Age-dependent NK cell dysfunctions in severe COVID-19 patients

Natural Killer (NK) cells are key innate effectors of antiviral immune response, and their activity changes in ageing and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we investigated the age-related changes of NK cell phenotype and function during SARS-CoV-2 infection, by comparing adult and elderly patients both requiring mechanical ventilation. Adult patients had a reduced number of total NK cells, while elderly showed a peculiar skewing of NK cell subsets towards the CD56lowCD16high and CD56neg phenotypes, expressing activation markers and check-point inhibitory receptors. Although NK cell degranulation ability is significantly compromised in both cohorts, IFN-γ production is impaired only in adult patients in a TGF-β-dependent manner. This inhibitory effect was associated with a shorter hospitalization time of adult patients suggesting a role for TGF-β in preventing an excessive NK cell activation and systemic inflammation. Our data highlight an age-dependent role of NK cells in shaping SARS-CoV-2 infection toward a pathophysiological evolution

Minimal clinically important difference for asthma endpoints: an expert consensus report

Minimal clinically important difference (MCID) can be defined as the smallest change or difference in an outcome measure that is perceived as beneficial and would lead to a change in the patient's medical management.The aim of the current expert consensus report is to provide a "state-of-the-art" review of the currently available literature evidence about MCID for end-points to monitor asthma control, in order to facilitate optimal disease management and identify unmet needs in the field to guide future research.A series of MCID cut-offs are currently available in literature and validated among populations of asthmatic patients, with most of the evidence focusing on outcomes as patient reported outcomes, lung function and exercise tolerance. On the contrary, only scant and partial data are available for inflammatory biomarkers. These clearly represent the most interesting target for future development in diagnosis and clinical management of asthma, particularly in view of the several biologic drugs in the pipeline, for which regulatory agencies will soon require personalised proof of efficacy and treatment response predictors

The inhibition of 45A ncRNA expression reduces tumor formation, affecting tumor nodules compactness and metastatic potential in neuroblastoma cells

open16noWe recently reported the in vitro over-expression of 45A, a RNA polymerase IIItranscribed non-coding (nc)RNA, that perturbs the intracellular content of FE65L1 affecting cell proliferation rate, short-term response to genotoxic stress, substrate adhesion capacity and, ultimately, increasing the tumorigenic potential of human neuroblastoma cells. In this work, to deeply explore the mechanism by which 45A ncRNA contributes to cancer development, we targeted in vitro and in vivo 45A levels by the stable overexpression of antisense 45A RNA. 45A downregulation leads to deep modifications of cytoskeleton organization, adhesion and migration of neuroblastoma cells. These effects are correlated with alterations in the expression of several genes including GTSE1 (G2 and S phaseexpressed- 1), a crucial regulator of tumor cell migration and metastatic potential. Interestingly, the downregulation of 45A ncRNA strongly affects the in vivo tumorigenic potential of SKNBE2 neuroblastoma cells, increasing tumor nodule compactness and reducing GTSE1 protein expression in a subcutaneous neuroblastoma mouse model. Moreover, intracardiac injection of neuroblastoma cells showed that downregulation of 45A ncRNA also influences tumor metastatic ability. In conclusion, our data highlight a key role of 45A ncRNA in cancer development and suggest that its modulation might represent a possible novel anticancer therapeutic approach.openPenna, Ilaria; Gigoni, Arianna; Costa, Delfina; Vella, Serena; Russo, Debora; Poggi, Alessandro; Villa, Federico; Brizzolara, Antonella; Canale, Claudio; Mescola, Andrea; Daga, Antonio; Russo, Claudio; Nizzari, Mario; Florio, Tullio; Menichini, Paola; Pagano, AldoPenna, Ilaria; Gigoni, Arianna; Costa, Delfina; Vella, SERENA LUISA; Russo, Debora; Poggi, Alessandro; Villa, Federico; Brizzolara, Antonella; Canale, Claudio; Mescola, Andrea; Daga, Antonio; Russo, Claudio; Nizzari, Mario; Florio, Tullio; Menichini, Paola; Pagano, Ald

