MHC class II/ESO tetramer-based generation of in vitro primed anti-tumor T-helper lines for adoptive cell therapy of cancer.

Generation of tumor-antigen specific CD4(+) T-helper (T(H)) lines through in vitro priming is of interest for adoptive cell therapy of cancer, but the development of this approach has been limited by the lack of appropriate tools to identify and isolate low frequency tumor antigen-specific CD4(+) T cells. Here, we have used recently developed MHC class II/peptide tetramers incorporating an immunodominant peptide from NY-ESO-1 (ESO), a tumor antigen frequently expressed in different human solid and hematologic cancers, to implement an in vitro priming platform allowing the generation of ESO-specific T(H) lines. We isolated phenotypically defined CD4(+) T-cell subpopulations from circulating lymphocytes of DR52b(+) healthy donors by flow cytometry cell sorting and stimulated them in vitro with peptide ESO(119-143), autologous APC and IL-2. We assessed the frequency of ESO-specific cells in the cultures by staining with DR52b/ESO(119-143) tetramers (ESO-tetramers) and TCR repertoire of ESO-tetramer(+) cells by co-staining with TCR variable β chain (BV) specific antibodies. We isolated ESO-tetramer(+) cells by flow cytometry cell sorting and expanded them with PHA, APC and IL-2 to generate ESO-specific T(H) lines. We characterized the lines for antigen recognition, by stimulation with ESO peptide or recombinant protein, cytokine production, by intracellular staining using specific antibodies, and alloreactivity, by stimulation with allo-APC. Using this approach, we could consistently generate ESO-tetramer(+) T(H) lines from conventional CD4(+)CD25(-) naïve and central memory populations, but not from effector memory populations or CD4(+)CD25(+) Treg. In vitro primed T(H) lines recognized ESO with affinities comparable to ESO-tetramer(+) cells from patients immunized with an ESO vaccine and used a similar TCR repertoire. In this study, using MHC class II/ESO tetramers, we have implemented an in vitro priming platform allowing the generation of ESO-monospecific polyclonal T(H) lines from non-immune individuals. This is an approach that is of potential interest for adoptive cell therapy of patients bearing ESO-expressing cancers.

International registry on splanchnic vein thrombosis: description of the study population

Background: Splanchnic vein thrombosis (SVT) is an uncommon, butpotentially life-threatening disease. Aim of this ISTH based registryis to improve the knowledge on SVT by studying a large, international,unselected population.Methods: Consecutive patients with objectively diagnosed SVT areeligible for the registry. Information on clinical presentations, diagnosticapproaches, risk factors, therapeutic approaches, and recurrencesof SVT, bleedings and deaths at a 2 year follow up are enteredon a website database (www.svt.altervista.org). We planned a samplesize of 500 patients, including all sites of thrombosis.Results: As of December 31st, 2010, 429 patients with SVT (85.8%of the planned sample) have been enrolled at 25 centres from sevencountries. The mean age is 52.6 years (range 16-85 years); 62.2% aremales, 67.8% are Caucasians, and 31.2% Asians. SVT occurred inmultiple vein segments in 36.4% of patients, 40.5% of patients hadisolated portal vein thrombosis, 11.9% of patients had mesentericvein thrombosis, 7.5% had supra-hepatic vein thrombosis, and 3.6%had splenic vein thrombosis. Abdominal pain was the most commonsymptom occurring in 56.6% of the patients; 9.5% of patients hadgastrointestinal bleeding at the time of diagnosis; 25.4% of patientswith SVT were asymptomatic. Mean time between onset of symptomsand diagnosis was 7.4 days. Objective diagnosis was obtained withabdominal CT in 79.9% of patients. Most common risk factors atthe time of diagnosis included cancer (24.1%), cirrhosis (23.1%), andhematological disorders (15.4%); in 15.9% of patients SVT was idiopathic.Most patients were treated with anticoagulant drugs: 30.8%with parenteral drugs only, 56.9% with parenteral drugs followed byvitamin K antagonists.Conclusions: SVT is a major challenge for experts in thrombosis andhemostasis. Large collaborative studies are necessary to improve theunderstanding and the management of this heterogeneous disease.

