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Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with hepatocellular carcinoma (HCC). In this study, 10 patients with HCC were remedied with anti-PD1, and pre-treatment biopsy samples were sequenced for 289 nanostring panel RNA to compare responsive and non-responsive tumors to identify possible pretreatment biomarkers or targets of anti-PD1 therapeutic responses. Fortunately, the expression of β-Glucuronidase (GUSB) in the non-responding tumors was found to be remarkably higher than that in responding tumors. Results of the cell counting kit 8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), transwell, wound healing test, and flow cytometry showed that GUSB facilitated proliferation, invasion, as well as migration of human HCC cells and downregulated PD-L1 expression by promoting miR-513a-5p. Additionally, as a GUSB inhibitor, amoxapine can reduce the progression of human HCC cells, and was an effective treatment for HCC and improved the sensitivity of anti-PD1 therapy. In summary, this study reveals that increased GUSB downregulates PD-L1 expression by promoting miR-513a-5p, leading to primary resistance to anti-PD1 treatment in HCC, and amoxapine enhances the sensitivity of anti-PD1 therapy by inhibiting GUSB, providing a new strategy and method for improving the efficacy of anti-PD1 therapy and bringing new prospects for therapy of HCC. [ABSTRACT FROM AUTHOR]

Due to the excellent shear deformation resistance of high-viscosity polymer-modified bitumen (HVPMB), the traditional methods based on time sweep and linear amplitude sweep (LAS) had problems with insufficient damage accumulation and inability to disrupt the integrity of HVPMB, making it difficult to accurately evaluate its fatigue and healing characteristics. To solve this problem, this study developed an effective evaluation proposal called continuous multiple LAS (MLAS) test and MLAS-based healing (MLASH) test. One base bitumen and three HVPMBs were selected for related experiments. MLAS test results confirmed that the percentage of strain energy attenuation (PSEA) can be used to evaluate the fatigue damage degree of HVPMBs. The lower the PSEA , the lesser damage. Combined with the fluorescence microscope and direct photography observation, the fatigue hairline cracks during MLAS test gradually expanded from the sample periphery to center until completely destroyed. Further, the MLASH test was developed to evaluate the healing performance of HVPMB by introducing intermittent duration into MLAS test. The variation of PSEA after tenth LAS loading (i.e. Δ PSEA) was proposed to evaluate the healing performance of HVPMB. The larger the Δ PSEA , the better the healing performance of HVPMB. All HVPMBs showed satisfactory healing performance once there was sufficient healing intermittent time (e.g. 180 s), and the healing performance was negatively correlated with the damage degree. Notably, the polymer structures had a dual effect on the healing performance of HVPMB, that is, they promoted the elastic healing recovery of HVPMB at lower temperature, while hindering the flow healing recovery at higher temperatures. Moreover, different temperatures caused a shift in the ranking of healing performance of various HVPMBs, thus the healing result at only single temperature cannot comprehensively represent the healing performance of HVPMB. Overall, the newly developed evaluation proposal can help to select HVPMB with excellent fatigue resistance and healing properties and provide a certain basis for accurately predicting HVPMB pavement life. [Display omitted] ● An effective evaluation proposal based on MLAS was developed. ● Percentage of strain energy attenuation (PSEA) can evaluate the fatigue degree of HVPMB. ● Variation of PSEA after tenth LAS loading can evaluate the healing performance of HVPMB. ● Polymer structures had a dual effect on the healing performance of HVPMB. ● Healing result at only single temperature cannot comprehensively represented the healing performance of HVPMB. [ABSTRACT FROM AUTHOR]

