1,720,978 research outputs found
Role of the inflammasome in chronic obstructive pulmonary disease (COPD)
No full textInflammation is central to the development of chronic obstructive pulmonary disease (COPD), a pulmonary disorder characterized by chronic bronchitis, chronic airway obstruction, emphysema, associated to progressive and irreversible decline of lung function. Emerging genetic and pharmacological evidence suggests that IL-1-like cytokines are highly detected in the sputum and broncho-alveolar lavage (BAL) of COPD patients, implying the involvement of the multiprotein complex inflammasome. So far, scientific evidence has focused on nucleotide-binding oligomerization domain-like receptors protein 3 (NLRP3) inflammasome, a specialized inflammatory signaling platform that governs the maturation and secretion of IL-1-like cytokines through the regulation of caspase-1-dependent proteolytic processing. Some studies revealed that it is involved during airway inflammation typical of COPD. Based on the influence of cigarette smoke in various respiratory diseases, including COPD, in this view we report its effects in inflammatory and immune responses in COPD mouse models and in human subjects affected by COPD. In sharp contrast to what reported on experimental and clinical studies, randomized clinical trials show that indirect inflammasome inhibitors did not have any beneficial effect in moderate to severe COPD patients
Drug resistance in non-small cell lung Cancer (NSCLC): Impact of genetic and non-genetic alterations on therapeutic regimen and responsiveness
No full textThe discovery of genetic alterations, that can be targeted therapeutically, has launched a new era for lung cancer research and personalized therapy. However, not all the identified new genetic driver mutations are therapeutically targetable due to high toxicity profile. On the other hand, those genetic alterations that could be pharmacologically targeted, are often subject of alternative mutations that lead to drug resistance, which represents one of the major clinical limitation. Mechanisms of acquired resistance in oncogene-driven malignancies occur after additional genetic alterations of the primary oncogene. In this scenario, the secondary genetic alteration can lead to up-regulation of bypass-signaling pathways, changes in tumor histology or alterations in drug metabolism, that are able to promote drug resistance with an ensuing lower survival rate of the patient. Another aspect to be considered is that non-genetically mutated patients still have poor pharmacological options and therefore still represent an unmet medical need. Therefore, identifying mechanisms underlying both drug resistance in genetically mutated patients and novel therapeutic alternatives for non-mutated NSCLC patients is still an area of intense investigation
IL-1α and IL-1β-producing macrophages populate lung tumor lesions in mice.
No full textMacrophages highly populate tumour microenvironment and are referred to as tumor-associated macrophages (TAMs). The inflammasome is a multiprotein complex responsible of IL-1 like cytokines release, which biology has been widely studied by using bone-marrow-derived macrophages to mimic a physiological and/or host defense condition. To understand the role of this complex in lung tumor-associated macrophages (TAMs), we isolated and cultured broncho-alveolar lavage (BAL)-derived cells of lung tumor-bearing mice. The stimulation of lung TAMs with LPS+ATP increased the release of IL-1β. The inhibition of NLRP3 by means of glybenclamide significantly reduced IL-1β release. Similarly, C3H-derived, caspase-1 ko and caspase-11 ko TAMs released significantly reduced levels of IL-1β. Moreover, the stimulation of lung TAMs with the sole LPS induced a significant release of IL-1α, which was significantly reduced after caspase-1 pharmacological inhibition, and in TAMs genetically lacking caspase-1 and caspase-11. The inhibition of calpain I/II by means of MDL28170 did not alter IL-1α release after LPS treatment of lung TAMs. To note, the inoculation of LPS-treated bone marrow-derived macrophages into carcinogen-exposed mice increased lung tumor formation. In contrast, the depletion of TAMs by means of clodronate liposomes reduced lung tumorigenesis, associated to lower in vivo release of IL-1α and IL-1β.In conclusion, our data imply lung tumor lesions are populated by macrophages which pro-tumor activity is regulated by the activation of the NLRP3 inflammasome that leads to the release of IL-1α and IL-1β in a caspase-11/caspase-1-dependent manner
The activation of the AIM2 inflammasome after cigarette smoke exposure leads to an immunosuppressive lung microenvironment.
