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Exosomes are bilayer lipid bodies and contain a variety of bioactive molecules such as proteins, lipids, and nucleic acids, and so forth. Exosomes derived from solid tumors may play critical roles in tumor development and immune evasion. However, the underlying effects of tumor-derived exosomes on immune function in modulating intercellular crosstalk within the bone marrow niche during acute myeloid leukemia (AML) development and immune evasion remain largely elusive. In this study, we aimed to explore the role of AML-exos in AML immune evasion. First, we isolated tumor-derived exosomes from AML cells (AML-exos) and revealed the presence of programmed cell death ligand-1 (PD-L1) protein in AML-exos. Next, we demonstrated that AML-exos can directly suppress the activation of natural killer (NK) cells and inhibit the cytotoxicity of NK cells, probably through activating the programmed cell death-1 (PD-1)/PD-L1 pathway. Furthermore, the inhibitory effect of AML-exos on NK cells could be alleviated by either PD-L1 inhibitor or antagonist. In summary, we demonstrated that AML-exos possess a PD-L1-dependent tumor-promoting effect which may contribute to immune tolerance in antitumor therapy, but blocking the PD-1/PD-L1 pathway may alleviate the tumor immunosuppression induced by AML-exos. Our findings in this study may offer a new immunotherapy strategy to cure AML.
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Triple-negative breast cancer (TNBC) is known for its strong invasiveness, high recurrence rates, and poor prognosis. Heme oxygenase-1 (HO-1) is closely related to tumor invasion, metastasis, recurrence and formation of tumor immunosuppression. The expression of HO-1 is high in TNBC and low in normal tissues. In this study, AgPPIX was synthesized as a heme oxygenase-1 (HO-1) inhibitor and a photosensitizer for TNBC therapy. PDA nanoparticles were synthesized and modified with anti-CD24 and p-toluenesulfonamide (PTSC) on their both sides to obtain PTSC@AgPPIX/PDA@anti-CD24 Janus nanoparticles (PAPC) for AgPPIX-targeted delivery. Anti-CD24 is targeted to CD24 on tumor cells and the PTSC moiety is targeted to endoplasmic reticulum (ER), where HO-1 is located. The results indicated that PAPC Janus nanoparticles exhibited higher cytotoxicity in 4T1 cells than that of the mono-modified nanoparticles. PAPC not only inhibited the expression of HO-1 and VEGF but also reduced TrxR activity significantly. Furthermore, PAPC not only promoted intracellular ROS production under laser irradiation for tumor photodynamic therapy (PDT) but also polarized TAMs from M2-type to M1 for tumor immunotherapy. In vivo experiments confirmed that PAPC could remodel the tumor immune microenvironment and almost completely inhibit the tumor growth in mouse models. Therefore, PAPC Janus nanoparticles are a promising nanoplatform with a dual-targeting capacity for TNBC immune/PDT synergistic therapy.
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Retículo Endoplasmático , Imunoterapia , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Camundongos , Feminino , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Nanopartículas/química , Retículo Endoplasmático/metabolismo , Humanos , Heme Oxigenase-1/metabolismo , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo , Prata/química , Prata/farmacologia , Porfirinas/química , Porfirinas/farmacologiaRESUMO
The advancement of co-processing solid wastes in coal-fired boilers is significant for waste recycling and contributes to the sustainable development of the coal-fired power industry. However, concerns over the emission of dioxins during co-processing have prompted a comprehensive investigation into the dioxin emission properties. In this study, the PCDD/F emission concentrations of seven coal-fired boilers, including three pulverized coal boilers and four circulating fluidized bed boilers were examined. The results indicate that co-processing solid wastes in coal-fired boilers did not lead to an increase in the mass concentration of dioxins in either the flue gas or solid samples, and the international toxic equivalents (I-TEQ) of dioxins in the flue gas complied with prevailing emission standards (0.1 ng I-TEQ/Nm3) in China, proving that coal-fired boilers co-processing would not raise the emission risk of dioxins. The types of waste during co-processing had minimal effect on the I-TEQ of dioxins. A significant proportion of PCDD/Fs was observed in the ash samples, while only 13.0-25.7% and 0.7-6.8% of dioxins were distributed in the boiler slag and the flue gas, respectively. The emission factor of dioxins under the blank conditions ranged from 0.009 to 0.327 ng I-TEQ/kg-coal, while it ranged from 0.015 to 0.129 ng I-TEQ/kg-(coal+waste) under the co-processing conditions. The reduction of emission factor under co-processing condition could be attributed to the significant decrease of dioxins I-TEQ.
