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Implementing novel technologies, including the "well factory" model and zipper fracturing techniques, has become prevalent in shale gas development. During completion operations such as lowering casing and multistage fracturing, the casing is subjected to many complex loads, reducing its strength and increasing the risk of casing deformation. By establishing a casing wear model and conducting multistage cyclic loading experiments and numerical simulations, we analyzed the change rule of casing anticollapse strength under complex loads, developed a calculation method for casing comprehensive anticollapse ability under complex loads, and applied the method to an illustrative calculation. The study shows that the wear effect during completion has a negligible impact on the strength of the casing. The casing anticollapse strength exhibits a linear decline in correlation with the number of cycles. The zipper fracturing operation resulted in a nonuniform distribution of geo-stress around the well, and the casing anticollapse strength demonstrated a nearly linear decline in correlation with the nonuniformity of geo-stress. In the presence of both internal and external effects, the casing anticollapse strength exhibited a decline exceeding 15%, thereby increasing the risk of casing deformation. This research method can provide computational guidance for preventing casing deformation in field fracturing construction.
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Owing to the dense extracellular matrix and high interstitial fluid pressure in the tumor microenvironment, methods which enhance the permeation and retention of nano drugs into liver tumors remain unsatisfactory for successful tumor treatment. We designed a near-infrared (NIR)- and ultrasound (US)-triggered Pt/Pd-engineered "cluster bomb" (Pt/Pd-CB) which actively penetrates liver cancer cell membranes and achieves photothermal and sonodynamic therapy (SDT). The physical forces generated by the fast expansion and collapse of perfluoropentane nanodroplets eject "sub bombs" (Pt/Pd nanoalloys) into liver cancer cells upon activation by NIR and US. Pt/Pd nanoalloys can then convert H2O2 into O2 to alleviate hypoxia and boost SDT efficiency while exhibiting a highly efficient photothermal response under NIR irradiation. Our findings might especially be promising for the treatment of solid tumors.
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Fluorocarbonos , Raios Infravermelhos , Neoplasias Hepáticas , Platina , Humanos , Animais , Fluorocarbonos/química , Fluorocarbonos/administração & dosagem , Neoplasias Hepáticas/terapia , Platina/química , Terapia por Ultrassom/métodos , Linhagem Celular Tumoral , Camundongos Nus , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Nanopartículas/química , Nanopartículas/administração & dosagem , Camundongos Endogâmicos BALB C , Células Hep G2 , Peróxido de Hidrogênio/química , Camundongos , PentanosRESUMO
Porcine reproductive and respiratory syndrome virus (PRRSV) causes a highly contagious disease that threatens the global swine industry. Recent studies have focused on the damage that PRRSV causes to the reproductive system of male pigs, although pathological research is lacking. Therefore, we examined the pathogenic mechanisms in male piglets infected with PRRSV. Gross and histopathological changes indicated that PRRSV affected the entire reproductive system, as confirmed via immunohistochemical analysis. PRRSV infected Sertoli cells and spermatogonia. To test the new hypothesis that PRRSV infection in piglets impairs blood - testis barrier (BTB) development, we investigated the pathology of PRRSV damage in the BTB. PRRSV infection significantly decreased the quantity and proliferative capacity of Sertoli cells constituting the BTB. Zonula occludens-1 and ß-catenin were downregulated in cell - cell junctions. Transcriptome analysis revealed that several crucial genes and signalling pathways involved in the growth and development of Leydig cells, Sertoli cells, and tight junctions in the testes were downregulated. Apoptosis, necroptosis, inflammatory, and oxidative stress-related pathways were activated, whereas hormone secretion-related pathways were inhibited. Many Sertoli cells and spermatogonia underwent apoptosis during early differentiation. Infected piglets exhibited disrupted androgen secretion, leading to significantly reduced testosterone and anti-Müllerian hormone levels. A cytokine storm occurred, notably upregulating cytokines such as tumour necrosis factor-α and interleukin-6. Markers of oxidative-stress damage (i.e. H2O2, malondialdehyde, and glutathione) were upregulated, whereas antioxidant-enzyme activities (i.e. superoxide dismutase, total antioxidant capacity, and catalase) were downregulated. Our results demonstrated that PRRSV infected multiple organs in the male reproductive system, which impaired growth in the BTB.
