CCR8 leads to eosinophil migration and regulates neutrophil migration in murine allergic enteritis

Allergic enteritis (AE) is a gastrointestinal form of food allergy. This study aimed to elucidate cellular and molecular mechanisms of AE using a murine model. To induce AE, BALB/c wild type (WT) mice received intraperitoneal sensitization with ovalbumin (an egg white allergen) plus ALUM and feeding an egg white (EW) diet. Microarray analysis showed enhanced gene expression of CC chemokine receptor (CCR) 8 and its ligand, chemokine CC motif ligand (CCL) 1 in the inflamed jejunum. Histological and FACS analysis showed that CCR8 knock out (KO) mice exhibited slightly less inflammatory features, reduced eosinophil accumulation but accelerated neutrophil accumulation in the jejunums, when compared to WT mice. The concentrations of an eosinophil chemoattractant CCL11 (eotaxin-1), but not of IL-5, were reduced in intestinal homogenates of CCR8KO mice, suggesting an indirect involvement of CCR8 in eosinophil accumulation in AE sites by inducing CCL11 expression. The potential of CCR8 antagonists to treat allergic asthma has been discussed. However, our results suggest that CCR8 blockade may promote neutrophil accumulation in the inflamed intestinal tissues, and not be a suitable therapeutic target for AE, despite the potential to reduce eosinophil accumulation. This study advances our knowledge to establish effective anti-inflammatory strategies in AE treatment.Fil: Blanco-Pérez, Frank. Paul-ehrlich-institut;Fil: Kato, Yoichiro. Tokyo Women's Medical University;Fil: Gonzalez-Menendez, Irene. Universitätsklinikum Tübingen Medizinische Fakultät;Fil: Laiño, Jonathan Emiliano. Paul-ehrlich-institut;Fil: Ohbayashi, Masaharu. Toyohashi Sozo University;Fil: Burggraf, Manja. Paul-ehrlich-institut;Fil: Krause, Maren. Paul-ehrlich-institut;Fil: Kirberg, Jörg. Paul-ehrlich-institut;Fil: Iwakura, Yoichiro. Tokyo University Of Science;Fil: Martella, Manuela. Universitätsklinikum Tübingen Medizinische Fakultät;Fil: Quintanilla-Martinez, Leticia. Universitätsklinikum Tübingen Medizinische Fakultät;Fil: Shibata, Noriyuki. Tokyo Women's Medical University;Fil: Vieths, Stefan. Paul-ehrlich-institut;Fil: Scheurer, Stephan. Paul-ehrlich-institut;Fil: Toda, Masako. Paul-ehrlich-institut; . Tohoku University

Development of a system based on artificial intelligence to identify visual problems in children: study protocol of the TrackAI project

Introduction Around 70% to 80% of the 19 million visually disabled children in the world are due to a preventable or curable disease, if detected early enough. Vision screening in childhood is an evidence-based and cost-effective way to detect visual disorders. However, current screening programmes face several limitations: training required to perform them efficiently, lack of accurate screening tools and poor collaboration from young children. Some of these limitations can be overcome by new digital tools. Implementing a system based on artificial intelligence systems avoid the challenge of interpreting visual outcomes. The objective of the TrackAI Project is to develop a system to identify children with visual disorders. The system will have two main components: a novel visual test implemented in a digital device, DIVE (Device for an Integral Visual Examination); and artificial intelligence algorithms that will run on a smartphone to analyse automatically the visual data gathered by DIVE. Methods and analysis This is a multicentre study, with at least five centres located in five geographically diverse study sites participating in the recruitment, covering Europe, USA and Asia. The study will include children aged between 6 months and 14 years, both with normal or abnormal visual development. The project will be divided in two consecutive phases: design and training of an artificial intelligence (AI) algorithm to identify visual problems, and system development and validation. The study protocol will consist of a comprehensive ophthalmological examination, performed by an experienced paediatric ophthalmologist, and an exam of the visual function using a DIVE. For the first part of the study, diagnostic labels will be given to each DIVE exam to train the neural network. For the validation, diagnosis provided by ophthalmologists will be compared with AI system outcomes. Ethics and dissemination The study will be conducted in accordance with the principles of Good Clinical Practice. This protocol was approved by the Clinical Research Ethics Committee of Aragón, CEICA, on January 2019 (Code PI18/346). Results will be published in peer-reviewed journals and disseminated in scientific meetings

