Showing papers on "Infiltration (HVAC) published in 2022"

Depletion of tumor associated macrophages enhances local and systemic platelet-mediated anti-PD-1 delivery for post-surgery tumor recurrence treatment

Abstract: Immunosuppressive cells residing in the tumor microenvironment, especially tumor associated macrophages (TAMs), hinder the infiltration and activation of T cells, limiting the anti-cancer outcomes of immune checkpoint blockade. Here, we report a biocompatible alginate-based hydrogel loaded with Pexidartinib (PLX)-encapsulated nanoparticles that gradually release PLX at the tumor site to block colony-stimulating factor 1 receptors (CSF1R) for depleting TAMs. The controlled TAM depletion creates a favorable milieu for facilitating local and systemic delivery of anti-programmed cell death protein 1 (aPD-1) antibody-conjugated platelets to inhibit post-surgery tumor recurrence. The tumor immunosuppressive microenvironment is also reprogrammed by TAM elimination, further promoting the infiltration of T cells into tumor tissues. Moreover, the inflammatory environment after surgery could trigger the activation of platelets to facilitate the release of aPD-1 accompanied with platelet-derived microparticles binding to PD-1 receptors for re-activating T cells. All these results collectively indicate that the immunotherapeutic efficacy against tumor recurrence of both local and systemic administration of aPD-1 antibody-conjugated platelets could be strengthened by local depletion of TAMs through the hydrogel reservoir.

Experimental Study on Failure Model of Tailing Dam Overtopping under Heavy Rainfall

Abstract: Unusual rainfall is the primary cause of the failure of the tailing dams, and overtopping is the most representative model of the tailing dam failure. The upstream tailing dam was selected as the research object to study the whole process of breach extension and the overtopping dam-failure mechanism under the full-scale rainfall condition. The results showed that the significant size grading phenomenon in the front, middle, and end of the tailing pond was obvious due to the flow separation effect, and its average particle diameter was D50. At different moments of rainfall, the height of the infiltration line at different positions of the dam body was different; at the rainfall of 3600 s, the height of the infiltration line lagged behind the height of the tailing pond, and this phenomenon from the tail of pond to the outside of the dam slope became more obvious. After the rainfall of 3600 s, the height of the infiltration line lagging behind the water level in the pond basically disappeared, and the rate of infiltration line rise kept pace with the rate of water level. The process of overtopping dam-failure experienced dam overtopping (gully erosion), formation of a multistepped small “scarp,” breach rapid expansion, formation of large “scarp,” and burst (fan-shaped formation). The width and depth of the breach showed a positive correlation, and the widening rate of the breach was 3 to 8 times of the deepening rate, especially in the middle of the dam break, widening behavior occupied the dominant factor. The shape of the dam body after failure was parabolic, and the dam body had obvious elevation changes. These results provide the theoretical guidance and engineering application value for improving the theory and early warning model of the upstream tailing dam.

Xuanfei Baidu Decoction reduces acute lung injury by regulating infiltration of neutrophils and macrophages via PD-1/IL17A pathway

Abstract: The pathogenic hyper-inflammatory response has been revealed as the major cause of the severity and death of the Corona Virus Disease 2019 (COVID-19). Xuanfei Baidu Decoction (XFBD) as one of the “three medicines and three prescriptions” for the clinically effective treatment of COVID-19 in China, shows unique advantages in the control of symptomatic transition from moderate to severe disease states. However, the roles of XFBD to against hyper-inflammatory response and its mechanism remain unclear. Here, we established acute lung injury (ALI) model induced by lipopolysaccharide (LPS), presenting a hyperinflammatory process to explore the pharmacodynamic effect and molecular mechanism of XFBD on ALI. The in vitro experiments demonstrated that XFBD inhibited the secretion of IL-6 and TNF-α and iNOS activity in LPS-stimulated RAW264.7 macrophages. In vivo, we confirmed that XFBD improved pulmonary injury via down-regulating the expression of proinflammatory cytokines such as IL-6, TNF-α and IL1-β as well as macrophages and neutrophils infiltration in LPS-induced ALI mice. Mechanically, we revealed that XFBD treated LPS-induced acute lung injury through PD-1/IL17A pathway which regulates the infiltration of neutrophils and macrophages. Additionally, one major compound from XFBD, i.e. glycyrrhizic acid, shows a high binding affinity with IL17A. In conclusion, we demonstrated the therapeutic effects of XFBD, which provides the immune foundations of XFBD and fatherly support its clinical applications.

