This retrospective, single-centre study would suggest there may be an association between serum FSH levels and time to CRPC for men treated palliatively with ADT for advancing prostate cancer. Further clinical investigation in a larger cohort of men is required to determine any clinical utility of FSH as a biomarker of progression or target for therapy.
We previously identified Fragile X-related protein 1 (FXR1) as an RNA-binding protein involved in the post-transcriptional control of TNF and other cytokines in macrophages. Macrophages derived from FXR1-KO mice overexpress several inflammatory cytokines including TNF. Recently, we showed that fenretinide (4HPR) is able to inhibit several inflammatory cytokines in the lungs of cystic fibrosis mice, which also have abnormal immune responses. Therefore, we hypothesized that 4HPR might also be able to downregulate excessive inflammation even in macrophages with ablated FXR1. Indeed, our results demonstrate that 4HPR inhibited the excessive production of inflammatory mediators, including TNF, IL-6, CCL2 and CCL-5 in LPS-stimulated FXR1-KO macrophages, by selectively inhibiting phosphorylation of ERK1/2, which is naturally more phosphorylated in FXR1-KO cells. We also found that LPS stimulation of FXR1-KO macrophages led to significantly higher ratio of arachidonic acid/docosahexaenoic acid than observed in FXR1-WT macrophages. Interestingly, treatment with 4HPR was associated with the normalization of arachidonic acid/docosahexaenoic acid ratio in macrophages, which we found to impact phosphorylation of ERK1/2. Overall, this study shows for the first time that 4HPR modulates inflammatory cytokine expression in macrophages by correcting a phospholipid-bound fatty acid imbalance that impacts the phosphorylation of ERK1/2.
Background
The impact of weight mismatch between donors and recipients (D‐R) undergoing living‐donor kidney transplant (LDKT) versus weight‐matched deceased donor kidney transplant (DDKT) is not established.
Aim
To determine whether absolute weight mismatch between D‐R affects graft survival following LDKT and how this relates to graft outcomes with DDKT when D‐R are weight matched.
Materials & Methods
We used multivariable Cox proportional hazards models and the Scientific Registry of Transplant Recipients to determine the association of weight‐mismatched D‐R (>50 kg, 30–50 kg or 10–30 kg ((D < R); (D > R) and <10 kg (D = R)) with death‐censored graft failure in US LDKT recipients from 2006 to 2017. We also explored outcomes relative to weight‐matched DDKT and finally, the impact of combined D‐R weight‐sex mismatch.
Results
In LDKT, the risk of graft loss was highest in the setting of D < R (HR 1.28, 95% CI 1.05–1.56 for >50 kg difference relative to D = R); however, this was still lower risk than weight‐matched DDKT. D‐R sex and combined weight‐sex mismatch were only important for male recipients (HR 1.47, 95% CI 1.27–1.71 for a male recipient >30 kg larger than their female donor, relative to weight‐matched male donor‐male recipient). This remained superior to weight‐sex‐matched DDKT however.
Conclusion
D‐R weight‐sex mismatch is important in LDKT; however, graft survival remains superior to proceeding with matched DDKT. Optimizing D‐R matching in LDKT could be facilitated through a national kidney‐paired donation registry. LDKT weight‐sex mismatch should not be deferred in favor of DDKT.
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