Comparison of latest generation supra-annular and intra-annular self-expanding transcatheter heart valves

BackgroundThis study compares two latest-generation self-expanding transcatheter heart valves (THV), the supra-annular ACURATE neo (Boston Scientific) and the intra-annular Centera THV (Edwards Lifesciences).MethodsIn this single center observational cohort trial 317 patients treated with the ACURATE neo and 78 patients treated with the Centera TVH were included. The main endpoints were device success and the early safety endpoint at 30 days.ResultsBesides higher incidence of diabetes mellitus and higher body mass index in patients treated with the ACURATE neo THV, there were no baseline differences between the groups. Device success was similar in both groups (neo: 91.8% vs. Centera: 93.6%; P=0.598), with numerically higher rates of moderate to severe paravalvular leakage in the ACURATE neo group (4.7% vs. 1.3%; P=0.214). At 30 days all-cause mortality rates were low in both groups (0.3% vs. 0%; P=0.620) and no difference occurred in the early safety at 30 days (19.3% vs. 16.7%; P=0.599). However, all-cause stroke rates were significantly higher in patients treated with the Centera THV (6.4 vs. 1.6%; P=0.015).ConclusionsThe ACURATE neo and the Centera THV show low mortality rates as well as comparable, favorable hemodynamics. The finding of higher stroke rates at 30 days with the repositionable Centera SE-THV needs further assessment.     

Fatty acid amide hydrolase ablation promotes ectopic lipid storage and insulin resistance due to centrally mediated hypothyroidism

Fatty acid amide hydrolase (FAAH) knockout mice are prone to excess energy storage and adiposity, whereas mutations in FAAH are associated with obesity in humans. However, the molecular mechanism by which FAAH affects energy expenditure (EE) remains unknown. Here we show that reduced energy expenditure in FAAH(-/-) mice could be attributed to decreased circulating triiodothyronine and thyroxine concentrations secondary to reduced mRNA expression of both pituitary thyroid-stimulating hormone and hypothalamic thyrotropin-releasing hormone. These reductions in the hypothalamic-pituitary-thyroid axis were associated with activation of hypothalamic peroxisome proliferating-activated receptor γ (PPARγ), and increased hypothalamic deiodinase 2 expression. Infusion of NAEs (anandamide and palmitoylethanolamide) recapitulated increases in PPARγ-mediated decreases in EE. FAAH(-/-) mice were also prone to diet-induced hepatic insulin resistance, which could be attributed to increased hepatic diacylglycerol content and protein kinase Cε activation. Our data indicate that FAAH deletion, and the resulting increases in NAEs, predispose mice to ectopic lipid storage and hepatic insulin resistance by promoting centrally mediated hypothyroidism.     

Safety and efficacy of the Yukon Choice Flex sirolimus-eluting coronary stent in an all-comers population cohort

Aims

The use of biodegradable-polymer drug-eluting stents has been shown to provide favorable results when compared with durable polymer drug-eluting stents and long-term follow up data have recently shown significant reductions in terms of very late stent thrombosis.Aim of the present study was to assess the safety and efficacy profile of a novel biodegradable polymer DES, the Yukon Choice Flex sirolimus-eluting stent.

Methods

We report here the one-year clinical outcomes associated with the use of the Yukon Choice Flex sirolimus-eluting stent in an all-comers patient population. The present stent represents a further refinement of the stent platform tested in the ISAR TEST 3 and 4 randomized clinical trials. A total of 778 consecutive patients undergoing implantation of this stent were enrolled in the present observational study and prospectively followed for one year.

Results

The use of the Yukon Choice Flex stent in a patient population with complex coronary lesion morphology was associated with optimal immediate angiographic results. At one year follow up the rates of death, myocardial infarction, definite stent thrombosis and ischemia-driven target lesion revascularization were respectively 2.4%, 1.9%, 0.3% and 11.3%.

