Sensitizing Leukemia Stem Cells to NF-κB Inhibitor Treatment in Vivo by Inactivation of Both TNF and IL-1 Signaling

We previously reported that autocrine TNF-α (TNF) is responsible for JNK pathway activation in a subset of acute myeloid leukemia (AML) patient samples, providing a survival/proliferation signaling parallel to NF-κB in AML stem cells (LSCs). In this study, we report that most TNF-expressing AML cells (LCs) also express another pro-inflammatory cytokine, IL1β, which acts in a parallel manner. TNF was produced primarily by LSCs and leukemic progenitors (LPs), whereas IL1β was mainly produced by partially differentiated leukemic blasts (LBs). IL1β also stimulates an NF-κB-independent pro-survival and proliferation signal through activation of the JNK pathway. We determined that co-inhibition of signaling stimulated by both TNF and IL1β synergizes with NF-κB inhibition in eliminating LSCs both ex vivo and in vivo. Our studies show that such treatments are most effective in M4/5 subtypes of AML

miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia

MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy

Factors Affecting Maintenance Probability and Resurfacing Thickness Based on the Pavement Management System

In order to investigate the key factors and analyze their effects on maintenance and rehabilitation (M&R) strategies, data for 2495 pavement sections were collected from the pavement management system (PMS), including pavement performance data, traffic data, material property data, and M&R record data. Logistic regression was first employed to explore the influential factors on maintenance probability. Afterward, the classification tree model was established to find out the key factors on resurfacing thickness. Results showed that road sections with higher IRI, rutting depth (RD), deterioration rate of surface friction coefficient (DRSFC), pavement patching ratio (PPR), and transverse cracking severity index (TCSI) before treatment had significantly higher maintenance probability, which could be quantified by the developed logistic model. Moreover, treatments implemented on bridge decks tended to have greater resurfacing thickness. For pavement M&R projects, with the tensile strength ratio (TSR) of top layer materials higher than 88.7% and pretreatment SFC higher than 49, the resurfacing thickness would be thinner. For bridge M&R projects, middle layer TSR higher than 88.3% led to thinner overlays, and much thinner resurfacing thickness can be observed if pretreatment RD was less than 8.72 mm. When middle layer TSR was lower than 88.3% and pretreatment IRI was higher than 2.383 m/km with larger AESAL, the resurfacing thickness would probably be the thickest. The two models built in this paper provided probabilistic estimation of maintenance probability and explored key factors together with their critical split points for resurfacing thickness, which could be regarded as an alternative decision-making tool for pavement engineers

Investigation of the Thermal Degradation of SBS Polymer in Long-Term Aged Asphalt Binder Using Confocal Laser Scanning Microscopy (CLSM)

Styrene–butadiene–styrene (SBS) polymer is extensively employed for asphalt pavement construction, and its degradation significantly damages the durability of asphalt concrete. However, the effect of aging protocols on the degradation of SBS polymer in asphalt binder has not been thoroughly investigated. In this study, confocal laser scanning microscopy (CLSM) was applied to characterize the change in morphology with SBS polymer degradation. Various aging protocols were considered, including accelerated aging processes in laboratory- and field-aged samples from three highway sections with different in-service periods. Scanned images of the polymer phase in the 2D plane at different depths were processed and further reconstructed in three dimensions. Furthermore, the three-dimensional polymer morphology indices derived from the semi-quantitative analysis of the images were correlated with the rheological indices. The results show that the polymer particles change from a relatively large ellipsoidal shape to a relatively small spherical shape as aging proceeds. The increase in aging temperature appears to accelerate the degradation of the polymer at the same rheological level. The effect of the laboratory aging method on the polymer was more pronounced during the early stages of aging compared to that in the field aging process

Investigation of the Thermal Degradation of SBS Polymer in Long-Term Aged Asphalt Binder Using Confocal Laser Scanning Microscopy (CLSM)

