Implantation of paclitaxel-eluting stents in saphenous vein grafts: clinical and angiographic follow-up results from a multicentre study.

Objective: To define the clinical and angiographic follow-up results after implantation of paclitaxel-eluting stents (PESs) in stenotic saphenous vein grafts (SVGs). Design: Prospective multicentre study. Comparison with a control group. Methods: 60 consecutive patients with 65 lesions located in 65 SVGs (mean (SD) age of vein grafts 11.3 (5.7) years) treated with PES (V-Flex Plus, 2.7 mg/mm2 paclitaxel, Cook) and 60 patients with 60 SVG lesions treated with bare metal stent (BMS) were included. Lesions had to be ,20 mm in length and in grafts of 2.75–3.5 mm diameter. The 6 month angiographic follow-up was obtained on 51 lesions (79%) of the PES group and on 51 lesions (85%) of the BMS group. Results: Baseline clinical and angiographic characteristics were comparable between both groups. At angiographic follow-up, three vein grafts in the PES group and five vein grafts in the BMS group were occluded. In-stent late lumen loss was lower in PES than in BMS (0.61 (0.81) vs 1.06 (0.72) mm, respectively; p = 0.021). In-stent binary restenosis rates were 12% vs 33%, respectively, (p = 0.012). Linear regression analysis showed BMS to be the only factor with an effect on late lumen loss (p = 0.011). Target-vessel failure rates were 18% in the PES group and 41% in the BMS group (p = 0.019), whereas major adverse cardiac event (MACE) rates at 180 days were 15% and 37%, respectively (p = 0.014). Conclusions: Implantation of non-polymer-based PES in SVG lesions is associated with a lower late lumen loss and restenosis rate than those of BMS. There remains a substantial target-vessel failure rate and MACE rate even at 6 months owing to graft occlusion or new lesions in the graft

Hic-5, an adaptor-like nuclear receptor coactivator

In recent years, numerous nuclear receptor-interacting proteins have been identified that influence nuclear transcription through their direct modification of chromatin. Along with coactivators that possess histone acetyltransferase (HAT) or methyltransferase activity, other coactivators that lack recognizable chromatin-modifying activity have been discovered whose mechanism of action is largely unknown. The presence of multiple protein-protein interaction motifs within mechanistically undefined coactivators suggests that they function as adaptor molecules, either recruiting or stabilizing promoter-specific protein complexes. This perspective will focus on a family of nuclear receptor coactivators (i.e., group III LIM domain proteins related to paxillin) that appear to provide a scaffold to stabilize receptor interactions with chromatin-modifying coregulators

Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: Evidence for an involvement of protein kinase C

Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: Evidence for an involvement of protein kinase C.BackgroundAngiotensin II infusion has been shown to cause hypertension and endothelial dysfunction and to increase superoxide (O-·2) production in vascular tissue, mainly via an activation of nicotinamide adenine dinucleotide (phosphate) [NAD(P)H]-dependent oxidase, the most significant O-·2 source in endothelial and/or smooth muscle cells. With these studies, we sought to determine whether endothelial dysfunction in renovascular hypertension is secondary to an activation of these oxidases.MethodsEndothelial function in aortas from rats with two kidney-one clip (2K-1C) hypertension and age-matched controls was assessed using isometric tension studies in organ chambers. Changes in vascular O-·2 production were measured using lucigenin-enhanced chemiluminescence and electron spin resonance spectroscopy.ResultsIn hypertensive animals, relaxation to endothelium-dependent (acetylcholine) and endothelium-independent nitrovasodilators (nitroglycerin) was impaired. Constriction to a direct activator of protein kinase C (PKC) phorbol ester 12,13 dibutyrate (PDBu) was enhanced, and vascular O-·2 was significantly increased compared with controls. Vascular O-·2 was normalized by the PKC inhibitor calphostin C, by the inhibitor of flavin-dependent oxidases, diphenylene iodonium, and recombinant heparin-binding superoxide dismutase, whereas inhibitors of the xanthine oxidase (oxypurinol), nitric oxide synthase (NG-nitro-L-arginine) and mitochondrial NADH dehydrogenase (rotenone) were ineffective. Studies of vascular homogenates demonstrated that the major source of O-·2 was a NAD(P)H-dependent oxidase. Incubation of intact tissue with PDBu markedly increased O-·2, the increase being significantly stronger in vessels from hypertensive animals as compared with vessels from controls. Endothelial dysfunction was improved by preincubation of vascular tissue with superoxide dismutase and calphostin C.ConclusionsWe therefore conclude that renovascular hypertension in 2K-1C rats is associated with increased vascular O-·2 leading to impaired vasodilator responses to endogenous and exogenous nitrovasodilators. Increased vascular O-·2 is likely secondary to a PKC-mediated activation of a membrane-associated NAD(P)H-dependent oxidase

Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer

Genomic alterations in metastatic prostate cancer remain incompletely characterized. Here we analyse 493 prostate cancer cases from the TCGA database and perform whole-genome plasma sequencing on 95 plasma samples derived from 43 patients with metastatic prostate cancer. From these samples, we identify established driver aberrations in a cancer-related gene in nearly all cases (97.7%), including driver gene fusions (TMPRSS2:ERG), driver focal deletions (PTEN, RYBP and SHQ1) and driver amplifications (AR and MYC). In serial plasma analyses, we observe changes in focal amplifications in 40% of cases. The mean time interval between new amplifications was 26.4 weeks (range: 5–52 weeks), suggesting that they represent rapid adaptations to selection pressure. An increase in neuron-specific enolase is accompanied by clonal pattern changes in the tumour genome, most consistent with subclonal diversification of the tumour. Our findings suggest a high plasticity of prostate cancer genomes with newly occurring focal amplifications as a driving force in progression

MUG Mel3 Cell Lines Reflect Heterogeneity in Melanoma and Represent a Robust Model for Melanoma in Pregnancy

Melanomas are aggressive tumors with a high metastatic potential and an increasing incidence rate. They are known for their heterogeneity and propensity to easily develop therapy-resistance. Nowadays they are one of the most common cancers diagnosed during pregnancy. Due to the difficulty in balancing maternal needs and foetal safety, melanoma is challenging to treat. The aim of this study was to provide a potential model system for the study of melanoma in pregnancy and to illustrate melanoma heterogeneity. For this purpose, a pigmented and a non-pigmented section of a lymph node metastasis from a pregnant patient were cultured under different conditions and characterized in detail. All four culture conditions exhibited different phenotypic, genotypic as well as tumorigenic properties, and resulted in four newly established melanoma cell lines. To address treatment issues, especially in pregnant patients, the effect of synthetic human lactoferricin-derived peptides was tested successfully. These new BRAF-mutated MUG Mel3 cell lines represent a valuable model in melanoma heterogeneity and melanoma pregnancy research. Furthermore, treatment with anti-tumor peptides offers an alternative to conventionally used therapeutic options—especially during pregnancy