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Carvão Mineral , Dibenzodioxinas Policloradas , Resíduos Sólidos , China , Dibenzodioxinas Policloradas/análise , Resíduos Sólidos/análise , Poluentes Atmosféricos/análise , Monitoramento Ambiental/métodos , Benzofuranos/análise , Dibenzofuranos Policlorados/análise , Centrais ElétricasRESUMO
Secondary alumina dross (SAD) has emerged as an alternative to bauxite in the production of flash setting admixtures (FSA), a critical admixture in shotcrete. However, the presence of hazardous components has hampered its large-scale adoption. This study conducted field tests at an FSA factory, utilizing SAD as the primary raw material, to evaluate the feasibility and environmental risks. The results confirmed that SAD can effectively replace bauxite in FSA production without compromising quality, as it closely resembled the chemical properties of bauxite. Emissions of fluorides, heavy metals, dioxins in flue gases during production met the relevant Chinese standards. The analysis of hazardous component distribution revealed that more than 50% of volatile components, such as Cl, Cd, Pb, and Zn, were directed into fly ash, exhibiting a significant internal accumulation pattern. In contrast, more than 95% of low-volatility components, including Cu, Cr, Mn, and F, were transferred to the FSA, and the introduction of CaCO3 was confirmed to effectively immobilize F. Moreover, the leaching risk of heavy metals and fluorides in FSA applications slightly increased but remained minimal and within acceptable limits. This technology provides an environmentally sound solution for the disposal of SAD.
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Óxido de Alumínio , Metais Pesados , Óxido de Alumínio/química , Metais Pesados/análiseRESUMO
Development of co-processing technology in the cement industry in China is important for environmentally sound disposal and recycling of waste, and contributes to sustainable development of the cement industry. However, dioxin pollution could negatively affect promotion of this technology. Therefore, it is necessary to study the emission characteristics of dioxins in cement kilns. In this study, the emission characteristics of dioxins and factors influencing their generation during co-processing solid wastes were studied in 14 new dry cement kilns. The dioxin concentrations were very similar regardless of whether solid wastes were fed into the kiln. In blank runs without co-processing, the average dioxin concentration was 0.0097 ng international toxic equivalents (I-TEQ)/Nm3. By comparison, that for co-processing solid wastes was 0.012 ng I-TEQ/Nm3. These values meet the relevant emission standards. The type of co-processed solid wastes had almost no effect on the dioxin concentration. At larger production scales, the concentration of dioxin emitted in the flue gas decreased. The dioxin concentrations in kiln dust were obviously higher than those in clinker and raw materials. The average emission factor of dioxin per ton of cement was 30 ng I-TEQ/t, which is equivalent to that in cement kilns in other countries.
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Field studies were conducted to study the emission and distribution characteristics of dioxins by elevating the chlorine concentration in feedstock in a circular fluidized bed boiler. The concentration and total equivalent quantity of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in all flue gas, electrostatic ash, bag filter ash, and bottom ash samples under blank condition (i.e., feedstock was normal coal) and chlorine labeling condition (i.e., feedstock mixed with coal and chlorine-containing labeling agent) were analyzed. Results illustrated that the concentration of PCDD/Fs in all gaseous and ash samples increased with the addition of chlorine in feedstock, with the largest and least increment in dioxin concentration observed in electrostatic ash and flue gas. PCDDs were the predominate congeners in flue gas, accounted for 50.1-60.4% of the total PCDD/F concentration under chlorine labeling and blank conditions, while PCDD/F distribution changed from PCDD- to PCDF-predominate by increasing chlorine content in feedstock under all field test conditions: 46.6-92.9%, 34.0-76.1%, and 47.0-53.1% of PCDFs were distributed in electrostatic ash, bag filter ash, and bottom ash, respectively. Highly chlorinated PCDD/F congeners such as O8CDD/F and 1,2,3,4,6,7,8-H7CDD/F were the primary contributors to dioxin concentration in flue gas and bottom ash samples, whereas low-chlorinated 2,3,7,8-T4CDF and 1,2,3,7,8-P5CDF congeners became critically dominating in electrostatic and bag filter ash.
