EGFR T790M-mutated non-small-cell lung cancer (NSCLC) cells.

Objective: To assess the ratio of the allele fractions of T790M (AF) to EGFR-activating mutations (AF) in patients treated with 1G and 2G EGFR TKIs who acquired T790M-mediated resistance and to determine the relationship between AF and the later efficacy of osimertinib.

Patients And Methods: The efficacy of osimertinib was reviewed for 54 T790M-positive EGFR-mutated NSCLC patients grouped by the generation of prior EGFR TKI use (1G vs.

IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death globally. The lack of effective treatments results from an incomplete understanding of the underlying mechanisms driving COPD pathogenesis.Interleukin (IL)-22 has been implicated in airway inflammation and is increased in COPD patients.

I_MDS: an inflammatory bowel disease molecular activity score to classify patients with differing disease-driving pathways and therapeutic response to anti-TNF treatment.

Crohn's disease and ulcerative colitis are driven by both common and distinct underlying mechanisms of pathobiology. Both diseases, exhibit heterogeneity underscored by the variable clinical responses to therapeutic interventions. We aimed to identify disease-driving pathways and classify individuals into subpopulations that differ in their pathobiology and response to treatment.

Contribution of airway eosinophils in airway wall remodeling in asthma: Role of MMP-10 and MET.

Background: Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma.

Methods: We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort.

"T2-high" in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin.

Type-2 (T2) immune responses in airway epithelial cells (AECs) classifies mild-moderate asthma into a T2-high phenotype. We examined whether currently available clinical biomarkers can predict AEC-defined T2-high phenotype within the U-BIOPRED cohort.The transcriptomic profile of AECs obtained from brushings of 103 patients with asthma and 44 healthy controls was obtained and gene set variation analysis used to determine the relative expression score of T2 asthma using a signature from interleukin (IL)-13-exposed AECs.

PGAM5 expression and macrophage signatures in non-small cell lung cancer associated with chronic obstructive pulmonary disease (COPD).

Background: COPD patients are at increased risk of developing non-small cell lung carcinoma that has a worse prognosis. Oxidative stress contributes to carcinogenesis and is increased in COPD patients due to mitochondrial dysfunction. We determined whether mitochondrial dysfunction is a contributing factor to the reduced survival of COPD patients with non-small cell lung carcinoma (NSCLC).

IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive antiviral immunity.

Background: Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immunopathogenesis of exacerbations has remained elusive.

Objective: We hypothesized that IL-33 is necessary to drive asthma exacerbations.