Two structurally constrained chelators based on a fused bicyclic scaffold, 4‐amino‐4‐methylperhydro‐pyrido1,2‐a1,4diazepin‐N,N′,N′‐triacetic acids (4R*,10aS*)‐PIDAZTA (L1) and (4R*,10aR*)‐PIDAZTA ...(L2), were designed for the preparation of GaIII‐based radiopharmaceuticals. The stereochemistry of the ligand scaffold has a deep impact on the properties of the complexes, with unexpected Ga(L2)OH species being superior in terms of both thermodynamic stability and inertness. This peculiar behavior was rationalized on the basis of molecular modeling and appears to be related to a better fit in size of GaIII into the cavity of L2. Fast and efficient formation of the GaIII chelates at room temperature was observed at pH values between 7 and 8, which enables 68Ga radiolabeling under truly physiological conditions (pH 7.4).
Getting into stride: Bicyclic ligands, namely 4‐amino‐4‐methylperhydro‐pyrido1,2‐a1,4diazepin‐N,N′,N′‐triacetic acids (PIDAZTAs), have been synthesized as building blocks for the development of 68Ga‐based radiopharmaceuticals (see graphic). Quantitative radiolabeling was achieved under mild conditions in minutes. The chelators show stereochemistry‐driven thermodynamic and kinetic stability
The Europa Thermal Emission Imaging System (E-THEMIS) on the Europa Clipper spacecraft will investigate the temperature and physical properties of Europa using thermal infrared (TIR) images in three ...wavelength bands centered from 7-14 μm, 14-28 μm and 28-80 μm. E-THEMIS will map >80% of the surface Europa at multiple times of day at a resolution of 8-km per pixel, ∼32% percent of the surface at ≤1 km/pixel resolution, and ∼6% percent at ≤100 m/pixel resolution. The specific objectives of the investigation are to 1) understand the formation of surface features, including sites of recent or current geologic activity, in order to understand regional and global processes and evolution and 2) to identify safe sites for future landed missions. E-THEMIS uses an uncooled microbolometer detector array for the IR focal plane. The E-THEMIS focal plane has 920 cross-track pixels (896 active) and 140 along-track pixels in each of the three spectral bands. The image data are collected at 14-bits per pixel at a frame rate of 60 Hz. The instrument can operate in framing mode, where full frame images are collected, and optionally co-added in time, in each band, or in time-delay-integration (TDI) mode where consecutive rows from each band are offset spatially to remove the spacecraft motion and then summed. In addition, the data in each band can be spatially aggregated from 2 × 2 to 5 × 5 pixels. These modes will be varied throughout each Europa flyby to optimize the data precision while fitting within the E-THEMIS data allocation. The expected temperature precision, measured as the noise equivalent spectral radiance, is 1.2 K at scene temperatures ≥90 K for a TDI of 16 with 4 × 4 pixel coaggregation in Band 2. The absolute accuracy at 90 K is 2−3 K in Band 2. E-THEMIS is an all-reflective, three-mirror anastigmat telescope with a 6.45-cm effective aperture and a speed of f/1.34 cross-track and 1.92 along-track. The mass of instrument Sensor Assembly, mounted on the spacecraft nadir deck, is 11.4 kg, the vault electronics are 1.8 kg, and the two are connected through a 3.1 kg harness. The Sensor volume is 23.7 cm x 31.8 cm x 29.8 cm. E-THEMIS consumes an average operation power of 34.8 W at 28 V. E-THEMIS was developed by Arizona State University with Raytheon Vision Systems developing the microbolometer focal plane assembly and Ball Aerospace developing the electronics. E-THEMIS was integrated, tested, and radiometrically calibrated on the Arizona State University campus in Tempe, AZ.
The purpose of the COMPLETE (International Acute Ischemic Stroke Registry With the Penumbra System Aspiration Including the 3D Revascularization Device) registry was to evaluate the generalizability ...of the safety and efficacy of the Penumbra System (Penumbra, Inc, Alameda) in a real-world setting.
COMPLETE was a global, prospective, postmarket, multicenter registry. Patients with large vessel occlusion-acute ischemic stroke who underwent mechanical thrombectomy using the Penumbra System with or without the 3D Revascularization Device as frontline approach were enrolled at 42 centers (29 United States, 13 Europe) from July 2018 to October 2019. Primary efficacy end points were successful postprocedure angiographic revascularization (modified Thrombolysis in Cerebral Infarction ≥2b) and 90-day functional outcome (modified Rankin Scale score 0-2). The primary safety end point was 90-day all-cause mortality. An imaging core lab determined modified Thrombolysis in Cerebral Infarction scores, Alberta Stroke Program Early CT Scores, clot location, and occurrence of intracranial hemorrhage at 24 hours. Independent medical reviewers adjudicated safety end points.
Six hundred fifty patients were enrolled (median age 70 years, 54.0% female, 49.2% given intravenous recombinant tissue-type plasminogen activator before thrombectomy). Rate of modified Thrombolysis in Cerebral Infarction 2b to 3 postprocedure was 87.8% (95% CI, 85.3%-90.4%). First pass and postprocedure rates of modified Thrombolysis in Cerebral Infarction 2c to 3 were 41.5% and 66.2%, respectively. At 90 days, 55.8% (95% CI, 51.9%-59.7%) had modified Rankin Scale score 0 to 2, and all-cause mortality was 15.5% (95% CI, 12.8%-18.3%).
Using Penumbra System for frontline mechanical thrombectomy treatment of patients with large vessel occlusion-acute ischemic stroke in a real-world setting was associated with angiographic, clinical, and safety outcomes that were comparable to prior randomized clinical trials with stringent site and operator selection criteria. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03464565.