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Barreira Hematotesticular , Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Células de Sertoli , Testículo , Animais , Masculino , Suínos , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Síndrome Respiratória e Reprodutiva Suína/patologia , Células de Sertoli/virologia , Células de Sertoli/metabolismo , Barreira Hematotesticular/virologia , Testículo/virologia , Testículo/patologia , Espermatogônias/virologia , Apoptose , Células Intersticiais do Testículo/virologia , Citocinas/metabolismo , Testosterona/sangue , Proteína da Zônula de Oclusão-1/metabolismo , Proteína da Zônula de Oclusão-1/genéticaRESUMO
Solar dermatitis, a form of acute radiation burn that affects the skin, results from overexposure to ultraviolet B (UVB) radiation in strong sunlight. Cell damage caused by the accumulation of reactive oxygen species (ROS) produced by UVB radiation plays an important role in UVB-induced inflammation in the skin. Here, for efficiently scavenging excess ROS, modulating the microenvironment, and alleviating solar dermatitis, a π-conjugated network polyphthalocyanine supporting a highly surface-exposed Ru active site-based artificial antioxidase (HSE-PPcRu) is designed and fabricated with excellent ROS-scavenging, antioxidant, and anti-inflammatory capabilities. In photodamaged human keratinocyte cells, HSE-PPcRu could modulate mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B signaling pathways, prevent DNA damage, suppress apoptosis, inhibit pro-inflammatory cytokine secretion, and alleviate cell damage. In vivo animal experiments reveal the higher antioxidant and anti-inflammatory efficacies of HSE-PPcRu by reversing the activation of p38 and c-Jun N-terminal kinase, inhibiting expression of cyclooxygenase-2, interleukin-6, interleukin-8, and tumor necrosis factor-α. This work not only provides an idea for alleviating solar dermatitis via catalytically scavenging ROS and modulating the microenvironment but also offers a strategy to design an intelligent conjugated network-based artificial antioxidase with a highly surface-exposed active site.
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Antioxidantes , Dermatite , Animais , Humanos , Antioxidantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Pele/metabolismo , Raios Ultravioleta , Anti-Inflamatórios/farmacologia , Dermatite/etiologia , Dermatite/metabolismoRESUMO
Background: Until now, there has been no systematic review or meta-analysis of direct head-to-head studies that compare two liver imaging reporting and data system (LI-RADS) algorithms, contrast-enhanced ultrasound (CEUS) LI-RADS and contrast-enhanced computed tomography/magnetic resonance imaging (CT/MRI) LI-RADS, for the diagnostic efficacy of hepatocellular carcinoma. The purpose of this study was to identify and head-to-head compare the diagnostic performance of both LI-RADS algorithms for hepatocellular carcinoma. Methods: We searched the PubMed, EMBASE, Web of Science, and Cochrane Library databases from the inception of each database to April 26, 2022, to find the comparative study of both LI-RADS algorithms for hepatocellular carcinoma at risk of patients who underwent both LI-RADS algorithms. Eligibility criteria included only studies published in English, full reports published, both retrospective and prospective studies. Liver histology or imaging follow-up results served as the reference standard. We analyzed the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and summary receiver operating characteristic curve to determine summary estimates. The Quality Assessment of Diagnostic Accuracy Studies was utilized to assess the methodological quality. Results: In 5 included studies (831 patients, 877 lesions), the pooled sensitivity and pooled specificity of CEUS LR-5 were 0.79, 0.81, and 0.78, 0.79 in CT/MRI LR-5, respectively. The pooled sensitivity and pooled specificity of CEUS LR-4/5 were 0.86, 0.70, and 0.93, 0.59 in CT/MRI LR-4/5, respectively. There was no obvious difference between the two LI-RADS algorithms for hepatocellular carcinoma, and there was no significant statistical difference between two LR-M algorithms for non-hepatocellular carcinoma malignancies. Conclusions: The results of our analysis demonstrated that CEUS LI-RADS has satisfactory diagnostic performance similar to that of CT/MRI LI-RADS, which provides a theoretical basis for the popularization of CEUS LI-RADS for diagnosing HCC. This work was supported by Sichuan Science and Technology Program (No. 2020YFS0211). We registered this study on the international prospective register of systematic reviews (PROSPERO, CRD42022328107) before the search step.
