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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
Get PDFIdiopathic 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
Optimization and Characterization of Bleomycin mice to better study the Idiopathic Pulmonary Fibrosis
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Successful treatment of life-threatening mycobacteriosis using adjunctive gamma-interferon therapy with genetic analysis
Get PDFIn our case series of 6 consecutive patients with severe disseminated mycobacterial infection and lymphocytopenia who did not responded to antimycobacterial drugs alone we used adjunctive IFN-γ treatment. IFN-gamma was effective in four out of the six cases. We identified two genes potentially correlating with NTM and TB severity (MUC5AC and FCGBP), and one (CCL4L2) suggesting a positive response to IFN-γ therapy. Further research is required to validate these findings. We propose the extended use of INF-γ as a rescue therapy in non-responder-severe cases of mycobacteriosis and encourage the use of genetic analysis to predict outcome and response to INF-γ treatment
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
Get PDFAlthough 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
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
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