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Abstract The deck-charge structure, also known as axially decoupled charge structure, has been widely applied in open-pit rock excavation to improve blasting performance. However, the relationships between blast-induced fragmentation and deck-charge structures remain not well understood. This paper aims to experimentally investigate the influences of deck ratio, deck position and deck material on blast-induced fragmentation. Concrete specimens with dimension of 400 × 400 × 200 mm3 were used for small-scale single-hole blasting experiments. The dynamic fracturing process under blast loading was recorded with a high-speed camera. Displacement and strain fields were analyzed employing a 3D digital image correlation (DIC) system, and the fragment size distribution (FSD) was quantified through ImageJ, an advanced image-processing tool. The borehole wall pressure (BWP) was monitored through the embedded PVDF gauges within the test specimens. The results indicate that during deck charge blasting, the host concrete undergoes three phases: crushing, further crushing and fracturing, and radial crack development. Fragmentation performance improves within an optimal air-deck ratio range, while excessive ratios lead to poorer fragmentation compared to fully coupled charge blasting. The center deck charge yields the superior fragmentation, followed by double-ends and top deck charges. Water-deck charge generates finer fragmentation than air deck and polyethylene (PE) deck charges. Expanded polystyrene (EPS) deck charge does not facilitate fragmentation but may reduce vibration and limit damage to the remaining rock mass. Based on experiment results, production blasts with fully coupled charge, center air-deck charge and center water-deck charge were performed in an open-pit mine. These field tests revealed that the proposed center deck charge blasting reduced median fragment size by at least 15%, with the center water-deck charge demonstrating superior fragmentation by maximizing explosive energy utilization for rock fracturing.

The dynamic response and failure characteristics of tunnels vary significantly under various dynamic disturbances. These characteristics are crucial for assessing structural stability and designing effective support for surrounding rock. In this study, the theoretical solution for the dynamic stress concentration factor (DSCF) of a circular tunnel subjected to cylindrical and plane P-waves was derived using the wave function expansion method. The existing equivalent blast stress wave was optimized and the Ricker wavelet was introduced to represent the seismic stress waves. By combining Fourier transform and Duhamel’s integral, the transient response of the underground tunnel under near-field blasts and far-field earthquakes was determined in both the frequency and time domains. The theoretical results were validated by comparing them with those obtained from numerical simulations using ANSYS LS-DYNA software. Numerical simulations were conducted to further investigate the damage characteristics of the underground tunnel and evaluate the effect of initial stress on structural failure under both types of disturbances. The theoretical and numerical simulation results indicated that the differences in the dynamic response and damage characteristics of the underground tunnel were primarily due to the curvature of the stress waves and transient load waveform. The locations of the maximum DSCF values differed between near-field blasts and far-field earthquakes, whereas the minimum DSCF values occurred at the same positions. Without initial stress, the blast stress waves caused spalling damage to the rock mass on the wave-facing side. Shear failure occurred near the areas with maximum DSCF values, and tensile failure occurred near the areas with minimum DSCF values. In contrast, damage occurred only near the areas with maximum DSCF values under seismic stress waves. Furthermore, the initial stress exacerbated spalling and shear damage while suppressing tensile failure. Hence, the blast stress waves no longer induced tensile failure on the tunnel sidewalls under initial stress.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality; it ranks as the second most common cause of cancer deaths in China. Most HCC patients are first diagnosed at an advanced stage. In recent years, targeted therapy combined with immunotherapy has become the preferred regimen for systemic treatment of intermediate-advanced HCC, while targeted therapy combined with immunotherapy plus local treatment could further improve the efficacy in many clinical studies. To better guide the clinical treatment for effective and safe combination therapy, our interdisciplinary panel on the treatment of intermediate-advanced HCC comprising hepatologists, hepatobiliary surgeons, oncologists, radiologists, interventional radiologists, and traditional Chinese medicine physicians have formulated this consensus based on current clinical studies and clinical medication experience for reference. The consensus contained 15 recommendations, including the applicable population and management, local treatment selection, conversion strategy, treatment strategy after tumor progression and management of common adverse reactions.

