Publications
1032 results found
Zadian SS, Adcock IM, Salimi B, et al., 2021, Circulating levels of monocytic myeloid-derived suppressor cells (M-MDSC) and CXCL-8 in non-small cell lung cancer (NSCLC), Tanaffos, Vol: 20, Pages: 15-21, ISSN: 1735-0344
BACKGROUND: Myeloid-derived suppressor cells (MDSC) are categorized as granulocytic (G-MDSCs) and monocytic (M-MDSCs) and their expansion play a role in cancer progression. Recruitment to the cancer site depends upon the presence of a chemoattractant. We aimed to investigate the presence of MDSC subtypes and of interleukin-8 (CXCL-8) in the peripheral blood in lung cancer subtypes including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients. MATERIALS AND METHODS: Peripheral blood samples of 26 NSCLC patients, 18 SCLC patients, and 8 healthy control donors (HDs) were harvested and the surface expression of CD14, CD15, CD11b, and HLA-DR on MDSCs was measured using flow cytometry. The level of serum CXCL8 was measured by the ELISA method. RESULTS: The frequency of circulating M-MDSCs was significantly higher in patients with NSCLC than in SCLC and HDs. In contrast, there was no statistical difference concerning the frequency of circulating G-MDSCs between the three groups. The concentration of CXCL-8 was significantly higher in the NSCLC and SCLC patients than in HD control with no significant difference between NSCLC and SCLC groups. There was no correlation between serum CXCL8 and G-MDSC levels. CONCLUSION: Our data confirm a higher frequency of circulating M-MDSCs, but not G-MDSCs, in the blood of those suffering from NSCLC but not for SCLC cases. Measuring MDSC subtypes and serum chemotactic factors may have implications for the differential diagnosis of NSCLC.
Holguin F, Cardet JC, Chung KF, et al., 2021, Management of severe asthma: A European Respiratory Society/American Thoracic Society guideline, Pulmonologiya, Vol: 31, Pages: 272-295, ISSN: 0869-0189
This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including metaanalyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force’s questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations: • suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes; • suggest using a blood eosinophil cut-point ≥150 μL−1 to guide anti-IL-5 initiation in adult patients with severe asthma; • suggest considering specific eosinophil (≥260 μL−1) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy; • suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4 – 5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies; • suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype; • suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These reco
Abdel-Aziz MI, Brinkman P, Vijverberg SJH, et al., 2021, Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12-18 months, Journal of Allergy and Clinical Immunology, Vol: 147, Pages: 123-134, ISSN: 0091-6749
BACKGROUND: Asthma is a heterogeneous disease characterized by distinct phenotypes with associated microbial dysbiosis. OBJECTIVES: To identify severe asthma phenotypes based on sputum microbiome profiles and assess their stability after 12-18 months. Furthermore, to evaluate clusters' robustness after inclusion of an independent mild-to-moderate asthmatics. METHODS: In this longitudinal multicenter cohort study, sputum samples were collected for microbiome profiling from a subset of the U-BIOPRED adult patient cohort at baseline and after 12-18 months of follow-up. Unsupervised hierarchical clustering was performed using the Bray-Curtis β-diversity measure of microbial profiles. For internal validation, partitioning around medoids, consensus cluster distribution, bootstrapping and topological data analysis were applied. Follow-up samples were studied to evaluate within-patient clustering stability in severe asthmatics. Cluster robustness was evaluated by an independent mild-moderate asthma cohort. RESULTS: Data were available for 100 severe asthma subjects (median age: 55 yrs, 42% males). Two microbiome-driven clusters were identified, characterized by differences in asthma onset, smoking status, residential locations, percentage of blood and/or sputum neutrophils and macrophages, lung spirometry, and concurrent asthma medications (all p-values <.05). Cluster 2 patients displayed a commensal-deficient bacterial profile which was associated with worse asthma outcomes compared to cluster 1. Longitudinal clusters revealed high relative stability after 12-18 months in the severe asthmatics. Further inclusion of 24 independent mild-to-moderate asthmatics was consistent with the clustering assignments. CONCLUSION: Unbiased microbiome-driven clustering revealed two distinct robust severe asthma phenotypes, which exhibited relative overtime stability. This suggests that the sputum microbiome may serve as a biomarker for better characterizing asthma phenotypes.