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Dioxinas , Dibenzodioxinas Policloradas , Cinza de Carvão/análise , Dibenzodioxinas Policloradas/análise , Cloro , Dibenzofuranos , Incineração , Dibenzofuranos Policlorados , Gases , Cloretos , Carvão MineralRESUMO
CD93 is a transmembrane receptor belonging to the Group XIV C-Type lectin family. It is expressed in a variety of cellular types such as monocytes, neutrophils, platelets, microglia, and endothelial cells. CD93 has been reported to play important roles in cell proliferation, cell migration, and tumor angiogenesis. Here, we show CD93 is highly expressed in M4 and M5 subtypes of acute myeloid leukemia (AML) patients, and highly expressed in leukemia stem cells, AML progenitor cells, as well as more differentiated AML cells. We found that CD93 promotes AML cell proliferation, while CD93 deficient AML cells commit to differentiation. We further show that CD93 exerts its proliferative function through downstream SHP-2/Syk/CREB cascade in AML cells. Moreover, human AML cells treated with CD93 mAb combined with αMFc-NC-DM1 (an IgG Fc specific antibody conjugated to maytansinoid DM1), showed a striking reduction of proliferation. Our study revealed that CD93 is a critical participator of AML development and provides a potential therapeutic cell surface target. (160 words).
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Leucemia Mieloide Aguda , Maitansina , Glicoproteínas de Membrana , Receptores de Complemento , Células Endoteliais/metabolismo , Humanos , Imunoglobulina G , Lectinas Tipo C , Leucemia Mieloide Aguda/patologia , Glicoproteínas de Membrana/genética , Receptores de Complemento/genéticaRESUMO
Heavy metals (HMs) in mixed hazardous waste can be volatilized in the kiln for preparing sintered bricks, which greatly increases the environmental risk. In this study, the volatilization, transformation, and leaching of HMs from bricks were evaluated. Field tests and laboratory leaching experiments were carried out. HM-contaminated soil was used to prepare sintered bricks at high-temperature in a tunnel kiln. Release of HMs from brick under rainfall conditions was investigated in laboratory simulation experiments. The field tests showed that the total amount of Pb, Zn, Cd distributed to the gas phase were all less than 2%, but the amount of Hg entering the gas phase 40.1%-60.5% in the particulate forms. The As leaching rate increased after sintering of bricks in the kiln, which was attributed to the increased formation of soluble arsenate and the reduced availability of sorption sites. The tank leaching test indicated that the release mechanism of trance elements (Cr, As, Zn, Cd, Pb and Ni) was mainly controlled by diffusion. This study provides useful knowledge for decreasing the volatilization and leaching of HMs from sintered bricks prepared using hazardous waste.
