Alveolar epithelial-to-mesenchymal transition in scleroderma interstitial lung disease: Technical challenges, available evidence and therapeutic perspectives

The alveolar epithelial-to-mesenchymal transition is the process of transformation of differentiated epithelial cells into mesenchymal-like cells through functional and morphological changes. A partial epithelial-to-mesenchymal transition process can indirectly contribute to lung fibrosis through a paracrine stimulation of the surrounding cells, while a finalized process could also directly enhance the pool of pulmonary fibroblasts and the extracellular matrix deposition. The direct demonstration of alveolar epithelial-to-mesenchymal transition in scleroderma-related interstitial lung disease is challenging due to technical pitfalls and the limited availability of lung tissue samples. Similarly, any inference on epithelial-to-mesenchymal transition occurrence driven from preclinical models should consider the limitations of cell cultures and animal models. Notwithstanding, while the occurrence or the relevance of this phenomenon in scleroderma-related interstitial lung disease have not been directly and conclusively demonstrated until now, pre-clinical and clinical evidence supports the potential role of epithelial-to-mesenchymal transition in the development and progression of lung fibrosis. Evidence consolidation on scleroderma-related interstitial lung disease epithelial-to-mesenchymal transition would pave the way for new therapeutic opportunities to prevent, slow or even reverse lung fibrosis, drawing lessons from current research lines in neoplastic epithelial-to-mesenchymal transition

The alien vascular flora of the Pantelleria Island National Park (Sicily Channel, Italy): new insights into the distribution of some potentially invasive species

Pantelleria is a volcanic island located in the Sicily Channel (Italy), between Sicily and Tunisia. The island, designated a National Park in 2016, hosts an interesting vascular flora of over 600 species including 9 narrow endemics. The island’s incredible biodiversity is, however, at risk due to anthropogenic influences, climate change, and, recently, the presence and spread of alien plant species. The Pantelleria alien flora has never been thoroughly investigated, probably because many non-native species were not yet present or so widespread on the island. Now, however, with the increased general awareness of the risks associated with invasive alien species, documentation of the presence of non-native species has been steadily increasing. In this study, field and literature research was carried out to investigate the alien flora of the island. Here, we report the status of a number of non-native plants with known invasive potential. Cenchrus setaceus (=Pennisetum setaceum) is reported for the first time as naturalized in the island with clear invasive behaviour, while, particularly remarkable for their invasive potential are other studied plants such as: Acacia saligna, Ailanthus altissima, Boheravia coccinea, Carpobrotus edulis, Leucaena leucocephala subsp. glabrata, Malephora crocea, Melia azedarach, Nicotiana glauca, Opuntia ficus-indica, Parkinsonia aculeata, Washingtonia robusta and a few others less important at the moment, but to be monitored. Although most taxa showed a relatively limited distribution, the trend is to observe an increased invasiveness, which indicates that they can potentially become invasive in Pantelleria as well in the next years or decades. Their limited current distribution suggests that these species are in the early stages of the general invasion curve, when intervention is feasible and most likely to succeed. Therefore, it is most prudent to prioritize management for as many potentially problematic nonnatives as possible, which will contribute greatly to the conservation of native species and ecosystems of Pantelleria. Prevention and management of invasive non-native species—both future arrivals and those already present—are necessary to preserve the peculiar volcanic landscape of Pantelleria, which was shaped by man over the last millennia

Circulating extracellular vesicles in the context of interstitial lung disease related to systemic sclerosis: A scoping literature review