Association Study of Common Genetic Variants and HIV-1 Acquisition in 6,300 Infected Cases and 7,200 Controls.

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10(-11)). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

Annual Review of the European Football Players' Labour Market / Etude annuelle du marché du travail européen des footballeurs

The key reference on the labour market and the logics of squad formation in the big-5 European leagues. One hundred richly coloured pages, illustrated by graphics, maps, rankings, statistical models and analysis in French and English which inform managers about potential strategies to put their clubs on the road to success help managers of federations and players' unions to understand current trends and to take decisions ... suggest to journalists new lines of investigation likely to interest the general public allow researchers and students to benefit from reliable and comparable sources, developed with the greatest possible rigour ... give fans the possibility to understand in detail the dynamics at work in their favourite sport and club.

Agents and intermediaries

Managing Football is the first book to directly respond to the rapid managerial, commercial and global development of the sport and offers a thorough analysis of how the football industry can meet the challenges that flow from these developments. Expertly edited by two well known specialists in football business management, it draws together the work of a world-class contributor team to form a comprehensive analysis of the most important issues facing the managers of football businesses across the world. The cutting edge analysis examines all the important business challenges in the football industry and the management of football businesses and covers all of the key football markets including England, Spain, France, Italy, Germany, Australia, North America, China, South Africa, South Korea, the Netherlands & Belgium, and Mexico. Managing Football is simply a must-read for anyone studying or working in football business management and is set to be an important landmark in this rapidly moving and globally expansive field.

Work-related stress according to the demand-control model and minor psychic disorders in nursing workers

This was a cross-sectional study that aimed to assess the association between work-related stress according to the Demand-Control Model, and the occurrence of Minor Psychic Disorder (MPD) in nursing workers. The participants were 335 professionals, out of which 245 were nursing technicians, aged predominantly between 20 and 40 years. Data were collected using the Job Stress Scale and the Self-Reporting Questionnaire-20. The analysis was performed using descriptive and analytical statistics. The prevalence of suspected MPD was 20.6%. Workers classified in the quadrants active job and high strain of the Demand-Control Model presented higher potential for developing MPD compared with those classified in the quadrant low strain. In conclusion, stress affects the mental health of workers and the aspects related to high psychological demands and high control still require further insight in order to understand their influence on the disease processes of nursing workers.

Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study.

The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genome-wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 ± 12.43 versus 21.49 ± 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 ± 13.79 versus 15.62 ± 14.94, P = 0.044). The mean diagnostic delay was 14.63 ± 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E-07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E-07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.

Comprendre les mécanismes des migrations « glo-balles » africaines. Les trajectoires transnationales et la diversification des filières

L'article décrypte certains rouages de l'expatriation des joueurs africains vers l'Europe. La précocité de leur migration et la fragmentation de leur trajectoire sont expliquées par les spéculations dont ils font l'objet. Les réseaux socio-économiques qui portent les filières spéculatives sont mis en lumière, ce qui permet de comprendre en particulier le rôle primordial qu'y jouent les clubs intermédiaires européens, et maintenant asiatiques, intermédiaires dans la chaîne à haute valeur ajoutée, au « taux d'éviction » le plus élevé du monde. This paper decodes various workings at play in the expatriation of African players to Europe. The early nature of their migration and the fragmentation of their trajectories are explained by the speculation that surrounds them. The socio-economic networks that carry speculative channels are brought to light, which helps us to understand in particular the major role played by the European, and now Asian, clubs, which serve as intermediaries in the high value-added chain, with the highest "eviction rate" in the world.

S'intégrer balle au pied: Le rôle des clubs de foot de migrants en Suisse

L'existence de clubs de foot de migrants favorise-t-elle ou empêche-t-elle le développement de liens sociaux avec les membres de clubs "autochtones" et plus largement avec les autres acteurs du tissu associatif régional ? Les auteurs de l'article portent particulièrement leur attention sur les relations crées et entretenues sur le terrain de jeu, à partir d'une recherche effectuée entre 2009 et 2011 auprès de douze clubs en Suisse. Ils s'intéressent tant à la composition de leurs effectifs, en terme d'origine nationale et culturelle, qu'au rôle de socialisation qu'ils peuvent jouer vis-à-vis de leurs membres et de passeur vers un processus dynamique d'intégration à construire et à assumer.