Dixey P, Abubakar-Waziri H, Raby K, et al., 2021, Adult Severe Asthma, Encyclopedia of Respiratory Medicine, Second Edition, Pages: 383-399, ISBN: 9780081027233
Severe asthma is “asthma which requires treatment with high dose inhaled corticosteroids plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy.” Asthma diagnosis and its severity requires systematic assessment of the underlying causative factors including suboptimal adherence to treatments and inhaler technique, comorbidities, risk factors and triggers. This is followed by asthma phenotyping using blood eosinophil counts and the fractional level of nitric oxide (FeNO) in exhaled breath to enable treatment with targeted anti-Type 2 inflammation-directed antibodies. Deeper molecular phenotyping of type 2 and non-type 2 airway inflammatory processes and elucidation of better selective biomarkers will lead to further precision medicine approaches linking mechanisms to treatable traits and biomarkers.
Adcock IM, Mumby S, 2021, Asthma: NSAID Exacerbated Respiratory Disease (NERD) Formerly Aspirin-Intolerant Asthma, Encyclopedia of Respiratory Medicine, Second Edition, Pages: 362-368, ISBN: 9780081027233
Ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin can trigger acute bronchoconstriction and the incidence of NSAID- exacerbated respiratory disease (NERD), formerly Aspirin-intolerant asthma (AIA), rises from 7% in asthma generally to over 15% in severe asthma and up to 30% in severe asthmatics with nasal polyposis. NSAIDS inhibit the synthesis of prostanoids by blockade of cyclooxygenase (COX). Acute reactions to NSAIDs can be life threatening and may be associated with rhinoconjunctival and dermal symptoms. The selectively for COX-1 inhibition determines the ability of NSAIDs to induce NERD. Pathologically, the bronchial and nasal airways of patients with NERD show chronic eosinophilia, with evidence of eosinophil and mast cell activation during acute reactions. The etiology of NERD is unclear, but involves inhibition by NSAIDs of prostaglandin E2 synthesis that would normally suppress local inflammatory reactions. The consequent synthesis of cysteinyl-leukotrienes and other leukocyte-derived mediators contributes to bronchoconstriction and other acute features. Recent evidence also implicates a role for type 2 (T2) inflammation in subtypes of NERD. Treatment of NERD involves avoidance of NSAIDs combined with conventional management of underlying asthma with combination inhaled corticosteroids/long-acting β2-agonists along with leukotriene modifiers and potentially anti-T2-directed antibody therapy. Controlled desensitization with regular doses of an NSAID can provide protection against acute reactions.
Caramori G, Nucera F, Coppolino I, et al., 2021, Transcription Factors, Encyclopedia of Respiratory Medicine, Second Edition, Pages: 733-749, ISBN: 9780081027233
Transcription factors (TFs) are a large family of regulatory proteins that can increase or decrease the transcription of a particular gene from deoxyribonucleic acid into the corresponding ribonucleic acid. The modular structure of TFs and the presence of distinct interacting domains determine the ability of these factors to associate with each other and with co-activating/repressing proteins. In addition, DNA polymorphisms or DNA methylation status cam alter TF-DNA binding and function. TFs control the expression of many inflammatory genes and they play a key role in the pathogenesis of a large number of human respiratory diseases contributing to determine disease severity and response to treatment.