Mast cells partly contribute to allergic enteritis development: Findings in two different mast cell-deficient mice

Allergic enteritis (AE) is a gastrointestinal form of food allergy. The presence of mast cells and granulocytes has been detected in the inflamed tissues in AE. In this study, we aimed to elucidate the role of mast cells in AE development using two mast cell-deficient mouse strains: KIT(W-sh/W-sh) bearing the W-sash (W(sh)) inversion mutation and Cpa3Cre/+, which lack mast cells due to Cre-mediated mast cell eradication, were used in an AE experimental model. The development of clinical symptoms (e.g. drop in body temperature and weight loss) were abolished in both strains, whereas inflammatory levels of AE (e.g. villous atrophy, edema, and granulocyte accumulation) were reduced mainly in KITW-sh/W-sh mice. FACS analysis of the KITW-sh/W-sh intestinal lamina propria, showed a reduction in the eosinophil (CD45+CD11b+SiglecF+cells) and neutrophil (CD45+CD11b+SiglecF−Ly6G+ cells) accumulation. Cpa3Cre/+ mice showed reduced eosinophil (CD45+CD11b+SiglecF+cells) accumulation, but neutrophil (CD45+CD11b+SiglecF−Ly6G+ cells) accumulation was retained at AE sites. The concentrations of CC chemokine ligand 1 (CCL1), a known CC chemokine receptor 8 ligand leading to eosinophil recruitment, was reduced in intestinal homogenates of both mast cell-deficient mouse strains. These results suggest that mast cells play a role in AE development in part by expressing CCL1 and contributing to eosinophil accumulation at AE. This study offers implications for establishing AE treatments that target infiltrating leucocytes in AE tissues.Fil: Blanco Pérez, Frank. No especifíca;Fil: Gonzalez Menendez, Irene. No especifíca;Fil: Stassen, Michael. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Kato, Yoichiro. Tokyo Women's Medical University; JapónFil: Laiño, Jonathan Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; ArgentinaFil: Kirberg, Jörg. No especifíca;Fil: Krause, Maren. No especifíca;Fil: Martella, Manuela. No especifíca;Fil: Shibata, Noriyuki. Tokyo Women's Medical University; JapónFil: Quintanilla-Martinez, Leticia. No especifíca;Fil: Feyerabend, Thorsten B.. No especifíca;Fil: Rodewald, Hans Reimer. No especifíca;Fil: Galli, Stephen J.. University of Stanford; Estados UnidosFil: Vieths, Stefan. No especifíca;Fil: Scheurer, Stephan. No especifíca;Fil: Toda, Masako. No especifíca

Omics approaches in pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients

Synthesis and biological evaluation of N-cyanoalkyl-, Naminoalkyl-, and N-guanidinoalkyl-substituted 4-aminoquinoline derivatives as potent, selective, brain permeable antitrypanosomal agents

YesCurrent drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. The search for novel, effective, brain permeable, safe, and inexpensive antitrypanosomal compounds is therefore an urgent need. We have recently reported that the 4-aminoquinoline derivative huprine Y, developed in our group as an anticholinesterasic agent, exhibits a submicromolar potency against Trypanosoma brucei and that its homo- and hetero-dimerization can result in to up to three-fold increased potency and selectivity. As an alternative strategy towards more potent smaller molecule anti-HAT agents, we have explored the introduction of ω-cyanoalkyl, ω-aminoalkyl, or ω-guanidinoalkyl chains at the primary amino group of huprine or the simplified 4-aminoquinoline analogue tacrine. Here, we describe the evaluation of a small in-house library and a second generation of newly synthesized derivatives, which has led to the identification of 13 side chain modified 4-aminoquinoline derivatives with submicromolar potencies against T. brucei. Among these compounds, the guanidinononyltacrine analogue 15e exhibits a 5-fold increased antitrypanosomal potency, 10-fold increased selectivity, and 100-fold decreased anticholinesterasic activity relative to the parent huprine Y. Its biological profile, lower molecular weight relative to dimeric compounds, reduced lipophilicity, and ease of synthesis, make it an interesting anti-HAT lead, amenable to further optimization to eliminate its remaining anticholinesterasic activity.Wellcome Trus