Milano accessibile, nessuno escluso

In March 2014, the Municipality of Milan has set up a task force for the accessibility at Expo 2015 with the goal to ensure the participation of citizens and tourists, "any excluded", in the activities planned in the exhibition area and around Milan. Promoting the right to the city, any excluded, the Municipality of Milan supports the principles of the UN Convention on the Rights of Persons with Disabilities (2006) and the EU Disability Strategy 2010-2020. These documents highlight an innovative concept of the disability, extended from a matter of strictly social policies to a matter of legal and human right: «Promote, protect and ensure the full and equal enjoyment of all human rights and fundamental freedoms by all persons with disabilities» (UN Convention, 2006). At the same time, the importance of the accessibility is confirmed as prerequisite for any action aimed at social inclusion. The principle of accessibility has as a corollary the "universal design", promoted by the Convention as «design of products, environments, programmes and services to be usable by all people, to the greatest extent possible, without the need for adaptation or specialized design». In order to ensure an accessible Milan, Departments and Sectors of the Municipality in partnership with associations of persons with disabilities, cooperatives, foundations, institutions and government agencies, including Lombardy Region, Regional Emergency Utility, Azienda Trasporti Milanesi, have worked with spirit of collaboration and cross-disciplinary, bringing together resources and expertises. The efficiency of the process has produced tangible results, which this paper will illustrate. Actions taken for the elimination of architectural and communication barriers are identified with the realization of 10 tourist and cultural itineraries in Milan, the online site EXPOFACILE and the educational and awareness actions addressed to commercial categories of hospitality. Among the qualifying elements: the reference to the principles of the Universal Design, the co-design with stakeholders, allowing to design starting from the needs identified by people with disabilities and to offer them the opportunity to control and verify the implemented projects, the promotion of the cultural dimension of disability. The task force is working to make permanent the comparison between the Municipality of Milan and the associations of people with disabilities, in order to undertake projects beyond the time limit of EXPO

Mediterranean catchments post-fire hydrogeological behavior and water quality: insights from the Pisano Mount area (Tuscany, Italy).

Wildfires are recognized as one of the most affecting ecological agents, altering geomorphological processes, hydrologic cycles, and water quality. On average from 50,000 to 65,000 fires occur in Europe every year, burning approximately 500,000 ha of forested areas. Between September 2018 and February 2019 two large wildfires burnt nearly 1,400 ha of forests and farmlands in the Pisano Mount area (northwestern Tuscany). The mountainous morphology of the area linked to the proximity to the sea causes high precipitation variability and intensity. This, joined with low permeability bedrock (mainly quartzites, schists, and phyllites) and with the extensive vegetation coverage, make the study site a hot spot for surface waters analysis. Moreover, burnt catchments are of primary importance in the recharge processes of the groundwater resources of the costal plain, which are exploited by a large number of inhabitants and agricultural facility. Consequently, the present study is aimed at understanding and quantifying the wildfire impacts on the hydrogeological dynamics and water quality in the studied catchments. Such impacts are being evaluated by comparing burnt and unburnt catchments, which were selected to be as similar as possible from geological, morphological, and vegetational perspectives. The multi-parameter selection method involved Principal Component Analysis and Distance analysis on many potentially feasible catchments. A network of automatic monitoring instruments was deployed on site. Five hydraulic sections of the main streams draining the area were monitored for hydraulic level and physico-chemical parameters. Hydrographs analysis was performed to infer differences in hydrogeological dynamics between burnt and unburnt basins. Monthly samples were collected for stream water and groundwater chemical analysis. In addition, four plate lysimeters were installed to sample soil water for its chemical characterization. The chemical analysis involved major anions and cations, trace elements, water isotopes, and organic compounds, to search for chemical perturbation potentially arising from the wildfire. The investigation highlighted various differences between the burnt and unburnt basin, mainly for the surface waters. The streams draining the burnt areas present different hydraulic behaviour and changes in physiochemical parameters in response to rainfall events. Moreover, the yearly variation of physiochemical parameters and chemical characteristics present an higher variance for those streams draining wildfire affected catchments

Simulative analysis for performance measurement of RFID implementation in cargo handler logistics

The research focuses on the Air Cargo Handler logistic activities that take place in warehouses. The performances of these activities are highly influenced by human errors. Radio-Frequency IDentification (RFID) implementation in warehouses allows to promptly detect human errors and to implement mitigation actions in order to reduce human error consequences. Consequences are analyzed in the paper in terms of delay in transit times. The paper proposes a methodology for evaluating RFID implementations in air cargo handler's warehouses. Different set-ups of RFID implementation in cargo handler logistics define different scenarios and the proposed methodology allows to compare the performances of these scenarios

A novel snRNA-like transcript affects amyloidogenesis and cell cycle progression through perturbation of Fe65L1 (APBB2) alternative splicing.