[Display omitted] • Decay pattern of self-healing temperature susceptibility of bitumens at various ageing states is examined. • Self-healing rate parabola evolution with temperature of bitumen is related to the frequent phase transition. • Superposition impacts of temperature and ageing on phase structures elicit the healing transition phenomena. • All-weather ageing causes more serious impact on self-healing temperature susceptibility than long-term ageing. • RA bitumen undergoes smaller ageing impact on self-healing temperature susceptibility than pure bitumen. Understanding the evolution law of the self-healing ability of bitumen under actual service environment is conductive to optimizing the design of self-healing bituminous pavement, while the changing temperatures and variety of ageing states complicate this issue. In this study, the decay pattern of self-healing temperature susceptibility of pure bitumen and rock-asphalt (RA) modified bitumen at the simulated ageing states of thermal oxidation and all-weather is analyzed by the dynamic shear rheometer based fatigue-healing-fatigue experiment. Through the thin layer chromatography, differential scanning calorimeter and rheological characterizations, the chemical composition, colloidal stability and macro phase transition (PT) behavior of bitumens with various ageing levels are examined. Results show that the self-healing rate parabola evolution with temperature of bitumen has to do with its frequent PT behaviors. The shift of self-healing curves and the appearance of healing inert temperature zone are the results of the growth of heavy components and decays of colloidal structure and phase structure caused by ageing. Notably, the superposition impacts of temperature and ageing on bitumen phase structures elicit the healing transition phenomena in the viscoelastic zone and viscous flow zone. Moreover, the multi-scale analysis reveals that the decay of self-healing temperature susceptibility with ageing is consistent with the deterioration tendency of the macro PT property, chemical composition and colloidal stability. Especially, all-weather ageing causes more serious impact on the self-healing temperature susceptibility of bitumens than thermal oxidative long-term ageing. RA bitumen with greater ageing resistance undergoes smaller ageing impact on self-healing temperature susceptibility than pure bitumen. [ABSTRACT FROM AUTHOR]

Healing characteristics of asphalt lay a foundation for the wide applications of permanent roads. However, the decay pattern of asphalt healing ability in actual climate environments still remains unclear. Hence, the weather accelerated ageing (WAA) influence on the healing temperature sensitivity of several representative asphalts is systematically investigated in this paper. Results from fatigue-healing-fatigue (FHF) experiment show that the WAA and terminal blend crumb rubber (TBCR) modification impart pronounced impacts to the healing temperature sensitivity of asphalts. Notably, it is found that the aged asphalt has a healing inertia zone with low healing temperature sensitivity, in which the healing ability of asphalt is at a relatively low level. Furthermore, four kinds of various index temperatures are put forward as the evaluation indicators to quantitatively characterize the influence of WAA on the healing temperature sensitivity, i.e. inert extended temperature at healing rate curve, inert extended temperature at healing percentage curve, top healing temperature (THT) shift value and complete healing temperature range (CHTR) shift value. Moreover, the greater the WAA resistance of asphalt, the smaller the WAA influence on its healing temperature sensitivity. The WAA reduces the differences of healing temperature sensitivity among various asphalts. Lastly, the thermal stability and phase behavior investigations reveal that the molecular compositions and phase state transition (PST) of asphalt will be changed after WAA, eventually inducing the healing temperature shift and the appearance of healing inertia zone. Image 1 • Four index temperatures are proposed to evaluate the influence of weather accelerated ageing (WAA). • Terminal blend rubber modification impart pronounced influence on healing temperature sensitivity of asphalt. • Weather accelerated aged asphalt has an obvious healing inertia zone with very low healing temperature sensitivity. • The greater the WAA resistance of asphalt, the smaller the WAA influence on healing temperature sensitivity. • WAA reduces the differences of healing temperature sensitivity among various asphalts. [ABSTRACT FROM AUTHOR]

