Triggering receptor expressed on myeloid cells 2 (TREM2) is a DAP12-associated receptor expressed in microglia, macrophages, and other myeloid-derived cells. Previous studies have suggested that ...TREM2/DAP12 signaling pathway reduces inflammatory responses and promotes phagocytosis of apoptotic neurons. Recently, TREM2 has been identified as a risk gene for Alzheimer disease (AD). Here, we show that DAP12 stabilizes the C-terminal fragment of TREM2 (TREM2-CTF), a substrate for γ-secretase. Co-expression of DAP12 with TREM2 selectively increased the level of TREM2-CTF with little effects on that of full-length TREM2. The interaction between DAP12 and TREM2 is essential for TREM2-CTF stabilization as a mutant form of DAP12 with disrupted interaction with TREM2 failed to exhibit such an effect. Silencing of either Trem2 or Dap12 gene significantly exacerbated pro-inflammatory responses induced by lipopolysaccharides (LPS). Importantly, overexpression of either full-length TREM2 or TREM2-CTF reduced LPS-induced inflammatory responses. Taken together, our results support a role of DAP12 in stabilizing TREM2-CTF, thereby protecting against excessive pro-inflammatory responses.
TREM2 is a DAP12-coupled receptor associated with neurodegenerative diseases.
Co-expression of DAP12 increased the level of TREM2 C-terminal fragment (TREM2-CTF) which suppressed the release of pro-inflammatory cytokines.
A major function of DAP12 is to stabilize TREM2-CTF, which regulates inflammatory responses in microglia.
Our studies unraveled a novel function of DAP12 and provided new link between TREM2/DAP12 complexes and neuroinflammation.
In locoregionally advanced nasopharyngeal carcinoma (LANPC) patients, variance of tumor response to induction chemotherapy (ICT) was observed. We developed and validated a novel imaging biomarker to ...predict which patients will benefit most from additional ICT compared with chemoradiotherapy (CCRT) alone.
All patients, including retrospective training (n = 254) and prospective randomized controlled validation cohorts (a substudy of NCT01245959, n = 248), received ICT+CCRT or CCRT alone. Primary endpoint was failure-free survival (FFS). From the multi-parameter magnetic resonance images of the primary tumor at baseline, 819 quantitative 2D imaging features were extracted. Selected key features (according to their interaction effect between the two treatments) were combined into an Induction Chemotherapy Outcome Score (ICTOS) with a multivariable Cox proportional hazards model using modified covariate method. Kaplan-Meier curves and significance test for treatment interaction were used to evaluate ICTOS, in both cohorts.
Three imaging features were selected and combined into ICTOS to predict treatment outcome for additional ICT. In the matched training cohort, patients with a high ICTOS had higher 3-year and 5-year FFS in ICT+CCRT than CCRT subgroup (69.3% vs. 45.6% for 3-year FFS, and 64.0% vs. 36.5% for 5-year FFS; HR = 0.43, 95% CI = 0.25-0.74, p = 0.002), whereas patients with a low ICTOS had no significant difference in FFS between the subgroups (p = 0.063), with a significant treatment interaction (p
< 0.001). This trend was also found in the validation cohort with high (n = 73, ICT+CCRT 89.7% and 89.7% vs. CCRT 61.8% and 52.8% at 3-year and 5-year; HR = 0.17, 95% CI = 0.06-0.51, p < 0.001) and low ICTOS (n = 175, p = 0.31), with a significant treatment interaction (p
= 0.019). Compared with 12.5% and 16.6% absolute benefit in the validation cohort (3-year FFS from 69.9 to 82.4% and 5-year FFS from 63.4 to 80.0% from additional ICT), high ICTOS group in this cohort had 27.9% and 36.9% absolute benefit. Furthermore, no significant survival improvement was found from additional ICT in both groups after stratifying low ICTOS patients into low-risk and high-risks groups, by clinical risk factors.
An imaging biomarker, ICTOS, as proposed, identified patients who were more likely to gain additional survival benefit from ICT+CCRT (high ICTOS), which could influence clinical decisions, such as the indication for ICT treatment.
ClinicalTrials.gov , NCT01245959 . Registered 23 November 2010.
