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Both epidemiologic and cellular studies in the context of autoimmune diseases have established that protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a key regulator of T cell receptor (TCR) signaling. However, its mechanism of action in tumors and its translatability as a target for cancer immunotherapy have not been established. Here, we show that a germline variant of PTPN22, rs2476601, portended a lower likelihood of cancer in patients. PTPN22 expression was also associated with markers of immune regulation in multiple cancer types. In mice, lack of PTPN22 augmented antitumor activity with greater infiltration and activation of macrophages, natural killer (NK) cells, and T cells. Notably, we generated a small molecule inhibitor of PTPN22, named L-1, that phenocopied the antitumor effects seen in genotypic PTPN22 knockout. PTPN22 inhibition promoted activation of CD8(+) T cells and macrophage subpopulations toward MHC-II–expressing M1-like phenotypes, both of which were necessary for successful antitumor efficacy. Increased PD-1/PD-L1 axis expression in the setting of PTPN22 inhibition could be further leveraged with PD-1 inhibition to augment antitumor effects. Similarly, cancer patients with the rs2476601 variant responded significantly better to checkpoint inhibitor immunotherapy. Our findings suggest that PTPN22 is a druggable systemic target for cancer immunotherapy.

T regulatory cells (Treg) restrain both the innate and adaptive immune systems to maintain homeostasis. Allergic airway inflammation, characterized by a type 2 (Th2) response that results from a breakdown of tolerance to innocuous environmental antigens, is negatively regulated by Treg. We previously reported that prostaglandin I2 (PGI2) promoted immune tolerance in models of allergic inflammation; however, the effect of PGI2 on Treg function was not investigated. Treg from mice deficient in the PGI2 receptor IP (IP KO) had impaired suppressive capabilities during allergic airway inflammatory responses compared to mice with PGI2 signaling was intact. IP KO Treg had significantly enhanced expression of immunoglobulin-like transcript 3 (ILT3) compared to wild-type Treg, which may contribute to the impairment of the IP KO Treg's ability to suppress Th2 responses. Using fate-mapping mice, we reported that PGI2 signaling prevents Treg reprogramming toward a pathogenic phenotype. PGI2 analogs promoted the differentiation of naive T cells to Treg in both mice and humans via repression of β-catenin signaling. Finally, a missense variant in IP in humans was strongly associated with chronic obstructive asthma. Together, these data support that PGI2 signaling licenses Treg suppressive function and that PGI2 is a therapeutic target to enhance Treg function.

Since 2006, the National Institutes of Health has provided institutional infrastructure grants, called Clinical and Translational Science Awards (CTSAs), to support adult and pediatric clinical and translational research in United States institutions. A CTSA Consortium Child Health Oversight Committee workgroup developed metrics to measure the impact of CTSAs on child health (CH) research. A cross-sectional survey to collect metric data was distributed to the 46 institutions that received CTSAs during 2006-09. Thirty-seven (80%) institutions responded to the survey. Data regarding 7 metrics were reported by >70% of responding institutions: the proportion of overall funding (median, interquartile range; 0.12, 0.06–0.19) and pilot grants (0.15, 0.11–0.21) supporting CH research; the proportion of active clinical research center studies involving children (0.23, 0.15–0.35); the proportion of IRB-approved (0.24, 0.16–0.30) and funded (0.22, 0.18–0.30) studies involving children; the proportion of mentored research training awards to CH investigators (0.18, 0.11–0.28); and, the proportion of CTSA leadership positions held by pediatricians (0.18, 0.12–0.28). CTSAs provide substantial support for CH research, although additional investment in CH research is needed to improve the health of children. These metrics provide an initial means to track the impact of CTSAs on CH research.

The hypothalamus plays a central role in the regulation of energy intake and feeding behavior. However, the presence of a functional abnormality in the hypothalamus in humans that may be related to excess energy intake and obesity has yet to be demonstrated in vivo. We, therefore, used functional magnetic resonance imaging (fMRI) to monitor hypothalamic function after oral glucose intake. The 10 obese (34 +/- 2 years of age, BMI 34.2 +/- 1.3 kg/m2) and 10 lean (32 +/- 4 years of age, BMI 22.0 +/- 0.9 kg/m2) subjects with normal glucose tolerance ingested 75 g of glucose while a midsagittal slice through the hypothalamus was continuously imaged for 50 min using a conventional T2*-weighted gradient-echo pulse sequence. After glucose ingestion, lean subjects demonstrated an inhibition of the fMRI signal in the areas corresponding to the paraventricular and ventromedial nuclei. In obese subjects, this inhibitory response was markedly attenuated (4.8 +/- 1.3 vs. 7.0 +/- 0.6% inhibition, P < 0.05) and delayed (9.4 +/- 0.5 vs. 6.4 +/- 0.5 min, P < 0.05) compared with that observed in lean subjects. The time taken to reach the maximum inhibitory response correlated with the fasting plasma glucose (r = 0.75, P < 0.001) and insulin (r = 0.47, P < 0.05) concentrations in both lean and obese subjects. These results demonstrate in vivo, for the first time, the existence of differential hypothalamic function in lean and obese humans that may be secondary to obesity.

Purpose: To review whether clavicle plates should be removed after union of the fracture. Materials and Methods: 48 patients with middle third clavicle fractures treated by plating were assessed with UCLA shoulder rating and Oxford shoulder scores. Results: At an average follow up of 13 months,96% of 27 patients with plates out recommended its removal. 86% of 21 patients with plates in were happy to keep them. Conclusions : We recommend leaving clavicle plates in unless requested by the patient. Level of Evidence: I V-retrospective study.

Assisted by technological advances, web-based instruction is being widely used to prepare learners for future challenges. The internet provides the possibility of erasing geographic and interpersonal boundaries among people from diverse backgrounds. The purposes of this article are: (1) to examine and discuss multiplicity and flexibility as essential elements in designing web-based courses integrating online collaborative learning; (2) to discuss implications of multiplicity and flexibility for future research and development of online collaborative learning environments.