Compared with CA, the use of intravascular imaging techniques for PCI guidance reduces the risk of cardiovascular death and adverse events.

BackgroundFKBP51 is a co-chaperone with isomerase activity, abundantly expressed in glioma. We previously identified a spliced isoform (FKBP51s) and highlighted a role for this protein in the upregulation of Programmed Death Ligand 1 (PD-L1) expression in melanoma. Because gliomas can express PD-L1 causing a defective host anti-tumoral immunity, we investigated whether FKBP51s was expressed in glioma and played a role in PD-L1 regulation in this tumour.MethodsWe used D54 and U251 glioblastoma cell lines that constitutively expressed PD-L1. FKBP51s was measured by immunoblot, flow cytometry and microscopy. In patient tumours, IHC and qPCR were used to measure protein and mRNA levels respectively. FKBP51s depletion was achieved by siRNAs, and its enzymatic function was inhibited using selective inhibitors (SAFit). We investigated protein maturation using N-glycosidase and cell fractionation approaches.ResultsFKBP51s was expressed at high levels in glioma cells. Glycosylated-PD-L1 was increased and reduced by FKBP51s overexpression or silencing, respectively. Naïve PD-L1 was found in the endoplasmic reticulum (ER) of glioma cells complexed with FKBP51s, whereas the glycosylated form was measured in the Golgi apparatus. SAFit reduced PD-L1 levels (constitutively expressed and ionizing radiation-induced). SAFit reduced cell death of PBMC co-cultured with glioma.ConclusionsHere we addressed the mechanism of post-translational regulation of PD-L1 protein in glioma. FKBP51s upregulated PD-L1 expression on the plasma membrane by catalysing the protein folding required for subsequent glycosylation. Inhibition of FKBP51s isomerase activity by SAFit decreased PD-L1 levels. These findings suggest that FKBP51s is a potential target of immunomodulatory strategies for glioblastoma treatment.

BackgroundLong‐term data on durability of currently available transcatheter heart valves are sparse. We sought to assess the incidence of long‐term (8‐year) structural valve dysfunction and bioprosthetic valve failure in a cohort of patients with transcatheter aortic valve replacement (TAVR) who reached at least 5‐year follow‐up.Methods and ResultsConsecutive patients with at least 5‐year follow‐up available undergoing TAVR from June 4, 2007 to March 30, 2012 were included. Structural valve dysfunction and bioprosthetic valve failure were defined according to newly standardized European Association of Percutaneous Cardiovascular Interventions/European Society of Cardiology/European Association for Cardio‐Thoracic Surgery criteria and reported as cumulative incidence function to account for the competing risk of death. A total of 288 consecutive patients with a mean age of 80.7±5.3 years and with a mean Society of Thoracic Surgery mortality score of 8.1±5.1% were analyzed. Survival rate at 8 years was 29.8%. Mean pressure gradients decreased from 53.3±15.9 mm Hg (pre‐TAVR) to 10.5±4.5 mm Hg (in‐hospital post‐TAVR) (P<0.001). There was a small, not significant, increase in the transaortic gradient throughout follow‐up. Bioprosthetic valve failure was observed in a total of 11 patients (8‐year cumulative incidence function: 4.51%; 95% confidence interval, 1.95%–8.76%). Severe and moderate structural valve dysfunctions were reported in 7 patients (8‐year cumulative incidence function: 2.39%; 95% confidence interval, 0.77%–5.71%) and 13 patients (8‐year cumulative incidence function: 5.87%; 95% confidence interval, 3.06%–9.96%), respectively. Aortic valve reintervention (redo TAVR) was successfully performed in 2 patients (0.7%) presenting with symptomatic severe restenosis and intraprosthetic regurgitation subsequent to endocarditis.ConclusionsIn an aged population of patients with symptomatic severe aortic stenosis treated with first‐generation bioprostheses, TAVR was associated with a survival rate of 30% but low rates of bioprosthetic valve failure and structural valve dysfunction at 8 years.

Aims To evaluate outcomes of transfemoral transcatheter aortic valve implantation (TF‐TAVI) using three different new‐generation devices. Background Although new generation transcatheter aortic valves (TAVs) have demonstrated to improve procedural outcomes, to date few head‐to‐head comparisons are available among these devices. Methods This is a single center, retrospective study. From September 2014 to February 2018, 389 patients underwent elective TF‐TAVI for native, severe aortic stenosis using a new‐generation transcatheter aortic valve (TAV) with a preprocedural multi‐detector computed tomography assessment. Among these, 346 patients received an Edwards SAPIEN 3 (n = 134), Medtronic Evolut R (n = 111), or Boston ACURATE neo (n = 101) prosthesis. Differences in baseline clinical characteristics between groups were accounted using the propensity score weighting method. RESULTS The mean age for the entire study cohort was 81.4 ± 5.2 years while the Society of Thoracic Surgery predicted risk of mortality was 4.0 ± 2.5%. After propensity score weighting adjustment, TAVs did not differently impact on 30‐day all‐cause and cardiovascular mortality. Evolut R device showed an increased risk of permanent pacemaker implantation (PPI) after the procedure (8.3% for SAPIEN 3 vs. 16.7% for Evolut R vs. 2.1% for ACURATE neo, p < .05). At 30 days, patients treated with SAPIEN 3 valve showed a higher mean transvalvular gradient (9.7 ± 7.5 mmHg vs. 6.1 ± 2.4 mmHg vs. 8.4 ± 3.5 mmHg for SAPIEN 3, Evolut R, and ACURATE neo, respectively, p < .01) and a lower rate of more‐than‐trace paravalvular regurgitation (PVR) (18.8 vs. 47.9 vs. 45.8%, for SAPIEN 3, Evolut R, and ACURATE neo, respectively, p < .01). At 1 year, SAPIEN 3, Evolut R, and ACURATE neo TAVs showed excellent and comparable outcomes with no difference in terms of freedom from major adverse cardiovascular and cerebrovascular event (MACCE) (plog‐rank = 0.534). Conclusions TAVI using new‐generation prostheses was associated with high device success (97.0% vs. 92.8% vs. 95.0% for SAPIEN 3, Evolut R and ACURATE neo, respectively) and low complications rates up to 1 year. Evolut R valve was associated with a higher rate of PPI whereas SAPIEN 3 valve was associated with a higher mean transvalvular gradient and lower rate of more‐than‐trace PVR. At 1‐year, MACCE rates were similar among the three groups.

