90 research outputs found
miR-200c prevents and reverts Lung fibrosis by down regulating Flt1 and promoting lung regeneration
No full textIdiopathic pulmonary fibrosis (IPF) is a devastating progressive fibrotic disease affecting the lungs and causing chronic respiratory failure. In IPF, adult alveolar type II stem cells (ATII) cannot trans-differentiate to alveolar type I cells (ATI), and therefore, represents a relevant target in the progression of lung fibrosis. There are only two FDA-approved drugs for the treatment of IPF, which can only ameliorate the disease, but a permanent cure is not yet available. In this work, we showed that human ATII cells isolated from IPF patients displayed impaired trans-differentiation in vitro. When transfected with miR-200c the ability of trans-differentiation was restored. The administration of miR-200c into mice lungs was performed using an aerosol delivery system, which resulted in an inhibited fibrosis in bleomycin-induced lung fibrosis mouse model. This data confirms miR-200c to be a powerful anti-fibrotic treatment in conditions of early onset fibrosis and when fibrosis was already established. We investigated if ATII differentiation could be rescued upon down-regulation of Flt1 a miR-200c target and highly expressed in endothelial cells. For this reason, we performed co-culture assays between endothelial cells from both Wild type (WT) and Cdh5 -ERT2-CreFlt1flox/flox mice, depleting Flt1 in endothelial cells, and ctrl and bleomycin ATII cells. We observed that the knock-out of Flt1 in endothelial cells prevented disease progression in a murine model of lung fibrosis, through releasing an increased amount of angiocrine factors, such as SerpinC1, Haptoglobin, Itih2 detected by mass spectrometry analysis of the secretome.
This work importantly contributed to the discovery of a new potential IPF treatment, such as miR-200c, and to the underlying molecular mechanisms involved in both lung fibrosis and lung regeneration.Idiopathic pulmonary fibrosis (IPF) is a devastating progressive fibrotic disease affecting the lungs and causing chronic respiratory failure. In IPF, adult alveolar type II stem cells (ATII) cannot trans-differentiate to alveolar type I cells (ATI), and therefore, represents a relevant target in the progression of lung fibrosis. There are only two FDA-approved drugs for the treatment of IPF, which can only ameliorate the disease, but a permanent cure is not yet available. In this work, we showed that human ATII cells isolated from IPF patients displayed impaired trans-differentiation in vitro. When transfected with miR-200c the ability of trans-differentiation was restored. The administration of miR-200c into mice lungs was performed using an aerosol delivery system, which resulted in an inhibited fibrosis in bleomycin-induced lung fibrosis mouse model. This data confirms miR-200c to be a powerful anti-fibrotic treatment in conditions of early onset fibrosis and when fibrosis was already established. We investigated if ATII differentiation could be rescued upon down-regulation of Flt1 a miR-200c target and highly expressed in endothelial cells. For this reason, we performed co-culture assays between endothelial cells from both Wild type (WT) and Cdh5 -ERT2-CreFlt1flox/flox mice, depleting Flt1 in endothelial cells, and ctrl and bleomycin ATII cells. We observed that the knock-out of Flt1 in endothelial cells prevented disease progression in a murine model of lung fibrosis, through releasing an increased amount of angiocrine factors, such as SerpinC1, Haptoglobin, Itih2 detected by mass spectrometry analysis of the secretome.