Background Interstitial lung disease (ILD) is a significant cause of disability and mortality in systemic sclerosis (SSc), where lung fibrosis stems from the interaction of cells within the epithelial, endothelial, interstitial, and immune cell compartments. Extracellular vesicles (EVs) are particles released by cells capable of transferring functionally active molecules, playing a crucial role in intercellular communication. This scoping review aims to identify and map existing evidence about the role of EVs as biomarkers or pathophysiological actors in SSc-ILD. It also retrospectively assesses the compliance of published articles with the current reporting guidelines established by the International Society of Extracellular Vesicles (ISEV). Methods This scoping review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. The searches were conducted up until 31 May 2023, with no restrictions on the starting year. Results Out of 778 publications identified and screened, 9 references were selected. The eligible studies collectively involved a total of 539 SSc patients, with 220 patients presenting with ILD, as demonstrated by high-resolution computed tomography. The studies largely focused on the quantitative assessment of EVs through flow cytometry, primarily concerning larger EVs. The studies primarily focused on the association of EV features with vascular complications, with fibrotic pulmonary involvement typically explored as a secondary finding. The evaluated patients' clinical characteristics were significantly heterogeneous across the studies as well as the association of EV features with the evidence of ILD but none of them longitudinally investigated the relationships with SSc-ILD prognosis. Adherence of these exploratory studies to ISEV reporting guidelines in terms of EV nomenclature, reporting of pre-analytic variables, and qualitative verification of EV separation products was incomplete. Conclusions The evidence concerning the clinical association of EV features is limited and conflicting. The interpretation of available data is substantially biased due to patient selection tailored for vascular complications, heterogeneity of separation methodology, and a lack of validation procedures

TGFβ activation primes canonical Wnt signaling through the downregulation of AXIN2

OBJECTIVES: Aberrant activation of Wnt signaling has been observed in systemic sclerosis (SSc) affected tissues. This study aimed to determine the role of transforming growth factor (TGF)β in driving the increased Wnt signaling, through modulation of AXIN2, a critical regulator of Wnt canonical pathway. METHODS: Canonical Wnt signaling activation was analyzed by TOPFlash TCF/LEF promoter assays. AXIN2 was evaluated in vitro by analysis of AXIN2 primary/mature transcripts expression and decay, TβRI blockade, siRNA-mediated TTP-1 depletion and through XAV-939-mediated AXIN2 stabilisation. In vivo, Axin2 mRNA and protein expression was determined in skin and lung biopsies from TβRIIΔk-fib transgenic mice and littermate controls. RESULTS: SSc fibroblasts display increased response to canonical Wnt ligands despite basal levels of Wnt signaling comparable to healthy control (HC) fibroblasts in vitro. Notably, we show that SSc fibroblasts express reduced basal expression of AXIN2, which is caused by endogenous TGFβ-dependent increase of AXIN2 mRNA decay. Accordingly, we observed that TGFβ decreased AXIN2 expression both in vitro in HC fibroblasts and in vivo, employing TβRIIΔk-fib transgenic mice. Additionally, we demonstrate by AXIN2 loss and gain of function experiments, that the TGFβ-induced increased response to Wnt activation characteristic of SSc fibroblasts is dependent on reduced AXIN2 bioavailability. CONCLUSIONS: This study highlights the importance of reduced AXIN2 bioavailability in mediating the increased canonical Wnt response observed in SSc fibroblasts. This novel mechanism extends our understanding of the processes involved in Wnt/β-catenin-driven pathology and supports the rationale for targeting the TGFβ pathway to regulate the aberrant Wnt signaling observed during fibrosis. This article is protected by copyright. All rights reserved

Impact of intrauterine growth restriction on cerebral and renal oxygenation and perfusion during the first 3 days after birth

Intrauterine growth restriction (IUGR) is associated with a higher incidence of perinatal complications as well as cardiovascular and renal diseases later on. A better insight into the disease mechanisms underlying these sequalae is important in order to identify which IUGR infants are at a higher risk and find strategies to improve their outcome. In this prospective case–control study we examined whether IUGR had any effect on renal and cerebral perfusion and oxygen saturation in term neonates. We integrated near-infrared spectroscopy (NIRS), echocardiographic, Doppler and renal function data of 105 IUGR infants and 105 age/gender-matched controls. Cerebral and renal regional oxygen saturation values were measured by NIRS during the first 12 h after birth. Echocardiography alongside Doppler assessment of renal and anterior cerebral arteries were performed at 6, 24, 48 and 72 h of age. Glomerular and tubular functions were also assessed. We found a left ventricular dysfunction together with a higher cerebral oxygen saturation and perfusion values in the IUGR group. IUGR term infants showed a higher renal oxygen saturation and a reduced oxygen extraction together with a subclinical renal damage, as indicated by higher values of urinary neutrophil gelatinase-associated lipocalin and microalbumin. These data suggest that some of the haemodynamic changes present in growth-restricted foetuses may persist postnatally. The increased cerebral oxygenation may suggest an impaired transition to normal autoregulation as a consequence of intra-uterine chronic hypoxia. The higher renal oxygenation may reflect a reduced renal oxygen consumption due to a subclinical kidney damage