Prendecki R, Adcock IM, 2021, Inflammatory Mechanisms in Asthma, Encyclopedia of Respiratory Medicine, Second Edition, Pages: 334-341, ISBN: 9780081027233
Asthma is a disease of the airways that is characterized by inflammation which induces bronchial hyperresponsiveness leading to reversible airways obstruction. Although asthma has traditionally been understood as a single disease process mediated by eosinophilic inflammation, over recent years increasing heterogeneity in asthma has been recognized. Asthma is currently classified into two main endotypes, Type 2 high and Type 2 low asthma. T2 high asthma is similar to the traditional allergic asthma model where allergens lead to the activation of Th2 cells to produce the main mediators of type 2 inflammation; IL-4, IL-5 and IL-13. Recent evidence suggests that the release of alarmins such as TSLP, IL25 and IL33 from damaged airway epithelial cells act on type 2 innate lymphoid (ILC2) cells to produce greater levels of IL-4, IL-5 and IL-13. T2 low asthma is more poorly understood process and is associated with steroid resistance. T2 low asthma is associated with inflammatory pathways activated by pollutants and sub-clinical infections to produce neutrophilic or paucigranular inflammation. T2-low asthma is triggered by cytokines IFNγ, TNFα, IL-17, IL-6 and IL-8 that are released by Th1 and Th17 CD4+ cells to act on neutrophils, smooth muscle and airway vasculature. This article provides an overview of these inflammatory pathways, it describes existing and potential treatments that target these pathways and discusses possible biomarkers derived from these pathways and how they could be utilized to measure disease activity and treatment response.
Barnes PJ, Adcock IM, Mumby S, et al., 2021, Asthmatic patients, Supporting Tobacco Cessation, Publisher: European Respiratory Society, Pages: 136-153
Roth-Walter F, Adcock IM, Benito-Villalvilla C, et al., 2021, Immune modulation via T regulatory cell enhancement: disease-modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases - An EAACI position paper of the Task Force on Immunopharmacology (TIPCO)., Allergy, Vol: 76, Pages: 90-113, ISSN: 0105-4538
Therapeutic advances using targeted biologicals and small molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell-based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in non-oncological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in non-oncological settings such as cardiovascular disease, obesity and chronic inflammatory disorders. After describing the general features of T cell-based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell-based approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders.
Kermani NZ, Saqi M, Agapow P, et al., 2021, Type 2-low asthma phenotypes by integration of sputum transcriptomics and serum proteomics., Allergy, Vol: 76, Pages: 380-383, ISSN: 0105-4538
Heaney LG, Busby J, Hanratty CE, et al., 2021, Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial, The Lancet Respiratory Medicine, Vol: 9, Pages: 57-68, ISSN: 2213-2600
BACKGROUND: Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control). METHODS: We did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defi
Guney T, Mumby S, Dunlop I, et al., 2020, Epithelial-stromal cell interactions and ECM mechanics drive the formation of airway-mimetic tubular morphology in lung organoids, Publisher: Bioarxiv
The complex cellular organisation of the human airway tract where interaction between epithelial and stromal lineages and the extracellular matrix (ECM) make it a difficult organ to study in vitro. Current in vitro lung models focus on modelling the lung epithelium such as air-liquid interface (ALI) cultures and bronchospheres, do not model the complex morphology and the cell-ECM interaction seen in vivo. Models that include stromal populations often separate them via a semipermeable barrier, which precludes the effect of cell-cell interaction or do not include the ECM or the effect of ECM mechanics such as viscoelasticity and stiffness. Here we investigated the effect of stromal cells on basal epithelial cell-derived bronchosphere structure and function through a triple culture of bronchial epithelial, lung fibroblast and airway smooth muscle cells. Epithelial-stromal cross talk enabled formation of epithelial cell-driven branching tubules consisting of luminal epithelial cells surrounded by stromal cells termed bronchotubules. Addition of agarose to the Matrigel scaffold (Agrigel) created a mechanically tunable ECM, where viscoelasticity and stiffness could be altered to enable long term tubule survival. Bronchotubule models enable the investigation of how epithelial-stromal cell and cell-ECM communication drive tissue patterning, repair and development of disease.
Bousquet J, Cristol J-P, Czarlewski W, et al., 2020, Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies, Clinical and Translational Allergy, Vol: 10, Pages: 1-18, ISSN: 2045-7022
There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT1R axis (AT1R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.
