Radiotherapy is used to treat many types of cancer, but many treated patients relapse with local tumor recurrence. Tumor-infiltrating myeloid cells (TIM), including CD11b (ITGAM)(+)F4/80 (EMR1)+ ...tumor-associated macrophages (TAM), and CD11b(+)Gr-1 (LY6G)+ myeloid-derived suppressor cells (MDSC), respond to cancer-related stresses and play critical roles in promoting tumor angiogenesis, tissue remodeling, and immunosuppression. In this report, we used a prostate cancer model to investigate the effects of irradiation on TAMs and MDSCs in tumor-bearing animals. Unexpectedly, when primary tumor sites were irradiated, we observed a systemic increase of MDSCs in spleen, lung, lymph nodes, and peripheral blood. Cytokine analysis showed that the macrophage colony-stimulating factor CSF1 increased by two-fold in irradiated tumors. Enhanced macrophage migration induced by conditioned media from irradiated tumor cells was completely blocked by a selective inhibitor of CSF1R. These findings were confirmed in patients with prostate cancer, where serum levels of CSF1 increased after radiotherapy. Mechanistic investigations revealed the recruitment of the DNA damage-induced kinase ABL1 into cell nuclei where it bound the CSF1 gene promoter and enhanced CSF1 gene transcription. When added to radiotherapy, a selective inhibitor of CSF1R suppressed tumor growth more effectively than irradiation alone. Our results highlight the importance of CSF1/CSF1R signaling in the recruitment of TIMs that can limit the efficacy of radiotherapy. Furthermore, they suggest that CSF1 inhibitors should be evaluated in clinical trials in combination with radiotherapy as a strategy to improve outcomes.
•Neither pH adjustment nor chloride introduction facilitated Hg removal from soil.•No correlation was found between Hg and total/dissolved soil organic matter.•Hg was firmly bound to soil making ...washing insufficient for soil clean-up.
Feasibility of soil washing to remediate Hg contaminated soil was studied. Dry sieving was performed to evaluate Hg distribution in soil particle size fractions. The influence of dissolved organic matter and chlorides on Hg dissolution was assessed by batch leaching tests. Mercury mobilization in the pH range of 3–11 was studied by pH-static titration. Results showed infeasibility of physical separation via dry sieving, as the least contaminated fraction exceeded the Swedish generic guideline value for Hg in soils. Soluble Hg did not correlate with dissolved organic carbon in the water leachate. The highest Hg dissolution was achieved at pH 5 and 11, reaching up to 0.3% of the total Hg. The pH adjustment was therefore not sufficient for the Hg removal to acceptable levels. Chlorides did not facilitate Hg mobilization under acidic pH either. Mercury was firmly bound in the studied soil thus soil washing might be insufficient method to treat the studied soil.
The formation of the potent neurotoxic methylmercury (MeHg) is a microbially mediated process that has raised much concern because MeHg poses threats to wildlife and human health. Since boreal forest ...soils can be a source of MeHg in aquatic networks, it is crucial to understand the biogeochemical processes involved in the formation of this pollutant. High-throughput sequencing of 16S rRNA and the mercury methyltransferase, hgcA, combined with geochemical characterisation of soils, were used to determine the microbial populations contributing to MeHg formation in forest soils across Sweden. The hgcA sequences obtained were distributed among diverse clades, including Proteobacteria, Firmicutes, and Methanomicrobia, with Deltaproteobacteria, particularly Geobacteraceae, dominating the libraries across all soils examined. Our results also suggest that MeHg formation is also linked to the composition of non-mercury methylating bacterial communities, likely providing growth substrate (e.g. acetate) for the hgcA-carrying microorganisms responsible for the actual methylation process. While previous research focused on mercury methylating microbial communities of wetlands, this study provides some first insights into the diversity of mercury methylating microorganisms in boreal forest soils.