The cardio-ankle vascular index (CAVI) measure of arterial stiffness is associated with prevalent cardiovascular risk factors, while its predictive value for cardiovascular events remains to be ...established. The aim was to determine associations of CAVI with cardiovascular morbimortality (primary outcome) and all-cause mortality (secondary outcome), and to establish the determinants of CAVI progression.
TRIPLE-A-Stiffness, an international multicentre prospective longitudinal study, enrolled >2000 subjects ≥40 years old at 32 centres from 18 European countries. Of these, 1250 subjects (55% women) were followed for a median of 3.82 (2.81–4.69) years.
Unadjusted cumulative incidence rates of outcomes according to CAVI stratification were higher in highest stratum (CAVI > 9). Cox regression with adjustment for age, sex, and cardiovascular risk factors revealed that CAVI was associated with increased cardiovascular morbimortality (HR 1.25 per 1 increase; 95% confidence interval, CI: 1.03–1.51) and all-cause mortality (HR 1.37 per 1 increase; 95% CI: 1.10–1.70) risk in subjects ≥60 years. In ROC analyses, CAVI optimal threshold was 9.25 (c-index 0.598; 0.542–0.654) and 8.30 (c-index 0.565; 0.512–0.618) in subjects ≥ or <60 years, respectively, to predict increased CV morbimortality. Finally, age, mean arterial blood pressure, anti-diabetic and lipid-lowering treatment were independent predictors of yearly CAVI progression adjusted for baseline CAVI.
The present study identified additional value for CAVI to predict outcomes after adjustment for CV risk factors, in particular for subjects ≥60 years. CAVI progression may represent a modifiable risk factor by treatments.
International Society of Vascular Health (ISVH) and Fukuda Denshi, Japan.
Pharmacogenetic testing is becoming more common; however, very few quality control and other reference materials that cover alleles commonly included in such assays are currently available. To ...address these needs, the Centers for Disease Control and Prevention's Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing community and the Coriell Cell Repositories, have characterized a panel of 107 genomic DNA reference materials for five loci (CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1) that are commonly included in pharmacogenetic testing panels and proficiency testing surveys. Genomic DNA from publicly available cell lines was sent to volunteer laboratories for genotyping. Each sample was tested in three to six laboratories using a variety of commercially available or laboratory-developed platforms. The results were consistent among laboratories, with differences in allele assignments largely related to the manufacturer's assay design and variable nomenclature, especially for CYP2D6. The alleles included in the assay platforms varied, but most were identified in the set of 107 DNA samples. Nine additional pharmacogenetic loci (CYP4F2, EPHX1, ABCB1, HLAB, KIF6, CYP3A4, CYP3A5, TPMT, and DPD) were also tested. These samples are publicly available from Coriell and will be useful for quality assurance, proficiency testing, test development, and research.
Colonic enterocytes form a rapidly renewing epithelium and barrier to luminal antigens. During renewal, coordinated expression of the claudin family of genes is vital to maintain the epithelial ...barrier. Disruption of this process contributes to barrier compromise and mucosal inflammatory diseases. However, little is known about the regulation of this critical aspect of epithelial cell differentiation. In order to identify claudin regulatory factors we utilized high-throughput gene microarrays and correlation analyses. We identified complex expression gradients for the transcription factors Hopx, Hnf4a, Klf4 and Tcf7l2, as well as 12 claudins, during differentiation. In vitro confirmatory methods identified 2 pathways that stimulate claudin expression; Hopx/Klf4 activation of Cldn4, 7 and 15, and Tcf7l2/Hnf4a up-regulation of Cldn23. Chromatin immunoprecipitation confirmed a Tcf7l2/Hnf4a/Claudin23 cascade. Furthermore, Hnf4a conditional knockout mice fail to induce Cldn23 during colonocyte differentiation. In conclusion, we report a comprehensive screen of colonic claudin gene expression and discover spatiotemporal Hopx/Klf4 and Tcf7l2/Hnf4a signaling as stimulators of colonic epithelial barrier differentiation.
Airway smooth muscle (ASM) hyperplasia in asthma likely contributes considerably to functional changes. Investigating the mechanisms behind proliferation of these cells may lead to therapeutic ...benefit. Platelet-derived growth factor (PDGF)-BB is a well known ASM mitogen in vitro but has yet to be directly explored using in vivo mouse models in the context of ASM proliferation and airway responsiveness. To determine the in vivo influence of PDGF-BB on gene transcripts encoding contractile proteins, ASM proliferation, and airway physiology, we used an adenovirus overexpression system and a model of chronic allergen exposure. We used adenovirus technology to selectively overexpress PDGF-BB in the airway epithelium of mice. Outcome measurements, including airway physiology, real time RT-PCR measurements, proliferating cell nuclear antigen staining, and airway smooth muscle quantification, were performed 7 days after exposure. The same outcome measurements were performed 24 hours and 4 weeks after a chronic allergen exposure model. PDGF-BB overexpression resulted in airway hyperresponsiveness, decreased lung compliance, increased airway smooth muscle cell numbers, positive proliferating cell nuclear antigen-stained airway smooth muscle cells, and a reduction in genes encoding contractile proteins. Chronic allergen exposure resulted in elevations in lung lavage PDGF-BB, which were observed in conjunction with changes in gene transcript expression encoding contractile proteins and ASM proliferation. We demonstrate for the first time in vivo that PDGF-BB induces ASM hyperplasia and changes in lung mechanics in mice and that, during periods of allergen exposure changes in lung, PDGF-BB are associated with changes in airway structure and function.
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