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Mercúrio , Metaloides , Metais Pesados , Arseniatos , Cádmio , Resíduos Perigosos , Chumbo , Metais Pesados/análise , SoloRESUMO
Cascade reaction systems, such as protein fusion and synthetic protein scaffold systems, can both spatially control the metabolic flux and boost the productivity of multistep enzymatic reactions. Despite many efforts to generate fusion proteins, this task remains challenging due to the limited expression of complex enzymes. Therefore, we developed a novel fusion system that bypasses the limited expression of complex enzymes via a post-translational linkage. Here, we report a split intein-mediated cascade system wherein orthogonal split inteins serve as adapters for protein ligation. A genetically programmable, self-assembled, and traceless split intein was utilized to generate a biocatalytic cascade to produce the ginsenoside compound K (CK) with various pharmacological activities, including anticarcinogenic, anti-inflammatory, and antidiabetic effects. We used two types of split inteins, consensus atypical (Cat) and Rma DnaB, to form a covalent scaffold with the three enzymes involved in the CK conversion pathway. The multienzymatic complex with a size greater than 240 kDa was successfully assembled in a soluble form and exhibited specific activity toward ginsenoside conversion. Furthermore, our split intein cascade system significantly increased the CK conversion rate and reduced the production time by more than 2-fold. Our multienzymatic cascade system that uses split inteins can be utilized as a platform for regulating multimeric bioconversion pathways and boosting the production of various high-value substances.
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Ginsenosídeos , Inteínas , Inteínas/genética , Processamento de Proteína , Proteínas/metabolismoRESUMO
Ferroptosis is a newly found promising cell death pathway, which bypasses apoptosis and overcomes multidrug resistance of tumor. In this study, acid and redox dual-responsive multifunctional magnetic nanoparticles loading with Sorafenib (Sor), namely FMMHG/Sor, were prepared for tumor ferroptosis therapy. Fe3O4 nanoparticles as the core provided sufficient iron ion for ferroptosis and magnetic targeting. Mesoporous organosilica nanoparticles (MON) was coated on the outside of Fe3O4 to form "core-shell" structure, which contained the disulfidebond with redox-responsive. MnO2 was dropped on the surface of MON as gatekeeper, which was decomposed at low pH into O2 to promote drug release. Glucose oxidase (GOD) catalyzed glucose to produce H2O2, which reacted with iron ion to generate hydroxylradical (OHâ¢) vie Fenton reaction. OH⢠inhibited GPX4 expression to induce ferroptosis with Sor as a synergistic inducer. Hyaluronic acid (HA) protected nanoparticles from removed by immune system and actively targeted to tumor cells. Overall, pH and redox dual-responsive FMMHG/Sor is a promising antitumor nanomedicine with magnetic targeting and active targeting for efficient tumor ferroptosis therapy.
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Ferroptose , Nanopartículas de Magnetita , Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio , Ferro , Nanopartículas de Magnetita/química , Compostos de Manganês , Nanopartículas/química , Neoplasias/tratamento farmacológico , ÓxidosRESUMO
A mixed natural preservative composed of ε-polylysine (ε-PL), chestnut 70% ethanol extract (NE), and cinnamon hydrothermal extract (CW), was investigated for the reduction of Staphylococcus aureus. The minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) of seven natural extracts were investigated against a cocktail of three strains of S. aureus (ATCC 25923, ATCC 33591, and ATCC 33594). Three important factors (ε-PL, NE, and CW) were selected by using the Plackett-Burman (PB) design for the response surface model (P < 0.001). Following a central composite design, S. aureus were treated with mixtures of natural preservatives that included ε-PL, NE, and CW. The MIC and MBC of ε-PL and the natural extracts and ranged from 1 to 16 mg/mL (R2 = 0.9857). The mixed natural preservative presented a synergistic antibacterial effect, at the optimum point. These results suggest that mixed natural preservatives of ε-PL, NE, and CW can lower the economic cost of food processing.
