Four-year clinical outcome following randomised use of zotarolimus-eluting stents versus everolimus-eluting stents in all-comers: Insights from the DUTCH PEERS trial

Background: The DUTCH PEERS (TWENTE II) trial (clinicaltrials.gov NCT01331707) is a randomised, multicenter, single-blinded, investigator initiated all-comers trial. All coronary syndromes were permitted with no limit for lesion length, reference size, or number of lesions or diseased vessels to be treated. In total, 1811 patients were 1:1 randomised to cobalt chromium-based zotarolimuseluting stents (ZES) versus platinum chromium-based everolimus-eluting stents (EES). These durable polymer-based drug-eluting stents (DES) were developed to facilitate device deliverability and to improve stent apposition to the vessel wall. Purpose: We assessed the 4-year clinical outcome of the DUTCH PEERS trial in terms of safety and efficacy. Methods: Clinical outcome was assessed by means of follow-up data of the trial participants. The primary endpoint target vessel failure (TVF) is a composite of cardiac death, target vessel-related myocardial infarction (MI) or target vessel revascularization. Secondary endpoints included the individual components of the TVF and the incidence of definite-or-probable stent thrombosis. Endpoints were analyzed by the logrank test by comparing the time to the endpoint, using the Kaplan-Meier method. Independent contract research organizations performed the study monitoring and clinical event adjudication. Results: The 4-year clinical follow-up data were available in 1802 patients (99.5%; 4 patients were lost to follow-up and 5 withdrew consent). The ZES and EES groups showed favourable outcomes with a similar incidence of TVF (12.1% vs. 12.1%; Logrank p=0.95). The rates of the individual components of TVF were also similar for both stent arms: cardiac death (3.9% vs. 3.7%; Logrank p=0.78); target vessel-related MI (3.2% vs. 2.5%; Logrank p=0.38); and target vessel revascularization (6.8% vs. 7.5%; Logrank p=0.55), respectively. In addition, the incidence of definite-or-probable stent thrombosis was similar for patients treated with ZES versus EES (1.5% vs. 1.2%; Logrank p=0.67). Conclusion: At 4-year follow-up, ZES and EES showed similar and sustained results in terms of safety and efficacy for treating all-comer patients

Necrosis binding of Ac-Lys(0)(IRDye800CW)-Tyr(3)-octreotate:a consequence from cyanine-labeling of small molecules

BACKGROUND: There is a growing body of nuclear contrast agents that are repurposed for fluorescence-guided surgery. New contrast agents are obtained by substituting the radioactive tag with, or adding a fluorescent cyanine to the molecular structure of antibodies or peptides. This enables intra-operative fluorescent detection of cancerous tissue, leading to more complete tumor resection. However, these fluorescent cyanines can have a remarkable influence on pharmacokinetics and tumor uptake, especially when labeled to smaller targeting vectors such as peptides. Here we demonstrate the effect of cyanine-mediated dead cell-binding of Ac-Lys0(IRDye800CW)-Tyr3-octreotate (800CW-TATE) and how this can be used as an advantage for fluorescence-guided surgery. RESULTS: Binding of 800CW-TATE could be blocked with DOTA0-Tyr3-octreotate (DOTA-TATE) on cultured SSTR2-positive U2OS cells and was absent in SSTR2 negative U2OS cells. However, strong binding was observed to dead cells, which could not be blocked with DOTA-TATE and was also present in dead SSTR2 negative cells. No SSTR2-mediated binding was observed in frozen tumor sections, possibly due to disruption of the cells in the process of sectioning the tissue before exposure to the contrast agent. DOTA-TATE blocking resulted in an incomplete reduction of 61.5 ± 5.8% fluorescence uptake by NCI-H69-tumors in mice. Near-infrared imaging and dead cell staining on paraffin sections from resected tumors revealed that fluorescence uptake persisted in necrotic regions upon blocking with DOTA-TATE. CONCLUSION: This study shows that labeling peptides with cyanines can result in dead cell binding. This does not hamper the ultimate purpose of fluorescence-guided surgery, as necrotic tissue appears in most solid tumors. Hence, the necrosis binding can increase the overall tumor uptake. Moreover, necrotic tissue should be removed as much as possible: it cannot be salvaged, causes inflammation, and is tumorigenic. However, when performing binding experiments to cells with disrupted membrane integrity, which is routinely done with nuclear probes, this dead cell-binding can resemble non-specific binding. This study will benefit the development of fluorescent contrast agents

Two Engineered OBPs with opposite temperature-dependent affinities towards 1-aminoanthracene

Engineered odorant-binding proteins (OBPs) display tunable binding affinities triggered by temperature alterations. We designed and produced two engineered proteins based on OBP-I sequence: truncated OBP (tOBP) and OBP::GQ20::SP-DS3. The binding affinity of 1-aminoanthracene (1-AMA) to these proteins revealed that tOBP presents higher affinity at 25°C (kd=0.45M) than at 37°C (kd=1.72M). OBP::GQ20::SP-DS3 showed an opposite behavior, revealing higher affinity at 37°C (kd=0.58M) than at 25°C (kd=1.17M). We set-up a system containing both proteins to evaluate their temperature-dependent binding. Our data proved the 1-AMA differential and reversible affinity towards OBPs, triggered by temperature changes. The variations of the binding pocket size with temperature, confirmed by molecular modelling studies, were determinant for the differential binding of the engineered OBPs. Herein we described for the first time a competitive temperature-dependent mechanism for this class of proteins.This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684). A.R. and F.G. thank FCT for funding their scholarships with the references SFRH/BPD/98388/2013 and SFRH/BD/114684/2016, respectively. T.G.C. thanks senior position funded by the European Union through the European Regional Development Fund (ERDF) under the Competitiveness Operational Program (COP-A1-A1.1.4-E nr.30/01.09.2016). C.S. thanks to the BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. Access to computing resources funded by the Project "Search-ON2: Revitalization of HPC infrastructure of UMinho" (NORTE-07-0162-FEDER-000086), co-funded by the North Portugal Regional Operational Programme (ON.2 - O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF), is also gratefully acknowledged.info:eu-repo/semantics/publishedVersio

Bacterial adhesion on bisphosphonate coated hydroxyapatite

Staphylococcus aureus (S. aureus) is commonly associated with microbial infection of orthopaedic implants. Such infections often lead to osteomyelitis, which may result in failure of the implant due to localised bone destruction. Bacterial adhesion and subsequent colonisation of the device may occur as a consequence of contamination during surgery, or by seeding from a distant site through the blood circulation. Coating of the hydroxyapatite (HA) ceramic component of artificial hip joints with the bisphosphonates clodronate (C) and pamidronate (P) has been proposed as a means to minimise osteolysis and thereby prevent loosening of the implant. However, the effect of the bisphosphonate coating on bacterial adhesion to the HA materials must be determined before this approach can be implemented. In this study coated HA materials were incubated with the S. aureus and the number of adherent bacteria determined using the Modified Vortex Device (MVD) method. The number of bacteria adherent to the P coated HA material was significantly greater than that adherent to uncoated HA (60-fold increase) or to the C coated HA (90-fold increase). Therefore, even though earlier studies suggested that P bound to HA may improve osseointegration, the results presented would suggest that the use of this coating may be limited by the potential increased susceptibility of the coated device to infection

Poly(acrylic acid)-block-poly(L-valine): Evaluation of β-sheet formation and its stability using circular dichroism technique

10.1021/bm700491qBiomacromolecules892801-280