Safety and immunogenicity of NVX-CoV2373 (TAK-019) vaccine in healthy Japanese adults: Interim report of a phase I/II randomized controlled trial

BackgroundWe evaluated the safety and immunogenicity of NVX-CoV2373, a recombinant SARS-CoV-2 nanoparticle vaccine, in healthy Japanese participants.MethodsThis phase 1/2, randomized, observer-blind, placebo-controlled trial conducted in Japan (two sites), enrolled healthy Japanese adults aged ≥ 20 years with no history/risk of SARS-CoV-2 infection and no prior exposure to other approved/investigational SARS-CoV-2 vaccines or treatments. Participants were stratified by age (< 65 or ≥ 65 years) and randomized to receive two doses of either NVX-CoV2373 (5 μg SARS-CoV-2 rS; 50 μg Matrix-M1) or placebo, 21 days apart. Primary outcomes were safety and immunogenicity assessed by serum IgG antibody levels against SARS-CoV-2 rS protein on day 36. Herein, we report the primary data analysis at 4 weeks after the second dose, ahead of 12-month follow-up completion (data cut-off: 8 May 2021).ResultsBetween 12 February 2021 and 17 March 2021, 326 subjects were screened, and 200 participants enrolled and randomized: NVX-CoV2373, n = 150; placebo, n = 50. Solicited adverse events (AEs) through 7 days after each injection occurred in 121/150 (80.7%) and 11/50 (22.0%) participants in the NVX-CoV2373 and placebo arms, respectively. In the NVX-CoV2373 arm, tenderness and injection site pain were the most frequently reported solicited AEs after each vaccination, irrespective of age. Robust immune responses occurred with NVX-CoV2373 (n = 150) by day 36: IgG geometric mean fold rise (95% confidence interval) 259 (219, 306); seroconversion rate 100% (97.6, 100). No such response occurred with placebo (n = 49).ConclusionTwo doses of NVX-CoV2373 given with a 21-day interval demonstrated acceptable safety and induced robust anti-SARS-CoV-2 immune responses in healthy Japanese adults. Funding: Takeda Pharmaceutical Company Limited and Japan Agency for Medical Research and Development (AMED). ClinicalTrials.gov identifier: NCT04712110.     

Validation of a fast method for quantification of intra‐abdominal and subcutaneous adipose tissue for large‐scale human studies

Central obesity is the hallmark of a number of non‐inheritable disorders. The advent of imaging techniques such as MRI has allowed for a fast and accurate assessment of body fat content and distribution. However, image analysis continues to be one of the major obstacles to the use of MRI in large‐scale studies. In this study we assess the validity of the recently proposed fat–muscle quantitation system (AMRA^TM Profiler) for the quantification of intra‐abdominal adipose tissue (IAAT) and abdominal subcutaneous adipose tissue (ASAT) from abdominal MR images. Abdominal MR images were acquired from 23 volunteers with a broad range of BMIs and analysed using sliceOmatic, the current gold‐standard, and the AMRA^TM Profiler based on a non‐rigid image registration of a library of segmented atlases. The results show that there was a highly significant correlation between the fat volumes generated by the two analysis methods, (Pearson correlation r = 0.97, p < 0.001), with the AMRA^TM Profiler analysis being significantly faster (~3 min) than the conventional sliceOmatic approach (~40 min). There was also excellent agreement between the methods for the quantification of IAAT (AMRA 4.73 ± 1.99 versus sliceOmatic 4.73 ± 1.75 l, p = 0.97). For the AMRA^TM Profiler analysis, the intra‐observer coefficient of variation was 1.6% for IAAT and 1.1% for ASAT, the inter‐observer coefficient of variation was 1.4% for IAAT and 1.2% for ASAT, the intra‐observer correlation was 0.998 for IAAT and 0.999 for ASAT, and the inter‐observer correlation was 0.999 for both IAAT and ASAT. These results indicate that precise and accurate measures of body fat content and distribution can be obtained in a fast and reliable form by the AMRA^TM Profiler, opening up the possibility of large‐scale human phenotypic studies. Copyright © 2015 John Wiley & Sons, Ltd.     

Feasibility of precise and reliable glucose quantification in human whole blood samples by 1 tesla benchtop NMR

