The biological activities of dehydrocostus lactone and its analogues are suggested to be mediated by the lactone ring and alpha,beta-methylene-gamma-lactone. However, few studies exist on the ...structure-activity relationship of 13-amino derivatives of dehydrocostus latone. In this study new 13-amino derivatives of dehydrocostus lactone DHLC (1-4) were synthesized through Michael addition reactions, and were screened against three different breast cancer cell lines, namely hormone receptor positive breast cancer (MCF-7), triple-negative breast cancer (HCC70), and non-tumorigenic mammary epithelial (MCF-12A) cell lines. Dehydrocostus lactone (DHLC) exhibited IC.sub.50 values of 1.11 (selectivity index (SI) = 0.06), 24.70 (SI = 0.01) and 0.07 muM against HCC70, MCF-7 and MCF-12A cells, respectively. All the amino derivatives, except DHLC-3 displayed low micromolar IC.sub.50 values (ranging from 0.07-4.24 muM) against both breast cancer cell lines, with reduced toxicity towards MCF-12A non-tumorigenic mammary epithelial cells (SI values ranging from 6.00-126.86). DHLC-1 and DHLC-2 demonstrated the greatest selectivity for the MCF-7 cells (with SI of 121 and 126.86 respectively) over the MCF-12A cells. This reveals that, overall, the derivatives display greatly improved selectivity for breast cancer over non-tumorigenic mammary epithelial cells, with between 100-fold and 12 000-fold higher SI values. The improved docking scores were recorded for all the 13-amino dehydrocostus lactone derivatives for the enzymes analyzed. Compounds DHLC-4, and DHLC-3 recorded higher docking scores of -7.33 and -5.97 Kca/mol respectively, compared to the parent structure, dehydrocostus lactone (-5.34 Kca/mol) for protein kinase (PKC) theta (1XJD) and -6.22 and -5.88 Kca/mol, respectively for protein kinase iota (1RZR). The compounds further showed promising predicted adsorption, distribution, metabolisms and excretion (ADME) properties. Predicting the ADME properties of these derivatives is of importance in evaluating their drug-likeness, which could in turn be developed into potential drug candidates.
Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90% of CVID-affected individuals, no genetic cause of the ...disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50—translated from the non-mutated alleles—were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.
Background. Assessing renal biopsies from patients with lupus nephritis (LN) is a difficult task and it is subject to interobserver variability. In this study the interobserver agreement amongst five ...nephropathologists was analysed. Methods. Five specialized nephropathologists scored 126 biopsies, comprising 87 first and 39 repeat biopsies from 87 patients with biopsy-proven proliferative LN, included in a randomized controlled trial. The interobserver agreement expressed as intraclass correlation coefficients (ICC) of the scored histopathological items was calculated. Also, the WHO1995 and ISN/RPS2003 classification systems for LN were compared, with extra attention being given to the comparison between patients with diffuse proliferative LN with either segmental (IV-S) or global (IV-G) lesions. Results. There was a wide range of agreement. A good interobserver agreement (ICC > 0.6) was present in 15%, and a moderate interobserver agreement (ICC 0.4–0.6) in 31% of the scored items. The activity index for LN showed a good (ICC 0.716) and the chronicity index a moderate (ICC 0.494) interobserver agreement. Both classification systems showed low agreement, although consensus was easily reached. Patients classified as IV-S (n = 15) had more favorable clinical parameters at study entry than those with class IV-G (n = 57). Although suggested by others, we found no differences in outcome between these two subclasses. Conclusions. This study shows that, although definitions were agreed upon beforehand, even specialized on nephropathologists have difficulties with scoring histopathological characteristics of LN, particularly with SLE the classification systems.
ABSTRACT The SDSS-III/Apache Point Observatory Galactic Evolution Experiment (APOGEE) survey operated from 2011-2014 using the APOGEE spectrograph, which collects high-resolution (R ∼ 22,500), ...near-IR (1.51-1.70 m) spectra with a multiplexing (300 fiber-fed objects) capability. We describe the survey data products that are publicly available, which include catalogs with radial velocity, stellar parameters, and 15 elemental abundances for over 150,000 stars, as well as the more than 500,000 spectra from which these quantities are derived. Calibration relations for the stellar parameters ( , , M/H, /M) and abundances (C, N, O, Na, Mg, Al, Si, S, K, Ca, Ti, V, Mn, Fe, Ni) are presented and discussed. The internal scatter of the abundances within clusters indicates that abundance precision is generally between 0.05 and 0.09 dex across a broad temperature range; it is smaller for some elemental abundances within more limited ranges and at high signal-to-noise ratio. We assess the accuracy of the abundances using comparison of mean cluster metallicities with literature values, APOGEE observations of the solar spectrum and of Arcturus, comparison of individual star abundances with other measurements, and consideration of the locus of derived parameters and abundances of the entire sample, and find that it is challenging to determine the absolute abundance scale; external accuracy may be good to 0.1-0.2 dex. Uncertainties may be larger at cooler temperatures ( ). Access to the public data release and data products is described, and some guidance for using the data products is provided.