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OBJECTIVES: There are presently a few viable ways to reduce cardiotoxicity of doxorubicin (Dox). The combination of chemotherapy agents with natural compounds delivers greater efficacy and reduces adverse effects in recent researches for cancer treatment. Here, we examined the potential effect of ginsenoside Rh2 on a Dox-based regimen in chemotherapy treatment. MATERIALS AND METHODS: Human breast tumour (MDA-MB-231) xenograft nude mice, human cardiac ventricle fibroblasts, and human umbilical vein endothelial cells (HUVEC) were employed in the present study. Histology, immunohistochemistry, immunofluorescence, western blot, antibody array, and RNA-sequencing analyses were utilized to assess the protective effect of Rh2 on cardiotoxicity induced by Dox and the underlying mechanisms. RESULTS: Rh2-reduced cardiotoxicity by inhibiting the cardiac histopathological changes, apoptosis and necrosis, and consequent inflammation. Pathological remodelling was attenuated by reducing fibroblast to myofibroblast transition (FMT) and endothelial-mesenchymal transition (EndMT) in hearts. RNA-sequencing analysis showed that Dox treatment predominantly targets cell cycle and attachment of microtubules and boosted tumour necrosis, chemokine and interferon-gamma production, response to cytokine and chemokine, and T cell activation, whereas Rh2 regulated these effects. Intriguingly, Rh2 also attenuated fibrosis via promoting senescence in myofibroblasts and reversing established myofibroblast differentiation in EndMT. CONCLUSIONS: Rh2 regulates multiple pathways in the Dox-provoked heart, proposing a potential candidate for cancer supplement and therapy-associated cardiotoxicity.
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Neoplasias da Mama , Cardiotoxicidade , Animais , Apoptose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Doxorrubicina/farmacologia , Células Endoteliais/metabolismo , Feminino , Ginsenosídeos , Humanos , Camundongos , Camundongos Nus , Miócitos Cardíacos/metabolismo , Necrose/metabolismo , Estresse Oxidativo , RNA/metabolismoRESUMO
Ferroptosis is a newly found cell death mechanism, which could bypass apoptosis and reverse multidrug resistance of tumors. However, efficient induction of tumor ferroptosis remains a challenge. In this study, multifunctional "ball-rod" Janus nanoparticles (FTG/L&SMD) were constructed for non-small cell lung cancer (NSCLC) ferroptosis treatment. Protected by tannic acid (TA), FTG/L&SMD maintains long-term function in blood circulation, while modification by 2, 3-dimethylmaleic anhydride (DMMA) confers the FTG/L&SMD with pH-responsive charge reversal. Glucose oxidase (GOD) on FTG/L&SMD catalyzes glucose to produce H2O2. Then, iron ion converts H2O2 to highly active hydroxyl radicals (OHâ¢) via Fenton reaction, leading to lethal lipid peroxidation (LPO) accumulation. Meanwhile, TA reduces Fe3+ to Fe2+ to boost Fenton reaction cycle. Sor down-regulated glutathione peroxidase 4 (GPX4) expression in another pathway to induce ferroptosis synergistically. In vitro studies have shown that compared with sorafenib (Sor), FTG/L&SMD not only has more efficient tumor targeting and higher cytotoxicity, but also inhibits tumor migration. In vivo antitumor therapy experiments demonstrate that FTG/L&SMD inhibits tumor growth efficiently, and its toxicity is negligible. In general, FTG/L&SMD can initiate Fenton reaction cycle and reinforced ferroptosis to kill tumor cells, which is a promising anti-tumor nano-drug for NSCLC.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Ferroptose , Neoplasias Pulmonares , Nanopartículas Multifuncionais , Nanopartículas , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/uso terapêuticoRESUMO
The improper disposal of large amounts of solid waste (SW) has led to serious ecological and environmental problems, especially heavy metal (HM) pollution. Converter steelmaking has the potential to co-process SW, but the distribution of heavy metals (HMs) during converter steelmaking is unclear. In this study, the effects of smelting temperature and slag alkalinity on the distribution of typical HMs in the SW of steel samples, steel slag, and the gas phase were investigated in a specially-made induction furnace. The results showed that upon increasing the smelting temperature, As (As2S3) was mainly distributed in the steel sample, and the HM-containing compounds Cr2O3, CrCl3, ZnCl2, ZnS, ZnO, PbCl2, PbS, and PbO were mainly distributed in the gas phase. Upon increasing the alkalinity within a certain range, the distribution of HMs in steel samples and steel slag increased gradually, while their distribution in the gas phase decreased. Thermodynamic calculations, Eh-pH diagrams, XRD patterns, and XPS spectra indicated that impurity elements in the hot metal and the CaO content affected the chemical reactions by which HM-containing compounds in the steel sample formed elemental HMs and those in steel slag existed as oxides; therefore, it is necessary to choose a suitable temperature and alkalinity for slag when disposing of different types of SW.
