Caught in the cROssfire: GSH Controls T Cell Metabolic Reprogramming

T cell activation and proliferation critical for protective immunity depend on appropriate rewiring of cellular metabolism. In this issue of Immunity, Mak et al. (2017) show that the antioxidant gluthathione (GSH) controls reactive oxygen species (ROS)-dependent engagement of metabolic signaling pathways that lead to protective T cell responses

Did changing primary care delivery models change performance? A population based study using health administrative data

<p>Abstract</p> <p>Background</p> <p>Primary care reform in Ontario, Canada started with the introduction of new enrollment models, the two largest of which are Family Health Networks (FHNs), a capitation-based model, and Family Health Groups (FHGs), a blended fee-for-service model. The purpose of this study was to evaluate differences in performance between FHNs and FHGs and to compare performance before and after physicians joined these new primary care groups.</p> <p>Methods</p> <p>This study used Ontario administrative claims data to compare performance measures in FHGs and FHNs. The study population included physicians who belonged to a FHN or FHG for at least two years. Patients were included in the analyses if they enrolled with a physician in the two years after the physician joined a FHN or FHG, and also if they saw the physician in a two year period prior to the physician joining a FHN or FHG. Performance was derived from the administrative data, and included measures of preventive screening for cancer (breast, cervical, colorectal) and chronic disease management (diabetes, heart failure, asthma).</p> <p>Results</p> <p>Performance measures did not vary consistently between models. In some cases, performance approached current benchmarks (Pap smears, mammograms). In other cases it was improving in relation to previous measures (colorectal cancer screening). There were no changes in screening for cervical cancer or breast cancer after joining either a FHN or FHG. Colorectal cancer screening increased in both FHNs and FHGs. After enrolling in either a FHG or a FHN, prescribing performance measures for diabetes care improved. However, annual eye examinations decreased for younger people with diabetes after joining a FHG or FHN. There were no changes in performance measures for heart failure management or asthma care after enrolling in either a FHG or FHN.</p> <p>Conclusions</p> <p>Some improvements in preventive screening and diabetes management which were seen amongst people after they enrolled may be attributed to incentive payments offered to physicians within FHGs and FHNs. However, these primary care delivery models need to be compared with other delivery models and fee for service practices in order to describe more specifically what aspects of model delivery and incentives affect care.</p

Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy

PD-1 blockade therapy has revolutionized cancer treatments. However, a substantial population of patients is unresponsive. To rescue unresponsive patients, the mechanism of unresponsiveness to PD-1 blockade therapy must be elucidated. Using a ‘bilateral tumor model’ where responsive and unresponsive tumors were inoculated into different sides of the mouse belly, we demonstrated that unresponsive tumors can be categorized into two groups: with and without systemic immunosuppressive property (SIP). The SIP-positive tumors released uncharacterized, non-proteinaceous small molecules that inhibited mitochondrial activation and T cell proliferation. By contrast, the SIP-negative B16 tumor escaped from immunity by losing MHC class I expression. Unresponsiveness of SIP-positive tumors was partially overcome by improving the mitochondrial function with a mitochondrial activator; this was not successful for B16, which employs immune ignorance. These results demonstrated that the ‘bilateral tumor model’ was useful for stratifying tumors to investigate the mechanism of unresponsiveness and develop a strategy for proper combination therapy

Dynamic Cardiolipin Synthesis Is Required for CD8⁺ T Cell Immunity

Mitochondria constantly adapt to the metabolic needs of a cell. This mitochondrial plasticity is critical to T cells, which modulate metabolism depending on antigen-driven signals and environment. We show here that de novo synthesis of the mitochondrial membrane-specific lipid cardiolipin maintains CD8+ T cell function. T cells deficient for the cardiolipin-synthesizing enzyme PTPMT1 had reduced cardiolipin and responded poorly to antigen because basal cardiolipin levels were required for activation. However, neither de novo cardiolipin synthesis, nor its Tafazzin-dependent remodeling, was needed for T cell activation. In contrast, PTPMT1-dependent cardiolipin synthesis was vital when mitochondrial fitness was required, most notably during memory T cell differentiation or nutrient stress. We also found CD8+ T cell defects in a small cohort of patients with Barth syndrome, where TAFAZZIN is mutated, and in a Tafazzin-deficient mouse model. Thus, the dynamic regulation of a single mitochondrial lipid is crucial for CD8+ T cell immunity

De-identification of primary care electronic medical records free-text data in Ontario, Canada

<p>Abstract</p> <p>Background</p> <p>Electronic medical records (EMRs) represent a potentially rich source of health information for research but the free-text in EMRs often contains identifying information. While de-identification tools have been developed for free-text, none have been developed or tested for the full range of primary care EMR data</p> <p>Methods</p> <p>We used <it>deid </it>open source de-identification software and modified it for an Ontario context for use on primary care EMR data. We developed the modified program on a training set of 1000 free-text records from one group practice and then tested it on two validation sets from a random sample of 700 free-text EMR records from 17 different physicians from 7 different practices in 5 different cities and 500 free-text records from a group practice that was in a different city than the group practice that was used for the training set. We measured the sensitivity/recall, precision, specificity, accuracy and F-measure of the modified tool against manually tagged free-text records to remove patient and physician names, locations, addresses, medical record, health card and telephone numbers.</p> <p>Results</p> <p>We found that the modified training program performed with a sensitivity of 88.3%, specificity of 91.4%, precision of 91.3%, accuracy of 89.9% and F-measure of 0.90. The validations sets had sensitivities of 86.7% and 80.2%, specificities of 91.4% and 87.7%, precisions of 91.1% and 87.4%, accuracies of 89.0% and 83.8% and F-measures of 0.89 and 0.84 for the first and second validation sets respectively.</p> <p>Conclusion</p> <p>The <it>deid </it>program can be modified to reasonably accurately de-identify free-text primary care EMR records while preserving clinical content.</p

Acetate Promotes T Cell Effector Function during Glucose Restriction.

Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in T cells impairs IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer