SUMMARY DNA methylation at the 5-position of cytosine (5-mC) is a key epigenetic mark critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the Ten-Eleven Translocation (TET) family of DNA hydroxylases. Here we report that “loss of 5-hmC” is an epigenetic hallmark of melanoma with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of 5-hmC landscape in the melanoma epigenome. We show that down-regulation of Isocitrate Dehydrogenase 2 (IDH2) and TET family enzymes is likely one of the mechanisms underlying 5-hmC loss in melanoma. Rebuilding the 5-hmC landscape in melanoma cells by reintroducing active TET2 or IDH2 suppresses melanoma growth and increases tumor-free survival in animal models. Thus, our study reveals a critical function of 5-hmC in melanoma development and directly links the IDH and TET activity-dependent epigenetic pathway to 5-hmC-mediated suppression of melanoma progression, suggesting a new strategy for epigenetic cancer therapy.

Summary Scratching triggers skin flares in atopic dermatitis (AD). We demonstrate that scratching of human skin, and tape stripping of mouse skin, causes neutrophil influx. This influx in mice was largely dependent on the generation of leukotriene B4 (LTB4) by neutrophils and their expression of the LTB4 receptor BLT1. Allergic skin inflammation in response to epicutaneous (EC) application of ovalbumin to tape-stripped skin was severely impaired in Ltb4r1−/− mice, and required expression of BLT1 on both T cells and non-T cells. Co-transfer of WT neutrophils, but not neutrophils deficient in BLT1 or the LTB4 synthesizing enzyme LTA4H, restored the ability of WT CD4+ effector T cells to transfer allergic skin inflammation to Ltb4r1−/− recipients. Pharmacologic blockade of LTB4 synthesis inhibited allergic skin inflammation elicited by cutaneous antigen challenge in previously EC-sensitized mice. Our results demonstrate that a neutrophil-T cell axis reliant on LTB4-BLT1 interaction is required for allergic skin inflammation.

Gender bias and discrimination have profound and far-reaching effects on the health care workforce, delivery of patient care, and advancement of science and are antithetical to the principles of professionalism. In the quest for gender equity, medicine, with its abundance of highly educated and qualified women, should be leading the way. The sheer number of women who comprise the majority of pediatricians in the United States suggests this specialty has a unique opportunity to stand out as progressively equitable. Indeed, there has been much progress to celebrate for women in medicine and pediatrics. However, many challenges remain, and there are areas in which progress is too slow, stalled, or even regressing. The fair treatment of women pediatricians will require enhanced and simultaneous commitment from leaders in 4 key gatekeeper groups: academic medical centers, hospitals, health care organizations, and practices; medical societies; journals; and funding agencies. In this report, we describe the 6-step equity, diversity, and inclusion cycle, which provides a strategic methodology to (1) examine equity, diversity, and inclusion data; (2) share results with stakeholders; (3) investigate causality; (4) implement strategic interventions; (5) track outcomes and adjust strategies; and (6) disseminate results. Next steps include the enforcement of a climate of transparency and accountability, with leaders prioritizing and financially supporting workforce gender equity. This scientific and data-driven approach will accelerate progress and help pave a pathway to better health care and science. Gender bias and discrimination have profound and far-reaching effects on the health care workforce, delivery of patient care, and advancement of science and are antithetical to the principles of professionalism. In the quest for gender equity, medicine, with its abundance of highly educated and qualified women, should be leading the way. Because women comprise the majority of pediatricians in the United States, pediatrics has a unique opportunity to stand out as progressively equitable. Indeed, there has been much progress to celebrate for women in medicine 1-7 and pediatrics. 3,4,7 However, many challenges remain, and there are areas in which progress is too slow, stalled, or regressing. 8-14 Moreover, women with intersectional identities (ie, simultaneously belonging to multiple underrepresented groups, including gender, race, sexual orientation, ability, age, or socioeconomic status 15) may experience heightened levels of bias and discrimination, sometimes called a "double bind." 16 Therefore, this report focuses on persistent disparities and highlights key a Executive Leadership in Academic Medicine Program,