Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis.

OBJECTIVE: The intestinal inflammation observed in patients with ankylosing spondylitis (AS) is characterized by an overexpression of interleukin-23 (IL-23). IL-23 is known to regulate IL-22 production through lamina propria NKp44+ natural killer (NK) cells, which are thought to be involved in protective mucosal mechanisms. This study was undertaken to evaluate the frequency of NKp44+ NK cells and the expression of IL-22 in the ileum of AS patients. METHODS: Tissue NKp44+ NK cells, NKp46+ NK cells, and IL-22-producing cells were analyzed by flow cytometry. Quantitative gene expression analysis of IL-22, IL-23, IL-17, STAT-3, and mucin 1 (MUC-1) was performed by reverse transcriptase-polymerase chain reaction on ileal samples from 15 patients with AS, 15 patients with Crohn's disease (CD), and 15 healthy controls. NKp44, pSTAT-3, and IL-22 expression was analyzed by immunohistochemistry. RESULTS: The frequency of NKp44+ but not NKp46+ NK cells was increased in the inflamed ileum of AS patients compared to CD patients and controls. The frequency of NKp46+ NK cells was significantly increased only in CD patients. Among CD4+ lymphocytes and NKp44+ NK cell subsets, the latter were the major source of IL-22 on lamina propria mononuclear cells from AS patients. Significant up-regulation of IL-22, IL-23p19, MUC-1, and STAT-3 transcripts in the terminal ileum of patients with AS was observed. Immunohistochemical analysis confirmed the increased IL-22 and pSTAT-3 expression in inflamed mucosa from AS and CD patients. CONCLUSION: Our findings indicate that overexpression of IL-22, together with an increased number of IL-22-producing NKp44+ NK cells, occurs in the gut of AS patients, where it appears to play a tissue-protective role

Targeting of surface alpha-enolase inhibits the invasiveness of pancreatic cancer cells

Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by rapid progression, invasiveness and resistance to treatment. We have previously demonstrated that most PDAC patients have circulating antibodies against the glycolytic enzyme alpha-enolase (ENO1), which correlates with a better response to therapy and survival. ENO1 is a metabolic enzyme, also expressed on the cell surface where it acts as a plasminogen receptor. ENO1 play a crucial role in cell invasion and metastasis by promoting plasminogen activation into plasmin, a serine-protease involved in extracellular matrix degradation. The aim of this study was to investigate the role of ENO1 in PDAC cell invasion. We observed that ENO1 was expressed on the cell surface of most PDAC cell lines. Mouse anti-human ENO1 monoclonal antibodies inhibited plasminogen-dependent invasion of human PDAC cells, and their metastatic spreading in immunosuppressed mice was inhibited. Notably, a single administration of Adeno-Associated Virus (AAV)-expressing cDNA coding for 72/1 anti-ENO1 mAb reduced the number of lung metastases in immunosuppressed mice injected with PDAC cells. Overall, these data indicate that ENO1 is involved in PDAC cell invasion, and that administration of an anti-ENO1 mAb can be exploited as a novel therapeutic option to increase the survival of metastatic PDAC patients

Vaccination with ENO1 DNA Prolongs Survival of Genetically Engineered Mice with Pancreatic Cancer.

BACKGROUND & AIMS:: Pancreatic ductal adenocarcinoma (PDA) is an aggressive tumor, and patients typically present with late-stage disease; rates of 5-year survival after pancreaticoduodenectomy are low. Antibodies against -enolase (ENO1), a glycolytic enzyme, are detected in more than 60% of patients with PDA, and ENO1-specific T cells inhibit the growth of human pancreatic xenograft tumors in mice. We investigated whether an ENO1DNA vaccine elicits anti-tumor immune responses and prolongs survival of mice that spontaneously develop autochthonous, lethal pancreatic carcinomas. METHODS:: We injected and electroporated a plasmid encoding ENO1 (or a control plasmid) into Kras(G12D)/Cre mice (KC) and Kras(G12D)/Trp53 (R172H) /Cre (KPC) mice when they were 4 weeks old (when pancreatic intraepithelial lesions are histologically evident). Anti-tumor humoral and cellular responses were analyzed by histology, immunohistochemistry, ELISAs, flow cytometry, and ELISpot and cytotoxicity assays. Survival was analyzed by Kaplan-Meier analysis. RESULTS:: The ENO1 vaccine induced antibody and a cellular responses and increased survival times by a median 138 days in KC mice and 42 days in KPC mice, compared with mice given the control vector. In histologic analysis, the vaccine appeared to slow tumor progression. The vaccinated mice had increased serum levels of anti-ENO1 immunoglobulin G, which bound the surface of carcinoma cells and induced complement-dependent cytotoxicity. ENO1 vaccination reduced numbers of myeloid-derived suppressor cells and T-regulatory cells, and increased T-helper 1 and 17 responses. CONCLUSIONS:: In a genetic model of pancreatic carcinoma, vaccination with ENO1DNA elicits humoral and cellular immune responses against tumors, delays tumor progression, and significantly extends survival. This vaccination strategy might be developed as a neo-adjuvant therapy for patients with PD

A novel community driven software for functional enrichment analysis of extracellular vesicles data.

