Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice

Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD

Residential density classification for sustainable housing development using a machine learning approach

Using Machine Learning (ML) algorithms for classification of the existing residential neighbourhoods and their spatial characteristics (e.g. density) so as to provide plausible scenarios for designing future sustainable housing is a novel application. Here we develop a methodology using a Random Forests algorithm (in combination with GIS spatial data processing) to detect and classify the residential neighbourhoods and their spatial characteristics within the region between Oxford and Cambridge, that is, the 'Oxford-Cambridge Arc'. The classification model is based on four pre-defined urban classes, that is, Centre, Urban, Suburban, and Rural for the entire region. The resolution is a grid of 500 m × 500 m. The features for classification include (1) dwelling geometric attributes (e.g. garden size, building footprint area, building perimeter), (2) street networks (e.g. street length, street density, street connectivity), (3) dwelling density (number of housing units per hectare), (4) building residential types (detached, semi-detached, terraced, and flats), and (5) characteristics of the surrounding neighbourhoods. The classification results, with overall average accuracy of 80% (accuracy per class: Centre: 38%, Urban 91%, Suburban 83%, and Rural 77%), for the Arc region show that the most important variables were three characteristics of the surrounding area: residential footprint area, dwelling density, and number of private gardens. The results of the classification are used to establish a baseline for the current status of the residential neighbourhoods in the Arc region. The results bring data-driven decision-making processes to the level of local authority and policy makers in order to support sustainable housing development at the regional scale

Combined paclitaxel and gemcitabine as first-line treatment in metastatic non-small cell lung cancer: a multicentre phase II study

The efficacy and toxicity of combined paclitaxel and gemcitabine was evaluated in 54 chemotherapy-naive patients with metastatic non-small cell lung cancer (NSCLC). Gemcitabine i.v. 1000 mg/m2was administered on days 1 and 8 and paclitaxel 200 mg/m2as a continuous 3-hour infusion on day 1. Treatment was repeated every 21 days. Patients had a median age of 53 years. ECOG performance status was 0 or 1 in 48 patients. 41 patients (75.9%) had initial stage IV disease; histology was mainly adenocarcinoma (46.3%). 2 patients (4.3%) achieved a complete response and 15 (31.9%) achieved a partial response giving an overall response rate of 36.2% (95% CI: 22.4–49.9%); 19 patients (40.4%) had stable disease and 10 (21.3%) had progressive disease. The median survival time was 51 weeks (95% CI: 46.5–59.3), with a 1-year survival probability of 0.48 (95% CI: 0.34–0.63). Grade 3/4 neutropenia and febrile neutropenia occurred in 15.2% and 2.2% of courses, respectively. Grade 3/4 thrombocytopenia was rare (1.8% of courses). Peripheral neurotoxicity developed in 25 patients (47.2%), mostly grade 1/2. Arthalgia/myalgia was observed in 30 patients (56.6%), generally grade 1 or 2. Grade 3 abnormal levels of serum glutamate pyruvate transaminase (SGPT) and serum glutamate oxaloacetate transaminase (SGOT) occurred in 5 patients (9.4%) and 1 patient (1.9%), respectively. Combined paclitaxel and gemcitabine is an active and well-tolerated regimen for the treatment of advanced NSCLC, and warrants further investigation in comparative, randomized trials. © 2001 Cancer Research Campaign http://www.bjcancer.co

A constant and similar assembly defect of mitochondrial respiratory chain complex I allows rapid identification of NDUFS4 mutations in patients with Leigh syndrome

AbstractIsolated complex I deficiency is a frequent cause of respiratory chain defects in childhood. In this study, we report our systematic approach with blue native PAGE (BN-PAGE) to study mitochondrial respiratory chain assembly in skin fibroblasts from patients with Leigh syndrome and CI deficiency. We describe five new NDUFS4 patients with a similar and constant abnormal BN-PAGE profile and present a meta-analysis of the literature. All NDUFS4 mutations that have been tested with BN-PAGE result in a constant and similar abnormal assembly profile with a complete loss of the fully assembled complex I usually due to a truncated protein and the loss of its canonical cAMP dependent protein kinase phosphorylation consensus site. We also report the association of abnormal brain MRI images with this characteristic BN-PAGE profile as the hallmarks of NDUFS4 mutations and the first founder NDUFS4 mutations in the North-African population

Artificial Intelligence for Sustainable Development: Synthesis Report, Mobile Learning Week 2019

(First paragraph) 2019’s Mobile Learning Week (MLW), UNESCO’s flagship event for information and communication technology (ICT) in education, focused on the theme ‘Artificial Intelligence for Sustainable Development’. Held over five days in Paris, it comprised a sequence of high-profile events (a global conference, a policy forum and workshops, a symposium and strategy labs), and involved more than 1,500 participants from 140 countries (including Ministers of Education and ICT, other representatives from Member States, the private sector, academia and international organizations)

Evaporation from a small water reservoir: Direct measurements and estimates

Summary Knowing the rate of evaporation from surface water resources such as chan¬nels and reservoirs is essential for precise management of the water balance. However, evaporation is difficult to measure experimentally over water surfaces and several tech¬niques and models have been suggested and used in the past for its determination. In this research, evaporation from a small water reservoir in northern Israel was measured and estimated using several experimental techniques and models during the rainless summer. Evaporation was measured with an eddy covariance (EC) system consisting of a three-dimensional sonic anemometer and a Krypton hygrometer. Measurements of net radia¬tion, air temperature and humidity, and water temperature enabled estimation of other energy balance components. Several models and energy balance closure were evaluated. In addition, evaporation from a class-A pan was measured at the site. EC evaporation measurements for 21 days averaged 5.48 mm day�1. Best model predictions were obtained with two combined flux-gradient and energy balance models (Penman–Mon¬teith–Unsworth and Penman–Brutsaert), which with the water heat flux term, gave sim¬ilar daily average evaporation rates, that were up to 3% smaller than the corresponding EC values. The ratio between daily pan and EC evaporation varied from 0.96 to 1.94. The bulk mass transfer coefficient was estimated using a model based on measurements of water surface temperature, evaporation rate and absolute humidity at 0.9 and 2.9 m above the water surface, and using two theoretical approaches. The bulk transfer coefficient

Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE. We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety. The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P = .0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic reference score by 1.6 (P = .0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P < .0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group). In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052