Environmental natural organic matters (NOMs) have great effects on the physicochemical properties of engineering nanoparticles, which may impact the transport of nanoparticles across plasma membrane ...and the cytotoxicity. Therefore, the kinetics, uptake pathway and mass of transporting into A549 cell membrane of silver nanoparticles (AgNPs) coated with citric acid (CA), tartaric acid (TA) and fulvic acid (FA) were investigated, respectively. CA, FA and TA enhanced the colloidal stability of AgNPs in culture medium and have greatly changed the surface plasmon resonance spectrum of AgNPs due to the absorption of CA, FA and TA on surface of AgNPs. Internalizing model showed that velocity of CA-, TA- and FA-nAg transporting into A549 cell were 5.82-, 1.69- and 0.29-fold higher than those of the control group, respectively. Intracellular mass of Ag was dependent on mass of AgNPs delivered to cell from suspension, which obeyed Logistic model and was affected by NOMs that CA- and TA-nAg showed a large promotion on intracellular mass of Ag. The lipid raft/caveolae-mediated endocytosis (LME) of A549 cell uptake of AgNPs were susceptible to CA, TA and FA that uptake of CA-, TA- and FA-nAg showed lower degree of dependent on LME than that of the control (uncoated AgNPs). Actin-involved uptake pathway and macropinocytosis would have less contribution to uptake of FA-nAg. Overall, transmembrane transport of NOMs-coated AgNPs differs greatly from that of the pristine AgNPs.
The solubility of nano-sized metal oxides (nZnO, nCuO, nTiO
2
, nCeO
2
, and nFe
3
O
4
, 17–42 nm) and some non-nano-mineral powders (ZnO, ZnSiO
3
, ZnS, and CuO) were evaluated by using ...gastrointestinal solubility bioavailability research consortium (SBRC), in vitro gastrointestinal (IVG) method, pulmonary artificial lysosomal fluid (ALF), and Gamble solution method, respectively. It is found that these nano-sized metal oxides aggregated more or less when suspending in the simulated biological fluids analyzed by dynamic light scattering (2 mg L
−1
) and UV-Vis spectrometry (100 mg L
−1
). The aggregation and sedimentation of nano-metal oxides in a simulated biofluid are influenced by its surface property and the ingredient of the liquid. The dissolution in fluids may decrease the aggregating radius of a nano-metal oxide. In return, the aggregative effect can influence the solubility of metal elements and result in their weakened bioaccessibility. The suspending stability was consistent in the order of nFe
3
O
4
< nCuO < nTiO
2
< nCeO
2
< nZnO in all the simulated biological fluids. Nano-ZnO and nCuO showed higher gastrointestinal and pulmonary bioaccessibility than nFe
3
O
4
, nTiO
2
, and nCeO
2
. The further comparisons on the bioaccessibility for nCuO and nZnO with non-nano-powder CuO and ZnO indicated that the aggregating size in suspension could play more important role in influencing the bioaccessibility than single particle size does. The present study reveals that aggregation of all studied nano-sized metal oxides occurred in body physiologic fluids and that nZnO and nCuO were easily dissolved in simulated physiologic fluids, suggesting more potential health risks from nZnO and nCuO’s exposure.
Graphical abstract
Aggregation and sedimentation of nano-sized metal oxides with its bioaccessibility: a hint to health risks
The in vitro cytotoxicity of nano silver nanoparticles (nAg, 99 ± 75 nm) and nano zinc oxide nanoparticles (nZnO, 27 ± 7 nm) pretreated with citric acid (CA), tartaric acid (TA), and fulvic acid (FA) ...to human pulmonary adenocarcinoma cells (A549 cells), a common model cell strain, was investigated. The LC
50
values of CA-, FA-, and TA-nZnO (19–22 μg ml
−1
) were higher than those of the pristine nZnO (15 μg ml
−1
), and CA, FA, and TA depressed ROS levels and inhibited the apoptosis process induced by nZnO since they decreased Zn
2+
release from nZnO in culture medium. The LC
50
values of CA-, FA-, and TA-nAg (111–120 μg ml
−1
) were lower than that of the pristine nAg (185 μg ml
−1
), and CA, FA, and TA significantly improved the ROS levels induced by nAg by increasing the cellular uptake of nAg. Therefore, CA, FA, and TA decrease the cytotoxicity of nZnO while increasing the cytotoxicity of nAg.