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•Various formats of biologics have been assessed for the molecular imaging of immune cells in the tumor microenvironment, whereby specificity for the target, tumor penetrating ...potential and high target-to-background contrast are important parameters.•The molecular imaging of myeloid cells, and more specifically tumor-associated macrophages, promises to have prognostic potential in cancer and may predict therapy responsiveness.•The molecular imaging of endogenously activated T cells, or adoptively transferred engineered T cells, is important to assess (immuno)therapy success and therapy follow-up.
The important role of tumor microenvironmental elements in determining tumor progression and metastasis has been firmly established. In particular, the presence and activity profile of tumor-infiltrating immune cells may be associated with the outcome of the disease and may predict responsiveness to (immuno)therapy. Indeed, while some immune cell types, such as macrophages, support cancer cell outgrowth and mediate therapy resistance, the presence of activated CD8+ T cells is usually indicative of a better prognosis. It is therefore of the utmost interest to obtain a full picture of the immune infiltrate in tumors, either as a prognostic test, as a way to stratify patients to maximize therapeutic success, or as therapy follow-up. Hence, the non-invasive imaging of these cells is highly warranted, with biologics being prime candidates to achieve this goal.
We introduce a novel transformation-induced plasticity mechanism, i.e., a martensitic transformation from fcc phase to bcc phase, in medium-entropy alloys (MEAs). A VCrFeCoNi MEA system is designed ...by thermodynamic calculations in consideration of phase stability between bcc and fcc phases. The resultantly formed bcc martensite favorably contributes to the transformation-induced plasticity, thereby leading to a significant enhancement in both strength and ductility as well as strain hardening. We reveal the microstructural evolutions according to the Co-Ni balance and their contributions to a mechanical response. The Co-Ni balance plays a leading role in phase stability and consequently tunes the cryogenic-temperature strength-ductility balance. The main difference from recently-reported metastable high-entropy dual-phase alloys is the formation of bcc martensite as a daughter phase, which shows significant effects on strain hardening. The hcp phase in the present MEA mostly acts as a nucleation site for the bcc martensite. Our findings demonstrate that the fcc to bcc transformation can be an attractive route to a new MEA design strategy for improving cryogenic strength-ductility.
Heparanase, a heparan sulfate (HS)–specific endoglucuronidase, mediates the onset of proteinuria and renal damage during experimental diabetic nephropathy. Glomerular heparanase expression is ...increased in most proteinuric diseases. Herein, we evaluated the role of heparanase in two models of experimental glomerulonephritis, being anti-glomerular basement membrane and lipopolysaccharide-induced glomerulonephritis, in wild-type and heparanase-deficient mice. Induction of experimental glomerulonephritis led to an increased heparanase expression in wild-type mice, which was associated with a decreased glomerular expression of a highly sulfated HS domain, and albuminuria. Albuminuria was reduced in the heparanase-deficient mice in both models of experimental glomerulonephritis, which was accompanied by a better renal function and less renal damage. Notably, glomerular HS expression was preserved in the heparanase-deficient mice. Glomerular leukocyte and macrophage influx was reduced in the heparanase-deficient mice, which was accompanied by a reduced expression of both types 1 and 2 helper T-cell cytokines. In vitro , tumor necrosis factor-α and lipopolysaccharide directly induced heparanase expression and increased transendothelial albumin passage. Our study shows that heparanase contributes to proteinuria and renal damage in experimental glomerulonephritis by decreasing glomerular HS expression, enhancing renal leukocyte and macrophage influx, and affecting the local cytokine milieu.
Background and aims
There is currently no cross‐national validation of a scale that measures problematic social media use (SMU). The present study investigated and compared the psychometric ...properties of the social media disorder (SMD) scale among young adolescents from different countries.
Design
Validation study.