Abstract Stemming is one of the main concerns in blast of rock engineering due to its impact on explosion energy consumption and rock excavation performance. In this study, blast-induced rock fragmentation under different stemming conditions is numerically studied using combined numerical modelling and image processing. After careful determination the parameters of constitutive material models, the developed numerical model in LS-DYNA is verified based on the blast testing results including rock fracturing and fragment size distribution (FSD). The calibrated constitutive models are then used to model the pressure variation and rock disintegration produced by blasting with different stemming structures. The size data of simulated rock fragmentation are obtained by image-processing the cut surfaces of the numerical model with the program ImageJ, and the blast-created rock FSD is characterized using a three-parameter generalized extreme value function. The effects of the combination of explosive, air/sand deck and stemming on blast-induced rock fragmentation are quantitatively analysed, considering various stemming modes, stemming lengths and air/sand deck lengths. The results show that the blast-created fragment size decreases with an increase in stemming length, a decreasing in air/sand deck length, replacement of top stemming (stemming at borehole collar with air deck) with bottom stemming (stemming directly contact explosive) and alteration of air deck to sand deck, while the FSD range exhibits the opposite tendency. Bottom stemming is recommended for practical blasting due to its efficiency in rock fragmentation and robustness with respect to stemming length.

Abstract Background Abnormal activation of NLRP3 inflammasome is related to a series of inflammatory diseases, including type 2 diabetes, gouty arthritis, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders. Therefore, targeting NLRP3 inflammasome is regarded as a potential therapeutic strategy for many inflammatory diseases. A growing number of studies have identified tanshinone I (Tan I) as a potential anti-inflammatory agent because of its good anti-inflammatory activity. However, its specific anti-inflammatory mechanism and direct target are unclear and need further study. Methods IL-1β and caspase-1 were detected by immunoblotting and ELISA, and mtROS levels were measured by flow cytometry. Immunoprecipitation was used to explore the interaction between NLRP3, NEK7 and ASC. In a mouse model of LPS-induced septic shock, IL-1β levels in peritoneal lavage fluid and serum were measured by ELISA. Liver inflammation and fibrosis in the NASH model were analyzed by HE staining and immunohistochemistry. Results Tan I inhibited the activation of NLRP3 inflammasome in macrophages, but had no effect on the activation of AIM2 or NLRC4 inflammasome. Mechanistically, Tan I inhibited NLRP3 inflammasome assembly and activation by targeting NLRP3-ASC interaction. Furthermore, Tan I exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including septic shock and NASH. Conclusions Tan I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC, and exhibits protective effects in mouse models of LPS-induced septic shock and NASH. These findings suggest that Tan I is a specific NLRP3 inhibitor and may be a promising candidate for treating NLRP3 inflammasome-related diseases. Graphical Abstract

Overbreak and underbreak are the crucial problems during the blasting excavation of underground tunnels owing to their effects on the construction costs and operational safety. A critical challenge facing overbreak and underbreak control is the difficulty in developing guidelines with respect to various and complex engineering conditions. In this study, a series of field measurements of overbreak and underbreak using the FocusS 150 laser scanner were performed in a deep roadway of the Kaiyang phosphate mine, China. The distribution and extent of the overbreak and underbreak surrounding the roadway contour were accurately analyzed in accordance with the collected point cloud data. Subsequently, a simplified three-dimensional model was established to simulate the blasting excavation of pre-stressed roadway using the explicit dynamic analysis code LS-DYNA. A comparison of numerical and measurement results revealed that the proposed model was a reliable tool to simulate the overbreak and underbreak induced by blasting excavation. Thereafter, the influences of uncontrollable geological factors such as in situ stress conditions and controllable blasting factors including contour hole spacing (S), charge concentration (β) and decoupled coefficient (ζ) as well as stemming were further numerically investigated. The simulation results indicated that the lateral pressure coefficient significantly affected the distribution pattern of the overbreak and underbreak, while the stress magnitude contributed to their extents. Moreover, a comparison of the simulation findings and the field measurement data indicated that the minimal extents of the overbreak and underbreak corresponding the optimal contour blasting results were obtained at S = 0.70 m, β = 0.9 kg/m and ζ = 2.5, respectively. Furthermore, the contour blastholes stemmed with sand created smaller damage to the periphery rock mass of roadway and enhanced the utilization efficiency of explosive energy. The research findings of this study provide important implications for similar blasting excavation projects.