• The survival rate of microcapsules during mixing and compaction of asphalt mixture was measured. • The survival rate of microcapsules could be improved by reducing the microcapsule size and the mixing temperature. • The bigger microcapsules were more easily activated by the stress at the crack tip. • It is suggested that the size of MUF microcapsules should be controlled within 15 μm ~ 25 μm. Microcapsule technology exhibits great potential in improving the healing efficiency of asphalt mixture and prolonging the service life of the pavement. The capsule should be kept intact in the mixing and compaction process of asphalt mixture, whereas broken to release the healing agents in time when cracks encounter it. This paper aims to investigate the survival and activation behavior of microcapsules in asphalt mixture during construction and service period. By means of the in situ polymerization method, the microcapsules of various sizes were prepared and their particle size distribution, core material content, shell permeability, and other properties were characterized. Based on the quantitative analysis principle of Fourier transform infrared spectrometer (FTIR), the influence of microcapsule size and mixing temperature on the survival rate of microcapsules was analyzed. Meanwhile, the morphology and size distribution of surviving microcapsules was obtained via fluorescence microscope (FM). In addition, the morphologies of microcapsules before and after the bitumen bond strength (BBS) test and dynamic shear rheological (DSR) test were observed by FM to examine the releasing behavior of microcapsules. Finally, the fatigue-rest-fatigue test was performed to investigate the influence of microcapsule size on the healing efficiency of aged asphalt mastic. The results showed that the survival rate could be improved by reducing the construction temperature and the microcapsules size. The loss of microcapsules was more likely to happen in the mixing process rather than in the compaction process. Microcapsules with larger sizes were easier to be activated to remarkably enhance the healing efficiency of the aged asphalt mastic. Notably, the microcapsules with appropriate size are recommended to be added to the mixtures to ensure that the microcapsules survive in the construction process and are activated when cracks appeared. [ABSTRACT FROM AUTHOR]

In this study, the fatigue-healing-fatigue (FHF) test is conducted to investigate influence pattern of temperature and thermal oxidative aging on the self-healing ability of styrene-butadiene-styrene (SBS) modified bitumen (SBS-MB) and polyethylene (PE) modified bitumen (PE-MB). Results display that the optimum healing temperature (OHT) of each bitumen (wherever unaged or aged) is in the phase transition (PT) zone, and is lower than its softening point, followed by its Newtonian flow temperature. Two types of healing crossover temperature points are found in the healing-temperature curves of polymer modified bitumen (PMB) samples with various aging degrees, indicating the complexity of self-healing transition phenomenon in the aged PMB samples. Hence, the evaluation of aging effects on the self-healing ability of PMBs should be performed in a wide temperature range. Furthermore, the self-healing ability of PMBs is gradually weakened with the deepening of aging extents. Notably, the thermal oxidative aging imparts totally different effects to the self-healing ability of SBS-MB and PE-MB at lower temperatures. Moreover, the results of softening point test, fluorescence microscopy test, frequency sweep test and differential scanning calorimeter test convey that the altered phase structure and polymer distribution of PMBs during aging elicit the healing-temperature curves shift and self-healing transition. Unlabelled Image • The optimum healing temperature of bitumen is lower than the softening point, followed by the Newtonian flow temperature. • Aging effects on healing ability of polymer modified bitumen should be examined in a wide temperature range. • Self-healing abilities of SBS bitumen and PE bitumen are gradually weakened with aging. • Thermal oxidative aging imparts various effects to healing abilities of SBS bitumen and PE bitumen at lower temperatures. • Altered phase structure and polymer distribution of modified bitumens during aging elicit healing curves shift and healing transition. [ABSTRACT FROM AUTHOR]

