Human T cell glycosylation and implications on immune therapy for cancer

Glycosylation is an important post-translational modification, giving rise to a diverse and abundant repertoire of glycans on the cell surface, collectively known as the glycome. When focusing on immunity, glycans are indispensable in virtually all signaling and cell-cell interactions. More specifically, glycans have been shown to regulate key pathophysiological steps within T cell biology such as T cell development, thymocyte selection, T cell activity and signaling as well as T cell differentiation and proliferation. They are of major importance in determining the interaction of human T cells with tumor cells. In this review, we will describe the role of glycosylation of human T cells in more depth, elaborate on the importance of glycosylation in the interaction of human T cells with tumor cells and discuss the potential of cancer immunotherapies that are based on manipulating the glycome functions at the tumor immune interface

Prior events predict cerebrovascular and coronary outcomes in the PROGRESS trial

<p><b>Background and Purpose:</b> The relationship between baseline and recurrent vascular events may be important in the targeting of secondary prevention strategies. We examined the relationship between initial event and various types of further vascular outcomes and associated effects of blood pressure (BP)–lowering.</p> <p><b>Methods:</b> Subsidiary analyses of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial that established the benefits of BP–lowering in 6105 patients (mean age 64 years, 30% female) with cerebrovascular disease, randomly assigned to either active treatment (perindopril for all, plus indapamide in those with neither an indication for, nor a contraindication to, a diuretic) or placebo(s).</p> <p><b>Results:</b> Stroke subtypes and coronary events were associated with 1.5- to 6.6-fold greater risk of recurrence of the same event (hazard ratios, 1.51 to 6.64; P=0.1 for large artery infarction, P<0.0001 for other events). However, 46% to 92% of further vascular outcomes were not of the same type. Active treatment produced comparable reductions in the risk of vascular outcomes among patients with a broad range of vascular events at entry (relative risk reduction, 25%; P<0.0001 for ischemic stroke; 42%, P=0.0006 for hemorrhagic stroke; 17%, P=0.3 for coronary events; P homogeneity=0.4).</p> <p><b>Conclusions:</b> Patients with previous vascular events are at high risk of recurrences of the same event. However, because they are also at risk of other vascular outcomes, a broad range of secondary prevention strategies is necessary for their treatment. BP–lowering is likely to be one of the most effective and generalizable strategies across a variety of major vascular events including stroke and myocardial infarction.</p&gt

Solid Particle Erosion Mechanisms of Protective Coatings for Aerospace Applications

Le progrès économique et technologique ainsi que les considérations environnementales nécessitent la conception d’équipements de plus en plus performants, sollicitant les composantes aux limites de leur capacité. Une conséquence importante de cette demande accrue au niveau de la performance est que les lacunes de type tribologique, telles que la dégradation du lubrifiant, l’usure excessive et la tribocorrosion, peuvent être amplifiées de façon significative, menant à des coûts d’exploitation additionnels, une efficacité moindre et une défaillance prématurée. Puisque les processus tribologiques découlent de l’interaction entre au moins deux corps en mouvement relatif dans un environnement donné, l’ingénierie de surface peut permettre de conférer aux surfaces la performance de pointe requise lorsque les conditions de fonctionnement sont très exigeantes. Dans ce contexte, la conception de systèmes de matériaux appropriés doit être guidée par une connaissance poussée des mécanismes de dégradation et de la réponse de la surface au chargement et à la déformation, qui agissent souvent de façon synergique. L’érosion par impact de particules solides (EIPS) survient lorsque des particules solides dures, présentes dans l’environnement, sont entraînées par un fluide et impactent les surfaces de composantes. Ce type de dommage est spécifiquement marqué dans la première section d’un moteur d’avion, où les pales du compresseur peuvent s’éroder à un point tel que la performance aérodynamique et même l’intégrité structurale sont compromises. Ainsi, de nombreux travaux de recherche ont été réalisés dans les secteurs académique et industriel afin de comprendre les mécanismes de perte de matière impliqués dans l’EIPS et afin de développer des technologies protectrices dans le but d’améliorer la durée de vie utile des composantes. Un exemple est l’utilisation de revêtements protecteurs durs afin de limiter l’érosion des composantes de moteur d’avion, qui sont pour la plupart métalliques. Dans cette optique, l’objectif principal de ce projet de doctorat est d’étudier les mécanismes de perte de matière pendant l’EIPS de couches dures protectrices, incluant les systèmes nanocomposites et nanostructurés. De plus, étant donné la nature complexe des mécanismes d’EIPS, des méthodologies expérimentales rigoureuses doivent être mises en oeuvre, et les effets de tous les paramètres de test impliqués doivent être entièrement compris. Dans cette thèse de doctorat, l’importance de la méthodologie expérimentale est mise de l’avant tout au long du ---------- Abstract Economic and technological progress, as well as environmental concerns, require that modern equipment be designed with ever more stringent performance criteria, frequently pushing components to the very limits of their capabilities. One major consequence of this increased demand on performance is that tribological deficiencies, such as lubrication breakdown, excessive wear and tribo-corrosion, can be significantly amplified, leading to unnecessary operational costs, decreased efficiency and premature failure. Because tribological processes result from the interaction of two or more bodies in relative motion in a particular environment, surface engineering can be used to confer to surfaces the high performance needed for demanding operational conditions. In this context, the design of the appropriate material system must be guided by an accurate understanding of the degradation mechanisms and the surface response to loading and deformation, frequently acting in synergy. Solid Particle Erosion (SPE) occurs in situations where hard solid particles present in the environment are entrained in a fluid stream, and impact component surfaces. This type of damage is most prominent in the first stage of the aircraft engine, where the compressor blades can be eroded to such an extent that aerodynamic performance and even structural integrity are compromised. Consequently, much work has been done in academia and industry in order to understand the material loss mechanisms present in SPE and to develop protective technologies that will increase component lifetimes. One such technology is the use of hard protective coatings to impede the erosion of the predominantly metallic engine components. Accordingly, the main objective of this PhD project is to investigate the material loss mechanisms during SPE of hard protective coatings, including nanocomposite and nanostructured systems. In addition, because of the complex nature of SPE mechanisms, rigorous testing methodologies need to be employed and the effects of all testing parameters need to be fully understood. In this PhD project, the importance of testing methodology is addressed throughout in order to effectively study the SPE mechanisms of brittle materials and coatings. In the initial stage of this thesis, we studied the effect of the addition of silicon (Si) on the microstructure, mechanical properties and, more specifically, on the SPE resistance of thick CrNbased coatings. It was found that the addition of Si significantly improved the erosion resistance and that SPE correlated with the microhardness values, i.e. the coating with the highes