Karimi A, Shahrooz R, Hobbenagh R, et al., 2020, Histological evidence for therapeutic induction of angiogenesis using mast cells and platelet-rich plasma within a bioengineered scaffold following rat hindlimb ischemia, Cell Journal, Vol: 21, Pages: 391-400, ISSN: 2228-5806
Objective: Peripheral arterial disease results from obstructed blood flow in arteries and increases the risk of amputationin acute cases. Therapeutic angiogenesis using bioengineered tissues composed of a chitosan scaffold that wasenriched with mast cells (MCs) and/or platelet-rich plasma (PRP) was used to assess the formation of vascular networksand subsequently improved the functional recovery following hindlimb ischemia. This study aimed to find an optimalapproach for restoring local vascularization.Materials and Methods: In this experimental study, thirty rats were randomly divided into six experimental groups: a.Ischemic control group with right femoral artery transection, b. Ischemia with phosphate-buffered saline (PBS) controlgroup, c. Ischemia with chitosan scaffold, d. Ischemia with chitosan and MCs, e. Ischemia with chitosan and PRP, andf. Ischemia with chitosan, PRP, and MCs. The left hind limbs served as non-ischemic controls. The analysis of capillarydensity, arterial diameter, histomorphometric analysis and immunohistochemistry at the transected locations and ingastrocnemius muscles was performed.Results: The group treated with chitosan/MC significantly increased capillary density and the mean number oflarge blood vessels at the site of femoral artery transection compared with other experimental groups (P<0.05). Thetreatment with chitosan/MC also significantly increased the muscle fiber diameter and the capillary-to-muscle fiber ratioin gastrocnemius muscles compared with all other ischemic groups (P<0.05).Conclusion: These findings suggested that chitosan and MCs together could offer a new approach for the therapeuticinduction of angiogenesis in cases of peripheral arterial diseases.
Bousquet J, Anto JM, Iaccarino G, et al., 2020, Is diet partly responsible for differences in COVID-19 death rates between and within countries?, Clinical and Translational Allergy, Vol: 10, ISSN: 2045-7022
Reported COVID-19 deaths in Germany are relatively low as compared to many European countries. Among the several explanations proposed, an early and large testing of the population was put forward. Most current debates on COVID-19 focus on the differences among countries, but little attention has been given to regional differences and diet. The low-death rate European countries (e.g. Austria, Baltic States, Czech Republic, Finland, Norway, Poland, Slovakia) have used different quarantine and/or confinement times and methods and none have performed as many early tests as Germany. Among other factors that may be significant are the dietary habits. It seems that some foods largely used in these countries may reduce angiotensin-converting enzyme activity or are anti-oxidants. Among the many possible areas of research, it might be important to understand diet and angiotensin-converting enzyme-2 (ACE2) levels in populations with different COVID-19 death rates since dietary interventions may be of great benefit.
Dezfuli NK, Adcock IM, Montazami N, et al., 2020, Update on immunology of COVID-19 disease and potential strategy for controlling., Tanaffos, Vol: 19, Pages: 274-290, ISSN: 1735-0344
Coronavirus disease 2019 (COVID-19) is caused by a novel form of the coronavirus that caused severe acute respiratory syndrome (SARS). SARS-CoV-2 raised in China and has broadcast to 261 countries globally. SARS-CoV-2 a member of β-coronavirus family and has an almost matching genome sequence to a bat coronavirus, pointing to the bat as the natural host before it was transmitted to humans. SARS-CoV-2 uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that used by SARS-CoV and principally infects the respiratory tract. The clinical symptoms of COVID-19 patients include fever, cough and fatigue whilst small populations of patients have gastrointestinal symptoms. The old people and people with underlying metabolic and cardiovascular diseases are more affected to infection and have worse outcomes. These may be associated with acute respiratory distress syndrome (ARDS) and a cytokine storm. In this review, we discuss the pathogenesis and clinical characteristics of disease and the pharmacologic approaches that may control COVID-19.