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Intratumoral immunotherapy is well studied and is ongoing, but few studies have evaluated the relationship between of cytotoxic drugs intratumoral injection (CDI) and hapten-enhanced cytotoxic drugs intratumoral injection (HECDI) and patient survival. The objectives of this study include comparisons to explore possible associations between the proportions of treatment-induced cytokines and autologous antibodies to tumor-associated antigens (TAAs) and the relative size of the abscopal effects concurring. CDIs contain oxidant and cytotoxic drugs, HECDIs contains the same drug plus penicillin as the new Hapten. Of the 33 patients with advanced pancreatic cancer, 9 received CDI, 20 received HECDI, and 4 (control group) received placebo. Serum levels of cytokines and autoantibodies of TAAs were detected and compared after therapy. The 1-year survival rate was 11.11% for CDI and 52.63% for HECDI (P= 0.035). In the general analysis of cytokines, HECDI exhibited an increasing level of IFN-γ and IL-4, and the non-hapten CDI showed a rising level of IL-12 (P = 0.125, 0.607, & 0.04). Participants who did not receive chemotherapy had significant differences in the level of Zeta autoantibody only before and after HECDI; However, IMP1 levels in patients with previous chemotherapy experience were significantly different before and after HECDI and CDI treatment (P≤0.05, P = 0.316). After HECDI treatment, TAA autoantibodies of RalA, Zeta, HCC1, p16 increased (P = 0.429, 0.416, 0.042, 0.112). The elevated levels of CXCL8, IFN-γ, HCC1, RalA, Zeta, and p16 observed in HECDI may be attributed to the abscopal effect (P = 0.012 & 0.013). Overall survival rates indicated that HECDI treatment extended participants' lives.
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Non-invasive cancer treatment strategies that enable local non-thermal ablation, hypoxia relief, and reactive oxygen species (ROS) production to achieve transiently destroying tumor tissue and long-term killing tumor cells would greatly facilitate their clinical applications. However, continuously generating oxygen cavitation nuclei, reducing the transient cavitation sound intensity threshold, relieving hypoxia, and improving its controllability in the ablation area still remains a significant challenge. Here, in this work, an Mn-coordinated polyphthalocyanine sonocavitation agent (Mn-SCA) with large d-π-conjugated network and atomic Mn-N sites is identified for the non-thermal sonocavitation and sonodynamic therapy in the liver cancer ablation. In the tumor microenvironment, the catalytical generation of oxygen assists cavitation formation and generates microjets to ablate liver cancer tissue and relieve hypoxia, this work reports for the first time to utilize the enzymatic properties of Mn-SCA to lower the cavitation threshold in situ. Moreover, under pHIFU irradiation, high reactive oxygen species (ROS) production can be achieved. The two merits in liver cancer ablation are demonstrated by cell destruction and high tumor inhibition efficiency. This work will help deepen the understanding of cavitation ablation and the sonodynamic mechanisms related to the nanostructures and guide the design of sonocavitation agents with high ROS production for solid tumor ablation.
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Ablação por Ultrassom Focalizado de Alta Intensidade , Neoplasias Hepáticas , Humanos , Espécies Reativas de Oxigênio , Hipóxia , Oxigênio , Neoplasias Hepáticas/terapia , Catálise , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
In order to identify the contamination and health risks of heavy metals in agricultural soils, a total of 56 surface soil samples (0-20 cm) were collected around a Pb-Zn smelter in Yunnan Province, and six heavy metals (Pb, Cd, Zn, As, Cu, and Hg) and pH were analyzed to assess heavy metal status, ecological risk, and probabilistic health risk. The results revealed that the average contents of six heavy metals (Pb:4413.93 mg·kg-1, Cd:6.89 mg·kg-1, Zn:1672.76 mg·kg-1, As:44.45 mg·kg-1, Cu:47.61 mg·kg-1, and Hg:0.21 mg·kg-1) were higher than their background values in Yunnan Province. Cd had the highest mean geo-accumulation index (Igeo) of 0.24, the highest mean pollution index (Pi) of 30.42, and the greatest average ecological risk index (Er) of 1312.60, indicating that Cd was the primary enriched and highest-ecological risk pollutant. The mean hazard index (HI) through exposure to six HMs was 2.42E-01 and 9.36E-01 for adults and children, respectively, with 36.63% of HI values for children exceeding the risk threshold of 1. Moreover, the mean total cancer risks (TCR) were 6.98E-05 and 5.93E-04 for adults and children, respectively, with 86.85% of TCR values for children exceeding the guideline value of 1E-04. The probabilistic health risk assessment suggested that Cd and As were the main contributors for the non-carcinogenic risks and carcinogenic risks. This work will provide scientific reference for the precise risk management and effective remediation strategy of soil heavy metal pollution in this study area.