Lower Body Positive Pressure Application with an Antigravity Suit in Acute Carotid Occlusion

The challenge in acute stroke is still to reperfuse as early as possible the ischemic territory. Since fibrinolytic therapies have a limited window with potential risk of bleeding, having a nonpharmacologic mean to recruit vessels in area surrounding necrosis might be useful. We propose here to use antigravity suit inflated at “venous” pressure levels to shift blood towards thoracic and brain territories. We report two cases of spectacular clinical recovery after acute carotid occlusion

Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study

Objective To evaluate the association of overall and specific headaches with volume of white matter hyperintensities, brain infarcts, and cognition

Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy.: The PROGRESS MRI Substudy.

International audienceBACKGROUND: The prevalence of white matter hyperintensities (WMHs) detected on cerebral MRI is associated with hypertension, but it is not known whether blood pressure lowering can arrest their progression. We report here the results of an MRI substudy of PROGRESS (Perindopril Protection Against Recurrent Stroke Study), a randomized trial of blood pressure lowering in subjects with cerebrovascular disease. METHODS AND RESULTS: The substudy comprised 192 participants who had a cerebral MRI both at baseline and after a mean follow-up time of 36 months (SD=6.0 months). At the first MRI, WMHs were graded with a visual rating scale from A (no WMH) to D (severe WMH). Participants were assigned to a combination of perindopril plus indapamide (or their placebos; 58%) or to single therapy with perindopril (or placebo). At the time of the second MRI, the blood pressure reduction in the active arm compared with the placebo arm was 11.2 mm Hg for systolic blood pressure and 4.3 mm Hg for diastolic blood pressure. Twenty-four subjects (12.5%) developed new WMHs at follow-up. The risk of new WMH was reduced by 43% (95% CI -7% to 89%) in the active treatment group compared with the placebo group (P=0.17). The mean total volume of new WMHs was significantly reduced in the active treatment group (0.4 mm3 [SE=0.8]) compared with the placebo group (2.0 mm3 [SE=0.7]; P=0.012). This difference was greatest for patients with severe WMH at entry, 0.0 mm3 (SE=0) in the active treatment group versus 7.6 mm3 (SE=1.0) in the placebo group (P<0.0001). CONCLUSIONS: These results indicate that an active blood pressure-lowering regimen stopped or delayed the progression of WMHs in patients with cerebrovascular disease

Design, data management, and population baseline characteristics of the PERFORM magnetic resonance imaging project

Quantitative information from magnetic resonance imaging (MRI) may substantiate clinical findings and provide additional insight into the mechanism of clinical interventions in therapeutic stroke trials. The PERFORM study is exploring the efficacy of terutroban versus aspirin for secondary prevention in patients with a history of ischemic stroke. We report on the design of an exploratory longitudinal MRI follow-up study that was performed in a subgroup of the PERFORM trial. An international multi-centre longitudinal follow-up MRI study was designed for different MR systems employing safety and efficacy readouts: new T2 lesions, new DWI lesions, whole brain volume change, hippocampal volume change, changes in tissue microstructure as depicted by mean diffusivity and fractional anisotropy, vessel patency on MR angiography, and the presence of and development of new microbleeds. A total of 1,056 patients (men and women ≥55 years) were included. The data analysis included 3D reformation, image registration of different contrasts, tissue segmentation, and automated lesion detection. This large international multi-centre study demonstrates how new MRI readouts can be used to provide key information on the evolution of cerebral tissue lesions and within the macrovasculature after atherothrombotic stroke in a large sample of patients

Rationale, design and population baseline characteristics of the PERFORM Vascular Project: an ancillary study of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) trial

&lt;p&gt;&lt;b&gt;Purpose&lt;/b&gt;&lt;/p&gt; &lt;p&gt;PERFORM is exploring the efficacy of terutroban versus aspirin for secondary prevention in patients with a history of ischemic stroke or transient ischemic attacks (TIAs). The PERFORM Vascular Project will evaluate the effect of terutroban on progression of atherosclerosis, as assessed by change in carotid intima-media thickness (CIMT) in a subgroup of patients.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods and results&lt;/b&gt;&lt;/p&gt; &lt;p&gt;The Vascular Project includes structural (CIMT, carotid plaques) and functional (carotid stiffness) vascular studies in all patients showing at least one carotid plaque at entry. Expected mean follow-up is 36 months. Primary endpoint is rate of change of CIMT. Secondary endpoints include emergent plaques and assessment of carotid stiffness. 1,100 patients are required for 90% statistical power to detect treatment-related CIMT difference of 0.025 mm. The first patient was randomized in April 2006.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions&lt;/b&gt;&lt;/p&gt; &lt;p&gt;The PERFORM Vascular Project will investigate terutroban’s effect on vascular structure and function in patients with a history of ischemic stroke or TIAs.&lt;/p&gt