This work importantly contributed to the discovery of a new potential IPF treatment, such as miR-200c, and to the underlying molecular mechanisms involved in both lung fibrosis and lung regeneration
Epithelial–Mesenchymal Transition in the Pathogenesis of Idiopathic Pulmonary Fibrosis
No full textIdiopathic pulmonary fibrosis (IPF) is a serious disease of the lung, which leads to extensive parenchymal scarring and death from respiratory failure. The most accepted hypothesis for IPF pathogenesis relies on the inability of the alveolar epithelium to regenerate after injury. Alveolar epithelial cells become apoptotic and rare, fibroblasts/myofibroblasts accumulate and extracellular matrix (ECM) is deposited in response to the aberrant activation of several pathways that are physiologically implicated in alveologenesis and repair but also favor the creation of excessive fibrosis via different mechanisms, including epithelial–mesenchymal transition (EMT). EMT is a pathophysiological process in which epithelial cells lose part of their characteristics and markers, while gaining mesenchymal ones. A role for EMT in the pathogenesis of IPF has been widely hypothesized and indirectly demonstrated; however, precise definition of its mechanisms and relevance has been hindered by the lack of a reliable animal model and needs further studies. The overall available evidence conceptualizes EMT as an alternative cell and tissue normal regeneration, which could open the way to novel diagnostic and prognostic biomarkers, as well as to more effective treatment options
Compliance mechanisms under selected multilateral environmental agreements, (Co-author Ulrich Beyerlin)
No full textLa difficoltà di studiare atteggiamenti e valori nella ricerca standard
No full textIl volume illustra con approccio critico gli strumenti più diffusi nella ricerca standard per lo studio di atteggiamenti e valori. Nel primo capitolo gli autori passano in rassegna la letteratura relativa alle diverse concezioni di atteggiamento e valore, sottolineando le difficoltà di indagare stati interiori tanto profondi dell'individuo di cui egli stesso non è sempre del tutto consapevole. Il secondo capitolo è dedicato alle tecniche di scaling, delle quali si sottolineano pregi e difetti. Il terzo capitolo riporta i risultati di una ricerca empirica relativa al funzionamento di due diverse tecniche di pretest utili a individuare eventuali limiti delle domande: il verbal interaction coding e l’intervista cognitiva. Lo studio evidenzia la complementarietà tra le due tecniche nel far luce su aspetti differenti relativi alla inadeguata formulazione di alcune domande, che rischiano di minare la fedeltà delle risposte raccolte con il questionario. L’ultimo capitolo affronta le sfide che lo studio dei valori pone a chi intende indagarli con tecniche strutturate come il rating o il ranking. Si fa riferimento, in particolar modo, alla tendenza dei soggetti intervistati a fraintendere il significato di alcune espressioni come ‘impegno politico’, ‘fiducia’, ‘impegno religioso’. I risultati delle due ricerche qui illustrate mostrano che nel trattare valori e atteggiamenti emergono in pieno i limiti delle procedure standard, che ingabbiano l’interazione tra intervistatore e intervistato, riducendo la possibilità di giungere a un’utile negoziazione dei significati
The Figure of the Limit: Metalepsis
No full textIn 1972, Gérard Genette introduced in narratology the figure of metalepsis, that is «any intrusion by the extradiegetic narrator or narratee into the diegetic universe (or by diegetic characters into a metadiegetic universe, etc.), or the inverse». In other words, metalepsis is a transgression of narrative levels, a perturbation of hierarchy that raises the question of the porosity of boundaries between diegetic and metadiegetic, author and reader, fact and fiction.
In my presentation, I will show how this phenomenon is ubiquitous nowadays, and how it is settled both in highbrow and lowbrow cultural representations across various media.
Furthermore, I wish I can discuss the role of metalepsis in poetics: in my opinion, it is possible to relate this device with the history of the novel. In XVIII and XIX centuries authorial narrators made extensive use of rhetoric metalepsis for humoristic purposes (such as playing with the story-time and the discourse-time) or to exhibit their authority (through the manipulation of different threads of the narration). With Naturalism and Modernism metalepsis disappeared, according to the poetic of impersonality: authors stopped being intrusive and eclipsed behind their characters. The golden era of the figure came in the temper of Postmodernism, where ontological metalepsis flourished and the public got used to author and reader literary entering the fiction or characters exiting from it and chitchatting with their creators
The Predictive and Prognostic Role of RAS–RAF–MEK–ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets
No full textAlthough gene alterations of the RAS/RAF/MEK/ERK pathway are uncommon in breast cancer, this pathway is frequently activated in breast tumors, implying its role in tumor progression. We describe, after a revision of the literature, the frequency and types of gene alterations affecting this pathway in breast cancer by analyzing some public datasets from cBioPortal. Moreover, we consider their prognostic and predictive impact on treatment response, along with the role of transcriptomic predictors of RAS pathway activation. Our analysis shows that the driver alterations in RAS/RAF/MEK/ERK pathway-related genes are detected in 11% of primary breast cancers. The most frequently mutated genes are NF1 and KRAS, while copy number alterations mainly affect KRAS and BRAF, especially in basal-like tumors. The subgroup of patients carrying these alterations shows a worse prognosis; alterations in NF1 and RAF1 are associated with significantly reduced breast-cancer-specific survival in multivariate analysis. The literature review shows that the pathway is implicated, either by genetic or epigenetic alterations or by signaling network adaptations, in the mechanisms of sensitivity and resistance to a wide range of drugs used in the treatment of breast cancer. A thorough understanding of these alterations is critical for developing combination therapies that can delay or overcome drug resistance