Background:
To explore the prognostic value of radiomics-based and digital pathology-based imaging biomarkers from macroscopic magnetic resonance imaging (MRI) and microscopic whole-slide images for ...patients with nasopharyngeal carcinoma (NPC).
Methods:
We recruited 220 NPC patients and divided them into training (n = 132), internal test (n = 44), and external test (n = 44) cohorts. The primary endpoint was failure-free survival (FFS). Radiomic features were extracted from pretreatment MRI and selected and integrated into a radiomic signature. The histopathological signature was extracted from whole-slide images of biopsy specimens using an end-to-end deep-learning method. Incorporating two signatures and independent clinical factors, a multi-scale nomogram was constructed. We also tested the correlation between the key imaging features and genetic alternations in an independent cohort of 16 patients (biological test cohort).
Results:
Both radiomic and histopathologic signatures presented significant associations with treatment failure in the three cohorts (C-index: 0.689–0.779, all p < 0.050). The multi-scale nomogram showed a consistent significant improvement for predicting treatment failure compared with the clinical model in the training (C-index: 0.817 versus 0.730, p < 0.050), internal test (C-index: 0.828 versus 0.602, p < 0.050) and external test (C-index: 0.834 versus 0.679, p < 0.050) cohorts. Furthermore, patients were stratified successfully into two groups with distinguishable prognosis (log-rank p < 0.0010) using our nomogram. We also found that two texture features were related to the genetic alternations of chromatin remodeling pathways in another independent cohort.
Conclusion:
The multi-scale imaging features showed a complementary value in prognostic prediction and may improve individualized treatment in NPC.
DNAX-activating protein of 12 kDa (DAP12) is a signaling adapter protein expressed in cells that participate in innate immune responses. By pairing with different triggering receptors expressed on ...myeloid cell (TREM) proteins, DAP12 can mediate both positive and negative cellular responses. In particular, TREM1 acts as an amplifier of the immune response, while TREM2 functions as a negative regulator. TREM2 has also been shown to stimulate the phagocytosis of apoptotic neurons and define the barrier function in microglia. Notably, loss-of-function mutations of either
or
result in a disorder known as Nasu-Hakola disease (NHD); and mutations of these genes have been associated with the risk for Alzheimer's disease (AD), suggesting that TREM2 and DAP12 may regulate common signaling pathways in the disease pathogenesis. In this study, we demonstrated an anti-inflammatory role of DAP12 in murine microglia that depends on the presence of TREM2. We also uncovered the JNK signaling pathway as the underlying molecular mechanism by which the TREM2/DAP12 complex suppresses the hyperactivation of microglia upon LPS stimulation. Interestingly, LPS down-regulates the expression of
via the activation of JNK and NF-κB signaling pathways, resulting in a vicious cycle that synergistically promotes the inflammatory responses. Our study provides insights into mechanism-based therapy for neuroinflammatory disorders.
A confirmatory and quantitative method based on liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI/MS/MS) has been developed for simultaneous determination of seven ...photoinitiator residues: benzophenone, (1-hydroxycyclohexyl)phenylketone (Irgacure 184), isopropylthioxanthone (ITX), 2-ethylhexyl-(4-dimethylamino)benzoate (EHA or EHDAB), 2-methyl-1-4-(methylthio)phenyl-2-(4-morpholinyl)-1-propanone (Irgacure 907), (2,4,6-trimethylbenzoyl)diphenylphosphine oxide (TPO) and 2-benzyl-2-(dimethylamino)-1-(4-morpholinophenyl)-1-butanone (Irgacure 369) in packaged milk and related packaging materials. Residues of photoinitiators were extracted from milk using acetonitrile, and further enriched and purified on HLB solid-phase extraction cartridges prior to being analyzed by LC-ESI/MS/MS with selected reaction monitoring mode, while photoinitiators in packaging materials were extracted using the same solvent. Satisfactory recovery (from 80 to 111%), intra- and inter-day precision (below 12%), and low limits of quantification (from 0.1 to 5.0 μg kg⁻¹) were evaluated from spiked samples at three concentration levels (5.0, 10.0 and 25.0 μg kg⁻¹ for Irgacure 184 and 2.5, 5.0 and 25.0 μg kg⁻¹ for others). These excellent validation data suggested the possibility of using the LC-ESI/MS/MS method for simultaneous determination of low-level photoinitiator residues migrating from printed food-packaging materials into milk. The method has been successfully applied to the analysis of real samples of different fat contents ranging from 8 to 30 g L⁻¹. The photoinitiator residues were revealed to be higher in milk with higher fat content and the most important contaminations were benzophenone and ITX in concentration ranges of 2.84-18.35 and 0.83-8.87 μg kg⁻¹, respectively. graphic removed
Post-radiation nasopharyngeal necrosis (PRNN) is a severe adverse event following re-radiotherapy for patients with locally recurrent nasopharyngeal carcinoma (LRNPC) and associated with decreased ...survival. Biological heterogeneity in recurrent tumors contributes to the different risks of PRNN. Radiomics can be used to mine high-throughput non-invasive image features to predict clinical outcomes and capture underlying biological functions. We aimed to develop a radiogenomic signature for the pre-treatment prediction of PRNN to guide re-radiotherapy in patients with LRNPC.