Bioinformatics tools are imperative for the in depth analysis of heterogeneous high-throughput data. Most of the software tools are developed by specific laboratories or groups or companies wherein they are designed to perform the required analysis for the group. However, such software tools may fail to capture "what the community needs in a tool". Here, we describe a novel community-driven approach to build a comprehensive functional enrichment analysis tool. Using the existing FunRich tool as a template, we invited researchers to request additional features and/or changes. Remarkably, with the enthusiastic participation of the community, we were able to implement 90% of the requested features. FunRich enables plugin for extracellular vesicles wherein users can download and analyse data from Vesiclepedia database. By involving researchers early through community needs software development, we believe that comprehensive analysis tools can be developed in various scientific disciplines

Joint Observation of the Galactic Center with MAGIC and CTA-LST-1

MAGIC is a system of two Imaging Atmospheric Cherenkov Telescopes (IACTs), designed to detect very-high-energy gamma rays, and is operating in stereoscopic mode since 2009 at the Observatorio del Roque de Los Muchachos in La Palma, Spain. In 2018, the prototype IACT of the Large-Sized Telescope (LST-1) for the Cherenkov Telescope Array, a next-generation ground-based gamma-ray observatory, was inaugurated at the same site, at a distance of approximately 100 meters from the MAGIC telescopes. Using joint observations between MAGIC and LST-1, we developed a dedicated analysis pipeline and established the threefold telescope system via software, achieving the highest sensitivity in the northern hemisphere. Based on this enhanced performance, MAGIC and LST-1 have been jointly and regularly observing the Galactic Center, a region of paramount importance and complexity for IACTs. In particular, the gamma-ray emission from the dynamical center of the Milky Way is under debate. Although previous measurements suggested that a supermassive black hole Sagittarius A* plays a primary role, its radiation mechanism remains unclear, mainly due to limited angular resolution and sensitivity. The enhanced sensitivity in our novel approach is thus expected to provide new insights into the question. We here present the current status of the data analysis for the Galactic Center joint MAGIC and LST-1 observations

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

The high activity of 3C 454.3 in autumn 2007: Monitoring by the WEBT during the AGILE detection

The quasar-type blazar 3C 454.3 underwent a phase of high activity in summer and autumn 2007, which was intensively monitored in the radio-to-optical bands by the Whole Earth Blazar Telescope (WEBT). The gamma-ray satellite AGILE detected this source first in late July, and then in November-December 2007. In this letter we present the multifrequency data collected by the WEBT and collaborators during the second AGILE observing period, complemented by a few contemporaneous data from UVOT onboard the Swift satellite. The aim is to trace in detail the behaviour of the synchrotron emission from the blazar jet, and to investigate the contribution from the thermal emission component. Optical data from about twenty telescopes have been homogeneously calibrated and carefully assembled to construct an R-band light curve containing about 1340 data points in 42 days. This extremely well-sampled optical light curve allows us to follow the dramatic flux variability of the source in detail. In addition, we show radio-to-UV spectral energy distributions (SEDs) at different epochs, which represent different brightness levels. In the considered period, the source varied by 2.6 mag in a couple of weeks in the R band. Many episodes of fast (i.e. intranight) variability were observed, most notably on December 12, when a flux increase of about 1.1 mag in 1.5 hours was detected, followed by a steep decrease of about 1.2 mag in 1 hour. The contribution by the thermal component is difficult to assess, due to the uncertainties in the Galactic, and possibly also intrinsic, extinction in the UV band. However, polynomial fitting of radio-to-UV SEDs reveals an increasing spectral bending going towards fainter states, suggesting a UV excess likely due to the thermal emission from the accretion disc

Lithospheric magma dynamics beneath El Hierro, Canary Islands: a fluid inclusion study

At active volcanoes, petrological studies have been proven to be a reliable approach in defining the depth conditions of magma transport and storage in both the mantle and the crust. Based on fluid inclusion and mineral geothermobarometry in mantle xenoliths, we propose a model for the magma plumbing system of the Island of El Hierro (Canary Islands). The peridotites studied here were entrained in a lava flow exposed in the El Yulan Valley. These lavas are part of the rift volcanism that occurred on El Hierro at approximately 40–30 ka. The peridotites are spinel lherzolites, harzburgites, and dunites which equilibrated in the shallow mantle at pressures between 1.5 and 2 GPa and at temperatures between 800 and 950 °C (low-temperature peridotites; LT), as well as at higher equilibration temperatures of 900 to 1100 °C (high-temperature peridotites; HT). Microthermometry and Raman analyses of fluid inclusions reveal trapping of two distinct fluid phases: early type I metasomatic CO2-N2 fluids (X N2 = 0.01–0.18; fluid density (d) = 1.19 g/cm3), coexisting with silicate-carbonate melts in LT peridotites, and late type II pure CO2 fluids in both LT (d = 1.11–1.00 and 0.75–0.65 g/cm3) and HT (d = 1.04–1.11 and 0.75–0.65 g/cm3) peridotites. While type I fluids represent metasomatic phases in the deep oceanic lithosphere (at depths of 60–65 km) before the onset of magmatic activity, type II CO2 fluids testify to two fluid trapping episodes during the ascent of xenoliths in their host mafic magmas. Identification of magma accumulation zones through interpretation of type II CO2 fluid inclusions and mineral geothermobarometry indicate the presence of a vertically stacked system of interconnected small magma reservoirs in the shallow lithospheric mantle between a depth of 22 and 36 km (or 0.67 to 1 GPa). This magma accumulation region fed a short-lived magma storage region located in the lower oceanic crust at a depth of 10–12 km (or 0.26–0.34 GPa). Following our model, the 40–30-ka-old volcanic activity of El Hierro is related to this mantle-based magma system, a system that we propose fed the recent 2011–2012 eruption