Andrea e gli argentieri Memingher in Sicilia
No full textAndrea Memingher è una tra le più enigmatiche figure di argentieri attivi a Palermo nella seconda metà del XVII secolo. Si può ritenere che la famiglia avesse origini nordiche e che, dopo un passaggio a Napoli, si stabilisse definitivamente a Palermo, inserendosi nella maestranza degli orafi e argentieri della città, probabilmente grazie ad un matrimonio con una figlia o una sorella o una vedova di un membro palermitano della maestranza. La presenza di Paolo Memingher nel capoluogo siciliano è attestata già nel 1660, due anni prima della data di inizio della sua attività, protrattasi fino al 1678. Il più importante esponente della famiglia fu Andrea, figlio di Paolo, il quale dovette la sua fama, al di là dell’abilità e dell’origine straniera, anche al suo status di padre gesuita. Il saggio studia la figura dell’artista, attivo dal 1670 al 1738, anno di morte, autore di un consistente corpus di opere giunto fino a noi, e dei congiunti che operarono nel medesimo contesto.Andrea Memingher is one of the most enigmatic figures of silversmiths active in Palermo in the second half of the seventeenth century. It can be assumed that the family had Nordic origins and that, after a passage to Naples, it settled permanently in Palermo, entering the mastery of the goldsmiths and silversmiths of the city, probably thanks to a marriage with a daughter or a sister or a widow of a Palermitan member of the mastery. The presence of Paolo Memingher in the Sicilian capital is attested as early as 1660, two years before the start of his activity, which lasted until 1678. The most important exponent of the family was Andrea, son of Paolo, who owed his fame, beyond the ability and foreign origin, even to his status as a Jesuit father. The essay studies the figure of the artist, active since 1670 to 1738, the year of his death, author of a substantial body of works that has come to us, and of the relatives who worked in the same context
Alveolar Epithelial Type II Cells
No full textThe two primary cell lineages that make up the endodermally-derived single-layer epithelium of alveoli are alveolar type I (ATI) cells and alveolar type II (ATII) cells.
The thin, frail and flat ATI cells cover more than 95% of the alveolar surface. As they are extremely thin, they permit efficient gas exchange by virtue of their squamous morphology. The smaller and cuboidal ATII cells (approximately 9 mm in diameter, 250 mm2 surface area) are more abundant than ATI cells, representing up to 60–88% of all alveolar epithelial cells by number and usually reside at the corners of alveoli.
As the cytoplasm of ATII cells contains phospholipid multilamellar bodies, they have a foamier appearance than ATI cells.
They have a large central nucleus, a high density of mitochondria and are connected to neighboring cells by intercellular and tight junctions. When these polarized epithelial cells are observed at electron microscopy, they have thin projections protruding from the apical cell surface called microvilli. A wonderful description of ATII cells comes from Robert Mason, who states the role they play as the defender of the alveolus microenvironment is similar to that of a tower in a medieval crenellated wall.
Indeed, ATII cells maintain the alveolar space relatively fluid-free and prevent it from collapsing by secreting a lipoprotein material called surfactant (promoting lung expansion on inspiration and preventing lung collapse on expiration), serve as progenitor cells to repopulate the alveolar epithelium after injury and play an important role in the innate immune system response. The most updated scientific contributions in the field come from bioinformatics and omics data, that have added insights to the “non-surfactant-related functions” of ATIIs, emphasizing their pivotal role in lung repair/regeneration after injury.
Dysfunctional alveolar epithelium is implicated to such an extent in almost every lung disease that, of late, it has been considered a possible therapeutic target. Therefore, studying its role from a cellular perspective can provide a novel understanding of lung diseases, implying that regenerative medicine in the treatment of degenerative parenchymal lung diseases may well become a reality
Regeneration or Repair? The Role of Alveolar Epithelial Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF)
No full textIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) with unknown etiology in which gradual fibrotic scarring of the lungs leads to usual interstitial pneumonia (UIP) and, ultimately, to death. IPF affects three million people worldwide, and the only currently available treatments include the antifibrotic drugs nintedanib and pirfenidone, which effectively reduce fibrosis progression are, unfortunately, not effective in curing the disease. In recent years, the paradigm of IPF pathogenesis has shifted from a fibroblast-driven disease to an epithelium-driven disease, wherein, upon recurrent microinjuries, dysfunctional alveolar type II epithelial cells (ATII) are not only unable to sustain physiological lung regeneration but also promote aberrant epithelial–mesenchymal crosstalk. This creates a drift towards fibrosis rather than regeneration. In the context of this review article, we discuss the most relevant mechanisms involved in IPF pathogenesis with a specific focus on the role of dysfunctional ATII cells in promoting disease progression. In particular, we summarize the main causes of ATII cell dysfunction, such as aging, environmental factors, and genetic determinants. Next, we describe the known mechanisms of physiological lung regeneration by drawing a parallel between embryonic lung development and the known pathways involved in ATII-driven alveolar re-epithelization after injury. Finally, we review the most relevant interventional clinical trials performed in the last 20 years with the aim of underlining the urgency of developing new therapies against IPF that are not only aimed at reducing disease progression by hampering ECM deposition but also boost the physiological processes of ATII-driven alveolar regeneration
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