One of the major reasons why depressed patients fail their treatment course is the existence of the blood-brain barrier (BBB), which prevents drugs from being delivered to the central nervous system ...(CNS). In recent years, nasal drug delivery has achieved better systemic bioavailability and activity in low doses in antidepressant treatment. In this review, we focused on the latest strategies for delivery carriers (or formation) of intranasal antidepressants. We began this review with an overview of the nasal drug delivery systems, including nasal drug delivery route, absorption mechanism, advantages, and limitations in the nasal drug delivery route. Next, we introduced the development of nasal drug delivery devices, such as powder devices, liquid-based devices, and so on. Finally, intranasal delivery carriers of antidepressants in clinical studies, including nanogels, nanostructured lipid, liposomes nanoparticles, nanoemulsions/microemulsion, were summarized. Moreover, challenges and future perspectives on recent progress of intranasal delivery carriers in antidepressant treatments were discussed.
Colony stimulating factor 1 (CSF-1) recruits tumor-infiltrating myeloid cells (TIM) that suppress tumor immunity, including M2 macrophages and myeloid-derived suppressor cells (MDSC). The CSF-1 ...receptor (CSF-1R) is a tyrosine kinase that is targetable by small molecule inhibitors such as PLX3397. In this study, we used a syngeneic mouse model of BRAF(V600E)-driven melanoma to evaluate the ability of PLX3397 to improve the efficacy of adoptive cell therapy (ACT). In this model, we found that combined treatment produced superior antitumor responses compared with single treatments. In mice receiving the combined treatment, a dramatic reduction of TIMs and a skewing of MHCII(low) to MHCII(hi) macrophages were observed. Furthermore, mice receiving the combined treatment exhibited an increase in tumor-infiltrating lymphocytes (TIL) and T cells, as revealed by real-time imaging in vivo. In support of these observations, TILs from these mice released higher levels of IFN-γ. In conclusion, CSF-1R blockade with PLX3397 improved the efficacy of ACT immunotherapy by inhibiting the intratumoral accumulation of immunosuppressive macrophages.
Microbial mercury (Hg) methylation in sediments can result in bioaccumulation of the neurotoxin methylmercury (MMHg) in aquatic food webs. Recently, the discovery of the gene hgcA, required for Hg ...methylation, revealed that the diversity of Hg methylators is much broader than previously thought. However, little is known about the identity of Hg-methylating microbial organisms and the environmental factors controlling their activity and distribution in lakes. Here, we combined high-throughput sequencing of 16S rRNA and hgcA genes with the chemical characterization of sediments impacted by a waste water treatment plant that releases significant amounts of organic matter and iron. Our results highlight that the ferruginous geochemical conditions prevailing at 1-2 cm depth are conducive to MMHg formation and that the Hg-methylating guild is composed of iron and sulfur-transforming bacteria, syntrophs, and methanogens. Deltaproteobacteria, notably Geobacteraceae, dominated the hgcA carrying communities, while sulfate reducers constituted only a minor component, despite being considered the main Hg methylators in many anoxic aquatic environments. Because iron is widely applied in waste water treatment, the importance of Geobacteraceae for Hg methylation and the complexity of Hg-methylating communities reported here are likely to occur worldwide in sediments impacted by waste water treatment plant discharges and in iron-rich sediments in general.
Depression has become the leading cause of disability worldwide and is a global health burden. Quantitative assessment of depression-related neurotransmitter concentrations in human fluids is highly ...desirable for diagnosis, monitoring disease, and therapeutic interventions of depression. In this review, we focused on the latest strategies of CD-based electrochemical biosensors for detecting a depression-related neurotransmitter. We began this review with an overview of the microstructure, optical properties and cytotoxicity of CDs. Next, we introduced the development of synthetic methods of CDs, including the "Top-down" route and "Bottom-up" route. Finally, we highlighted detecting an application of CD-based electrochemical sensors in a depression-related neurotransmitter. Moreover, challenges and future perspectives on the recent progress of CD-based electrochemical sensors in depression-related neurotransmitter detection were discussed.
