ADENOSINE RECEPTORS IN RESPIRATORY DISORDERS AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND MALIGNANT PLEURAL MESOTHELIOMA

Adenosine is a purine nucleoside that is commonly expressed in the body and involved in a wide range of physiological processes. The effects of adenosine are mediated through specific G-protein coupled cell surface receptors, named A1, A2A, A2B and A3 adenosine receptors (ARs). It is now well recognized that extracellular levels of adenosine markedly increase under metabolically stressful conditions and in the last two decades it has become clear that adenosine is a mediator involved in the pathogenesis of lung inflammatory disorders and in cancer. Indeed adenosine induces bronchoconstriction in animal models and in patients with airway diseases such as asthma and chronic obstructive pulmonary diseases (COPD). COPD is defined as an inflammatory respiratory disease, largely caused by exposure to tobacco smoke. The disease is characterized by a progressive and incompletely reversible airflow obstruction. The key elements of COPD are exposure to cigarette smoke, airway inflammation, and airflow obstruction that is not fully reversible. In addition, an high concentration of adenosine have been reported in cancer tissues, where it appears to be implicated in the growth of tumors, and in the regulation of cell death and proliferation. The development of pleural-based abnormalities such as malignant pleural mesothelioma (MPM), is caused by inhalation of asbestos fibers. To study the interaction between adenosine and pulmonary diseases, the presence and functionality of ARs were explored in human healthy subjects in comparison with COPD patients by using lung tissues and bronchoalveolar lavage (BAL). The aim of this study was to investigate the expression, affinity and density of ARs in peripheral lung parenchyma and in BAL from age-matched smokers with COPD and smokers with normal lung function. The data, obtained in lung samples from COPD patients, suggest a downregulation of A2BARs and an upregulation of A2A and A3ARs. A correlation among ARs expression and clinical parameters such as FEV1/FVC ratio, an established index of airflow obstruction, was observed. Moreover the subcellular location of A2BARs in BAL macrophages of patients with COPD and healthy smokers was investigated, revealing a significant decrease in A2BARs expression in BAL from COPD patients compared to an age-matched group of control smokers with normal lung function. This reduction was associated with a decrease in A2BARs mRNA expression, suggesting a regulation at the transcriptional level. ARs were also studied in MPM patients by using membranes or primary cultures from pleura of MPM patients in comparison with healthy tissues or cells. Furthermore, to better understand the interaction between adenosine and MPM, the presence and the functionality of ARs were explored in healthy mesothelial cells (HMC) and malignant mesothelioma cells (MMC). ARs were analyzed by using RT-PCR, western blotting and saturation binding assays. HMC were treated with crocidolite asbestos, which is the principal risk factor of MPM. The dual effect of ARs stimulation on healthy and cancer cell growth was studied by means of proliferation, apoptosis and cytotoxicity assays. The main result was that A3ARs were up-regulated in MPM when compared with healthy mesothelial pleura. Stimulation of A3ARs decreases proliferation and exerts cytotoxic and pro-apoptotic effect on MMC and on HMC exposed to asbestos and TNF-�, but not in control HMC. These data support the potential for modulating ARs function in pulmonary diseases such as inflammation and cancer. In particular, the modulation of A2BARs by using selective antagonists in alveolar macrophages as a new potential pharmacological tool could be used in the COPD disease. Moreover, the stimulation of A3ARs by selective agonists could be involved as novel pharmacological treatment for malignant pleural mesothelioma

A2A and A3 adenosine receptor expression in rheumatoid arthritis: upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release

Introduction The reduction of the inflammatory status represents one of the most important targets in rheumatoid arthritis (RA). A central role of A2A and A3 adenosine receptors (ARs) in mechanisms of inflammation has been reported in different pathologies. The primary aim of this study was to investigate the A2A and A3ARs and their involvement in RA progression measured by Disease Activity Score in 28 or 44 joints (DAS28 or DAS). Methods ARs were analyzed by saturation binding assays, mRNA and Western blotting analysis in lymphocytes from early and established RA patients. The effect of A2A and A3AR agonists in nuclear factor kB (NF-kB) pathway was evaluated. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) release was carried out by A2A and A3AR activation. AR pharmacological regulation in matrix metalloproteinase-1 (MMP-1) and metalloproteinase-3 (MMP-3) release was also studied. Results In lymphocytes obtained from RA patients, A2A and A3ARs were up-regulated if compared with healthy controls. A2A and A3AR activation inhibited the NF-kB pathway and diminished inflammatory cytokines such as TNF-α, IL-1β and IL-6. A2A and A3AR agonists mediated a reduction of MMP-1 and MMP-3 release. A2A and A3AR density inversely correlated with DAS28 and DAS suggesting a direct role of the endogenous activation of these receptors in the control of RA joint inflammation. Conclusions Taken together these data demonstrate that the inflammatory and clinical responses in RA are regulated by A2A and A3ARs and support the use of A2A and/or A3AR agonists as novel and effective pharmacological treatment in RA patients

A new chronological framework and site formation history for Cova del Gegant (Barcelona): Implications for Neanderthal and Anatomically Modern Human occupation of NE Iberian Peninsula