IntroductionCD11c+CD8+ T cells are an unconventional CD8+ T cell subset that exerts antiviral activity in infectious diseases. However, its characteristics in hepatocellular carcinoma (HCC) have not been elucidated.MethodsTwenty-six patients with hepatitis B virus (HBV)-related HCC and 25 healthy controls (HC) were enrolled. The frequency and phenotype of CD11c+CD8+ T cells in peripheral blood and tumors in situ were detected by flow cytometry and immunohistochemistry.ResultsBoth the HCC group and HC group had similar frequency and phenotype characteristics of CD11c+CD8+ T cells in the periphery. CD11c+CD8+ T cells were mainly composed of effector T cells, most of which were CD45RA+CCR7-. Compared with CD11c-CD8+ T cells, CD11c+CD8+ T cells had a higher proportion of CD38 and HLA-DR double positive, and expressed high levels of granzyme-B (GB) and degranulation marker CD107a, and produced high levels of interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ). However, the ability of degranulation and TNF-α production of CD11c+CD8+ T cells in patients with HCC were significantly lower than that in healthy controls. The GB expression level of peripheral CD11c+CD8+ T cells in patients with advanced stage of HCC was significantly lower than that in patients with early stage of HCC, and the GB expression level of liver-infiltrating CD11c+CD8+ T cells in tumor tissues was lower than that in non-tumor tissues. More importantly, the GB expression level of peripheral CD11c+CD8+ T cells was negatively correlated with tumor volume. ConclusionsThese findings indicate that CD11c+CD8+ T cells may have potential anti-tumor activity and that GB+CD11c+CD8+ T cells are associated with disease progression in patients with HBV-related HCC.

Objective: Hepatocellular carcinoma (HCC), the main type of liver cancer, has a high morbidity and mortality, and a poor prognosis. RNA helicase DDX5, which acts as a transcriptional co-regulator, is overexpressed in most malignant tumors and promotes cancer cell growth. Heat shock protein 90 (HSP90) is an important molecular chaperone in the conformational maturation and stabilization of numerous proteins involved in cell growth or survival. Methods: DDX5 mRNA and protein expression in surgically resected HCC tissues from 24 Asian patients were detected by quantitative real-time PCR and Western blot, respectively. The interaction of DDX5-HSP90 was determined by molecular docking, immunoprecipitation, and laser scanning confocal microscopy. The autophagy signal was detected by Western blot. The cell functions and signaling pathways of DDX5 were determined in 2 HCC cell lines. Two different murine HCC xenograft models were used to determine the function of DDX5 and the therapeutic effect of an HSP90 inhibitor. Results: HSP90 interacted directly with DDX5 and inhibited DDX5 protein degradation in the AMPK/ULK1-regulated autophagy pathway. The subsequent accumulation of DDX5 protein induced the malignant phenotype of HCC by activating the β-catenin signaling pathway. The silencing of DDX5 or treatment with HSP90 inhibitor both blocked in vivo tumor growth in a murine HCC xenograft model. High levels of HSP90 and DDX5 protein were associated with poor prognoses. Conclusions: HSP90 interacted with DDX5 protein and subsequently protected DDX5 protein from AMPK/ULK1-regulated autophagic degradation. DDX5 and HSP90 are therefore potential therapeutic targets for HCC.

The molecularly targeted agent anlotinib offers a novel therapeutic strategy against advanced hepatocellular carcinoma (HCC). With this study, we aimed to solve the technical problem of anlotinib being insoluble in injectable solutions; we also aimed to assess the antitumor activity of anlotinib on hepatocellular carcinoma cells. We prepared an anlotinib nanocrystal injection by wet grinding, and we optimized the prescription process using a transmission electron microscope (TEM) and a laser particle size analyzer (LPSA). The release of anlotinib from the injected nanocrystals was evaluated using LC-MS/MS in vitro, and the drug’s anti-tumor effects were assessed in a nude mice tumor model. The anlotinib nanocrystals had a uniform particle size distribution (the average nanoparticle size was ~200 nm). The preparation of anlotinib into nanocrystals did not change the original crystal structure. The intravenous injection of anlotinib nanocrystals achieved anti-tumor activity at very low doses compared to those required for oral administration of an anlotinib suspension: anlotinib nanocrystals at a dose of 50 μg/kg inhibited the subcutaneous growth of the HCC cell line MHCC97-H; whereas the dose of anlotinib suspension required for an equivalent effect was 1 mg/kg. Therefore, our novel anlotinib nanocrystal injection preparation provides an option for achieving a safe and effective molecularly targeted therapy against advanced HCC.