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Mercúrio , Metais Pesados , Poluentes do Solo , Criança , Adulto , Humanos , Zinco , Solo/química , Chumbo , Cádmio , Monitoramento Ambiental , Poluentes do Solo/análise , China , Metais Pesados/análise , Medição de Risco , Receptores de Antígenos de Linfócitos TRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Weierning tablet (WEN) is a traditional Chinese patent medicine widely used in clinical for chronic atrophic gastritis (CAG) therapy for years. However, the underlying mechanisms of WEN on anti-CAG are still unveiled. AIM OF THE STUDY: The present study aimed to elucidate the characteristic function of WEN on anti-CAG and to illuminate its potential mechanism. METHODS: The CAG model was established by gavage rats with a modeling solution (consisting of 2% sodium salicylate and 30% alcohol) with irregular diets and free access to 0.1% ammonia solution for two months on end. An enzyme-linked immunosorbent assay was used to measure the serum levels of gastrin, pepsinogen, and inflammatory cytokines. qRT-PCR was applied to measure mRNA expressions of IL-6, IL-18, IL-10, TNF-α, and γ-IFN in gastric tissue. Pathological changes and the ultrastructure of gastric mucosa were examined by hematoxylin and eosin staining and transmission electron microscopy, respectively. AB-PAS staining was applied to observe the intestinal metaplasia of gastric mucosa. Immunohistochemistry and Western blot were used to measure the expression levels of mitochondria apoptosis-related proteins and Hedgehog pathway-related proteins in gastric tissues. Expressions of Cdx2 and Muc2 protein were determined by immunofluorescent staining. RESULTS: WEN could dose-dependently lower the serum level of IL-1ß and the mRNA expressions of IL-6, IL-8, IL-10, TNF-α, and γ-IFN in gastric tissue. Also, WEN significantly alleviated the collagen deposition in gastric submucosa, regulated the expressions of Bax, Cleaved-caspase9, Bcl2, and Cytochrome c to reduce the apoptosis of gastric mucosa epithelial cells, and maintained the integrity of the gastric mucosal barrier. Moreover, WEN could reduce protein expressions of Cdx2, Muc2, Shh, Gli1, and Smo, and reverse intestinal metaplasia of gastric mucosa to block the progress of CAG. CONCLUSION: This study demonstrated a positive effect of WEN on improving CAG and reverse intestinal metaplasia. These functions were related to the suppression of gastric mucosal cells' apoptosis and the inhibition of Hedgehog pathways' activation.
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Gastrite Atrófica , Ratos , Animais , Gastrite Atrófica/metabolismo , Interleucina-10/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Proteínas Hedgehog/metabolismo , Mucosa Gástrica/patologia , Metaplasia/metabolismo , Metaplasia/patologia , RNA Mensageiro/metabolismoRESUMO
Background: Microwave dynamic therapy (MDT) as a novel reactive oxygen species (ROS)-based therapeutic modality has been explored as a promising modality for cancer treatment. However, the intrinsic hypoxic tumor microenvironment (TME) restricted the effectiveness of the MDT. The aim of this study is to develop an oxygen-sufficient nanoplatform with multi-modal imaging capability for enhanced MDT against hypoxic tumors. Methods and Materials: The liquid perfluorocarbon-based nanoplatform PFP@IR780@O2 was constructed by the phospholipid hydration and sonication method. Then, the characteristics, intracellular uptake process, and subcellular localization of PFP@IR780@O2 were verified. Additionally, the abilities of ROS generation, the anti-hypoxia capability, multi-mode imaging capabilities, and MDT efficacy of the nanoplatform were evaluated via in vitro and in vivo experiments. Finally, the in vivo biocompatibility and toxicity were also evaluated. Results: The prepared nanoparticles PFP@IR780@O2 exhibited suitable size, improved stability, elevated dissolved oxygen level, enhanced cellular uptake, and mitochondria targeting capacity. Additionally, PFP@IR780@O2 demonstrated in vitro and in vivo multimodal imaging capabilities involving ultrasound, fluorescence, and photoacoustic imaging. In vivo studies also indicated that nanoparticles were safe and capable of accumulating in the tumor site after intravenous injection. Furthermore, the PFP@IR780@O2 nanoplatform mediated MDT could effectively alleviate the hypoxic TME, and elevate ROS concentration, thereby resulting in significant tumor growth inhibition. Conclusion: Overall, the oxygen-sufficient nanoplatform with multi-bimodal imaging capability demonstrated improved MDT efficiency, indicating a promising strategy for treating hypoxic tumors.