The standard procedure for blood glucose measurements is enzymatic testing. This method is cheap, but requires small samples of open blood with direct contact to the test medium. In principle, NMR provides non‐contact analysis of body fluids, but high‐field spectrometers are expensive and cannot be easily utilized under clinical conditions. Low‐field NMR systems with permanent magnets are becoming increasingly smaller and more affordable. The studies presented here aim at exploring the capabilities of low‐field NMR for measuring glucose concentrations in whole blood. For this purpose, a modern 1 T benchtop NMR spectrometer was used. Challenges arise from broad spectral lines, the glucose peak locations close to the water signal, low SNR and the interference with signals from other blood components. Whole blood as a sample comprises even more boundary conditions: crucial for reliable results are avoiding the separation of plasma and cells by gravitation and reliable reference values. First, the accuracy of glucose levels measured by NMR was tested using aqueous glucose solutions and commercially available bovine plasma. Then, 117 blood samples from oral glucose tolerance testing were measured with minimal preparation by simple pulse‐acquire NMR experiments. The analysis itself is the key to achieve high precision, so several approaches were investigated: peak integration, orthogonal projection to latent structure analysis and support vector machine regression. Correlations between results from the NMR spectra and the routine laboratory automated analyzer revealed an RMSE of 7.90 mg/dL for the best model. 91.5% of the model output lies within the limits of the German Medical Association guidelines, which require the glucose measurement to be within 11% of the reference method. It is concluded that spectral quantification of glucose in whole blood samples by high‐quality NMR spectrometers operating at 1 T is feasible with sufficient accuracy.     

Design,synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure–activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.     

Cross-Calibrated Dual-Energy X-Ray Absorptiometry Scanners Demonstrate Systematic Bias in Pediatric and Young Adult Females

Consistency of dual-energy X-ray absorptiometry (DXA) scan results is critical for data integrity. For pediatric subjects, the extent to which cross-calibration of DXA scanners alleviates model-to-model scanner differences is unclear. In the current study, DXA bone outcomes were compared for same-day measurements performed using different scanners, cross-calibrated to alleviate discrepancies (Hologic; Discovery A [DISCO] and QDR 4500W [QDR]). Interscanner differences were evaluated in approximately 130 females aged 8–24?yr. Scans were performed in a single session on both QDR and DISCO scanners to compare projected area, bone mineral content, and areal bone mineral density (BMD) outputs for the whole body (total, subhead, head, arm, and leg), forearm (1/3 and ultradistal radius), lumbar spine (vertebra L3 and L1–L4), and proximal femur (femoral neck). Paired t tests evaluated interscanner differences; concordance correlation coefficients (CCCs) evaluated interscanner correlations. Root mean square error coefficients of variation were compared to same-day duplicate DISCO scan root mean square error coefficients of variation for approximately 30 adult females. Deming regression equations were generated for conversion of QDR to DISCO results and vice versa. Interscanner correlations were very high (95% confidence interval for CCC?>?0.90), for all outcomes except for femoral neck area and subhead area (95% confidence interval for CCC?=?0.83–0.94, 0.57–073). However, QDR values were systematically lower than Discovery values (p?<?0.05), except for head area, head bone mineral content, head BMD, ultradistal BMD (QDR?>?Discovery, p?≤?0.05) and L1–L4 area, L3 area, and femoral neck BMD (no differences). Most Bland-Altman and Deming regression plots indicated good interscanner agreement, with little systematic variation based on bone or body size. In pediatric and young adult females, subtle but systematic differences were noted between scans obtained on DISCO and QDR scanners, despite cross-calibration, such that most outcomes are systematically higher for DISCO than for QDR. The use of conversion equations is warranted.     

iTRAQ技术鉴定小鼠睾丸发育差异表达蛋白的研究

目的 用同量异位素标记的相对和绝对定量(isobaric tags for relative and absolute quantitation,iTRAQ)技术结合液相色谱质谱技术构建3周龄小鼠与成年小鼠睾丸蛋白差异表达谱系。 方法 分别抽提3周龄小鼠与成年小鼠睾丸总蛋白质,iTRAQ标记,液相色谱（LC）分离蛋白质,LTQ Orbitrap^{TM质谱仪进行蛋白质鉴定。 结果 鉴定出20个差异表达蛋白质,其中18个为3周龄小鼠睾丸高表达蛋白质,2个为成年睾丸高表达蛋白质。差异表达蛋白质主要参与细胞的有丝分裂、减数分裂、细胞增殖、分化、凋亡及精子发生等重要细胞事件。 结论 用目前最新的定量蛋白质组技术,构建的3周龄小鼠睾丸与成年睾丸差异表达蛋白谱系对研究睾丸功能、精子发生有一定理论价值,为定量蛋白组学技术在雄性生殖领域的应用奠定了基础。}     

A Weight Index for the Standardized Uptake Value in 2-Deoxy-2-[F-18]fluoro-<Emphasis Type="SmallCaps">d</Emphasis>-glucose-Positron Emission Tomography