Setting and participants
Data came from 222 532 adolescents from 44 countries participating in the health behaviour in school‐aged children (HBSC) survey (2017/2018). The HBSC survey was conducted in the European region and Canada. Participants were on average aged 13.54 years (standard deviation = 1.63) and 51.24% were girls.
Measurement
Problematic SMU was measured using the nine‐item SMD scale with dichotomous response options.
Findings
Confirmatory factor analyses (CFA) showed good model fit for a one‐factor model across all countries (minimum comparative fit index (CFI) and Tucker–Lewis index (TLI) = 0.963 and 0.951, maximum root mean square error of approximation (RMSEA) and standardized root mean square residual (SRMR) = 0.057 and 0.060), confirming structural validity. The internal consistency of the items was adequate in all countries (minimum alpha = 0.840), indicating that the scale provides reliable scores. Multi‐group CFA showed that the factor structure was measurement invariant across countries (ΔCFI = −0.010, ΔRMSEA = 0.003), suggesting that adolescents’ level of problematic SMU can be reliably compared cross‐nationally. In all countries, gender and socio‐economic invariance was established, and age invariance was found in 43 of 44 countries. In line with prior research, in almost all countries, problematic SMU related to poorer mental wellbeing (range βSTDY = 0.193–0.924, P < 0.05) and higher intensity of online communication (range βSTDY = 0.163–0.635, P < 0.05), confirming appropriate criterion validity.
Conclusions
The social media disorder scale appears to be suitable for measuring and comparing problematic social media use among young adolescents across many national contexts.
Objectives
Specific guidelines for initial dosing of warfarin in ischaemic stroke patients have not been developed. Therefore, we have developed an age‐ and weight‐adjusted warfarin initiation ...nomogram (AW‐WIN) for ischaemic stroke patients and then evaluated the efficacy and safety of AW‐WIN compared with physician‐determined warfarin dosing (PDWD).
Methods
The age‐ and weight‐adjusted warfarin initiation nomogram was administered to 104 acute ischaemic stroke patients between January 2008 and February 2009. A historical control group (PDWD) of 96 patients was selected from comparable patients who were discharged with warfarin during the previous year. Time‐to‐therapeutic international normalized ratios (INRs) and the incidence of excessive anticoagulation were compared in the AW‐WIN and PDWD groups.
Results
The general characteristics, risk factors, and stroke mechanism of the AW‐WIN and PDWD groups did not differ significantly. The mean time to INR ≥ 2.0 was significantly shorter in the AW‐WIN than in the PDWD group (4.9 ± 0.7 vs. 6.2 ± 0.8 days, P = 0.0008). After adjustment for potential confounding variables, the AW‐WIN group reached target INR faster than the PDWD group (hazard ratio, 1.76; 95% confidence interval, 1.26–2.45; P = 0.001). The time‐to‐therapeutic INR ≥1.7 was shorter (P = 0.0002), the proportion of patients with therapeutic INR (2–3) at 5 days was higher (P = 0.002), and the rate of excessive anticoagulation of ≥3.5 INR during hospitalization was lower (P = 0.024) in the AW‐WIN than in the PDWD group.
Conclusions
AW‐WIN reduces the time to target INR and the risk of excessive anticoagulation. AW‐WIN may be an efficient and safe method of anticoagulation during the acute phase of ischaemic stroke.
The glomerular endothelial glycocalyx is postulated to be an important modulator of permeability and inflammation. The glycocalyx consists of complex polysaccharides, the main functional constituent ...of which, heparan sulfate (HS), is synthesized and modified by multiple enzymes. The N-deacetylase-N-sulfotransferase (Ndst) enzymes initiate and dictate the modification process. Here we evaluated the effects of modulation of HS in the endothelial glycocalyx on albuminuria and glomerular leukocyte influx using mice deficient in endothelial and leukocyte Ndst1 (TEKCre+/Ndst1flox/flox). In these mice, glomerular expression of a specific HS domain was significantly decreased, whereas the expression of other HS domains was normal. In the endothelial glycocalyx, this specific HS structure was not associated with albuminuria or with changes in renal function. However, glomerular leukocyte influx was significantly reduced during antiglomerular basement membrane nephritis, which was associated with less glomerular injury and better renal function. In vitro decreased adhesion of wild-type and Ndst1-deficient granulocytes to Ndst1-silenced glomerular endothelial cells was found, accompanied by a decreased binding of chemokines and L-selectin. Thus, modulation of HS in the glomerular endothelial glycocalyx significantly reduced the inflammatory response in antiglomerular basement membrane nephritis.
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