Direct tumor recognition by a human CD4(+) T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses.

Tumor antigen-specific CD4(+) T cells generally orchestrate and regulate immune cells to provide immune surveillance against malignancy. However, activation of antigen-specific CD4(+) T cells is restricted at local tumor sites where antigen-presenting cells (APCs) are frequently dysfunctional, which can cause rapid exhaustion of anti-tumor immune responses. Herein, we characterize anti-tumor effects of a unique human CD4(+) helper T-cell subset that directly recognizes the cytoplasmic tumor antigen, NY-ESO-1, presented by MHC class II on cancer cells. Upon direct recognition of cancer cells, tumor-recognizing CD4(+) T cells (TR-CD4) potently induced IFN-γ-dependent growth arrest in cancer cells. In addition, direct recognition of cancer cells triggers TR-CD4 to provide help to NY-ESO-1-specific CD8(+) T cells by enhancing cytotoxic activity, and improving viability and proliferation in the absence of APCs. Notably, the TR-CD4 either alone or in collaboration with CD8(+) T cells significantly inhibited tumor growth in vivo in a xenograft model. Finally, retroviral gene-engineering with T cell receptor (TCR) derived from TR-CD4 produced large numbers of functional TR-CD4. These observations provide mechanistic insights into the role of TR-CD4 in tumor immunity, and suggest that approaches to utilize TR-CD4 will augment anti-tumor immune responses for durable therapeutic efficacy in cancer patients.

Vinculando escuela, familia y comunidad a través de los fondos de conocimiento e identidad : un estudio de caso con una familia de origen marroquí

The purpose of the study presented in this article, grounded in sociocultural theory, was to describe the funds of knowledge and identity of Moroccan family and student in Catalonia, Spain, and to document how teachers can detect families’ “funds of knowledge” and students’ “funds of identity” to make direct links from students’ lives to classroom instruction. It is used a qualitative design, employing several techniques: interview, self-portrait, meaningful circle, genogram and photographs to illustrate family educational routines

Judicialisation and Direct Democracy. Switzerland's Ban on Minaret Construction

Launched by representatives from the Union démocratique du centre (UDC) with the aim of circumventing political and judicial decisions made at both local and national levels, the 2009 federal popular initiative calling for a ban on the construction of minarets rekindled the stigmatisation of Muslims living in Switzerland. Within the prevalent institutional configuration it moreover revived controversies surrounding issues such as direct democracy versus fundamental rights, or "the will of the people" versus "the power of the judges", whether national or international. "Judicialisation" is a polysemous concept. It is not understood here as the transfer to the courts of matters of political significance - in this instance the public regulation of religion - but as a process of juridification (or juridicalisation) in which court rulings were constantly anticipated in the political debate provoked by the popular initiative.

L'utilisation des anticoagulants oraux directs chez les patients âgés : les limites de la médecine fondée sur les preuves [The use of the new direct oral anticoagulants among older subjects: The limits of the evidence-based medicine?].

The growing use of direct oral anticoagulants, in particular among older subjects, raises questions about the limits of the evidence-based medicine. The phase III studies that have validated the efficacy and the safety profile of these molecules (dabigatran, rivaroxaban, apixaban, edoxaban) in their both indications, the venous thromboembolic disease and the non-valvular atrial fibrillation raise concerns in four major fields: the financial support of pharmaceutical companies, the links of interest for many authors with the industry, the study design (exclusively non-inferiority studies), and the poor representativeness of the older subjects included. All these points are discussed, using data of sub-groups studies, post-marketing studies and recent meta-analysis. The lack of data for the very old subjects, with frailty or comorbidities, remains the main concern from these phase III studies.

The transatlantic business community faced with US direct investment in Western Europe, 1958-1968

This article examines the position of US and European business in the debate about American direct investment in Western Europe in a historical perspective, from the establishment of the Common Market to the introduction of US regulation of foreign direct investment (FDI) a decade later. Based on abundant and diverse archival documents, it sheds new light on the process of Americanisation and contributes to existing research on transnational networks, by revealing the active role industrial leaders on both sides of the Atlantic played in shaping the political responses to problems raised by the American firms' massive presence in the Common Market.