Introduction Known errors in the standardized uptake value (SUV) caused by variations in subject weights W encountered can be corrected by lean body mass or body surface area (bsa) algorithms replacing W in calculations. However this is infrequently done. The aims of the work here are: quantify sensitivity to W, encourage SUV correction with an approach minimally differing from tradition, and show what improvements in the SUV coefficient of variation (cv) for a population can be expected. Methods Selected for analyses were 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) SUV data from positron emission tomography (PET) and PET/computed tomography (CT) scans at the University of Tennessee as well as from the literature. A weight sensitivity index was defined as −n=slope of ln(SUV/W) vs. lnW. The portion of the SUV variability due to this trend is removed by using the defined , or a virtually equal SUV _m using , with Q and ID being tissue specific-activity and injected dose. measures performance. Adapting to animal studies’ tradition, is preferred over the conventional . Results For FDG in adults from averaging over most tissues. In children, however, . Tissues have the same index if their influx constants are independent of W. Suggested, therefore, is a very simplified , which is dimensionless and keeps the same population averages as traditional SUVs. It achieves . Hence, for cv’s of SUVs below ∼1/3 improvements over tradition are possible, leading to F’s<0.95. Accounting additionally for height, as in SUV_bsa, gives very little improvement over the simplified approach here and gives essentially the same F’s as SUV _m . Conclusions Introduced here is a weight index useful in reducing variability and further understanding the SUV. Addressing weight sensitivity is appropriate where the cv of the SUVs is below about 1/3. Proposed is the very simple approach of using an average of an adult patient’s weight and ∼70 kg for FDG SUV calculations. Unlike other approaches the dimensionless population average of SUV _m s is unchanged from tradition.     

A protocol for quantifying cardiogenic oscillations in dynamic 129Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis

The spectral parameters of hyperpolarized ¹²⁹Xe exchanging between airspaces, interstitial barrier, and red blood cells (RBCs) are sensitive to pulmonary pathophysiology. This study sought to evaluate whether the dynamics of ¹²⁹Xe spectroscopy provide additional insight, with particular focus on quantifying cardiogenic oscillations in the RBC resonance. ¹²⁹Xe spectra were dynamically acquired in eight healthy volunteers and nine subjects with idiopathic pulmonary fibrosis (IPF). ¹²⁹Xe FIDs were collected every 20 ms (T_E = 0.932 ms, 512 points, dwell time = 32 μs, flip angle ≈ 20°) during a 16 s breathing maneuver. The FIDs were pre‐processed using the spectral improvement by Fourier thresholding technique (SIFT) and fit in the time domain to determine the airspace, interstitial barrier, and RBC spectral parameters. The RBC and gas resonances were fit to a Lorentzian lineshape, while the barrier was fit to a Voigt lineshape to account for its greater structural heterogeneity. For each complex resonance the amplitude, chemical shift, linewidth(s), and phase were calculated. The time‐averaged spectra confirmed that the RBC to barrier amplitude ratio (RBC:barrier ratio) and RBC chemical shift are both reduced in IPF subjects. Their temporal dynamics showed that all three ¹²⁹Xe resonances are affected by the breathing maneuver. Most notably, several RBC spectral parameters exhibited prominent oscillations at the cardiac frequency, and their peak‐to‐peak variation differed between IPF subjects and healthy volunteers. In the IPF cohort, oscillations were more prominent in the RBC amplitude (16.8 ± 5.2 versus 9.7 ± 2.9%; P = 0.008), chemical shift (0.43 ± 0.33 versus 0.083 ± 0.05 ppm; P < 0.001), and phase (7.7 ± 5.6 versus 1.4 ± 0.8°; P < 0.001). Dynamic ¹²⁹Xe spectroscopy is a simple and sensitive tool that probes the temporal variability of gas exchange and may prove useful in discerning the underlying causes of its impairment.     

A method for multiparametric statistical quantification of the heterogeneity of free Na+ concentration by 19F MR spectroscopy: Proof of principle in silico and in vitro

Sodium(I) (Na⁺) is one of the most important cations in mammalian tissues. Since Na⁺ plays a key role in basic cell function, noninvasive methods for measuring intracellular concentrations of free sodium ions in biological tissue have been developed on the basis of ¹⁹F NMR spectroscopy. However, intracellular Na⁺ levels are often not uniform throughout a tissue volume (or voxel) being measured. In such cases, [Na⁺] heterogeneity is not reflected in results obtained by the classical technique, and may even result in biased average values. For this reason, we have designed an approach for quantifying [Na⁺] heterogeneity. First, the ¹⁹F MRS resonance from FCrown‐1 serving as a “Na⁺ probe” is transformed into a [Na⁺] curve. Then the digital points of the resulting [Na⁺] profile are used to construct a histogram with specially developed algorithms. From each [Na⁺] histogram, at least eight quantitative parameters describing the underlying statistical [Na⁺] distribution were computed: weighted median, weighted mean, standard deviation, range, mode(s), kurtosis, skewness, and entropy. In addition to our new paradigm, we present a first validation based on (i) computer simulations and (ii) experimentally obtained ¹⁹F MR spectra of model solutions. This basic proof of principle warrants future in vivo experiments, in particular because of its ability to provide quantitative information complementary to that made available by commonly used ²³Na MRI: (i) multiparametric statistical characterization of [Na⁺] distributions; (ii) total [Na⁺] heterogeneity analysis not intrinsically limited by the size of any MRI voxels; and (iii) analysis of unequivocally intracellular [Na⁺], as opposed to measurement of a combination of intra‐ and extracellular [Na⁺].