Le marché des footballeurs. Réseaux et circuits dans l'économie globale

Fin assemblage entre démarches théoriques et empiriques, l'ouvrage illustre les logiques sous-jacentes à la mondialisation du marché des footballeurs. Il présente des informations de première main sur le fonctionnement des réseaux de transfert, collectées par l'auteur au cours de dix années de recherches menées en Europe et en Afrique. Des données statistiques inédites, élaborées par l'Observatoire des footballeurs professionnels, et de nombreuses illustrations cartographiques rendent la lecture particulièrement agréable. L'analyse des réseaux et circuits migratoires des footballeurs permet de saisir le rôle décisif joué par de nombreux intermédiaires dans le développement d'un marché global de talents. L'ouvrage dévoile la manière dont agents, dirigeants de clubs et spéculateurs privés investissent sur des joueurs dans l'optique de mettre en place des chaînes de transferts à valeur ajoutée. Ce processus est exemplifié à travers l'étude du cas des footballeurs africains

Opinions on smoking policies in Switzerland

Purpose: to assess the opinions regarding smoking ban policies in Switzerland. Methods: cross sectional study on 2,601 women and 2,398 men, aged 35-75 years, living in Lausanne, Switzerland. Nine questions on smoking policies (restrictions, advertising, taxes and prevention) were applied. Results: 95% of responders supported policies that would help smokers to quit, 92% supported no selling of tobacco to subjects aged less than 16 years, 87% a smoking ban in public places and 86% a national campaign against smoking. A further 77% supported a total ban on tobacco advertising, 74% the reimbursement of nicotine replacement therapies and 70% increasing the price of cigarettes. Conversely, a lower support was found for a total ban of tobacco sales (35%) or the promotion of light cigarettes (22%). Multivariate analysis showed that women, lower educational level, older age, being physically active or non-smoker were associated with tougher policies against tobacco, whereas current drinking or smoking and higher educational level were associated with lower levels of support. Conclusion: opinions regarding smoking poli ci es vary considerably according to the policy type considered and also the characteristics of the subjects. Those findings provide interesting data regarding which anti-smoking policies would be more acceptable by the lay public, as well as the subjects who might oppose them.

Restoration of anti-tetanus toxoid responses in patients initiating highly active antiretroviral therapy with or without a boost immunization: an INITIO substudy.

INITIO is an open-labelled randomized trial evaluating first-line therapeutic strategies for human immunodeficiency virus-1 (HIV-1) infection. In an immunology substudy a tetanus toxoid booster (TTB) immunization was planned for 24 weeks after initiation of highly active antiretroviral therapy (HAART). All patients had received tetanus toxoid immunization in childhood. Generation of proliferative responses to tetanus toxoid was compared in two groups of patients, those receiving a protease inhibitor (PI)-sparing regimen (n = 21) and those receiving a PI-containing (n = 54) regimen. Fifty-two participants received a TTB immunization [PI-sparing (n = 15), PI-containing (n = 37)] and 23 participants did not [PI-sparing (n = 6) or PI-containing (n = 17)]. Cellular responses to tetanus antigen were monitored by lymphoproliferation at time of immunization and every 24 weeks to week 156. Proportions with a positive response (defined as stimulation index > or = 3 and Delta counts per minute > or = 3000) were compared at weeks 96 and 156. All analyses were intent-to-treat. Fifty-two participants had a TTB immunization at median 25 weeks; 23 patients did not. At weeks 96 and 156 there was no evidence of a difference in tetanus-specific responses, between those with or without TTB immunization (P = 0.2, P = 0.4). There was no difference in the proportion with response between those with PI-sparing or PI-containing regimens at both time-points (P = 0.8, P = 0.7). The proliferative response to tetanus toxoid was unaffected by initial HAART regimen. Anti-tetanus responses appear to reconstitute eventually in most patients over 156 weeks when treated successfully with HAART, irrespective of whether or not a TTB immunization has been administered.