This study was supported by the Medical Society of Göteborg, FoU

This study was supported by the Medical Society of Göteborg, FoU Västra Götaland, Gunnar Nilsson

Cancer Foundation, the Swedish Cancer Society and the Swedish Medical Society. The authors declare no conflict of interest. “
“Farnesyl pyrophosphate synthase (FPPS)-catalysed isoprenoid intermediates are important for the activation of Ras homologue gene family, member A (RhoA) in angiotensin (Ang) II-induced cardiac fibrosis. This study was designed to investigate the specific role of FPPS in the development of cardiac fibrosis. We demonstrated that FPPS expression was elevated in both in-vivo and in-vitro models of Ang II-mediated cardiac fibrosis. FPPS inhibition by zolendronate and FPPS knock-down by a silencing Galunisertib price lentivirus decreased the expression of cardiac fibrosis marker genes, including collagen I, collagen III and transforming growth factor (TGF)-β1. FPPS inhibition was reversed by geranylgeraniol Lapatinib in vivo (GGOH) and mimicked by RhoA knock-down with siRhoA. The antagonistic effect of GGOH on the zolendronate-mediated modulation of RhoA activation in Ang II-stimulated cardiac fibroblasts was demonstrated by a pull-down assay. Furthermore, FPPS knock-down also prevented RhoA activation by Ang II in vitro. In conclusion, FPPS and RhoA may be part of a signalling pathway that plays an important role in Ang II-induced cardiac fibrosis in vitro. “
“Post-transplantation

lymphoproliferative disorders (PTLD) are life-threatening complications of organ transplantation caused by EBV infection and the use of chronic immunosuppression. While T-cell impairment is known

to play a critical role in the immunopathogenesis of EBV complications post-transplantation, the role of NK cells is still under investigation. Here, we have characterized NK-cell phenotype and function in peripheral HSP90 blood from asymptomatic pediatric thoracic transplant patients, patients with PTLD, and healthy controls. Overall, asymptomatic pediatric solid organ transplant (Tx) patients presented significant expansion of the CD56brightCD16± subset and displayed effective NK-cell function, while PTLD patients accumulated CD56dimCD16− and CD56−CD16+ NK-cell subsets. In addition, NK cells from PTLD patients down-regulated NKp46 and NKG2D, and significantly up-regulated PD-1. These phenotypic changes were associated with NK functional impairment, resembling cellular exhaustion. Disrupting PD-1 inhibitory pathway improved IFN-γ release, but did not enhance cytotoxicity in PTLD patients, suggesting that these defects were partially PD-1 independent. Our results indicate the important role of NK cells during EBV surveillance post-transplantation, with implications for the immunopathogenesis of EBV complications, and suggest that monitoring NK cells in transplant patients may hold clinical value.

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