This multicenter study included 761 re-irradiated patients with LRNPC at four centers in NPC endemic area and divided them into training, internal validation, and external validation cohorts. We built a machine learning (random forest) radiomic signature based on the pre-treatment multiparametric magnetic resonance images for predicting PRNN following re-radiotherapy. We comprehensively assessed the performance of the radiomic signature. Transcriptomic sequencing and gene set enrichment analyses were conducted to identify the associated biological processes.
The radiomic signature showed discrimination of 1-year PRNN in the training, internal validation, and external validation cohorts (area under the curve (AUC) 0.713-0.756). Stratified by a cutoff score of 0.735, patients with high-risk signature had higher incidences of PRNN than patients with low-risk signature (1-year PRNN rates 42.2-62.5% vs. 16.3-18.8%, P < 0.001). The signature significantly outperformed the clinical model (P < 0.05) and was generalizable across different centers, imaging parameters, and patient subgroups. The radiomic signature had prognostic value concerning its correlation with PRNN-related deaths (hazard ratio (HR) 3.07-6.75, P < 0.001) and all causes of deaths (HR 1.53-2.30, P < 0.01). Radiogenomics analyses revealed associations between the radiomic signature and signaling pathways involved in tissue fibrosis and vascularity.
We present a radiomic signature for the individualized risk assessment of PRNN following re-radiotherapy, which may serve as a noninvasive radio-biomarker of radiation injury-associated processes and a useful clinical tool to personalize treatment recommendations for patients with LANPC.
•In vivo inhalation bioavailability of Pb in simulated PM2.5 to mice was investigated.•In vitro inhalation bioaccessibility was studied by Gamble Solution, SLF, SELF and ALF.•In vivo-in vitro ...correlation for the assessment of in vitro procedures.•Gamble Solution was further optimized by using in vivo-in vitro correlation.
In order to assess and optimize frequently used in vitro inhalation bioaccessibility procedures for heavy metals in the inhalation risk assessment, in vivo inhalation bioavailability of Pb in simulated atmosphere fine particles (PM2.5) from aging soils spiked with lead compounds and field soils in lead-zinc mining areas was investigated via intranasally instilled experiments with these PM2.5 suspensions to mice and Pb bioaccessibility was extracted by using four frequently used in vitro procedures (Gamble Solution, simulated lung fluid, simulated epithelial lung fluid and artificial lysosomal fluid). Mouse exposure experiments showed that Pb was mainly distributed in the liver, kidneys, blood and spleen. Based on the kidney model, in vitro inhalation bioaccessibility of Pb extracted with optimized Gamble Solution, in which solid to liquid ratio (S/L) was optimized to 1:1000 g ml−1 and DTPA was proved to be the key effective component, showed a strong linear relationship with its in vivo inhalation bioavailability (y = 1.07x – 3.86, R2 = 0.73). Moreover, in vitro bioaccessible and bioavailable fractions of Pb were mainly from acid exchangeable and reducible fractions of Pb in PM2.5. Altogether, optimized Gamble Solution was suggested for the analysis of in vitro bioaccessibility for risk-based assessments.
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