Children diagnosed at age ≥ 18 months with metastatic MYCN-nonamplified neuroblastoma (NBL-NA) are at high risk for disease relapse, whereas those diagnosed at age < 18 months are nearly always ...cured. In this study, we investigated the hypothesis that expression of genes related to tumor-associated inflammatory cells correlates with the observed differences in survival by age at diagnosis and contributes to a prognostic signature.
Tumor-associated macrophages (TAMs) in localized and metastatic neuroblastomas (n = 71) were assessed by immunohistochemistry. Expression of 44 genes representing tumor and inflammatory cells was quantified in 133 metastatic NBL-NAs to assess age-dependent expression and to develop a logistic regression model to provide low- and high-risk scores for predicting progression-free survival (PFS). Tumors from high-risk patients enrolled onto two additional studies (n = 91) served as independent validation cohorts.
Metastatic neuroblastomas had higher infiltration of TAMs than locoregional tumors, and metastatic tumors diagnosed in patients at age ≥ 18 months had higher expression of inflammation-related genes than those in patients diagnosed at age < 18 months. Expression of genes representing TAMs (CD33/CD16/IL6R/IL10/FCGR3) contributed to 25% of the accuracy of a novel 14-gene tumor classification score. PFS at 5 years for children diagnosed at age ≥ 18 months with NBL-NA with a low- versus high-risk score was 47% versus 12%, 57% versus 8%, and 50% versus 20% in three independent clinical trials, respectively.
These data suggest that interactions between tumor and inflammatory cells may contribute to the clinical metastatic neuroblastoma phenotype, improve prognostication, and reveal novel therapeutic targets.
Microplastics (MPs) pollution has become a serious environmental issue worldwide, but its potential effects on health remain unknown. The administration of polystyrene MPs (PS-MPs) to mice for eight ...weeks impaired learning and memory behavior. PS-MPs were detected in the brain especially in the hippocampus of these mice. Concurrently, the hippocampus had decreased levels of immediate-early genes, aberrantly enhanced synaptic glutamate AMPA receptors, and elevated neuroinflammation, all of which are critical for synaptic plasticity and memory. Interestingly, ablation of the vagus nerve, a modulator of the gut-brain axis, improved the memory function of PS-MPs mice. These results indicate that exposure to PS-MPs in mice alters the expression of neuronal activity-dependent genes and synaptic proteins, and increases neuroinflammation in the hippocampus, subsequently causing behavioral changes through the vagus nerve-dependent pathway. Our findings shed light on the adverse impacts of PS-MPs on the brain and hippocampal learning and memory.
Display omitted
•PS-MPs can accumulate in the brain of mice.•Learning and memory deficits are found in mice by PS-MPs administration.•Exposure to PS-MPs decreases synaptic protein levels and induces neuroinflammation.•Elimination of vagus nerve rescues learning and memory in PS-MPs-treated mice.
Inhibition of cardiac late sodium current (late I(Na)) is a strategy to suppress arrhythmias and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. Current ...inhibitors of late I(Na) are unselective and can be proarrhythmic. This study introduces GS967 (6-4-(trifluoromethoxy)phenyl-3-(trifluoromethyl)-1,2,4triazolo4,3-apyridine), a potent and selective inhibitor of late I(Na), and demonstrates its effectiveness to suppress ventricular arrhythmias. The effects of GS967 on rabbit ventricular myocyte ion channel currents and action potentials were determined. Anti-arrhythmic actions of GS967 were characterized in ex vivo and in vivo rabbit models of reduced repolarization reserve and ischemia. GS967 inhibited Anemonia sulcata toxin II (ATX-II)-induced late I(Na) in ventricular myocytes and isolated hearts with IC(50) values of 0.13 and 0.21 µM, respectively. Reduction of peak I(Na) by GS967 was minimal at a holding potential of -120 mV but increased at -80 mV. GS967 did not prolong action potential duration or the QRS interval. GS967 prevented and reversed proarrhythmic effects (afterdepolarizations and torsades de pointes) of the late I(Na) enhancer ATX-II and the I(Kr) inhibitor E-4031 in isolated ventricular myocytes and hearts. GS967 significantly attenuated the proarrhythmic effects of methoxamine+clofilium and suppressed ischemia-induced arrhythmias. GS967 was more potent and effective to reduce late I(Na) and arrhythmias than either flecainide or ranolazine. Results of all studies and assays of binding and activity of GS967 at numerous receptors, transporters, and enzymes indicated that GS967 selectively inhibited late I(Na). In summary, GS967 selectively suppressed late I(Na) and prevented and/or reduced the incidence of experimentally induced arrhythmias in rabbit myocytes and hearts.
Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic ...etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations.
We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (K
) channel variants were assessed using patch clamp recording and Western blot.
Nine of 13 (69%) patients with ten different pathogenic variants (7 in
, 2 in
and 1 in
) were identified by the combined sequencing. The variant
p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F K
channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C K
channels were defective in trafficking. One patient had a
dominant mutation in the
gene (p.I211F), and WES revealed mosaicism of this variant from another patient.
Pathogenic variants in K
channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the
gene is highly suggestive of a founder effect. The I211F mutation in the
gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) K
channels are also associated with the diazoxide-unresponsive phenotype.
Hierarchical two-dimensional (2D) lamellar zeolites represent a young emerging field and a novel expression of the zeolite frameworks. Accompanied with synthesis and catalytic performance ...investigation, assessment on the local environment and catalytic behavior of acid sites in 2D zeolites are needed. Here, we described the local environment of Lewis acid sites and evaluated catalytic activities of external acid sites (i.e. sites on external surface and in mesopores) in 2D lamellar titanium silicalite-1 (TS-1) zeolites. For comparison purpose, four TS-1 zeolites, including 3D TS-1, multilamellar 2D TS-1 without pillarization and with pillarization by silica and silica/titania, respectively, were prepared. The local environment of Ti-sites, including coordination status of Ti-atom, speciation of hydroxyl (-OH) group that hints degree of confinement, acid site strength and accessibility, was collectively assessed by spectroscopic and organic base titration measurements. Kinetic studies of cyclooctene (C8H14) epoxidation with hydrogen peroxide (H2O2) discerned catalytic activity of external Ti-sites that decreased with increasing mesoporosity due to decrease in site confinement.
Display omitted
•External Lewis acid sites in 2D TS-1 zeolites were quantified.•2D TS-1 zeolites have high density of isolated surface silanol and titanol groups.•Reactivity of external sites decreases with increasing mesoporosity in 2D TS-1.•Decrease in reactivity of external sites is caused by loss of partial confinement.•Kinetic decoupling of epoxidation pathways enabled catalytic behavior assessment.
Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein ...cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.
PDF