Background FKBP51 (FKBP5 Official Symbol) is a large molecular weight component of the family of FK506 binding proteins (FKBP). In recent years, research studies from our laboratory highlighted functions for FKBP51 in the control of apoptosis and melanoma progression. FKBP51 expression correlated with the invasiveness and aggressiveness of melanoma. Since a role for TGF‐β in the enhanced tumorigenic potential of melanoma cells is widely described, we hypothesized a cooperative effect between FKBP51 and TGF‐β in melanoma progression. Methods SAN and A375 melanoma cell lines were utilized for this study. Balb/c IL2γ NOD SCID served to assess the ability to colonize organs and metastasize of different cell lines, which was evaluated by in vivo imaging. Realtime PCR and western blot served for measurement of mRNA and protein expression, respectively. Results By comparing the metastatic potential of two melanoma cell lines, namely A375 and SAN, we confirmed that an increased capability to colonize murine organs was associated with increased levels of FKBP51. A375 melanoma cell line expressed FKBP51 mRNA levels 30‐fold higher in comparison to the SAN mRNA level and appeared more aggressive than SAN melanoma cell line in an experimental metastasis model. In addition, A375 expressed, more abundantly than SAN, the TGF‐β and the pro angiogenic TGF‐β receptor type III (TβRIII) factors. FKBP51 silencing produced a reduction of TGF‐β and TβRIII gene expression in A375 cell line, in accordance with previous studies. We found that the inducing effect of TGF‐β on Sparc and Vimentin expression was impaired in condition of FKBP51 depletion, suggesting that FKBP51 is an important cofactor in the TGF‐β signal. Such a hypothesis was supported by co immunoprecipitation assays, showing that FKBP51 interacted with either Smad2,3 and p300. In normal melanocytes, FKBP51 potentiated the effect of TGF‐β on N‐cadherin expression and conferred a mesenchymal‐like morphology to such round‐shaped cells. Conclusions Overall, our findings show that FKBP51 enhances some pro oncogenic functions of TGF‐β, suggesting that FKBP51‐overexpression may help melanoma to take advantage of the tumor promoting activities of the cytokine.

No abstract

FKBP51 (gene FKBP5) is an immunophilin capable of immunosuppression expressed in melanoma and lymphocytes. We found increased levels of a spliced FKBP5 variant in the PBMCs of 124 patients with melanoma. This variant encodes for an unknown isoform (FKBP51s). We hypothesized that FKBP51s resulted from tumour interaction with immune cells, through PDL-1/PD-1. To address this issue, we performed melanoma/PBMC cocultures. Furthermore, the immunohistochemistry of 76 melanoma specimens served to investigate whether FKBP51s stained tumour infiltrating lymphocytes. Our results showed that PBMCs expressed FKBP51s when cocultured with melanoma. Tumour PDL-1 knockdown or anti-PD-1 reduced FKBP51s expression in cocultured PBMCs. IHC showed a strong FKBP51s signal in tumour infiltrating lymphocytes, and lymphocytes of the invasion front of the tumour, along with melanoma PDL-1 expression. When overexpressed in melanoma, FKBP51s facilitated PDL-1 expression on the cell surface. In conclusion, our study shows that FKBP51s marks the PBMCs of patients with melanoma and is exploited by the tumour to immunomodulate through PDL-1.

Gliomas aberrantly express programmed cell death ligand-1 (PD-L1), which has a pivotal role in immunoevasion. The splicing isoform of FKBP5, termed FKBP51s, is a PD-L1 foldase, assisting the immune checkpoint molecule in maturation and expression on the plasma membrane. The concept that PD-L1 supports tumor-intrinsic properties is increasingly emerging. The aim of the present work was to confirm the pro-tumoral effect of PD-L1 on human glioma cell survival, stemness capacity and resistance, and to address the issue of whether, by targeting its foldase either chemically or by silencing, the aggressive tumor features could be attenuated. PD-L1-depleted glioma cells have a reduced threshold for apoptosis, while PD-L1 forced expression increases resistance. Similar results were obtained with FKBP51s modulation. The ability of PD-L1 to counteract cell death was hampered by FKBP51s silencing. PD-L1 expression was particularly high in glioma cells with a cancer-stem-cell profile. Moreover, PD-L1 sustained the spheroid formation capability of glioma cells. Targeting of FKBP51s by small-interfering RNA (siRNA) or the specific inhibitor SAFit2, reduced the number of formed spheroids, along with PD-L1 expression. Finally, in an orthotopic mouse model of glioblastoma, daily treatment with SAFit2 significantly reduced tumor PD-L1 expression, and tumor growth. In treated mice, caspase-3 activation and reduced vimentin expression were observed in excised tumors. In conclusion, targeting of FKBP51s hampers PD-L1 and its pro-tumoral properties, thereby affecting the self-renewal and growth capacities of glioblastoma cells in vitro and in vivo.