This paper aims to reveal the fatigue damage and instability behaviors of mud-shale under multistage increasing-amplitude fatigue loading. The fatigue loading tests combined with real-time acoustic ...emission (AE) monitoring technique were employed to investigate the influence of water content on the deformation, damage, and fracture characteristics. Testing results show that rock fatigue life decreases with the increase of water content, and the hysteresis curve changes regularly with time. The failure process can be divided into three stages: initial stage, stable development stage and acceleration stage. The acoustic emission output activities were also influenced by the water content. The acoustic emission ring count and acoustic emission energy both decrease with increasing water ratio and the accumulative count and energy are the least for a sample having high water ratio. The acoustic emission activity shows a sudden increase trend at the amplitude-increasing moment, indicating the occurrence of strong damage within rock sample. The damage propagation within a cyclic loading stage is relatively small compared to the stress-increasing moment. The results are helpful to understand the fatigue mechanical responses of water-sensitive soft rock, as well as the slope stability of the open-pit mine. The research results have important theoretical and practical significance for promoting slope treatment and disaster prevention.
Development of targeted therapies for triple-negative breast cancer (TNBC) is an unmet medical need. Cisplatin has demonstrated its promising potential for the treatment of TNBC in clinical trials; ...however, cisplatin treatment is associated with hypoxia that, in turn, promotes cancer stem cell (CSC) enrichment and drug resistance. Therapeutic approaches to attenuate this may lead to increased cisplatin efficacy in the clinic for the treatment of TNBC. In this report we analyzed clinical datasets of TNBC and found that TNBC patients possessed higher levels of EGFR and hypoxia gene expression. A similar expression pattern was also observed in cisplatin-resistant ovarian cancer cells. We, thus, developed a new therapeutic approach to inhibit EGFR and hypoxia by combination treatment with metformin and gefitinib that sensitized TNBC cells to cisplatin and led to the inhibition of both CD44+/CD24- and ALDH+ CSCs. We demonstrated a similar inhibition efficacy on organotypic cultures of TNBC patient samples ex vivo. Since these drugs have already been used frequently in the clinic; this study illustrates a novel, clinically translatable therapeutic approach to treat patients with TNBC.
Carbon nanotube supported platinum (Pt/CNTs) catalysts prepared by different Pt deposition methods and on different CNT supports were studied. Colloidal based methods were demonstrated to be more ...effective than other wet chemistry deposition methods (e.g., impregnation and precipitation) for the preparation of highly dispersed Pt/CNTs. Pt catalyst supported on CNTs with a dispersion uniformity comparable to that supported on carbon powder was achieved using a zwitterionic surfactant 3-(
N,N-dimethyldodecylammonio) propanesulfonate (SB12) as stabilizer in a monitored pH environment. It was experimentally observed that oxygen-containing surface functionalities on CNTs can greatly affect the catalyst particle dispersion by manipulating Pt anchoring and/or nucleating sites. Furthermore, it was revealed that the performance of Pt/CNTs based fuel cell is strongly dependent on the electrode fabrication method.
On the basis of DRASTIC model index system, combined with the actual situation in Horqin district in Tongliao City, this paper removed the influence of the topography, added land use effects, ...modified the new model DRASLIC, used analytic Hierarchy Process (AHP), and calculated the new evaluation results. Groundwater management and protection decisions in Tongliao Horqin area provide a reliable basis for the application to design the groundwater monitoring network, site selection of waste landfill, evaluation and control of groundwater pollution, and provide a basis for other work. such as groundwater contamination and protection.
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, accounting for the majority of breast cancer-related death. Due to the lack of specific therapeutic targets, ...chemotherapeutic agents (e.g., paclitaxel) remain the mainstay of systemic treatment, but enrich a subpopulation of cells with tumor-initiating capacity and stem-like characteristics called cancer stem cells (CSCs); thus development of a new and effective strategy for TNBC treatment is an unmet medical need. Cancer nanomedicine has transformed the landscape of cancer drug development, allowing for a high therapeutic index. In this study, we developed a new therapy by co-encapsulating clinically approved drugs, such as paclitaxel, verteporfin, and combretastatin (CA4) in polymer-lipid hybrid nanoparticles (NPs) made of FDA-approved biomaterials. Verteporfin is a drug used in the treatment of macular degeneration and has recently been found to inhibit the Hippo/YAP (Yes-associated protein) pathway, which is known to promote the progression of breast cancer and the development of CSCs. CA4 is a vascular disrupting agent and has been tested in phase II/III of clinical trials. We found that our new three drug-NP not only effectively inhibited TNBC cell viability and cell migration, but also significantly diminished paclitaxel-induced and/or CA4-induced CSC enrichment in TNBC cells, partially through inhibiting the upregulated Hippo/YAP signaling. Combination of verteporfin and CA4 was also more effective in suppressing angiogenesis in an in vivo zebrafish model than single drug alone. The efficacy and application potential of our triple drug-NPs were further assessed by using clinically relevant patient-derived xenograft (PDX) models. Triple drug-NP effectively inhibited the viability of PDX organotypic slide cultures ex vivo and stopped the growth of PDX tumors in vivo. This study developed an approach capable of simultaneously inhibiting bulk cancer cells, CSCs, and angiogenesis.