Casting, as a fundamental process in metal forming, finds widespread applications in the manufacturing industry. The advent of 3D printing hollow sand mold technology presents a novel method for ...casting technology to revolutionize traditional dense sand molds, offering increased flexibility in achieving quality control and improvement in casting processes. Consequently, this study delves into an examination of the mechanical strengths of 3D-printed sand molds with complex hollow structures and further investigates the influence of hollow sand mold concession on castings. The results indicate that compressive and high-temperature residual tensile and bending strengths vary in hollow structures. Multi-layer shells have greater high-temperature residual tensile, compressive, and bending strengths than truss hollow sand molds with roughly the same hollow volume fraction. Compared to dense sand molds, hollow sand molds, which have a lower mechanical strength, have better retractability, which helps reduce the residual stress and crack tendency of castings. The breaking of hollow structures is limited to local areas, unlike the penetrative cracking of dense sand molds. The I-beam-shaped casting test results indicate that a hollow structure is beneficial for the preservation of the integrity of a sand mold during the casting process. Compared to dense and truss hollow molds, a multi-layer shell hollow sand structure has the comprehensive advantages that it improves retractability while maintaining strength relatively well, reduces the residual stress, and avoids cracks in castings and itself.
Co-combustion is the most attractive option for extending the utilization of Zhundong coals from the newly discovered and the largest intact coalfield in China. However, operational practices have ...shown that power plants frequently encounter ash deposition problems during co-combustion with Zhundong coals. To address such an issue, in the present work, coal blends of a bituminous coal and a Zhundong sub-bituminous coal, with blending ratios of 90:10, 70:30, 50:50, 30:70, and 10:90 on a weight basis, were burned on a laboratory drop tube furnace at 1350 °C. For comparison, combustion experiments of the component coals were also carried out under the same conditions. The resulting ash samples were thoroughly characterized by using a Malvern particle size analyzer and a computer controlled scanning electron microscope. The obtained data were correlated to the ash deposition behavior in co-combustion with Zhundong coals in power plant boilers. The results show that particle mass size distributions of the ash samples from combustion of low-ZD-loaded fuels (with the proportion of the Zhundong coal investigated ≤50 wt %) are similar. The basic and acidic elements are partitioned similarly into ash particles. Ash deposition propensities, evaluated as the ratio of basic to acidic oxides (B/A) of the ash, are all low and show insignificant differences. These are consistent with the similarities in ash deposition behavior during co-combustion with Zhundong coals with low proportions in practical coal-fired boilers. In contrast, the ash properties are apparently different for the fuels with the proportion of the Zhundong coal higher than 50 wt % (denoted as high-ZD-loaded fuels). Small particles of <10 μm are more abundant in the ash samples and are more enriched in basic elements (especially Ca, Fe, and Mg) for the high-ZD-loaded fuels than for the low-ZD-loaded fuels. These data could well explain the more serious ash deposition problems arising during co-combustion with higher proportions of the Zhundong coals in practical boilers. It is also found that, for the ashes from combustion of the high-ZD-loaded fuels, both the amount of the small ash particles and the contents of basic elements in them increase with increasing the proportion of the Zhundong coal in the fuel. These data agree well with field observations of higher ash deposition propensities for coal blends with higher proportions of the Zhundong coals.
Endothelial cells and macrophages are known to engage in tight and specific interactions that contribute to the modulation of vascular function. Here we show that adult endothelial cells provide ...critical signals for the selective growth and differentiation of macrophages from several hematopoietic progenitors. The process features the formation of well-organized colonies that exhibit progressive differentiation from the center to the periphery and toward an M2-like phenotype, characterized by enhanced expression of Tie2 and CD206/Mrc1. These colonies are long-lived depending on the contact with the endothelium; removal of the endothelial monolayer results in rapid colony dissolution. We further found that Csf1 produced by the endothelium is critical for the expansion of the macrophage colonies and that blockade of Csf1 receptor impairs colony growth. Functional analyses indicate that these macrophages are capable of accelerating angiogenesis, promoting tumor growth, and effectively engaging in tight associations with endothelial cells in vivo. These findings uncover a critical role of endothelial cells in the induction of macrophage differentiation and their ability to promote further polarization toward a proangiogenic phenotype. This work also highlights some of the molecules underlying the M2-like differentiation, a process that is relevant to the progression of both developmental and pathologic angiogenesis.
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