Gorlanova O, Tischhauser E, Adcock IM, et al., 2020, Discordant use of short-acting beta(2) agonists in children and adults with severe, uncontrolled asthma from the U-BIOPRED cohort, Pediatric Pulmonology, Pages: 1-3, ISSN: 1099-0496
Dezfuli NK, Adcock IM, Alipoor SD, et al., 2020, The miR-146a SNP Rs2910164 and miR-155 SNP rs767649 are risk factors for non-small cell lung cancer in the Iranian population, Canadian Respiratory Journal, Vol: 2020, Pages: 1-8, ISSN: 1198-2241
Background. Lung cancer is one of the leading causes of death worldwide. MicroRNAs (miRNAs) are small noncoding RNAs thatregulate gene expression and may act as both tumor suppressors and as oncogenes. *e presence of single nucleotide polymorphisms (SNPs) inside the miRNA genomic region could affect target miRNA maturation, expression, and binding to its targetmRNA and contribute to cancer development. Previous studies on the SNPs Rs2910164 in miR-146a and Rs767649 in miR-155showed association with non-small cell lung cancer (NSCLC) development. *us, the aim of this study was to detect anycorrelation between those SNPs in Iranian NSCLC patients. Methods. In a small cohort study, 165 NSCLC patients and 147noncancer controls were enrolled between Apr 2015 and Sep 2019 at the Masih Daneshvari Hospital, Tehran, Iran. Allelefrequencies from the genomic DNA of blood cells were studied using PCR-RFLP and their association with the risk of lung cancerwas evaluated. Results. *e rs2910164C allele (OR � 1.56, 95% CI � 1.10–2.21, p � 0.012) and CC genotype (OR � 2.93, 95%CI � 1.07–7.9, p � 0.034, respectively) were associated with a significantly increased risk for lung cancer compared to that for theGG genotype. When patients were stratified according to smoking exposure, no association with rs2910164 variants was found.*e AT genotype (OR � 0.57, 95% CI � 0.33–0.99, p � 0.048) and the A allele frequency (OR � 0.58, 95% CI � 0.35–0.98,p � 0.043) in rs767649 were lower in NSCLC patients in comparison with the control group. In addition, the rs767649 ATgenotype frequency in smoking controls was higher than in smoking NSCLC patients (OR � 0.44, 95% CI � 0.21–0.90, p � 0.024).No association was found between rs2910164 and rs767649 variants and stage or type of NSCLC. Conclusion. Our finding suggeststhat miR-146a rs2910164 and miR-155 rs767649 polymorphisms may be considered as genetic risk factors for the susceptibility toNSCLC in the Iranian populatio
Adcock I, Alderawi A, Caramori G, et al., 2020, FN3K expression in COPD: A potential comorbidity factor for cardiovascular disease, BMJ Open Respiratory Research, Vol: 7, ISSN: 2052-4439
Introduction Cigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels.Methods The distribution and expression of FN3K protein in lung tissues from stable COPD and control subjects, as well as an animal model of COPD, was assessed by immunohistochemistry. Serum FN3K protein and AGE levels were assessed by ELISA in patients with COPD exacerbations receiving metformin. Genetic variants within the FN3K and FN3K-RP genes were evaluated for associations with cardiorespiratory function in the Subpopulations and Intermediate Outcome Measures in COPD Study cohort.Results This pilot study demonstrates that FN3K expression in the blood and human lung epithelium is distributed at either high or low levels irrespective of disease status. The percentage of lung epithelial cells expressing FN3K was higher in control smokers with normal lung function, but this induction was not observed in COPD patients nor in a smoking model of COPD. The top five nominal FN3K polymorphisms with possible association to decreased cardiorespiratory function (p<0.008–0.02), all failed to reach the threshold (p<0.0028) to be considered highly significant following multi-comparison analysis. Metformin enhanced systemic levels of FN3K in COPD subjects independent of their high-expression or low-expression status.Discussion The data highlight that low and high FN3K expressors exist within our study cohort and metformin induces FN3K levels, highlighting a potential mechanism to reduce the risk of CVD comorbidity and mortality.
Mortaz E, Malkmohammad M, Jamaati H, et al., 2020, Correction to: Silent hypoxia: higher NO in red blood cells of COVID-19 patients., BMC Pulmonary Medicine, Vol: 20, Pages: 294-294, ISSN: 1471-2466
An amendment to this paper has been published and can be accessed via the original article.