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Neoplasias , Oxigênio , Camundongos , Animais , Espécies Reativas de Oxigênio , Micro-Ondas , Camundongos Nus , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Hipóxia/diagnóstico por imagem , Microambiente TumoralRESUMO
Objective: To prepare a fucoidan-modified phase-transitional contrast agent (FPCA) and to evaluate its in vitro capabilities for ultrasound imaging and targeting of hepatoma cells. Methods: Nano-liposomes encapsulated with perfluoropentane were prepared using thin-film hydration and ultrasonic emulsification methods. Then, FPCA nanoparticles were prepared through chemical grafting of fucoidan and the characterization of their physical and chemical properties was performed. After applying external stimuli of heating with hot water bath and microwave irradiation, the phase-transition status of FPCA was observed with microscope. The imaging abilities of phase-transited FPCA on two-dimensional ultrasound and contrast-enhanced ultrasound were observed with ultrasonic diagnostic instrument. The ability of FPCA to target at hepatoma cells was evaluated and verified with fluorescence confocal observation and flow cytometry analysis. Results: The FPCA prepared in the study had an average diameter of (222.1±32.5) nm, displaying spherical appearance, good dispersion, good stability, and good biocompatibility. The phase-transition of FPCA was induced by both heating with hot water bath and microwave irradiation. For phase transition, the optimal temperature was found to be 50 â and the preferred microwave power was 1.5 W/cm 2. Moreover, after phase transition, FPCA showed significant imaging enhancement on both two-dimensional ultrasonography and contrast-enhanced ultrasonography. Through fluorescein isothiocyanate (FITC) labeling, FPCA could specifically bind with hepatoma cells at a high binding rate of (96.19±1.62)%, while it rarely bound with normal liver cells, showing a binding rate of less than 10%. Conclusion: A new type of phase-transitional ultrasound contrast agent with good stability and biocompatibility was successfully prepared. It not only could enhance ultrasound imaging through phase transition, but also had specific active hepatoma cell-targeting properties.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Meios de Contraste , Fluoresceína-5-Isotiocianato , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Nanopartículas/química , Polissacarídeos , Ultrassonografia , Água , p-Cloroanfetamina/análogos & derivadosRESUMO
Objective: To demonstrate the effectiveness of Huangqin decoction (Huangqin Tang in Chinese, HQT) combined with Radix Actinidiae chinensis (Tengligen in Chinese, TLG) under the guidance of "dampness-heat theory" in preventing and treating colorectal cancer (CRC) with dampness-heat accumulation and to preliminarily reveal its mechanism. Methods: The mice model of CRC was established by intraperitoneal injection of AOM combined with consumption of 2.5% DSS solution, and celecoxib, HQT, TLG, and their combination (HQT + TLG) were administered at the same time. The physical signs and death of the mice were observed daily. At the end of the experiment, the colorectal tissue was dissected, and the tumor was observed and counted. HE staining and Masson's staining were used to observe the histopathological changes of colon. Expression levels of TNF-α, IL-6, and IL-10 in colorectal tissue were detected by ELISA, and the expression of TNF-α was observed by immunofluorescence. TUNEL assay was used to observe the apoptosis of tumor tissues, and immunohistochemistry was used to observe the expression of Ki-67 and occludin. The mRNA expression levels of claudin-1, occludin, ZO-1, and IL-6 and IL-17 were detected by RT-PCR, and occludin, ZO-1, NF-κB, and STAT3 protein levels were detected by Western blot. The composition of intestinal flora was analyzed by 16S rRNA. Results: HQT + TLG could significantly reduce the mortality of model mice and improve the intestinal mucosal inflammatory cell infiltration and high-grade intraepithelial neoplasia in model mice. All administration groups show a great reduction in the levels of IL-6 and TNF-α in the colorectal tissues of model mice, and increase in the level of IL-10, the total number of CD3+ T cells, the proportion of CD3+CD4+ T cells, and the ratio of CD4/CD8. HQT and HQT + TLG could significantly change the composition of intestinal flora and increase the abundance of Firmicutes and Patescibacteria. Conclusion: HQT and TLG combination has a good effect on inhibiting AOM-DSS-induced CRC. This function may be related to improving the composition of the intestinal flora, regulating the proportion of T-cell subsets in colorectal lymphoid tissue to improve inflammatory response, and downregulating the expression of claudin-1, inhibiting the activation of IL-6/STAT3 signaling pathway to improving abnormal hyperplasia.
