\u00a9 2020 Background: Currently, five biologic treatment options are available for use in patients with uncontrolled persistent asthma: three interleukin (IL)-5 antagonists, which either bind to the anti-IL-5 ligand (mepolizumab, reslizumab) or to the IL-5 receptor (benralizumab); one anti-immunoglobulin E (anti-IgE) therapy (omalizumab); and one anti-IL-4/IL-13 therapy (dupilumab). To date, no comparative data from head-to-head clinical trials are available for these biologics. Objective: An indirect treatment comparison (ITC) of dupilumab versus each of the anti-IL-5 and anti-IgE therapies using the endpoints of annualized severe asthma exacerbation rates and change in pre-bronchodilator forced expiratory volume in 1 s (FEV1). Methods: Embase\u00ae, MEDLINE\u00ae, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for studies published between January 1, 1980 and March 25, 2019. Eligible articles included randomized controlled trials (RCTs) in patients aged \u2265 12 years with persistent/uncontrolled asthma using at least medium-to-high dose inhaled corticosteroid plus long-acting \u03b22-agonist with add-on biologic therapy. Bucher ITCs were performed to compare subgroups of dupilumab patients with the anti-IL-5s and anti-IgE trial populations. Results: Fourteen RCTs were included in the analyses. The matched dupilumab subgroups were associated with greater reductions in annualized severe exacerbation rates compared with benralizumab, mepolizumab, reslizumab, and omalizumab (54%, 28%, 38%, and 26% greater reduction, respectively). A greater improvement in FEV1 was also observed for dupilumab at week 12 and/or week 24/52 than for the other biologics (0.06\u20130.14 L). Conclusion: In this ITC, dupilumab was associated with lower severe asthma exacerbation rates and greater improvements in lung function than anti-IL-5s and omalizumab.
\n \n\n \n \n\u00a9 ERS 2019. Asthma is characterised by typical symptoms in combination with variable airway obstruction and, in many cases, eosinophilic airway inflammation. Most patients with asthma have well-controlled symptoms and a low risk of asthma exacerbations when treated with ICSs. However, \u223c5\u201310% remain symptomatic and/or at risk of asthma exacerbations despite maximum inhaled therapy with ICSs and long-acting \u03b22-agonists. Such patients with severe asthma are responsible for a significant proportion of healthcare costs attributable to asthma and have a large unmet need for better treatment. An important advance in recent years has been the recognition that severe asthma is heterogeneous with respect to clinical presentation, response to treatment and the pattern of lower airway inflammation. Type 2-high airway inflammation is seen in >50% of patients with severe asthma and is driven by innate and adaptive immune mechanism and associated mediators, including IgE, IL-5, IL-13 and IL-4, resulting in the presence of airway eosinophilia. Biological agents blocking IgE, IL-5, and both IL-4 and IL-13 are effective treatments in selected patients with severe asthma with type 2 airway inflammation.
\n \n\n \n \n<jats:p>The SARS-CoV-2 can lead to severe illness with COVID-19. Outcomes of patients requiring mechanical ventilation are poor. Awake proning in COVID-19 improves oxygenation, but on data clinical outcomes is limited. This single-centre retrospective study aimed to assess whether successful awake proning of patients with COVID-19, requiring respiratory support (continuous positive airways pressure (CPAP) or high-flow nasal oxygen (HFNO)) on a respiratory high-dependency unit (HDU), is associated with improved outcomes. HDU care included awake proning by respiratory physiotherapists. Of 565 patients admitted with COVID-19, 71 (12.6%) were managed on the respiratory HDU, with 48 of these (67.6%) requiring respiratory support. Patients managed with CPAP alone 22/48 (45.8%) were significantly less likely to die than patients who required transfer onto HFNO 26/48 (54.2%): CPAP mortality 36.4%; HFNO mortality 69.2%, (p=0.023); however, multivariate analysis demonstrated that increasing age and the inability to awake prone were the only independent predictors of COVID-19 mortality. The mortality of patients with COVID-19 requiring respiratory support is considerable. Data from our cohort managed on HDU show that CPAP and awake proning are possible in a selected population of COVID-19, and may be useful. Further prospective studies are required.</jats:p>
\n \n\n \n \n<jats:sec><jats:title>Introduction</jats:title><jats:p>In asthma, lung function measures are often discordant with clinical features such as disease activity or control.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We investigated a novel technique that provides a measure (\u03c3CL) of unevenness (inhomogeneity) in lung inflation/deflation. In particular, we compared \u03c3CL with FEV<jats:sub>1</jats:sub>% predicted (FEV<jats:sub>1</jats:sub>%pred) as measures of disease activity in the asthmatic lung.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>\u03c3CL correlated modestly with FEV<jats:sub>1</jats:sub>%pred. However, \u03c3CL is not simply a proxy for FEV<jats:sub>1</jats:sub>%pred as the effects of salbutamol on the two parameters were unrelated. Importantly, \u03c3CL reflected disease control better than FEV<jats:sub>1</jats:sub>.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>We conclude that \u03c3CL shows promise as an objective measure of disease activity in asthma.</jats:p></jats:sec>