Abstract Background Patients suffering from advanced stage hepatocellular carcinoma (HCC) often exhibit a poor prognosis or dismal clinical outcomes due to ineffective chemotherapy or a multi-drug resistance (MDR) process. Thus, it is urgent to develop a new chemotherapeutic sensitivity testing system for HCC treatment. The presence study investigated the potential application of a novel chemotherapeutic sensitivity-testing system based on a collagen gel droplet embedded 3D–culture system (CD-DST). Methods Primary cells were separating from surgical resection specimens and then tested by CD-DST. To identify whether HCC cell lines or cells separating from clinical specimens contain MDR features, the cells were treated with an IC 50 (half maximal inhibitory concentration) or IC max (maximal inhibitory concentration) concentration of antitumor agents, e.g., 5-furuolouracil (5-FU), paclitaxel (PAC), cisplatin (CDDP), epirubicin (EPI), or oxaliplatin (L-OHP), and the inhibitory rates (IRs) were calculated. Results HepG2 cells were sensitive to 5-FU, PAC, CDDP, EPI, or L-OHP; the IC 50 value is 0.83 ± 0.45 μg/ml, 0.03 ± 0.02 μg/ml, 1.15 ± 0.75 μg/ml, 0.09 ± 0.03 μg/ml, or 1.76 ± 0.44 μg/ml, respectively. Only eight (8/26), nine (9/26), or five (5/26) patients were sensitive to the IC max concentration of CDDP, EPI, or L-OHP; whereas only three (3/26), four (4/26), or two (2/26) patients were sensitive to the IC 50 concentration of CDDP, EPI, or L-OHP. No patients were sensitive to 5-FU or PAC. Conclusions The in vitro drug sensitivity exanimation revealed the MDR features of HCC and examined the sensitivity of HCC cells from clinical specimens to anti-tumor agents. CD-DST may be a useful method to predict the potential clinical benefits of anticancer agents for HCC patients.

Excavation-damaged zones (EDZs) induced in underground mining and civil engineering potentially threaten tunnel safety and stability, and increase construction and support costs. In this paper, an investigation of the excavation damaged zone (EDZ) around roadways in Fankou lead-zinc mine in Guangzhou, China is performed by applying a seismic velocity method accompanied by SET-PLT-01 nonmetallic ultrasonic detector. Meanwhile, the in situ stress in the mining area was measured based on the stress relief method with the Swedish high-precision LUT system. The results indicate that the stress field is dominated by the maximum horizontal tectonic stress, and the extents of the EDZ on the roof-floor region are greater than that on the sidewall. In addition, both of the in situ stresses and EDZs show an increasing trend with an increase of depth. Analytical solutions of EDZ around circular openings in the brittle rock mass subjected to non-hydrostatic stress fields are presented in terms of the Mohr−Coulomb and generalized Hoek−Brown criteria, and validated by several cases mentioned above. The extents of EDZ solved by closed-form solutions were found to be in a great agreement with those obtained in the field. Finally, a series of parametric studies are conducted to investigate the effects of cohesion (c), friction angle (φ), geological strength index (GSI), mi, uniaxial compressive strength (σc), and disturbance factor (D) on EDZ. It is shown that the effects of c, φ, GSI, and σc are significant; however, more attention should be paid to consider the dynamic disturbances induced by mechanical drilling, blasting, and seismic waves in tunnel excavations or operations.

Introduction: CD11c+CD8+ T cells are an unconventional CD8+ T cell subset that exerts antiviral activity in infectious diseases. However, its characteristics in hepatocellular carcinoma (HCC) have not been elucidated. Methods: Twenty-six patients with hepatitis B virus (HBV)-related HCC and 25 healthy controls (HC) were enrolled. The frequency and phenotype of CD11c+CD8+ T cells in peripheral blood and tumors in situ were detected by flow cytometry and immunohistochemistry. Results: Both the HCC group and HC group had similar frequency and phenotype characteristics of CD11c+CD8+ T cells in the periphery. CD11c+CD8+ T cells were mainly composed of effector T cells, most of which were CD45RA+CCR7-. Compared with CD11c-CD8+ T cells, CD11c+CD8+ T cells had a higher proportion of CD38 and HLA-DR double positive, and expressed high levels of granzyme-B (GB) and degranulation marker CD107a, and produced high levels of interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ). However, the ability of degranulation and TNF-a production of CD11c+CD8+ T cells in patients with HCC were significantly lower than that in healthy controls. The GB expression level of peripheral CD11c+CD8+ T cells in patients with advanced stage of HCC was significantly lower than that in patients with early stage of HCC, and the GB expression level of liver-infiltrating CD11c+CD8+ T cells in tumor tissues was lower than that in non-tumor tissues. More importantly, the GB expression level of peripheral CD11c+CD8+ T cells was negatively correlated with tumor volume. Conclusions: These findings indicate that CD11c+CD8+ T cells may have potential anti-tumor activity and that GB+CD11c+CD8+ T cells are associated with disease progression in patients with HBV-related HCC. [ABSTRACT FROM AUTHOR]