English as a medium of instruction in teaching other languages: attitudes and practices

Internationalisation of HE and emergence of English as a global academic lingua franca used by people who share neither a common native tongue nor cultural and educational background have not only offered more opportunities but also raised challenges. According to recent European surveys, the percentage of pupils attaining the level of independent user in English varies from 14% to 82%, which evidences the potential and the complexity for English as a medium of instruction at tertiary level. This study aims to present the model of foreign language instruction at Vytautas Magnus University where one third of 30 languages are taught through English. It investigates the attitudes and practices of teachers in delivering their English-medium language courses by discussing the questions whether teaching other languages through English is psychologically, culturally and educationally preferable for teachers and students, whether it can limit the content taught and require a special methodology, how the teaching process changes with multiple languages used in the classroom and what level of English is necessary for teachers and students to ensure high quality of English-medium language teaching. The study is based on qualitative methodology with 12 language teachers participating as respondents. The results reveal areas in need of improvement.

Transcranial Direct Current Stimulation for the Treatment of Chronic Tinnitus: A Randomized Controlled Study.

BACKGROUND: Tinnitus is an often disabling condition for which there is no effective therapy. Current research suggests that tinnitus may develop due to maladaptive plastic changes and altered activity in the auditory and prefrontal cortex. Transcranial direct current stimulation (tDCS) modulates brain activity and has been shown to transiently suppress tinnitus in trials. OBJECTIVE: To investigate the efficacy and safety of tDCS in the treatment of chronic subjective tinnitus. METHODS: In a randomized, parallel, double-blind, sham-controlled study, the efficacy and safety of cathodal tDCS to the auditory cortex with anode over the prefrontal cortex was investigated in five sessions over five consecutive days. Tinnitus was assessed after the last session on day 5, and at follow-up visits 1 and 3 months post stimulation using the Tinnitus Handicap Inventory (THI, primary outcome measure), Subjective Tinnitus Severity Scale, Hospital Anxiety and Depression scale, Visual Analogue Scale, and Clinical Global Impression scale. RESULTS: 42 patients were investigated, 21 received tDCS and 21 sham stimulation. There were no beneficial effects of tDCS on tinnitus as assessed by primary and secondary outcome measures. Effect size assessed with Cohen's d amounted to 0.08 (95% CI: -0.52 to 0.69) at 1 month and 0.18 (95% CI: -0.43 to 0.78) at 3 months for the THI. CONCLUSION: tDCS of the auditory and prefrontal cortices is safe, but does not improve tinnitus. Different tDCS protocols might be beneficial.

Direct Interrogation of Viral Peptides Presented by the Class I HLA of HIV-Infected T Cells

Identification of CD8+ cytotoxic T lymphocyte (CTL) epitopes has traditionally relied upon testing of overlapping peptide libraries for their reactivity with T cells in vitro. Here, we pursued deep ligand sequencing (DLS) as an alternative method of directly identifying those ligands that are epitopes presented to CTLs by the class I human leukocyte antigens (HLA) of infected cells. Soluble class I HLA-A*11:01 (sHLA) was gathered from HIV-1 NL4-3-infected human CD4+ SUP-T1 cells. HLA-A*11:01 harvested from infected cells was immunoaffinity purified and acid boiled to release heavy and light chains from peptide ligands that were then recovered by size-exclusion filtration. The ligands were first fractionated by high-pH high-pressure liquid chromatography and then subjected to separation by nano-liquid chromatography (nano-LC)–mass spectrometry (MS) at low pH. Approximately 10 million ions were selected for sequencing by tandem mass spectrometry (MS/MS). HLA-A*11:01 ligand sequences were determined with PEAKS software and confirmed by comparison to spectra generated from synthetic peptides. DLS identified 42 viral ligands presented by HLA-A*11:01, and 37 of these were previously undetected. These data demonstrate that (i) HIV-1 Gag and Nef are extensively sampled, (ii) ligand length variants are prevalent, particularly within Gag and Nef hot spots where ligand sequences overlap, (iii) noncanonical ligands are T cell reactive, and (iv) HIV-1 ligands are derived from de novo synthesis rather than endocytic sampling. Next-generation immunotherapies must factor these nascent HIV-1 ligand length variants and the finding that CTL-reactive epitopes may be absent during infection of CD4+ T cells into strategies designed to enhance T cell immunity.