No full textCigarette smoke is widely known as contributing to chronic inflammation underlying several airway diseases, such as chronic obstructive pulmonary disease (COPD) and lung cancer. In our previous studies we found that the lung of both COPD and cancer patients were characterized by the presence and activation of the AIM2 inflammasome. Here, we wanted to investigate the upstream step during the establishment of chronic lung inflammation after cigarette smoke exposure. We took advantage of a mouse model of smoking exposure and public scRNAseq data. We found that AIM2 mRNA was expressed in both alveolar type II, B cells, T regulatory (Treg) and macrophages detected in the lung of non-smokers (n = 4) and smokers (n = 3). The activation of AIM2 in smoking mice by using PolydA:dT did not alter cigarette-smoke-induced alveoli enlargement and mucus production, rather it induced higher recruitment of immunosuppressive cells, such as non-active dendritic cells (DCs), Arginase I+ macrophages, myeloid-derived suppressor cells (MDSC) and Tregs. In addition, the inflammatory environment after AIM2 activation in smoking mice was characterized by higher levels of IL-1α, IL-1β, IL-33, TNFα, LDH, IL-10 and TGFβ. This scenario was not altered after the pharmacological inhibition of both caspase-1 and STING pathway
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Absent in melanoma 2 (AIM2) positive profile identifies a poor prognosis of lung adenocarcinoma patients
Full text linkThe absent in melanoma 2 (AIM2) inflammasome has been demonstrated as involved in tumor growth. In this study we used human samples of lung adenocarcinoma (LUAD) patients, taking advantage of a mouse model of smoking cessation. Human samples were stratified according to the smoking status, high-risk factor for this type of tumor. Both public transcriptomic and human samples obtained by a clinical trial proved that AIM2 was upregulated either in terms of mRNA or protein, respectively, in the tumor mass according to the TNM stage, but it did not relate to the smoking status, age and sex. The upregulation of AIM2 was correlated to an immunosuppressive environment according to resting/non-active dendritic cells (DCs) and T regulatory cells, as demonstrated in both human samples and by means of an experimental model of smoking mice. Computational analysis showed that AIM2 upregulation was correlated to both an inflammasome profile, responsible for the poor prognosis of non-smoker and smoker LUAD patients, and to a non-inflammasome profile for former smoker. In conclusion, our study demonstrated that AIM2 is involved in lung carcinogenesis either in a canonical and non-canonical manner due to an immunosuppressive microenvironment associated to a dismal prognosis of LUAD patients
Is the inflammasome at the crosstalk between COPD and lung cancer?
Full text link2018 - 2019Background. Chronic obstructive pulmonary disease (COPD) is considered as a risk factor for lung cancer establishment. Epidemiological evidence indicate that patients with COPD have a 6.35-fold higher risk to develop lung cancer compared to the normal population.
Aim. Based on the notion that chronic inflammation is common to both COPD and lung cancer and that in our laboratory we found that the inflammasome is involved in lung carcinogenesis, we focused our attention on this multimeric complex, which role in both pathologies still counts many controversies in literature.
Therefore, the main goal of this PhD project was to evaluate whether the inflammasome was at the crosstalk between COPD and lung cancer. In particular, we focused our attention on air pollution and smoking as inflammasome inducers.
1st year results. The exposure of peripheral blood mononuclear cells (PBMCs) isolated from smokers to ultrafine particles (UFPs), which mimic small size air pollutants, led to an inflammatory process that was responsible for IL-1-like cytokines release and was associated to the activation of the canonical, caspase-1-dependent, NLRP3 inflammasome. This effect was not observed in non-smoker subjects, who instead released higher levels immunesuppressive IL-10 (Chapter 1). Instead, UFPs induced the release of IL-18 and IL-33 from exacerbated COPD-derived circulating cells in a NLRP3-/caspase-1- and caspase-8-independent manner (Chapter 2)... [edited by Author]Background. La broncopneumopatia cronica ostruttiva (BPCO) è considerata un fattore di rischio per l'insorgenza del carcinoma polmonare. Evidenze epidemiologiche indicano che i pazienti con BPCO hanno un rischio 6.35 volte maggiore di sviluppare il cancro ai polmoni rispetto alla popolazione normale.
Scopo. Basandoci sul concetto che l'infiammazione cronica è comune sia alla BPCO che al cancro del polmone e che nel nostro laboratorio abbiamo scoperto che l'inflammosoma è coinvolto nella carcinogenesi polmonare, abbiamo concentrato la nostra attenzione su questo complesso multimerico, il cui ruolo in entrambe le patologie conta ancora molte controversie in letteratura.
Pertanto, l'obiettivo principale di questo progetto di Dottorato di Ricerca era valutare se l'inflammosoma fosse al crosstalk tra BPCO e tumore al polmone. In particolare, abbiamo focalizzato la nostra attenzione sull'inquinamento ambientale e sul fumo come induttori dell’inflammosoma.
Risultati del I anno. L'esposizione delle cellule mononucleate del sangue periferico (PBMC) isolate dai fumatori alle particelle ultrafini (UFP), che mimano gli inquinanti ambientali di piccole dimensioni, ha portato a un processo infiammatorio responsabile del rilascio di citochine della famiglia IL-1 ed è stato associato all'attivazione canonica, dipendente dalla caspasi-1, dell'inflammosoma NLRP3. Questo effetto non è stato osservato nei soggetti non fumatori, che invece hanno rilasciato livelli più elevati di IL-10 immunosoppressiva (Capitolo 1). Invece, le UFP hanno indotto il rilascio di IL-18 e IL-33 dalle cellule circolanti isolate da pazienti con BPCO esacerbata in modo indipendente da NLRP3-/caspase-1 e caspase-8 (Capitolo 2)... [a cura dell'Autore]XXXII cicl
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