Conclusions

The use of the sirolimus-eluting biodegradable polymer Yukon Choice Flex stent in an all-comers population of patients with complex coronary artery disease is associated with a favorable safety and efficacy profile up to one year follow up.     

Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Mutations in related RNA-binding proteins TDP-43, FUS/TLS and TAF15 have been connected to ALS. These three proteins share several features, including the presence of a bioinformatics-predicted prion domain, aggregation-prone nature in vitro and in vivo and toxic effects when expressed in multiple model systems. Given these commonalities, we hypothesized that a related protein, EWSR1 (Ewing sarcoma breakpoint region 1), might also exhibit similar properties and therefore could contribute to disease. Here, we report an analysis of EWSR1 in multiple functional assays, including mutational screening in ALS patients and controls. We identified three missense variants in EWSR1 in ALS patients, which were absent in a large number of healthy control individuals. We show that disease-specific variants affect EWSR1 localization in motor neurons. We also provide multiple independent lines of in vitro and in vivo evidence that EWSR1 has similar properties as TDP-43, FUS and TAF15, including aggregation-prone behavior in vitro and ability to confer neurodegeneration in Drosophila. Postmortem analysis of sporadic ALS cases also revealed cytoplasmic mislocalization of EWSR1. Together, our studies highlight a potential role for EWSR1 in ALS, provide a collection of functional assays to be used to assess roles of additional RNA-binding proteins in disease and support an emerging concept that a class of aggregation-prone RNA-binding proteins might contribute broadly to ALS and related neurodegenerative diseases.     

Radiotherapeutic efficacy of (153)Sm-CMDTPA-Tyr(3)-octreotate in tumor-bearing rats

A number of radiolabeled somatostatin analogs have been evaluated in animal tumor models for radiotherapeutic efficacy. The majority of the agents tested have used either high-energy beta-emitters, such as Y-90 or Re-188, or the Auger electron-emitting radionuclide, In-111. Because a medium-energy beta-emitter might have equivalent efficacy compared to high-energy emitters, and lower toxicity to non-target tissues, we have evaluated the therapeutic potential of the beta-emitting nuclide, Sm-153, chelated to the somatostatin analog, CMDTPA-Tyr(3)-octreotate. Using an in vitro binding assay, this octreotate derivative was shown to have high affinity for the somatostatin subtype-2 receptor (IC(50) = 2.7 nM). Biodistribution studies in CA20948 tumor-bearing Lewis rats demonstrate that the Sm-153 labeled compound has high uptake and retention in tumor tissue (1.7% injected dose/g tissue, 4 hrs post injection) and has rapid overall clearance properties from non-target tissue. Radiotherapy studies were carried out using (153)Sm-CMDTPA-Tyr(3)-octreotate and CA20948 tumor bearing Lewis rats at 7 days post implant. Dose regimens consisting of single and multiple i.v. injections of 5.0 mCi/rat (185 MBq) were employed over a time span of 7 days. Suppression of tumor growth rate was observed in all treated animals compared to untreated controls. Greater inhibition of tumor growth was observed in animals that received multiple doses. These studies indicate that medium-energy beta-emitting isotopes have considerable potential for the treatment of somatostatin receptor-positive tumors.     

Computer-aided drug design strategies used in the discovery of fructose 1, 6-bisphosphatase inhibitors

Computational assessment of the binding affinity of enzyme inhibitors prior to synthesis is an important component of computer-aided drug design (CADD) paradigms. The free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities between two inhibitors. However, due to its complexity and computation-intensive nature, practical applications are restricted to analysis of structurally-related inhibitors. Accordingly, there is a need for methods that enable rapid assessment of a large number of structurally-unrelated molecules in a suitably accurate manner. In this review, the FEP method is compared with molecular mechanics (MM) methods to assess the advantages of each in the estimation of relative binding affinities of inhibitors to an enzyme. Qualitative predictions of relative binding free energies of fructose 1, 6-bisphosphatase inhibitors using MM methods are discussed and compared with the corresponding FEP results. The results indicate that the MM based methods and the FEP method are useful in the qualitative and quantitative assessment of relative binding affinities of enzyme inhibitors, respectively, prior to synthesis.     

