Cell surface engineering of renal cell carcinoma with glycosylphosphatidylinositol-anchored TIMP-1 blocks TGF-beta 1 activation and reduces regulatory ID gene expression

Tissue inhibitor of metalloproteinase 1 (TIMP-1) controls matrix metalloproteinase activity through 1:1 stoichiometric binding. Human TIMP-1 fused to a glycosylphosphatidylinositol (GPI) anchor (TIMP-1-GPI) shifts the activity of TIMP-1 from the extracellular matrix to the cell surface. TIMP-1-GPI treated renal cell carcinoma cells show increased apoptosis and reduced proliferation. Transcriptomic profiling and regulatory pathway mapping were used to identify the potential mechanisms driving these effects. Significant changes in the DNA binding inhibitors, TGF-beta 1/SMAD and BMP pathways resulted from TIMP-1-GPI treatment. These events were linked to reduced TGF-beta 1 signaling mediated by inhibition of proteolytic processing of latent TGF-beta 1 by TIMP-1-GPI

Peritumoral administration of GPI-anchored TIMP-1 inhibits colon carcinoma growth in Rag-2 gamma chain-deficient mice

Exogenous application of recombinant TIMP-1 protein modified by addition of a glycosylphosphatidylinositol (GPI) anchor allows efficient insertion of the fusion protein into cell membranes. This `cell surface engineering' leads to changes in the proteolytic environment. TIMP-1-GPI shows enhanced as well as novel in vitro biological activities including suppression of proliferation, reduced migration, and inhibition of invasion of the colon carcinoma cell line SW480. Treatment of SW480 tumors implanted in Rag (-/-) common gamma chain (-/-) C57BL/6 mice with peritumorally applied TIMP-1-GPI, control rhTIMP-1 protein, or vehicle shows that TIMP-1-GPI leads to a significant reduction in tumor growth

Impact of Home- and Hospital-Based Exercise in Cardiac Rehabilitation on Hopelessness in Patients With Coronary Heart Disease

Hopelessness is associated with increased adverse events and decreased survival in patients with coronary heart disease (CHD). The purpose of this research was to examine the effect of regular home- and hospital-based cardiac rehabilitation (CR) exercise on hopelessness levels in patients with CHD, hypothesizing that increased exercise in either setting would lead to decreased state hopelessness

Corporate Security Responsibility: Towards a Conceptual Framework for a Comparative Research Agenda

The political debate about the role of business in armed conflicts has increasingly raised expectations as to governance contributions by private corporations in the fields of conflict prevention, peace-keeping and postconflict peace-building. This political agenda seems far ahead of the research agenda, in which the negative image of business in conflicts, seen as fuelling, prolonging and taking commercial advantage of violent conflicts,still prevails. So far the scientific community has been reluctant to extend the scope of research on ‘corporate social responsibility’ to the area of security in general and to intra-state armed conflicts in particular. As a consequence, there is no basis from which systematic knowledge can be generated about the conditions and the extent to which private corporations can fulfil the role expected of them in the political discourse. The research on positive contributions of private corporations to security amounts to unconnected in-depth case studies of specific corporations in specific conflict settings. Given this state of research, we develop a framework for a comparative research agenda to address the question: Under which circumstances and to what extent can private corporations be expected to contribute to public security

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Adenosine A2a receptors form distinct oligomers in protein detergent complexes

The human adenosine A2a receptor (A2aR) tunes its function by forming homo-oligomers and hetero-oligomers with other GPCRs, but the biophysical characterization of these oligomeric species is limited. Here, we show that upon reconstitution into an optimized mixed micelle system, and purification via an antagonist affinity column, full length A2aR exists as a distribution of oligomers. We isolated the dimer population from the other oligomers via size exclusion chromatography and showed that it is stable upon dilution, thus supporting the hypotheses that the A2aR dimer has a defined structure and function. This study presents a crucial enabling step to a detailed biophysical characterization of A2aR homodimers

The State-Trait Hopelessness Scale: Development and Testing

Hopelessness is predictive in the development of coronary heart disease (CHD) and can persist in patients after a CHD event, adversely affecting recovery. Hopelessness may represent a temporary response (state) or a chronic outlook (trait). Common hopelessness measures fail to differentiate state from trait hopelessness, a potentially important differentiation for treatment. The State-Trait Hopelessness Scale (STHS) was developed and pilot tested with two groups of college students (n = 39 and 190) and patients with CHD (n = 44). The instrument was then used with 520 patients, confirming reliability (Cronbach\u27s ) for the State (.88) and Trait (.91) subscales and concurrent and predictive validity. Separate exploratory factor analyses showed two factors (hopelessness present or hopelessness absent) for the State and Trait subscales, accounting for 58.9% and 57.3% of variance, respectively. These findings support future use of the tool in clinical settings and in intervention studies focused on hopelessness

Deux épaves d'époque moderne à Bouliac (Gironde)

The accidental discovery of the archaeological site of Godefroy has put to light a harbour. It is constituted by rocky blocks walling the bank of the river and by a pier built out perpendicularly to the river-bed. It was created in the middle of the XVIIth century and was abandonned during the last tens of the century. Two wrecks have been discovered during the digging of the site. A flat bottom fluvial boat was lying within the mud that has gradually covered over the dock. It dates back to 1680. The palynological studies of the calking moss have evidenced that this craft might have been built in the upper part of the Lot or of the Dordogne river region. The second one, a maritime craft of smaller size, was sunk during the building of the embankment. It was moved either with a sail or with oars and seems to have been perfectly adapted to estuary navigation.La découverte fortuite du site archéologique de Godefroy a révélé un aménagement portuaire constitué d’un enrochement de berge et d’ une avancée perpendiculaire au lit du fleuve. Créé au milieu du XVIIe siècle, cet ensemble fut abandonné dans les dernières décennies du siècle. Deux épaves ont été exhumées au cours des terrassements entrepris sur le site. Une embarcation fluviale à fond plat gisait dans les vases venues recouvrir la cale. Elle a été datée des années 1680. D’après les résultats des analyses palynologiques des mousses de calfatage, cette coque aurait été construite dans le cours supérieur du Lot ou de la Dordogne. La seconde embarcation, une construction maritime en forme de proportions plus modestes, a été coulée au moment de la construction des aménagements de berge. Propulsé à la voile et à l’aviron, ce bateau paraît parfaitement adapté à la navigation en estuaire.Bizot Bruno, Rieth Éric, Bourgeois Guy, Diot Marie-Françoise, Haritchecort André, Haritchecort Jean-Pierre, Herault Marianne, Gourdon-Platel Nicole, Guibal Frédéric, Regaldo-Saint-Blancard Pierre, Salomon Jean-Noël, Szepertyski Béatrice, Werno Jérôme. Deux épaves d'époque moderne à Bouliac (Gironde). In: Aquitania : une revue inter-régionale d'archéologie, tome 9, 1991. pp. 177-241