Inhibition of TGF-ß1 signaling promotes central memory T cell differentiation.

This study affirmed that isolated CD8(+) T cells express mRNA and produce TGF-ß following cognate peptide recognition. Blockage of endogenous TGF-ß with either a TGF-ß-blocking Ab or a small molecule inhibitor of TGF-ßRI enhances the generation of CD62L(high)/CD44(high) central memory CD8(+) T cells accompanied with a robust recall response. Interestingly, the augmentation within the central memory T cell pool occurs in lieu of cellular proliferation or activation, but with the expected increase in the ratio of the Eomesoderm/T-bet transcriptional factors. Yet, the signal transduction pathway(s) seems to be noncanonical, independent of SMAD or mammalian target of rapamycin signaling. Enhancement of central memory generation by TGF-ß blockade is also confirmed in human PBMCs. The findings underscore the role(s) that autocrine TGF-ß plays in T cell homeostasis and, in particular, the balance of effector/memory and central/memory T cells. These results may provide a rationale to targeting TGF-ß signaling to enhance Ag-specific CD8(+) T cell memory against a lethal infection or cancer.

Understanding the performance and impact of public knowledge translation funding interventions: protocol for an evaluation of Canadian Institutes of Health Research knowledge translation funding programs.

BACKGROUND: The Canadian Institutes of Health Research (CIHR) has defined knowledge translation (KT) as a dynamic and iterative process that includes the synthesis, dissemination, exchange, and ethically-sound application of knowledge to improve the health of Canadians, provide more effective health services and products, and strengthen the healthcare system. CIHR, the national health research funding agency in Canada, has undertaken to advance this concept through direct research funding opportunities in KT. Because CIHR is recognized within Canada and internationally for leading and funding the advancement of KT science and practice, it is essential and timely to evaluate this intervention, and specifically, these funding opportunities. DESIGN: The study will employ a novel method of participatory, utilization-focused evaluation inspired by the principles of integrated KT. It will use a mixed methods approach, drawing on both quantitative and qualitative data, and will elicit participation from CIHR funded researchers, knowledge users, KT experts, as well as other health research funding agencies. Lines of inquiry will include an international environmental scan, document/data reviews, in-depth interviews, targeted surveys, case studies, and an expert review panel. The study will investigate how efficiently and effectively the CIHR model of KT funding programs operates, what immediate outcomes these funding mechanisms have produced, and what impact these programs have had on the broader state of health research, health research uptake, and health improvement. DISCUSSION: The protocol and results of this evaluation will be of interest to those engaged in the theory, practice, and evaluation of KT. The dissemination of the study protocol and results to both practitioners and theorists will help to fill a gap in knowledge in three areas: the role of a public research funding agency in facilitating KT, the outcomes and impacts KT funding interventions, and how KT can best be evaluated.

Brachyury, a driver of the epithelial-mesenchymal transition, is overexpressed in human lung tumors: an opportunity for novel interventions against lung cancer.

PURPOSE: The epithelial-mesenchymal transition (EMT) is emerging as a critical factor for the progression and metastasis of carcinomas, as well as drug resistance. The T-box transcription factor Brachyury has been recently characterized as a driver of EMT in human carcinoma cells. The purpose of this study was to characterize Brachyury as a potential target for lung cancer therapy. EXPERIMENTAL DESIGN: The expression of Brachyury was evaluated by PCR and by immunohistochemistry in human lung tumors and adult normal tissues. Brachyury gene copy number and promoter methylation status were analyzed in tumor tissues with various levels of Brachyury expression. Lung carcinoma cells' susceptibility to T-cell lysis and EGF receptor (EGFR) kinase inhibition were also evaluated relative to the levels of Brachyury. RESULTS: Our results showed Brachyury protein expression in 41% of primary lung carcinomas, including 48% of adenocarcinomas and 25% of squamous cell carcinomas. With the exception of normal testis and some thyroid tissues, the majority of normal tissues evaluated in this study were negative for the expression of Brachyury protein. Brachyury-specific T cells could lyse Brachyury-positive tumors and the level of Brachyury corresponded to resistance of tumor cells to EGFR kinase inhibition. CONCLUSION: We hypothesize that the elimination of Brachyury-positive tumor cells may be able to prevent and/or diminish tumor dissemination and the establishment of metastases. The ability of Brachyury-specific T-cell lines to lyse Brachyury-positive tumor cells, in vitro, supports the development of Brachyury-based immunotherapeutic approaches for the treatment of lung cancer.

Reducing hunger-associated symptoms: the midmorning nutrition break.

This study measured the effectiveness of a 9 a.m. nutrition break after it had been implemented for 1 academic year at an inner-city high school. Effectiveness was measured by student participation rates, student and teacher evaluations of hunger-associated symptoms experienced by students, and teacher evaluations of the effects on the learning environment. Sixty-nine percent of students participated. The most frequently cited reason for nonparticipation was dislike of the food offered (53%), with an additional 15% citing problems with food distribution. As the frequency of participation rose, the frequency of inability to focus, tiredness, stomachache, headache, and midmorning hunger fell. All of the associations were statistically significant except for headache. Seventy-four percent of staff stated that the nutrition break had positive effects on the learning environment, and 71% referred fewer students to the school nurse.