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Breast cancer is the most common malignant tumor in women. Researchers have found that the combined use of multiple methods to treat tumors is a promising strategy. Here, we have developed a biomimetic nano-platform PDA@MB for tumor targeted photothermal therapy (PTT) combined with chemotherapy. The 4T1 cell membrane loaded with cucurbitacin B (CuB) was used to coat polydopamine (PDA) nanoparticles, which gave PDA@MB nanoparticles the ability to target tumors and escape immune cells from phagocytosis. PDA@MB showed excellent photothermal performance including high photothermal conversion efficiency and photostability, and exhibited outstanding in vitro PTT effect under NIR laser irradiation. The high temperature ruptured the PDA@MB membrane to release CuB, which changed the tumor hypoxic environment, down-regulated the FAK/MMP signaling pathway, and significantly inhibited the metastasis and proliferation of tumor cells. The results of in vivo experiments indicated that the tumor growth of the 4T1 mouse tumor model was significantly inhibited. Additionally, toxicity studies showed that PDA@MB had good biocompatibility and safety. In conclusion, this study provides a promising chemo-photothermal therapy (CPT) nano-platform for precise and effective breast cancer therapy.
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The treatment efficiency of the Fenton reaction is expected to be greatly restricted due to problems such as inefficient delivery of Fenton catalysis, limited H2O2 concentration and uneven tumour tissue. Accurate photothermal therapy (PTT) could improve the efficiency of Fenton catalysis to some extent by raising the temperature. However, the heat shock response (HSR) of tumour cells caused by PTT and Fenton reaction would attenuate the treatment effect. In this study, we developed an iron ions-mediated Fenton reaction combined with a PTT treatment platform based on a metal-organic framework, i.e., PPy-CTD@MIL-100@MPCM nanoparticles (PCMM NPs), and further explored the inhibitory effect of PCMM NPs on the heat shock response (HSR). PCMM NPs could accumulate in tumour tissue via the coated macrophage cell membranes (MPCMs) to target inflammatory tissues. The photothermal effect of polypyrrole (PPy) accelerated the release of cantharidin (CTD) and iron ions loaded in the PCMM NPs. CTD, as an HSR inhibitor, could inhibit this response of tumour cells and improve the effect of PTT. Meanwhile, the heat generated during the PTT process could improve the efficiency of the Fenton reaction. This study suggested that PCMM NPs could serve as a combined treatment platform to enhance the Fenton reaction based on amplified photothermal therapy.
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Cantaridina , Nanopartículas , Biomimética , Peróxido de Hidrogênio , Fototerapia , Terapia Fototérmica , Polímeros , PirróisRESUMO
A field test was conducted to study the emission and distribution characteristics of dioxins during co-processing of hazardous waste in a multicomponent slurry gasifier (MCSG). The toxicity equivalent concentrations of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in all exhaust gas, waste water, and solid waste under both blank condition (i.e., feedstock was normal coal-water slurry) and test condition (i.e., feedstock mixed with hazardous waste and labeling reagents) were analyzed. Results showed that organic matter was fully degraded in the MCSG. The dioxin amount in the black water flash steam increased with the addition of hazardous waste and chlorine in the feedstock, and octachlorodibenzo-p-dioxins (OCDD) with the largest increase is the most easily formed monomer in dioxins. The dioxin amount in all samples was far below the standard limit in China and other countries. This indicates the low environmental risk from dioxins during the co-processing process. The dioxin distribution trend in solid, liquid, and gas phase during co-processing did not change: 86.63%-94.18%, 0.02%-0.13%, and 5.8%-13.23% of PCDDs were distributed in the exhaust gas, waste water, and solid waste, respectively, while 6.10%-22.95%, 0.59%-0.80%, and 76.45%-93.10% of PCDFs were distributed in the exhaust gas, waste water, and solid waste, respectively.