Alipoor SD, Adcock IM, Tabarsi P, et al., 2020, MiRNAs in tuberculosis: Their decisive role in the fate of TB, European Journal of Pharmacology, Vol: 886, ISSN: 0376-6357
Tuberculosis (TB) is one of the most lethal global infectious diseases. Despite the availability of much higher levels of technology in health and medicine, tuberculosis still remains a serious global health problem. Mycobacterium tuberculosis has the capacity for prolonged survival inside macrophages by exploiting host metabolic and energy pathways and perturbing autophagy and apoptosis of infected cells. The mechanism(s) underlying this process are not completely understood but evidence suggests that mycobacteria subvert the host miRNA network to enable mycobacterial survival. We present here a comprehensive review on the role of miRNAs in TB immune escape mechanisms and the potential for miRNA-based TB therapeutics. Further validation studies are required to (i) elucidate the precise effect of TB on host miRNAs, (ii) determine the inhibition of mycobacterial burden using miRNA-based therapies and (iii) identify novel miRNA biomarkers that may prove useful in TB diagnosis and treatment monitoring.
Zhou J, Zhang J, Zhou J, et al., 2020, Clinical characteristics of re-positive COVID-19 patients in Huangshi, China: A retrospective cohort study, PLoS One, Vol: 15, ISSN: 1932-6203
A cluster of patients with coronavirus disease 2019 (COVID-19) underwent repeated positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA tests after they were discharged from the hospital. We referred to them as re-positive (RP) patients in this study. We aimed to describe the clinical characteristics of these patients in a retrospective cohort study. After being treated for COVID-19, the patients underwent 14 days of quarantine following their discharge from the Huangshi Hospital of Traditional Chinese Medicine and the Huangshi Hospital of Youse. Two additional sequential SARS-CoV-2 RNA tests were performed at the end of quarantine. The median age of the 368 patients was 51 years, and 184 (50%) patients were female. A total of 23 RP patients were observed at follow-up. Using multivariate Cox regression analysis, risk factors associated with RP included a higher ratio of lymphocyte/white blood cell on admission (adjusted HR 7.038; 95% CI, 1.911-25.932; P = 0.0034), lower peak temperature during hospitalization (adjusted HR, 0.203; 95% CI, 0.093-0.443; P<0.0001), and the presence of comorbidities, particularly hypertension or chronic diseases in the respiratory system (adjusted HR, 3.883; 95% CI, 1.468-10.273; P = 0.0063). Antivirus treatment with arbidol was associated with a lower likelihood of re-positive outcomes (adjusted HR, 0.178; 95% CI, 0.045-0.709; P = 0.0144).
Uwagboe I, Mumby S, Dunlop I, et al., 2020, Tissue engineering of lung organoids with advanced biomaterials for in-vitro disease modelling, International Conference of the American-Thoracic-Society (ATS), Publisher: American Thoracic Society, Pages: 1-1, ISSN: 1073-449X
Abdel-Aziz MI, Brinkman P, Vijverberg SJH, et al., 2020, eNose breath prints as a surrogate biomarker for classifying patients with asthma by atopy, Journal of Allergy and Clinical Immunology, Vol: 146, Pages: 1045-1055, ISSN: 0091-6749
BACKGROUND: Electronic noses (eNoses) are emerging point-of-care tools that may help in the subphenotyping of chronic respiratory diseases such as asthma. OBJECTIVE: We aimed to investigate whether eNoses can classify atopy in pediatric and adult patients with asthma. METHODS: Participants with asthma and/or wheezing from 4 independent cohorts were included; BreathCloud participants (n = 429), Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes adults (n = 96), Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes pediatric participants (n = 100), and Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory Effects 2 participants (n = 30). Atopy was defined as a positive skin prick test result (≥3 mm) and/or a positive specific IgE level (≥0.35 kU/L) for common allergens. Exhaled breath profiles were measured by using either an integrated eNose platform or the SpiroNose. Data were divided into 2 training and 2 validation sets according to the technology used. Supervised data analysis involved the use of 3 different machine learning algorithms to classify patients with atopic versus nonatopic asthma with reporting of areas under the receiver operating characteristic curves as a measure of model performance. In addition, an unsupervised approach was performed by using a bayesian network to reveal data-driven relationships between eNose volatile organic compound profiles and asthma characteristics. RESULTS: Breath profiles of 655 participants (n = 601 adults and school-aged children with asthma and 54 preschool children with wheezing [68.2% of whom were atopic]) were included in this study. Machine learning models utilizing volatile organic compound profiles discriminated between atopic and nonatopic participants with areas under the receiver operating characteristic curves of at least 0.84 and 0.72 in the training and validation sets, respectively. The unsupervised approach revealed t