Styrene–butadiene–styrene (SBS) polymer is extensively employed for asphalt pavement construction, and its degradation significantly damages the durability of asphalt concrete. However, the effect of aging protocols on the degradation of SBS polymer in asphalt binder has not been thoroughly investigated. In this study, confocal laser scanning microscopy (CLSM) was applied to characterize the change in morphology with SBS polymer degradation. Various aging protocols were considered, including accelerated aging processes in laboratory- and field-aged samples from three highway sections with different in-service periods. Scanned images of the polymer phase in the 2D plane at different depths were processed and further reconstructed in three dimensions. Furthermore, the three-dimensional polymer morphology indices derived from the semi-quantitative analysis of the images were correlated with the rheological indices. The results show that the polymer particles change from a relatively large ellipsoidal shape to a relatively small spherical shape as aging proceeds. The increase in aging temperature appears to accelerate the degradation of the polymer at the same rheological level. The effect of the laboratory aging method on the polymer was more pronounced during the early stages of aging compared to that in the field aging process

Evaluation of the Rheological Property of Binder-Filler Systems after Oxidation Based on a Simple Film Oven Aging Method

Asphalt mastic is a combination of binder and filler. The binder-filler system within asphalt mixtures plays an important role in adhesion between mineral aggregates. The aging of binders in pavement always happens with fillers inside or contact with mineral aggregates, so it is critical to investigate the evolved rheological property of binder-filler systems during oxidative aging. In this study, simple film oven aging methods for the aging of mastics (binder-filler system) were conducted and verified by comparing the master-curves of aged mastics at different oven positions or different aging times. The frequency sweep test was performed to measure the changing stiffness of mastics with a different combination of binders and filler contents. Test results show that oven positions could influence the aging effect of the mastics significantly, given the influence of circulation. With increasing aging times, the complex modulus increases while phase angle decreases. Comparing the mastics which were first aged then mixed with mastics which were first mixed then aged, it was observed that fillers inside the binder could accelerate aging of the mastics. Additionally, the aging index of mastics with different combinations showed that both the modification of binders and filler contents could affect the aging rate of the mastics

Nanosecond pulsed laser-induced formation of nanopattern on Fe-based metallic glass surface

Fe-based metallic glasses (MGs) have attracted much attention because of their cheap raw materials, outstanding soft magnetic properties and superior catalytic activity. Meanwhile, the fabrication of micro/nano-structures on its surface could further improve its functional properties. In this study, it was attempted to fabricate micro/ nano-structures on a Fe-based MG (Fe52Cr13Mo12C15B6Er2, in at. %) surface by nanosecond pulsed laser irradiation technology. The surface characteristics and microstructural evolution of Fe-based MG were investigated. The experimental results showed that under different laser fluences, the laser-irradiated areas exhibited distinguished microstructures, i.e., nanoparticles, the network nanostructures or a combination of these two microstructures. Furthermore, oxygen and erbium were enriched inside the network nanostructures. By analyzing the microstructural evolution, formation mechanisms of the nanoparticles and the network nanostructures were discussed. The nanoparticles were actually caused by laser-induced element enrichment (i.e. amorphous erbium oxide) and the mismatch of its wettability with the substrate; the formation of the network nanostructures was attributed to the diffusion and connection of nanoparticles under the combined influence of recoil pressure and surface topography

Fatigue Cracking Resistance of Engineered Cementitious Composites (ECC) under Working Condition of Orthotropic Steel Bridge Decks Pavement

In order to investigate the fatigue cracking resistance of engineered cementitious composites (ECC) used in in total life pavement, the semi-circular bending (SCB) test and improved three-point bending fatigue test (ITBF) were utilized in this study. The digital image correlation (DIC) method was also utilized to track the surface strain fields of specimens during the SCB test. X-ray computed tomography (CT) and digital image processing (DIP) technologies were applied to measure the internal-crack distribution of the ITBF specimen. The results of the SCB test showed that the fatigue cracking damage process of ECC can be divided into three stages and that the cracking stable propagating stages occupied the main part, which indicates that ECC has excellent ductility and toughness and could work very well with existing cracks. The ITBF results showed that the fatigue cracking resistance of ECC was better than epoxy asphalt concrete (EAC). In addition, the internal-crack distribution along the depth direction of the ITBF specimen could be presented well by the image pixel statistical (IPS) method based on CT scanning of image slices. It could be found that multiple cracks propagate simultaneously in ECC, instead of a single crack, under the OSBD pavement working condition