• The self-healing capability of bitumens can not be evaluated comprehensively and accurately at only one given temperature. • The healing peak temperature (HPT) and healing critical temperature range (HCTR) can be applied as the optimum healing temperature. • The temperature induced self-healing capability transition phenomenon of bitumens is significantly affected by the bitumen type, polymer type and content. • The temperature induced phase structure and property transition of bitumen is the essential reason for the self-healing capability transition. The temperature may induce the inconsistent order of self-healing capability between two bituminous materials, which could be called as the temperature induced self-healing capability transition phenomenon. To confirm this phenomenon, two base bitumens and four different styrene–butadiene-styrene polymer modified bitumen (SPMB) binders are selected to systematically investigate their self-healing capability through establishing the healing rate temperature (HR-T) curves and healing index temperature (HI-T) curves. Fluorescence microscopy (FM) is applied to study the internal morphology of different SPMB binders. The phase transition (PT) temperature range is determined by the differential scanning calorimeter (DSC) test. Within the PT temperature range, three kinds of special temperatures are discovered, i.e. healing peak temperature (HPT), healing critical temperature range (HCTR) and healing cross temperature (HCT). The HPT and HCTR are both lower than the high temperature PT range, followed by the softening point, and can be applied as the optimum healing temperature to guide the formulation of energy efficient pavement induction healing strategies. The HCT clearly divides the HR-T curves or HI-T curves of bitumens into different parts, thus leading to an opposite order of self-healing capability between two bitumens, which confirms the self-healing capability transition phenomenon. Therefore, the self-healing capability can not be evaluated comprehensively and accurately at only one given temperature. Most notably, it can be inferred that the temperature induced phase structure and property transition of bitumen is the essential reason for the self-healing capability transition phenomenon, which is significantly affected by the bitumen type, polymer type and content. [ABSTRACT FROM AUTHOR]

• Aged SBS modified asphalt was rejuvenated by different rejuvenation methods. • Fatigue resistance of aged binder can be well recovered by reactive rejuvenation. • Reactive rejuvenated binder shows good self-healing performance. Reclaimed bituminous mixture can be used in new pavement after rejuvenation. Common rejuvenation method and reactive rejuvenation method can be used to restore the properties of aged SBS modified asphalt(ASMB). This work focused on the recovery effect of fatigue resistance for ASMB by different rejuvenation methods. The effect of common and reactive rejuvenation on the fatigue behavior of ASMB was investigated by multi-stress creep and recovery test, linear amplitude sweep test and fatigue-healing-fatigue test. The results show that, as compared with common rejuvenation method, reactive rejuvenation method is more conducive to restoring the creep recovery rate and the non-recovered creep compliance of ASMB. Linear amplitude sweep test indicates that reactive rejuvenated ASMB shows the good fatigue stress cracking resistance, the fatigue life of which at 2.5% and 5.0% strain levels is increased by 30% and 71% as compared with that of common rejuvenated binder. Meanwhile, the self-healing index of reactive rejuvenated ASMB is also enhanced by 28.7%, which indicates its better self-healing potential and fatigue damage resistance. Furthermore, the fatigue life of SMB is reduced by 77.7% after aging, while that of ASMB is extended by 93.5% after common rejuvenation, and the fatigue life of reactive rejuvenated ASMB is almost twice than that of common rejuvenated binder. It means that reducing the adverse effects of aged asphalt and reconstructing the broken SBS cross-linking structure during rejuvenation process of ASMB are all crucial for restoring its fatigue resistance. [ABSTRACT FROM AUTHOR]

Asphalt aging and fatigue cracking are common forms of distresses in flexible pavements. Microencapsulated rejuvenator has been generating significant interest in the feasibility and potentiality applications of asphalt materials self-healing over the past decade and is likely to remain so for the foreseeable future. Despite multiple attempts, the prerequisite is crack propagation through the microcapsules and resulting in the broken shell, which is a passive release. Strategies toward self-healing of uncracked aged asphalt by microcapsules remain a significant challenge. Herein, numerous successful applications of controlled release microcapsules in other fields, including biomedical engineering, food industry, agriculture, smart coating, textile industry, and cosmetics, are classified and referenced. Special attention is given to the mechanisms of release and their triggers, followed by recent advances of microencapsulation technologies with detailed experimental demonstrations. In particular, the challenges and promising solutions of novel controlled release systems for asphalt materials are proposed in detail for the first time. This review aims to present future directions for research in this field, which provides new ideas for the smart maintenance of asphalt pavements. [ABSTRACT FROM AUTHOR]