Bousquet J, Anto JM, Iaccarino G, et al., 2020, Is diet partly responsible for differences in COVID-19 death rates between and within countries? (vol 10, 16, 2020), Clinical and Translational Allergy, Vol: 10, Pages: 1-3, ISSN: 2045-7022
Mortaz E, Malkmohammad M, Jamaati H, et al., 2020, Silent hypoxia: higher NO in red blood cells of COVID-19 patients, BMC Pulmonary Medicine, Vol: 20, ISSN: 1471-2466
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has spread to almost 100 countries, infected over 31 M patients and resulted in 961 K deaths worldwide as of 21st September 2020. The major clinical feature of severe COVID-19 requiring ventilation is acute respiratory distress syndrome (ARDS) with multi-functional failure as a result of a cytokine storm with increased serum levels of cytokines. The pathogenesis of the respiratory failure in COVID-19 is yet unknown, but diffuse alveolar damage with interstitial thickening leading to compromised gas exchange is a plausible mechanism. Hypoxia is seen in the COVID-19 patients, however, patients present with a distinct phenotype. Intracellular levels of nitric oxide (NO) play an important role in the vasodilation of small vessels. To elucidate the intracellular levels of NO inside of RBCs in COVID-19 patients compared with that of healthy control subjects. METHODS: We recruited 14 COVID-19 infected cases who had pulmonary involvement of their disease, 4 non-COVID-19 healthy controls (without pulmonary involvement and were not hypoxic) and 2 hypoxic non-COVID-19 patients subjects who presented at the Masih Daneshvari Hospital of Tehran, Iran between March-May 2020. Whole blood samples were harvested from patients and intracellular NO levels in 1 × 106 red blood cells (RBC) was measured by DAF staining using flow cytometry (FACS Calibour, BD, CA, USA). RESULTS: The Mean florescent of intensity for NO was significantly enhanced in COVID-19 patients compared with healthy control subjects (P ≤ 0.05). As a further control for whether hypoxia induced this higher intracellular NO, we evaluated the levels of NO inside RBC of hypoxic patients. No significant differences in NO levels were seen between the hypoxic and non-hypoxic control group. CONCLUSIONS: This pilot study demonstrates increased levels of intracel
Haji G, Wiegman C, Michaeloudes C, et al., 2020, Mitochondrial dysfunction in airways and quadriceps muscle of patients with Chronic Obstructive Pulmonary Disease, Respiratory Research, Vol: 21, ISSN: 1465-9921
BackgroundMitochondrial damage and dysfunction have been reported in airway and quadriceps muscle cells of patients with chronic obstructive pulmonary disease (COPD). We determined the concomitance of mitochondrial dysfunction in these cells in COPD.MethodsBronchial biopsies were obtained from never- and ex-smoker volunteers and COPD patients (GOLD Grade 2) and quadriceps muscle biopsies from the same volunteers in addition to COPD patients at GOLD Grade 3/4 for measurement of mitochondrial function.ResultsDecreased mitochondrial membrane potential (ΔΨm), increased mitochondrial reactive oxygen species (mtROS) and decreased superoxide dismutase 2 (SOD2) levels were observed in mitochondria isolated from bronchial biopsies from Grade 2 patients compared to healthy never- and ex-smokers. There was a significant correlation between ΔΨm and FEV1 (% predicted), transfer factor of the lung for carbon monoxide (TLCOC % predicted), 6-min walk test and maximum oxygen consumption. In addition, ΔΨm was also associated with decreased expression levels of electron transport chain (ETC) complex proteins I and II. In quadriceps muscle of Grade 2 COPD patients, a significant increase in total ROS and mtROS was observed without changes in ΔΨm, SOD2 or ETC complex protein expression. However, quadriceps muscle of GOLD Grade 3/4 COPD patients showed an increased mtROS and decreased SOD2 and ETC complex proteins I, II, III and V expression.ConclusionsMitochondrial dysfunction in the airways, but not in quadriceps muscle, is associated with airflow obstruction and exercise capacity in Grade 2 COPD. Oxidative stress-induced mitochondrial dysfunction in the quadriceps may result from similar disease processes occurring in the lungs.
