T H 17 cells play important yet complex roles in cancer development and progression. We previously reported that T H 17 cells and IL-17 mediate resistance to anti-VEGF therapy by inducing recruitment of immunosuppressive and proangiogenic myeloid cells to the tumor microenvironment. Here, we demonstrate that IL-22, a key effector cytokine expressed by T H 17 cells, directly acts on endothelial cells to promote tumor angiogenesis. IL-22 induces endothelial cell proliferation, survival, and chemotaxis in vitro and neovascularization in an ex vivo mouse choroid explant model. Blockade of IL-22, with a neutralizing antibody, significantly inhibits tumor growth associated with reduced microvascular density. No synergistic effect of IL-22 with VEGF was observed. These results identify IL-22 as a potential therapeutic target for blocking tumor angiogenesis.
OBJECTIVE To provide continued follow-up of a cohort of ophthalmology clinician-scientists who received National Institutes of Health (NIH) K career development grants. DESIGN, SETTING, AND PARTICIPANTS Cohort study from an electronic database review of ophthalmologists who have received either a K08 or K23 career development grant from the NIH. Data were analyzed between December 30, 2015, and December 30, 2017. MAIN OUTCOMES AND MEASURES Receipt of an NIH R01 grant. RESULTS We previously characterized a group of more than 100 ophthalmologists who received K awards from 1996 to 2010, of whom 29 were awarded R01 grants. In follow-up of this cohort in 2017, 27 additional K awardees of this initial cohort were awarded an R01 from 2011 to 2017, leading to a total of 62 of 128 ophthalmologists receiving an R01. The mean time to receiving an R01 grant after the K award ended was 2.8 years. The data did not identify a definitive association with sex, having a PhD degree, or research tier of university in obtaining an R01 grant in this cohort. CONCLUSIONS AND RELEVANCE In comparison with our previous report of the same cohort, there was a 93% increase in the number of K awardees who have received an R01 award, with the mean time to award being nearly 3 years after completing their K grant. This suggests that most K awardees in ophthalmology are successful in obtaining R01 grants, but one should recognize this may be several years after their K grant has ended.
Purpose:
Uveal melanomas are associated with characteristic genetic changes. Germline mutations in mismatch repair (MMR) genes and microsatellite instability have been implicated in the development of numerous malignant neoplasms such as colon and ovarian cancers. The frequency of MMR defects in uveal melanomas has yet to be determined.
Methods:
Here, we analyzed the frequency of MMR gene mutations in uveal melanoma specimens from the University of California, San Diego (UCSD), The Cancer Genome Atlas (TGCA), and the Catalogue of Somatic Mutations in Cancer (COSMIC).
Results:
We identified only two mutations in a MMR gene: one premature stop codon in the PMS gene within the UCSD cohort (0.5% frequency) and one in-frame deletion in MSH3 within the COSMIC database (0.8% frequency). We report copy number variation of MLH1 in monosomy 3 and show decreased mRNA expression of MLH1 in uveal melanoma specimens with monosomy 3. Expression levels of MLH1 were not found to correlate with the observed number of total mutations.
Conclusion:
Overall, we show that mutations in MMR genes in uveal melanoma specimens are exceedingly rare, and although one copy of MLH1 is lost in monosomy 3, it does not seem to have pathologic consequences in uveal melanoma pathogenesis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.