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This study aimed to assess liver fibrosis in rabbits by deep learning models based on acoustic nonlinearity maps. Injection of carbon tetrachloride was used to induce liver fibrosis. Acoustic nonlinearity maps, which were built by data of echo signals, were used as input data for deep learning model. Convolutional neural network (CNN), CNN combined with support vector machine (SVM), CNN combined with random forest and CNN combined with logistic regression were used as deep learning model. Nested 10-fold cross-validation was used to search hyperparameters and evaluate performance of models. Histologic examination of liver specimens of the rabbits was performed to evaluate the fibrosis stage. Receiver operator characteristic curve and area under curve (AUC) were used for estimating the probability of the correct prediction of liver fibrosis stages. A total of 600 acoustic nonlinearity maps were used. Model of CNN combined with SVM demonstrated the best diagnostic performance compared with all other methods for diagnosis of significant fibrosis (≥F2, AUC = 0.82), advanced fibrosis (≥F3, AUC = 0.88) and cirrhosis (F4, AUC = 0.90). Model of CNN showed the second highest AUCs. The deep learning model based on acoustic nonlinearity maps demonstrated potential for evaluation of liver fibrosis.
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Aprendizado Profundo , Acústica , Animais , Fibrose , Humanos , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Redes Neurais de Computação , CoelhosRESUMO
Ultrasound (US)-augmented tumor ablation with sono-catalysts has emerged as a promising therapeutic modality due to high tissue penetration, nonionizing performance, and low cost of US-based therapies. Developing peroxisome-mimetic cascade biocatalysts for US-augmented synergistic treatment would further effectively reduce the dependence of the microenvironment H2O2 and enhance the tumor-localized reactive oxygen species (ROS) generation. Here, we proposed and synthesized a novel spiky cascade biocatalyst as peroxisome-mimics that consist of multiple enzyme-mimics, i.e., glucose oxidase-mimics (Au nanoparticles for producing H2O2) and heme-mimetic atomic catalytic centers (Fe-porphyrin for ROS generation), for US-augmented cascade-catalytic tumor therapy. The synthesized spiky cascade biocatalysts exhibit an obvious spiky structure, uniform nanoscale size, independent of endogenous H2O2, and efficient US-responsive biocatalytic activities. The enzyme-mimetic biocatalytic experiments show that the spiky cascade biocatalysts can generate abundant ·OH via a cascade chemodynamic path and also 1O2 via US excitation. Then, we demonstrate that the spiky cascade biocatalysts show highly efficient ROS production to promote melanoma cell apoptosis under US irradiation without extra H2O2. Our in vivo animal data further reveal that the proposed US-assisted chemodynamic cascade therapies can significantly augment the therapy efficacy of malignant melanoma. We suggest that these efficient peroxisome-mimetic cascade-catalytic strategies will be promising for clinical tumor therapies.
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Nanopartículas Metálicas , Nanopartículas , Animais , Linhagem Celular Tumoral , Ouro/farmacologia , Peróxido de Hidrogênio/química , Nanopartículas Metálicas/uso terapêutico , Nanopartículas/uso terapêutico , Peroxissomos , Espécies Reativas de Oxigênio , Microambiente TumoralRESUMO
Hepatocellular carcinoma (HCC) is an often-fatal malignant tumor with high lethality. Despite advances and significant efficacy in monotherapy, cancer therapy continues to pose several challenges. Novel combination regimens are an emerging strategy for anti-HCC and have demonstrated to be effective. Here, we propose a potential combination for HCC treatment named arsenic trioxide cooperate cryptotanshinone (ACCS). A remarkable synergistic therapeutic effect has been achieved compared with drugs alone in both in vivo and in vitro experiments. Mechanism study indicated that ACCS exerts its therapeutic actions by regulating macrophage-related immunity and glycolysis. ACCS potentiates the polarization of M1 macrophages and elevates the proportion of M1/M2 to remodel tumor immunity. Further molecular mechanism study revealed that ACCS intensifies the glucose utilization and glycolysis in the macrophage by increasing the phosphorylation of AMPK to activating the AMPK singling pathway. In conclusion, ACCS is a highly potential combination regimen for HCC treatment. The therapeutic potential of ACCS as a candidate option for anticancer drugs in restoring the balance of immunity and metabolism deserves further investigation.