Kermani NZ, Pavlidis S, Xie J, et al., 2020, Instability of sputum molecular phenotypes in U-BIOPRED severe asthma, European Respiratory Journal, Vol: 57, Pages: 1-5, ISSN: 0903-1936
Zhu J, Mallia P, Footitt J, et al., 2020, Bronchial mucosal inflammation and illness severity in response to experimental rhinovirus infection in COPD, Journal of Allergy and Clinical Immunology, Vol: 146, Pages: 840-850.e7, ISSN: 0091-6749
BackgroundRespiratory viral infection causes chronic obstructive pulmonary disease (COPD) exacerbations. We previously reported increased bronchial mucosa eosinophil and neutrophil inflammation in patients with COPD experiencing naturally occurring exacerbations. But it is unclear whether virus per se induces bronchial mucosal inflammation, nor whether this relates to exacerbation severity.ObjectivesWe sought to determine the extent and nature of bronchial mucosal inflammation following experimental rhinovirus (RV)-16–induced COPD exacerbations and its relationship to disease severity.MethodsBronchial mucosal inflammatory cell phenotypes were determined at preinfection baseline and following experimental RV infection in 17 Global Initiative for Chronic Obstructive Lung Disease stage II subjects with COPD and as controls 20 smokers and 11 nonsmokers with normal lung function. No subject had a history of asthma/allergic rhinitis: all had negative results for aeroallergen skin prick tests.ResultsRV infection increased the numbers of bronchial mucosal eosinophils and neutrophils only in COPD and CD8+ T lymphocytes in patients with COPD and nonsmokers. Monocytes/macrophages, CD4+ T lymphocytes, and CD20+ B lymphocytes were increased in all subjects. At baseline, compared with nonsmokers, subjects with COPD and smokers had increased numbers of bronchial mucosal monocytes/macrophages and CD8+ T lymphocytes but fewer numbers of CD4+ T lymphocytes and CD20+ B lymphocytes. The virus-induced inflammatory cells in patients with COPD were positively associated with virus load, illness severity, and reductions in lung function.ConclusionsExperimental RV infection induces bronchial mucosal eosinophilia and neutrophilia only in patients with COPD and monocytes/macrophages and lymphocytes in both patients with COPD and control subjects. The virus-induced inflammatory cell phenotypes observed in COPD positively related to virus load and illness severity. Antiviral/anti-inflamma
Lo Bello F, Hansbro PM, Donovan C, et al., 2020, New drugs under development for COPD, Expert Opinion on Emerging Drugs, Vol: 25, Pages: 419-431, ISSN: 1361-9195
IntroductionChronic obstructive pulmonary disease (COPD) is a lung disease characterized by chronic bronchitis, emphysema, and remodeling. Its prevalence is increasing worldwide; however, there are few effective therapies, and none of the treatments currently available prevent the progression of the disease or target all of the hallmark features. The development and progression of COPD are heterogeneous, which has hampered the development of new therapies.Areas coveredIn this review, we cover the emergence of the improvement of existing classes of drugs including glucocorticoids, β2-adrenoceptor agonists, phosphodiesterase inhibitors, PDE4 selective inhibitors, PDE3/PDE4 inhibitors, protease inhibitors, recombinant α1-antitrypsin and neutrophil elastase inhibitors. We also highlight new compounds that target recently identified mechanisms of COPD, new dual-action muscarinic antagonists, and β2-agonists, kinase inhibitors, cytokine modifiers, chemokines modifiers, NF-κB inhibitors, senolytics, antioxidants, inhaled antiviral agents, anti-fibrotic compounds, and compounds stimulating lung regeneration.Expert opinionGiven the myriad of potential therapeutic avenues that can be pursued, careful consideration of the phenotypes/endotypes of COPD patients will be important for personalized treatment options in the future, and a full understanding of disease mechanisms in patient subsets will ensure these emerging therapies are targeted appropriately.
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