\n \n\n \n \nBACKGROUND:Airway ecology is altered in asthma and chronic obstructive pulmonary disease (COPD). Anti-microbial interventions might have benefit in subgroups of airway disease. Differences in sputum microbial profiles at acute exacerbation of airways disease are reflected by the \u03b3Proteobacteria:Firmicutes (\u03b3P:F) ratio. We hypothesized that sputum microbiomic clusters exist in stable airways disease, which can be differentiated by the sputum \u03b3P:F ratio. METHODS:Sputum samples were collected from 63 subjects with severe asthma and 78 subjects with moderate-to-severe COPD in a prospective single centre trial. Microbial profiles were obtained through 16S rRNA gene sequencing. Topological data analysis was used to visualize the data set and cluster analysis performed at genus level. Clinical characteristics and sputum inflammatory mediators were compared across the clusters. RESULTS:Two ecological clusters were identified across the combined airways disease population. The smaller cluster was predominantly COPD and was characterized by dominance of Haemophilus at genus level (n\u00a0=\u00a020), high \u03b3P:F ratio, increased H\u00a0influenzae, low diversity measures and increased pro-inflammatory mediators when compared to the larger Haemophilus-low cluster (n\u00a0=\u00a0121), in which Streptococcus demonstrated the highest relative abundance at the genus level. Similar clusters were identified within disease groups individually and the \u03b3P:F ratio consistently differentiated between clusters. CONCLUSION:Cluster analysis by airway ecology of asthma and COPD in stable state identified two subgroups differentiated according to dominance of Haemophilus. The \u03b3P:F ratio was able to distinguish the Haemophilus-high versus Haemophilus-low subgroups, whether the Haemophilus-high group might benefit from treatment strategies to modulate the airway ecology warrants further investigation.
\n \n\n \n \n\u00a9 The Royal Society of Chemistry. Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10-14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery.
\n \n\n \n \nAn amendment to this paper has been published and can be accessed via a link at the top of the paper.
\n \n\n \n \nSARS-CoV-2 IgG screening of 1,000 antenatal serum samples in the Oxford area, United Kingdom, between 14 April and 15 June 2020, yielded a 5.3% seroprevalence, mirroring contemporaneous regional data. Among the 53 positive samples, 39 showed in vitro neutralisation activity, correlating with IgG titre (Pearson's correlation p<0.0001). While SARS-CoV-2 seroprevalence in pregnancy cohorts could potentially inform population surveillance, clinical correlates of infection and immunity in pregnancy, and antenatal epidemiology evolution over time need further study.
\n \n\n \n \n<jats:p>Malignant pleural mesothelioma (MPM) is an aggressive cancer, associated with poor prognosis. We assessed the feasibility of patient-derived cell cultures to serve as an ex vivo model of MPM. Patient-derived MPM cell cultures (n=16) exhibited stemness features and reflected intratumour and interpatient heterogeneity. A subset of the cells were subjected to high-throughput drug screening and coculture assays with cancer-specific cytotoxic T cells and showed diverse responses. Some of the biphasic MPM cells were capable of processing and presenting the neoantigen SSX-2 endogenously. In conclusion, patient-derived MPM cell cultures are a promising and faithful ex vivo model of MPM.</jats:p>
\n \n\n \n \nAutophagy is an evolutionarily conserved mechanism for intracellular substance degradation, responsible for the recycling of metabolic substances and the maintenance of intracellular stability. It has early been demonstrated to play a significant role in tumorigenesis, but whether it acts as a promoter or a suppressor during tumorigenesis seems to be context-specific. Moreover, autophagy is also implicated in promoting chemoresistance of cancer cells so as to attenuate therapeutic efficacy of chemotherapy. On the contrary, other reports highlight a tumor-killing role of autophagy during cancer treatment. Herein, this review aims to revisit the key features of autophagy, summarize the seemingly contradictory roles of autophagy during both tumorigenesis and cancer chemotherapy, and evaluate the feasibility of altering the level of cellular autophagy as part of cancer adjuvant treatment.
\n \n\n \n \nMiRNAs are a new class of small RNA molecules that regulate gene expression at the post-transcriptional and translational levels. MiRNAs have been implicated in the control of many vital biological processes including development, cell proliferation, differentiation, and apoptosis. A growing number of studies have shown that miRNAs also play an important role in carcinogenesis and other diseases. Among the miRNAs identified, miRNA-21 is dramatically up-regulated in cancer cells of various origins. It regulates a wide range of genes and pathways involved in cancer initiation, transformation, invasion, and metastasis. MiRNA-21 also acts as a pro-survival factor in cardiovascular diseases. Aberrant expression in these diseases makes miRNA-21 a potential marker for disease diagnosis and prognosis. This review highlights the complex roles that miRNA-21 plays in cancer and cardiovascular diseases and its potential clinical applications.
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