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Antineoplásicos/uso terapêutico , Trióxido de Arsênio/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Macrófagos/metabolismo , Fenantrenos/uso terapêutico , Animais , Diferenciação Celular , Citocinas/metabolismo , Combinação de Medicamentos , Sinergismo Farmacológico , Glicólise , Humanos , Imunidade Inata , Imunomodulação , Ativação de Macrófagos , Camundongos , Camundongos Endogâmicos BALB C , Células Th1/imunologiaRESUMO
Purpose: To establish a clinically applicable genomic clustering system, we investigated the interactive landscape of driver mutations in intrahepatic cholangiocarcinoma (ICC). Methods: The genomic data of 1481 ICCs from diverse populations was analyzed to investigate the pair-wise co-occurrences or mutual exclusivities among recurrent driver mutations. Clinicopathological features and outcomes were compared among different clusters. Gene expression and DNA methylation profiling datasets were analyzed to investigate the molecular distinctions among mutational clusters. ICC cell lines with different gene mutation backgrounds were used to evaluate the cluster specific biological behaviors and drug sensitivities. Results: Statistically significant mutation-pairs were identified across 21 combinations of genes. Seven most recurrent driver mutations (TP53, KRAS, SMAD4, IDH1/2, FGFR2-fus and BAP1) showed pair-wise co-occurrences or mutual exclusivities and could aggregate into three genetic clusters: Cluster1: represented by tripartite interaction of KRAS, TP53 and SMAD4 mutations, exhibited large bile duct histological phenotype with high CA19-9 level and dismal prognosis; Cluster2: co-association of IDH/BAP1 or FGFR2-fus/BAP1 mutation, was characterized by small bile duct phenotype, low CA19-9 level and optimal prognosis; Cluster3: mutation-free ICC cases with intermediate clinicopathological features. These clusters showed distinct molecular traits, biological behaviors and responses to therapeutic drugs. Finally, we identified S100P and KRT17 as "cluster-specific", "lineage-dictating" and "prognosis-related" biomarkers, which in combination with CA19-9 could well stratify Cluster3 ICCs into two biologically and clinically distinct subtypes. Conclusions: This clinically applicable clustering system can be instructive to ICC prognostic stratification, molecular classification, and therapeutic optimization.
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Neoplasias dos Ductos Biliares/genética , Biomarcadores Tumorais/genética , Colangiocarcinoma/genética , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , PrognósticoRESUMO
Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with very few treatment options. Although tumor-targeted nanomedicines hold great promise for the treatment of TNBC, the tumor microenvironment (TME) continues to be a major cause of failure in nanotherapy and immunotherapy. To overcome this barrier, we designed a new synergistic cascade strategy (SCS) that uses mild hyperthermia and smart drug delivery system (SDDS) to alter TME resistance in order to improve drug delivery and therapeutic efficacy of TNBC. Methods: Mild hyperthermia was produced by microwave (MW) irradiation. SDDS were formulated with thermosensitive polymer-lipid nanoparticles (HA-BNPs@Ptx), composed of polymer PLGA, phospholipid DPPC, hyaluronic acid (HA, a differentiation-44-targeted molecule, also known as CD44), 1-butyl-3-methylimidazolium-L-lactate (BML, a MW sensitizer), and paclitaxel (Ptx, chemotherapy drug). 4T1 breast tumor-bearing mice were treated with two-step MW combined with HA-BNPs@Ptx. Tumors in mice were pretreated with first MW irradiation prior to nanoparticle injection to modify and promote TME and promoting nanoparticle uptake and retention. The second MW irradiation was performed on the tumor 24 h after the injection of HA-BNPs@Ptx to produce a synergistic cascade effect through activating BML, thus, enhancing a hyperthermia effect, and instantly releasing Ptx at the tumor site. Results: Multifunctional CD44-targeted nanoparticles HA-BNPs@Ptx were successfully prepared and validated in vitro. After the first MW irradiation of tumors in mice, the intratumoral perfusion increased by two times, and the nanoparticle uptake was augmented by seven times. With the second MW irradiation, remarkable antitumor effects were obtained with the inhibition rate up to 88%. In addition, immunohistochemical analysis showed that SCS therapy could not only promote tumor cell apoptosis but also significantly reduce lung metastasis. Conclusion: The SCS using mild hyperthermia combined with SDDS can significantly improve the efficacy of TNBC treatment in mice by modifying TME and hyperthermia-mediated EPR effects.