Olive oil could attenuate carbon tetrachloride (CCl
) induced liver fibrosis (LF) in mouse model. This study aimed to evaluate the effects of other common oils on CCl
induced LF. Healthy male ICR ...mice were administered with CCl
intraperitoneally at 2.5 ml/kg twice a week for total 3 weeks. Mice were pre-treated with olive oil, soybean oil, corn oil or lard oil. After treatment, histopathological changes were observed using Masson trichrome staining, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), hydroxyproline (HYP) and triglyceride (TG) were measured by commercial kits. The expression of LF related genes was detected by quantitative real-time PCR. We found that soybean oil or olive oil significantly reduced ALT and AST levels in serum, and MDA, HYP and TG levels in the liver, compared to corn oil or lard oil. Moreover, Masson trichrome staining and real-time PCR showed that the mice treated with CCl
dissolved in soybean oil or olive oil had less fibrosis and apoptosis in the liver comparted to the mice treated with CCl
dissolved in corn oil or lard oil. In conclusion, soybean oil but not corn or lard oil exerts protective effects against CCl
induced LF in mice, possibly due to its antioxidant activity.
Outbreaks of the highly pathogenic avian influenza H5N1 and H7N9 viruses have spurred an unprecedented research effort to develop antivirals and vaccines against influenza. Standardized methods for ...vaccine evaluation are critical for facilitating vaccine development. Compared with hemagglutination inhibition assays, mounting evidence suggest that microneutralization tests (MNTs) is a better choice for the evaluation of candidate pandemic influenza vaccines because they measure neutralizing antibody activity in cell cultures and are more sensitive in detecting H5 and H7. Here, we report a MNT measuring neuraminidase activity as the read-out (NA-MNT) for quantitative analysis of neutralizing antibodies against avian influenza viruses. Compared to the conventional microneutralization assay (ELISA-MNT), the NA-MNT is faster with lower intra- and inter-assay variations, while no difference in geometric mean titers was found between these two assays for the evaluation of H5N1 and H7N9 vaccines. These results suggest that NA-MNT is a reliable and high throughput method which could facilitate the development of candidate pandemic influenza vaccine.
Global spread and regional endemicity of H5Nx Goose/Guangdong avian influenza viruses (AIV) pose a continuous threat for poultry production and zoonotic, potentially pre-pandemic, transmission to ...humans. Little is known about the role of mutations in the viral neuraminidase (NA) that accompanied bird-to-human transmission to support AIV infection of mammals. Here, after detailed analysis of the NA sequence of human H5N1 viruses, we studied the role of A46D, L204M, S319F and S430G mutations in virus fitness in vitro and in vivo. Although H5N1 AIV carrying avian- or human-like NAs had similar replication efficiency in avian cells, human-like NA enhanced virus replication in human airway epithelia. The L204M substitution consistently reduced NA activity of H5N1 and nine other influenza viruses carrying NA of groups 1 and 2, indicating a universal effect. Compared to the avian ancestor, human-like H5N1 virus has less NA incorporated in the virion, reduced levels of viral NA RNA replication and NA expression. We also demonstrate increased accumulation of NA at the plasma membrane, reduced virus release and enhanced cell-to-cell spread. Furthermore, NA mutations increased virus binding to human-type receptors. While not affecting high virulence of H5N1 in chickens, the studied NA mutations modulated virulence and replication of H5N1 AIV in mice and to a lesser extent in ferrets. Together, mutations in the NA of human H5N1 viruses play different roles in infection of mammals without affecting virulence or transmission in chickens. These results are important to understand the genetic determinants for replication of AIV in mammals and should assist in the prediction of AIV with zoonotic potential.
Histone deacetylases (HDAC) are frequently overexpressed in tumors, and their inhibition has shown promising anti-tumor effects. However, the synergistic effects of HDAC inhibition with immune cell ...therapy have not been fully explored. Natural killer (NK) cells are cytotoxic lymphocytes for anti-tumor immune surveillance, with immunotherapy potential. We showed that a pan-HDAC inhibitor, panobinostat, alone demonstrated anti-tumor and anti-proliferative activities on all tested tumors
. Additionally, panobinostat co-treatment or pretreatment synergized with NK cells to mediate tumor cell cytolysis. Mechanistically, panobinostat treatment increased the expression of cell adhesion and tight junction-related genes, promoted conjugation formation between NK and tumor cells, and modulates NK cell-activating receptors and ligands on tumor cells, contributing to the increased tumor cytolysis. Finally, panobinostat therapy led to better tumor control and synergized with anti-PD-L1 therapy. Our data highlights the anti-tumor potential of HDAC inhibition through tumor-intrinsic toxicity and enhancement of NK -based immunotherapy.
The impact loading of a notched semi-circular bend (NSCB) specimen of outcrop shale in Changning Sichuan was carried out using a split Hopkinson pressure bar (SHPB) to study the effect of shale ...bedding on the dynamic crack initiation toughness. Three loading configurations were tested: Crack-divider, Crack-splitter and Crack-arrester loading. Bedding plane has a significant effect on the crack initiation of shale. Under the Crack-divider and Crack-splitter modes, shale had lower dynamic crack initiation toughness. The dynamic crack initiation toughness of the shale was affected by the loading rate for all three loading configurations. The correlation between loading rate and dynamic crack initiation toughness was most significant for the Crack-arrester mode, while the Crack-splitter mode was the weakest. When loading was carried out on Crack-arrester, the bedding plane could change the direction of crack growth. In the Crack-splitter mode, only a small impact energy was needed to achieve effective expansion of a crack. The research results provide a theoretical basis for shale cracking.
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