Integrating internationalization in the user-centered software development process

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-642-39143-9_27Proceedings of 5th International Conference, CCD 2013, Held as Part of HCI International 2013, Las Vegas, NV, USA, July 21-26, 2013Internationalization is a common practice today in software development. In the most basic sense, internationalization is carried out by applying localization design guidelines to face language translation, icon representation, character sets and so on. However, this practice is mostly intended for design purposes, which results insufficient when applying internationalization in huge projects and, specifically, through a concrete development process. In this paper, a broader framework is provided in order to ensure internationalization through a software development process. To this end, a set of activities and sub-activities will be presented involving not only design but pre-development, analysis, implementation and evaluation issues that need to be considered for a right internationalization assurance in international software development. The idea behind is to bridge the gap between simple and usual localization activities and the user-centered software development process as internationalization assurance also helps increase the quality and usability of the software overall.This work has been supported by the founded projects TIN2011-24139, S2009/TIC-1650 and TIN2011-15009-

Junctional adhesion molecule-A is abnormally expressed in diffuse cutaneous systemic sclerosis skin and mediates myeloid cell adhesion.

OBJECTIVE: To investigate the role of junctional adhesion molecule-A (JAM-A) in the pathogenesis of systemic sclerosis (SSc). METHODS: Biopsy specimens from proximal and distal arm skin and serum were obtained from patients with SSc and normal volunteers. To determine the expression of JAM-A on SSc dermal fibroblasts and in SSc skin, cell surface ELISAs and immunohistology were performed. An ELISA was designed to determine the amount of soluble JAM-A (sJAM-A) in serum. Myeloid U937 cell-SSc dermal fibroblast and skin adhesion assays were performed to determine the role of JAM-A in myeloid cell adhesion. RESULTS: The stratum granulosum and dermal endothelial cells (ECs) from distal arm SSc skin exhibited significantly decreased expression of JAM-A in comparison with normal volunteers. However, sJAM-A was increased in the serum of patients with SSc compared with normal volunteers. Conversely, JAM-A was increased on the surface of SSc compared with normal dermal fibroblasts. JAM-A accounted for a significant portion of U937 binding to SSc dermal fibroblasts. In addition, JAM-A contributed to U937 adhesion to both distal and proximal SSc skin. CONCLUSIONS: JAM-A expression is dysregulated in SSc skin. Decreased expression of JAM-A on SSc ECs may result in a reduced response to proangiogenic basic fibroblast growth factor. Increased JAM-A expression on SSc fibroblasts may serve to retain myeloid cells, which in turn secrete angiogenic factors

Smoking in Systemic Sclerosis: a Longitudinal European Scleroderma Trials and Research Group Study

Data on the role of tobacco exposure in systemic sclerosis (SSc) severity and progression are scarce. We aimed to assess the effects of smoking on the evolution of pulmonary and skin manifestations in the EUSTAR database

Silencing of Histone Deacetylase 6 Decreases Cellular Malignancy and Contributes to Primary Cilium Restoration, Epithelial-to-Mesenchymal Transition Reversion, and Autophagy Inhibition in Glioblastoma Cell Lines

Glioblastoma multiforme, the most common type of malignant brain tumor as well as the most aggressive one, lacks an effective therapy. Glioblastoma presents overexpression of mesenchymal markers Snail, Slug, and N-Cadherin and of the autophagic marker p62. Glioblastoma cell lines also present increased autophagy, overexpression of mesenchymal markers, Shh pathway activation, and lack of primary cilia. In this study, we aimed to evaluate the role of HDAC6 in the pathogenesis of glioblastoma, as HDAC6 is the most overexpressed of all HDACs isoforms in this tumor. We treated glioblastoma cell lines with siHDAC6. HDAC6 silencing inhibited proliferation, migration, and clonogenicity of glioblastoma cell lines. They also reversed the mesenchymal phenotype, decreased autophagy, inhibited Shh pathway, and recovered the expression of primary cilia in glioblastoma cell lines. These results demonstrate that HDAC6 might be a good target for glioblastoma treatment