Nonadherence to immunosuppressive medications may partly explain the worse allograft outcomes among black recipients of renal transplants. In a prospective cohort study of recipients of deceased donor renal transplants, microelectronic cap monitors were placed on bottles of one immunosuppressive medication to (1) measure average daily percentage adherence during the first posttransplantation year and (2) determine the factors associated with adherence. A total of 278 transplant recipients who provided sufficient microelectronic adherence data were grouped into four categories of average daily percentage adherence: 95 to 100% adherence (41.0% of patients), 80 to 95% adherence (32.4%), 50 to 80% adherence (12.9%), and 0 to 50% adherence (13.7%). In the unadjusted ordinal logistic regression model, black race was associated with decreased adherence (odds ratio [
Purpose
p53 is mutated in about 50% of human cancers, mostly through missense mutations. Expression of mutant p53 is associated with poor clinical outcomes or metastasis. Although mutant p53 is inherently instable, various stressors such as DNA damage or expression of the oncogenic Kras or c-myc affect the oncogenic properties of mutant p53. However, the effects of inflammation on mutant p53 are largely unknown. Interleukin-27 (IL-27) is an important immunomodulatory cytokine but its impact on mutant p53-driven tumorigenesis has not been reported.
Experimental Design
IL27RA−/− mice were bred with mutant p53 heterozygous (p53R172H/+) mice to obtain IL27RA−/−p53H/+ and IL27RA−/−p53H/H mice. Mouse survival and tumor spectra for the cohort were analyzed. Stability of p53 protein was analyzed via immunohistochemistry and western blot.
Results
this study unraveled that lack of IL-27 signaling significantly shortened the survival duration of mice with tumors expressing both copies of the mutant p53 gene (Li-Fraumeni mouse model). Interestingly, in mice that were heterozygous for mutant p53, lack of IL-27 signaling not only significantly shortened survival time but also doubled the incidence of osteosarcomas. Furthermore, lack of IL-27 signaling is closely associated with increased mutant p53 stability in vivo from early age.
Conclusions
These results suggest that IL-27 signaling modulates the oncogenic properties of mutant p53 in vivo.
The susceptibility of African American recipients to acute rejection and to DGF was not confirmed to be associated with DARC alleles or genotype. Future studies should exclude a potential role of donor-related DARC in transplant outcomes.
Establishment of a permissive pre-malignant niche in concert with mutant stem are key triggers to initiate skin carcinogenesis. An understudied area of research is finding upstream regulators of both these triggers. IL27, a pleiotropic cytokine with both pro- and anti-inflammatory properties, was found to be a key regulator of both. Two step skin carcinogenesis model and K15-KRASG12D mouse model were used to understand the role of IL27 in skin tumors. CD11b−/− mice and small-molecule of ETAR signaling (ZD4054) inhibitor were used in vivo to understand mechanistically how IL27 promotes skin carcinogenesis. Interestingly, using in vivo studies, IL27 promoted papilloma incidence primarily through IL27 signaling in bone-marrow derived cells. Mechanistically, IL27 initiated the establishment of the pre-malignant niche and expansion of mutated stem cells in K15-KRASG12D mouse model by driving the accumulation of Endothelin A receptor (ETAR)-positive CD11b cells in the skin—a novel category of pro-tumor inflammatory identified in this study. These findings are clinically relevant, as the number of IL27RA-positive cells in the stroma is highly related to tumor de-differentiation in patients with squamous cell carcinomas.
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