Radiolabeled RGD-DTPA-Tyr3-octreotate for receptor-targeted radionuclide therapy

The aim of this study was to develop and investigate a radiopeptide for the treatment of cancers which overexpress cell surface somatostatin receptors. The new radiopharmaceutical is composed of a somatostatin receptor-targeting peptide, a chelator (DTPA) to enable radiolabeling, and an apoptosis-inducing RGD (arginine-glycine-aspartate) peptide moiety. The receptor-targeting peptide portion of the molecule, Tyr3-octreotate, is specific for the somatostatin subtype-2 cell surface receptor (sst2), which is overexpressed on many tumor cells. Because of the rapid endocytosis of the somatostatin receptor, the entire molecule can thus be internalized, allowing the RGD portion to activate intracellular caspases, which in turn promotes apoptosis. In this paper, we present the synthesis and the in vitro and in vivo tumor binding and internalization characteristics of this hybrid peptide. In vitro internalization into sst2-positive tumor cells of the radiolabeled hybrid peptide appeared to be a rapid process and could be blocked by an excess of unlabeled octreotide, indicating an sst2-specific process. Tumor uptake in vivo in rats of radiolabeled RGD-DTPA-Tyr3-octreotate was in agreein vitro data and similar to that of radiolabeled DOTA-Tyr3-octreotate. The combined molecule is expected to significantly enhance the therapeutic efficacy of the somatostatin-based agent.     

The addition of DTPA to [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate prior to administration reduces rat skeleton uptake of radioactivity

Peptide receptor-targeted radionuclide therapy is nowadays also being performed with DOTA-conjugated peptides, such as [DOTA(0),Tyr(3)]octreotate, labelled with radionuclides like (177)Lu. The incorporation of (177)Lu is typically >/=99.5%; however, since a total patient dose can be as high as 800 mCi, the amount of free (177)Lu(3+) (= non-DOTA-incorporated) can be substantial. Free (177)Lu(3+) accumulates in bone with unwanted irradiation of bone marrow as a consequence. (177)Lu-DTPA is reported to be stable in serum in vitro, and in vivo it has rapid renal excretion. Transforming free Lu(3+) to Lu-DTPA might reroute this fraction from accumulation in bone to renal clearance. We therefore investigated: (a) the biodistribution in rats of (177)LuCl(3), [(177)Lu-DOTA(0),Tyr(3)]octreotate and (177)Lu-DTPA; (b) the possibilities of complexing the free (177)Lu(3+) in [(177)Lu-DOTA(0),Tyr(3)]octreotate to (177)Lu-DTPA prior to intravenous injection; and (c) the effects of free (177)Lu(3+) in [(177)Lu-DOTA(0),Tyr(3)]octreotate, in the presence and absence of DTPA, on the biodistribution in rats. (177)LuCl(3) had high skeletal uptake (i.e. 5% ID per gram femur, with localization mainly in the epiphyseal plates) and a 24-h total body retention of 80% injected dose (ID). [(177)Lu-DOTA(0),Tyr(3)]octreotate had high and specific uptake in somatostatin receptor-positive tissues, and 24-h total body retention of 19% ID. (177)Lu-DTPA had rapid renal clearance, and 24-h total body retention of 4% ID. Free (177)Lu(3+) in [(177)Lu-DOTA(0),Tyr(3)]octreotate could be complexed to (177)Lu-DTPA. Accumulation of (177)Lu in femur, blood, liver and spleen showed a dose relation to the amount of free (177)Lu(3+), while these accumulations could be normalized by the addition of DTPA. After labelling [DOTA(0),Tyr(3)]octreotate with (177)Lu the addition of DTPA prior to intravenous administration of [(177)Lu-DOTA(0),Tyr(3)]octreotate is strongly recommended.