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Pathogenic drug-resistant bacteria represent a threat to human health, for instance, the methicillin-resistant Staphylococcus aureus (MRSA). There is an ever-growing need to develop non-antibiotic strategies to fight bacteria without triggering drug resistance. Here, we design a hedgehog artificial macrophage with atomic-catalytic centers to combat MRSA by mimicking the "capture and killing" process of macrophages. The experimental studies and theoretical calculations reveal that the synthesized materials can efficiently capture and kill MRSA by the hedgehog topography and substantial generation of â¢O2- and HClO with its Fe2N6O catalytic centers. The synthesized artificial macrophage exhibits a low minimal inhibition concentration (8 µg/mL Fe-Art M with H2O2 (100 µM)) to combat MRSA and rapidly promote the healing of bacteria-infected wounds on rabbit skin. We suggest that the application of this hedgehog artificial macrophage with "capture and killing" capability and high ROS-catalytic activity will open up a promising pathway to develop antibacterial materials for bionic and non-antibiotic disinfection strategies.
Assuntos
Antibacterianos/farmacologia , Materiais Biomiméticos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Macrófagos , Animais , Antibacterianos/química , Materiais Biomiméticos/química , Catálise , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/metabolismo , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nanomedicina , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Infecções Estafilocócicas/tratamento farmacológico , Cicatrização/efeitos dos fármacosRESUMO
Porphyrin-based nanozymes (Porzymes) have shown promising application potential to fight against tumors using catalytically generated reactive oxygen species from the excessively produced H2O2 in the tumor microenvironment. However, the low coordination porphyrin (CP) loading ratio, difficult controllable nanostructure, low bioavailability, and low biocatalytic activities of current established Porzymes have severely limited their antitumor applications. Here, a novel malignant melanoma cell membrane-coated Pd-based CP nanoplatform (Trojan Porzymes) has been synthesized for biocatalytic and homologous tumor therapies. The Trojan Porzymes exhibit a high CP loading ratio, uniform nanoscale size, single-atom nanostructure, homologous targeted ability, and high-efficiency photo/sono-augmented biocatalytic activities. The enzyme-like biocatalytic experiments display that the Trojan Porzymes can generate abundant â¢OH via chemodynamic path and 1O2 via visible light or ultrasound excitation. Then we demonstrate that the Trojan Porzymes show homologous targeting ability to tumor cells and can achieve efficient accumulation and long-term retention in cancer tissues. Our in vivo data further disclose that the photo/sono-assisted chemodynamic therapies can significantly augment the treatment efficiency of malignant melanoma. We believe that our work will afford a new biocatalytic and homologous strategy for future clinical malignant melanoma treatments, which may inspire and guide more future studies to develop individualized biomedicine in precise tumor therapies.
Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Porfirinas/uso terapêutico , Radiossensibilizantes/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Catálise , Membrana Celular/química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Complexos de Coordenação/uso terapêutico , Células Endoteliais da Veia Umbilical Humana , Humanos , Radical Hidroxila/metabolismo , Luz , Camundongos , Nanopartículas/química , Nanopartículas/efeitos da radiação , Porfirinas/química , Porfirinas/efeitos da radiação , Radiossensibilizantes/química , Radiossensibilizantes/efeitos da radiação , Ondas UltrassônicasRESUMO
Sonocatalytic nanoagents (SCNs), a kind of sonosensitizers, could catalyze oxygen to generate abundant reactive oxygen species (ROS) under stimulations of noninvasive and deep-penetrating ultrasound (US), which is commonly used for sonodynamic therapy (SDT) of tumors such as malignant melanoma. However, poor bioavailability of most SCNs and fast quenching of extracellular-generating ROS from SDT limit further applications of SCNs in the SDT of tumors. Herein, we synthesized a new kind of TiO2-based SCN functionalized with the malignant melanoma cell membrane (B16F10M) and programmed cell death-ligand 1 antibody (aPD-L1) for homology and immune checkpoint dual-targeted and enhanced sonodynamic tumor therapy. Under US irradiation, the synthesized SCN can catalytically generate a large amount of 1O2. In vitro experiments validate that functionalized SCNs exhibit precise targeting effects, high tumor cell uptake, and intracellular sonocatalytic killing of the B16F10 cells by a large amount of localized ROS. Utilizing the melanoma animal model, the functionalized SCN displays visible long-term retention in the tumor area, which assists the homology and immune checkpoint synergistically dual-targeted and enhanced in vivo SDT of the tumor. We suggest that this highly bioavailable and dual-functionalized SCN may provide a promising strategy and nanoplatform for enhancing sonodynamic tumor therapies.