FE65 proteins constitute a family of adaptors which modulates the processing of amyloid precursor protein and the consequent amyloid \u3b2 production. Thus, they have been involved in the complex and partially unknown cascade of reactions at the base of Alzheimer's disease etiology. However, FE65 and FE65-like proteins may be linked to neurodegeneration through the regulation of cell cycle in post-mitotic neurons. In thiswork we disclose novel molecular mechanisms by which APBB2 can modulate APP processing. We show that APBB2 mRNA splicing, driven by the over-expression of a novel non-coding RNA named 45A, allow the generation of alternative protein forms endowed with differential effects on A\u3b2 production, cell cycle control, and DNA damage response. 45A overexpression also favors cell transformation and tumorigenesis leading to a marked increase of malignancy of neuroblastoma cells. Therefore, our results highlight a novel regulatory pathway of considerable interest linking APP processing with cell cycle regulation and DNA-surveillance systems, that may represent amolecular mechanism to induce neurodegeneration in post-mitotic neurons

Conservative oxygen supplementation during helmet continuous positive airway pressure therapy in patients with COVID-19 and respiratory failure: a pilot study

Background Respiratory failure is a severe complication in coronavirus disease 2019 (COVID-19) pneumonia that, in addition to oxygen therapy, may require continuous positive airway pressure (CPAP) support. It has been postulated that COVID-19 lung injury may share some features with those observed in hyperoxic acute lung injury. Thus, a correct target arterial oxygen tension (PaO2) during oxygen supplementation may be crucial to protect the lung from further tissue damage. The aims of this study were: 1) to evaluate the effects of conservative oxygen supplementation during helmet CPAP therapy on mortality and intensive care unit (ICU) admission in patients with COVID-19 and respiratory failure, and 2) to evaluate the effect of conservative oxygen supplementation on new-onset organ failure and secondary pulmonary infections. Methods This was a single-centre, historically controlled study of patients with severe respiratory failure due to COVID-19 pneumonia, receiving either conservative or nonconservative oxygen supplementation during helmet CPAP. A cohort receiving conservative oxygen supplementation was studied prospectively in which oxygen supplementation was administered with a target PaO2 <100 mmHg. Results of this cohort were compared with those of a cohort who had received liberal oxygen supplementation. Results 71 patients were included in the conservative cohort and 75 in the nonconservative cohort. Mortality rate was lower in the conservative cohort (22.5% versus 62.7%; p<0.001). Rates of ICU admission and new-onset organ failure were lower in the conservative cohort (14.1% versus 37.3%; p=0.001 and 9.9% versus 45.3%; p<0.001, respectively). Conclusions In patients with COVID-19 and severe respiratory failure, conservative oxygen supplementation during helmet CPAP was associated with improved survival, lower ICU admission rate and less new-onset organ failure

NEAT1 long isoform is highly expressed in chronic lymphocytic leukemia irrespectively of cytogenetic groups or clinical outcome

The biological role and therapeutic potential of long non-coding RNAs (lncRNAs) in chronic lymphocytic leukemia (CLL) are still open questions. Herein, we investigated the significance of the lncRNA NEAT1 in CLL. We examined NEAT1 expression in 310 newly diagnosed Binet A patients, in normal CD19+ B-cells, and other types of B-cell malignancies. Although global NEAT1 expression level was not statistically different in CLL cells compared to normal B cells, the median ratio of NEAT1_2 long isoform and global NEAT1 expression in CLL samples was significantly higher than in other groups. NEAT1_2 was more expressed in patients carrying mutated IGHV genes. Concerning cytogenetic aberrations, NEAT1_2 expression in CLL with trisomy 12 was lower with respect to patients without alterations. Although global NEAT1 expression appeared not to be associated with clinical outcome, patients with the lowest NEAT1_2 expression displayed the shortest time to first treatment; however, a multivariate regression analysis showed that the NEAT1_2 risk model was not independent from other known prognostic factors, particularly the IGHV mutational status. Overall, our data prompt future studies to investigate whether the increased amount of the long NEAT1_2 isoform detected in CLL cells may have a specific role in the pathology of the disease.This work was financially supported by grants to Antonino Neri [from Associazione Italiana Ricerca sul Cancro (AIRC) (IG16722, IG10136, and the “Special Program Molecular Clinical Oncology-5 per mille” #9980, 2010/15)]; to Giovanna Cutrona and Gilberto Fronza [from the Italian Ministry of Health 5 × 1000 funds 2014, 2015, 2016, and from the Compagnia S. Paolo Turin Italy (project 2017.0526)]; to Manlio Ferrarini (the “Special Program Molecular Clinical Oncology-5 per mille” #9980 and AIRC I.G. n.14326); to Fortunato Morabito (the “Special Program Molecular Clinical Oncology-5 per mille” #9980 and AIRC and Fondazione CaRiCal co-financed Multi-Unit Regional Grant 2014 n.16695); Elisa Taiana was supported by a fellowship (#19370) from the Fondazione Italiana Ricerca sul cancro (FIRC