The chronological framework for Neanderthal occupation and demise across Europe continues to be debated. In particular, there is still uncertainty regarding the nature, timing and regional expressions of the Middle to Upper Palaeolithic transition associated with the disappearance of Neanderthals and the broader expansion of modern human populations in Europe around 42e40 thousand years ago (ka). The geographical and chronological distribution of Neanderthal populations also remains difficult to evaluate owing to the practical challenges of directly dating human fossils at many sites, and the fact that a large proportion of Neanderthals sites lie close to, or well-beyond, the limits of radiocarbon dating. Cova del Gegant e one of the few sites in north-eastern Iberian Peninsula to yield Neanderthal fossil remains, associated Mousterian archaeological layers, and occupations related to the Middle and Upper Palaeolithic transition e is a key locality for informing these ongoing debates. Here we provide a comprehensive chronological framework for the Cova del Gegant site using multiple radiometric dating techniques (uranium-thorium (UeTh), radiocarbon and luminescence dating), sedimentological and micromorphological analyses, and Bayesian modelling. This integrated chronostratigraphic approach enables us to reliably reconstruct site formation processes and history, and undertake improved correlations with other sites regionally. The results allow us to sub-divide the Cova del Gegant sequence into three sections spanning ~94 ka to ~32 ka, namely: a Middle Palaeolithic sequence covering ~94e59 ka, a Châtelperronian/Aurignacian section spanning ~43e39 ka, and a Late Aurignacian/Gravettian section spanning ~34e32 ka. The Neanderthal fossil remains accumulated in the cave between the end of Marine Isotope Stage (MIS) 5/MIS 4 and the beginning of MIS 3, during two different events dated to ~72e67 ka and ~60e52 ka. The chronological framework for Cova del Gegant is in accordance with that reported for other Middle and Upper Palaeolithic sites in north-eastern Iberian Peninsula, and reveals a record of successive human occupation coinciding with a period of progressive global cooling and lowering sea levels (end of MIS 5 through to MIS 2). Sedimentological evidence points to the emergence of a coastal platform in front of the cave and indicates that local palaeoenvironmental conditions likely benefited human displacements along the littoral margin, and favoured repeated occupation of the cave during the Late Pleistocene

Highlights of the ERS Lung Science Conference and Sleep and Breathing Conference 2021 and the new ECMC members

The Lung Science Conference (LSC) and the Sleep and Breathing Conference (SBC) are two conferences organised by the European Respiratory Society (ERS), the latter held in association with the European Sleep Research Society. This year, the LSC and SBC were both held in a virtual format with the participation of researchers and clinicians from around the world. The participation of Early Career Members (ECMs) was notable in both events: 216 of 363 (60%) delegates attending the LSC were under 40?years old, and 315 of 920 (34%) delegates were ?40?years of age at the SBC. Both conferences included outstanding talks on the most recent advances in respiratory medicine and science, oral/poster communication sessions on novel research, exciting opportunities to network with peers, and much more!This paper provides a brief overview of some of the most remarkable sessions of the LSC and SBC, written by ECMs attending the sessions.We also present the new members of the Early Career Member Committee (ECMC) of the ERS from Assemblies 1, 4, 10, 12 and 13, who were elected in the latest round of ERS elections. Welcome aboard

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Immunotherapy in NSCLC Patients with Brain Metastases

Approximately 40% of unselected non-small cell lung cancer (NSCLC) patients develop brain metastases (BMs) during their disease, with considerable morbidity and mortality. The management of BMs in patients with NSCLC is a clinical challenge and requires a multidisciplinary approach to gain effective intracranial disease control. Over the last decade, immune checkpoint inhibitors (ICIs) have emerged as a game-changer in the treatment landscape of advanced NSCLC, with significant improvements in survival outcomes, although patients with BMs are mostly underrepresented in randomized clinical trials. Moreover, the safety and activity of ICIs and radiotherapy combinations compared with single-agent or sequential modalities is still under evaluation to establish the optimal management of these patients. The aim of this review is to summarize the state-of-the-art of clinical evidence of ICIs intracranial activity and the main challenges of incorporating these agents in the treatment armamentarium of NSCLC patients with BMs

Effect of pulsed electromagnetic field exposure on adenosine receptors in rat brain

Different effects of pulsed electromagnetic field (PEMF) exposure on brain tissue have been described in pre-clinical models and in clinical settings. Nevertheless, the mechanism of action and the possible interaction with membrane receptors such as adenosine receptors (ARs) has not been investigated. The present study focused on the effect of PEMFs on A 1 and A 2A ARs in the rat cerebral cortex and cortical neurons. Affinity and density of ARs were evaluated by means of saturation binding experiments while mRNA expression was investigated through retro-transcription polymerase chain reaction (RT-PCR). PEMF treatment of the intact rat cerebral cortex or cortical neurons at 1.5mT mediated a transient and significant increase in A 2A ARs after 4h (2.0-fold increase) and 6h (1.4- and 1.8-fold increase, respectively) of exposure. In addition, PEMF treatment of the rat cerebral cortex and rat cortical neurons at 3mT upregulated A 2A ARs after 2h (2.0- and 2.2-fold increase, respectively) and 4h (1.6- and 1.9-fold increase, respectively). The treatment of rat cortex membranes with PEMFs at 1.5 and 3mT induced an increase in A 2A AR density after 2h (1.9- and 2.2-fold increase, respectively) and was constant at all incubation times investigated. In rat cortical neurons, mRNA levels of A 1 and A 2A ARs were not affected by PEMF exposure for the times and intensities used. These results suggest that PEMF treatment has different biological effects in whole organs or cells in comparison with isolated membranes. © 2011 Wiley Periodicals, Inc