Frequency and Characteristics of familial melanoma in Spain: the FAM-GEM-1 Study.

Familial history of melanoma is a well-known risk factor for the disease, and 7% melanoma patients were reported to have a family history of melanoma. Data relating to the frequency and clinical and pathological characteristics of both familial and non-familial melanoma in Spain have been published, but these only include patients from specific areas of Spain and do not represent the data for the whole of Spain. PATIENTS AND METHODS: An observational study conducted by the Spanish Group of Melanoma (GEM) analyzed the family history of patients diagnosed with melanoma between 2011 and 2013 in the dermatology and oncology departments. RESULTS: In all, 1047 patients were analyzed, and 69 (6.6%) fulfilled criteria for classical familial melanoma (two or more first-degree relatives diagnosed with melanoma). Taking into account other risk factors for familial melanoma, such as multiple melanoma, pancreatic cancer in the family or second-degree relatives with melanoma, the number of patients fulfilling the criteria increased to 165 (15.8%). Using a univariate analysis, we determined that a Breslow index of less than 1 mm, negative mitosis, multiple melanoma, and a history of sunburns in childhood were more frequent in familial melanoma patients, but a multivariate analysis revealed no differences in any pathological or clinical factor between the two groups. CONCLUSIONS: Similar to that observed in other countries, familial melanoma accounts for 6.6% of melanoma diagnoses in Spain. Although no differences in the multivariate analysis were found, some better prognosis factors, such as Breslow index, seem more frequent in familial melanoma, which reflect a better early detection marker and/or a different biological behavior

Risk factors and outcome of COVID-19 in patients with hematological malignancies

Background: Prognostic factors of poor outcome in patients with hematological malignancies and COVID-19 are poorly defned. Patients and methods: This was a Spanish transplant group and cell therapy (GETH) multicenter retrospective observational study, which included a large cohort of blood cancer patients with laboratory-confrmed SARS-CoV-2 infection through PCR assays from March 1st 2020 to May 15th 2020. Results: We included 367 pediatric and adult patients with hematological malignancies, including recipients of autologous (ASCT) (n=58) or allogeneic stem cell transplantation (allo-SCT) (n=65) from 41 hospitals in Spain. Median age of patients was 64 years (range 1-93.8). Recipients of ASCT and allo-SCT showed lower mortality rates (17% and 18%, respectively) compared to non-SCT patients (31%) (p=0.02). Prognostic factors identifed for day 45 overall mortality (OM) by logistic regression multivariate analysis included age>70 years [odds ratio (OR) 2.1, 95% con‑ fdence interval (CI) 1.2-3.8, p=0.011]; uncontrolled hematological malignancy (OR 2.9, 95% CI 1.6-5.2, p20 mg/dL (OR 3.3, 95% CI 1.7-6.4, p<0.0001). In multivariate analysis of 216 patients with very severe COVID-19, treatment with azithromycin or low dose corticosteroids was associated with lower OM (OR 0.42, 95% CI 0.2-0.89 and OR 0.31, 95% CI 0.11-0.87, respectively, p=0.02) whereas the use of hidroxycloroquine did not show signifcant improvement in OM (OR 0.64, 95% CI 0.37-1.1, P=0.1). Conclusions: In most patients with hematological malignancies COVID-19 mortality was directly driven by older age, disease status, performance status, as well as by immune (neutropenia) parameters and level of infammation (high CRP). Use of azithromycin and low dose corticosteroids may be of value in very severe COVID-19

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected