Angiotensin II type 2 receptor (AT2R) as a novel modulator of inflammation in rheumatoid arthritis synovium

Abstract Despite increasing evidence suggesting that angiotensin II type 2 receptor (AT2R) may regulate tissue inflammation, no study has yet analyzed its possible implication in rheumatoid arthritis (RA) synovitis. In this study, we investigated the expression and function of AT2R in synovial tissue and cultured fibroblast-like synoviocytes (FLS) from RA patients. AT2R expression was strongly increased in RA compared with osteoarthritis (OA) synovium, as well as in in cultured RA-FLS respect to OA-FLS and healthy FLS. Treatment with pro-inflammatory cytokines was able not only to boost AT2R expression in RA-FLS and OA-FLS, but also to induce its de novo expression in healthy FLS. The stimulation of AT2R with the specific agonist CGP42112A significantly reduced gene expression of interleukin (IL)-1β and IL-6 and activation of NF-κB in RA-FLS, while opposite effects were elicited by AT2R small interfering RNA. Moreover, AT2R agonism efficiently decreased RA-FLS proliferation and migration either at baseline or under pro-inflammatory cytokine challenge. In conclusion, AT2R is strongly expressed in key effector cells of rheumatoid synovitis, namely RA-FLS, and the activation of AT2R with a specific agonist may effectively dampen their pro-inflammatory and aggressive behavior. AT2R agonism might represent a novel therapeutic strategy for patients with RA

???Pull-through??? Resection for Total and Subtotal Glossectomy Involving the Posterior Third of Tongue

The lower lip-splitting incision associated with different types of mandibulotomy, in order to obtain wide access to total or subtotal glossectomy, is described. In those cases, high rates of functional and aesthetic deficit and postoperative morbidity (more in cases of patients in which adjuvant radiotherapy has been performed) are described. We present our experience in the treatment of patients undergoing total or subtotal glossectomy and contemporary reconstruction with flaps, and without lip-splitting incision and mandibulotomy. Materials and Methods: Data about patients affected by malignant tumors requiring total or subtotal (posterior third of the tongue) resection that were treated at our department from January 2004 to December 2014 were retrospectively reviewed. Data evaluated included: T and N stage, resection margins, operation time, and post-operative complications, such as fistula and flap necrosis. Results: 41 patients were identified. In two cases microscopic infiltration of one margin was found (R1); in one case a close margin was identified. In 26 cases reconstruction was performed using free flaps, and in the remaining cases a pectoralis major flap was used. In three cases postoperative complications were observed. Discussion and conclusions: In theory, lip-splitting and mandible discontinuity could allow for increased access and tumor visualization, and could facilitate flap positioning. Nevertheless, in our experience, it is not necessary in the case of total or subtotal glossectomy

An Exploratory Study of Field Failures

Field failures, that is, failures caused by faults that escape the testing phase leading to failures in the field, are unavoidable. Improving verification and validation activities before deployment can identify and timely remove many but not all faults, and users may still experience a number of annoying problems while using their software systems. This paper investigates the nature of field failures, to understand to what extent further improving in-house verification and validation activities can reduce the number of failures in the field, and frames the need of new approaches that operate in the field. We report the results of the analysis of the bug reports of five applications belonging to three different ecosystems, propose a taxonomy of field failures, and discuss the reasons why failures belonging to the identified classes cannot be detected at design time but shall be addressed at runtime. We observe that many faults (70%) are intrinsically hard to detect at design-time

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

Angiotensin II type 2 receptor (AT2R) is over-expressed in synovial OA and RA tissue and increases steadily with inflammatory stimuli: a potential new target for pain and anti-inflammatory therapies.

Background Activation of transient potential type I vanilloid receptor (TRPV1) is crucial for pain perception and inflammation. During rheumatoid arthritis (RA) direct stimulation of TRPV1 positive fibroblast-like synoviocites (FLS) promotes secretion of inflammatory citokynes, like IL-6 and IL-8. Despite these data there aren’t TRPV1 antagonist available for human therapies. Recently, a new membrane receptor, the angiotensin II type 2 receptor (AT2R) has been discovered as crucial activator of TRPV1. Objective (s) To demonstrate the presence of AT2R in synovial tissues of RA and OA patients. To evaluate expression of AT2R in FLS, macrophages, T and B cells of RA tissue. To evaluate differences of expression of AT2R in cultured healthy FLS (H-FLS), osteoarthritis FLS (OA-FLS), RA-FLS at baseline and after IL1β or TNF-α incubation. Materials and method (s) Synovial biopsies were collected from 8 patients with active knee-RA and 8 with OA-knee. For immunohistochemistry, immunocytochemistry and western blotting analysis AT2R antibody were used. For fluorescence immunohistochemistry analysis specimens were also incubated with anti-CD3, anti-CD20, anti-CD68 and anti-vimentin. Nuclei were counterstained with 4’,6-diamidino-2-phenylindole (DAPI). For fluorescence immunocytochemistry and western blotting analysis FLS were serum-starved for 24 hours or incubated with TNF-α, IL-1β alone or in combination. For statistical analysis the Student’s t-test was used (p value < 0.05 was considered statistically significant). Results AT2R was express from every layers of OA and RA synovial samples (fig 1, A-D). RA lining layer had significantly higher levels of AT2R than OA (p=0,035) (fig 1, A,C,E). Furthermore expression of AT2R was significantly higher in RA sub-lining layer than OA lining layer (p=0,002) (fig 1, B,D,E). Merge immunohistochemistry of RA samples showed that FLS, macrophage and T and B cells strongly expressed AT2R (fig 2, A-D). Immunocytochemistry and western blotting analysis showed that quantitative AT2R baseline expression was significantly higher in OA-FLS than H-FLS (p<0,001), nevertheless RA-FLS showed the higher levels of baseline AT2R (p<0,001)(fig 3). Incubation with TNF-α and IL-1β significantly increased expression of AT2R-FLS baseline levels in all cellular lines (p<0,05)(fig 3). Discussion This study demonstrates, for the first time, the presence of AT2R in human synovial specimens. AT2R was found in every RA and OA samples suggesting a possible constitutive role in RA and OA pathogenesis. However RA samples had higher AT2R expression than OA, both in lining and sub-lining layers. Macrophages, FLS, T and B lymphocytes, leading cells in inducing and sustaining RA inflammation, strongly expressed AT2R. Moreover, inflammatory stimuli induce AT2R expression, as demonstrated by levels of AT2R in H-FLS, OA-FLS and RA-FLS at baseline and after incubation with TNF-α and IL-1β. These evidences suggest that AT2R could act as pro-inflammatory receptor in OA and RA. AT2R antagonism could be a potentially new target for OA and RA treatment