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Dioxinas , Dibenzofuranos Policlorados/análise , Monitoramento Ambiental , Resíduos Perigosos , Incineração , Resíduos SólidosRESUMO
CRISPR/Cas9 system has been used as the most powerful gene editing tool for precision medicine and advanced gene therapy. However, its wide applications are limited by the poor biosafety of lentivirus delivery vectors though with high-efficiency transduction. To construct a safer vector and promote genome integration, the CRISPR/Cas9 gene is cloned into a plasmid-based non-viral safe vector Sleeping-Beauty (SB) transposon in this study to obtain pT2SpCas9. Meanwhile, PDA/DEX-PEI@HA (PDPH) nanoparticles are constructed to facilitate the precise CRISPR/Cas9 targeting delivery, by using polydopamine (PDA) as the carrier, hyaluronic acid (HA) as the cell-targeting ligand and dexamethasone (DEX) as the nuclear localization signal (NLS). The results showed that PDPH could deliver pDNA efficiently into the cell and further into the nucleus. The transfection efficiency of PDPH is much higher than that of NPs without HA and DEX. Remarkably, the cytotoxicity of PDPH is negligible in comparison to PEI25k and PEI10k. Western blots showed that after the transfection of PDPH/pT2SpCas9-Nanog/SB11, Nanog protein in HeLa cells is knocked out, and the proliferation and migration abilities of tumor cells are significantly decreased. This study demonstrates that PDA/DEX-PEI25k@HA/pT2SpCas9 (PDPH25 K/pT2SpCas9) has the great potential as a non-viral gene vector for CRISPR/Cas9 delivery and clinical medication.
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Proteína 9 Associada à CRISPR/genética , Técnicas de Transferência de Genes , Nanopartículas , Transposases/genética , Dexametasona/metabolismo , Edição de Genes/métodos , Técnicas de Inativação de Genes , Terapia Genética/métodos , Vetores Genéticos/genética , Células HeLa , Humanos , Ácido Hialurônico/metabolismo , Indóis/química , Ligantes , Proteína Homeobox Nanog/genética , Plasmídeos/genética , Polietilenoimina/química , Polímeros/química , TransfecçãoRESUMO
Ca2+/calmodulin (CaM) signaling is important for a wide range of cellular functions. It is not surprised the role of this signaling has been recognized in tumor progressions, such as proliferation, invasion, and migration. However, its role in leukemia has not been well appreciated. The multifunctional Ca2+/CaM-dependent protein kinases (CaMKs) are critical intermediates of this signaling and play key roles in cancer development. The most investigated CaMKs in leukemia, especially myeloid leukemia, are CaMKI, CaMKII, and CaMKIV. The function and mechanism of these kinases in leukemia development are summarized in this study.
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Persistent organic pollutants in soil are not readily degraded in the short term. The utilization of co-processing solid waste in cement kilns has received increasing attention in recent years. Co-processing may be a good way of disposing of dichlorodiphenyltrichloroethane-contaminated soil (CS). The feasibility of co-processing CS pretreated to desorb dichlorodiphenyltrichloroethane, was assessed by performing an industrial-scale trial, focusing on the risks posed by emissions to the environment. Samples of the input and output in cement kiln were collected for determining clinker quality, production operation, pollutant emissions, cement kiln system destruction efficiency, and distribution profiles of persistent organic pollutants unintentionally produced from kiln. The destruction efficiency and destruction removal efficiency both were > 99.99% in cement kiln system at the appropriate CS feeding rate. Emissions of stack gases produced by cement kilns co-processing CS were within the reasonable range set in China. Dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), and polychlorinated biphenyls (PCBs) concentrations and distribution profiles in flue gases and particulate samples from two tests showed PCBs mainly formed at the same sites as PCDD/Fs, indicating they are may formed in a similar way in cement kiln. A comparison with the processing parameters in the clinker, cement kiln dust, and flue gas under baseline and co-processing conditions, manifested that co-processing had no effect on the operation or cement quality of the cement kiln. Thus co-processing CS at a rate of 20 t/h with pretreatment process, is an environmentally sound and highly efficient treatment for CS.