Spatial transcriptomics of macrophage infiltration in non-small cell lung cancer reveals determinants of sensitivity and resistance to anti-PD1/PD-L1 antibodies

Abstract: Background Tumor-associated macrophages (TAMs) having immunosuppressive properties are one of the most abundant immune cells in the tumor microenvironment (TME). Preclinical studies have highlighted the potential role of TAMs in resistance to immune checkpoint blockers (ICBs). Here, we investigated the predictive value of TAM infiltration in patients with non-small cell lung cancer (NSCLC) treated with ICBs and characterized their transcriptomic profiles. Methods Tumor samples were collected from 152 patients with NSCLC before ICB treatment onset. After immunohistochemical staining and image analysis, the correlation between CD163+ cell infiltration and survival was analyzed. Spatial transcriptomic analyses were performed using the NanoString GeoMx Immune Pathways assay to compare the gene expression profile of tumors with high or low levels of CD163+ cell infiltration and to identify determinants of response to ICBs in tumors with high CD163+ infiltration. Results Low intratumoral CD163+ cell infiltration was associated with longer progression-free survival (PFS; HR 0.61, 95% CI 0.40 to 0.94, p=0.023) and overall survival (OS; HR 0.48, 95% CI 0.28 to 0.80, p=0.004) under ICB treatment. Spatial transcriptomic profiles of 16 tumors revealed the upregulation of ITGAM, CD27, and CCL5 in tumors with high CD163+ cell infiltration. Moreover, in tumors with high macrophage infiltration, the upregulation of genes associated with the interferon-γ signaling pathway and the M1 phenotype was associated with better responses under immunotherapy. Surprisingly, we found also a significantly higher expression of CSF1R in the tumors of responders. Analysis of three independent data sets confirmed that high CSF1R expression was associated with an increased durable clinical benefit rate (47% vs 6%, p=0.004), PFS (median 10.89 months vs 1.67 months, p=0.001), and OS (median 23.11 months vs 2.66 months, p<0.001) under ICB treatment. Conclusions Enrichment of TAMs in the TME of NSCLC is associated with resistance to immunotherapy regardless of the programmed death ligand 1 status and is driven by upregulation of CD27, ITGAM, and CCL5 gene expression within the tumor compartment. Our transcriptomic analyses identify new potential targets to alter TAM recruitment/polarization and highlight the complexity of the CSF1R pathway, which may not be a suitable target to improve ICB efficacy.

Tumor Microenvironment in Glioma Invasion

Abstract: A major malignant trait of gliomas is their remarkable infiltration capacity. When glioma develops, the tumor cells have already reached the distant part. Therefore, complete removal of the glioma is impossible. Recently, research on the involvement of the tumor microenvironment in glioma invasion has advanced. Local hypoxia triggers cell migration as an environmental factor. The transcription factor hypoxia-inducible factor (HIF) -1α, produced in tumor cells under hypoxia, promotes the transcription of various invasion related molecules. The extracellular matrix surrounding tumors is degraded by proteases secreted by tumor cells and simultaneously replaced by an extracellular matrix that promotes infiltration. Astrocytes and microglia become tumor-associated astrocytes and glioma-associated macrophages/microglia, respectively, in relation to tumor cells. These cells also promote glioma invasion. Interactions between glioma cells actively promote infiltration of each other. Surgery, chemotherapy, and radiation therapy transform the microenvironment, allowing glioma cells to invade. These findings indicate that the tumor microenvironment may be a target for glioma invasion. On the other hand, because the living body actively promotes tumor infiltration in response to the tumor, it is necessary to reconsider whether the invasion itself is friend or foe to the brain.

Postischemic Neuroprotection Associated With Anti-Inflammatory Effects by Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles in Aged Mice

Abstract: Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) were shown to induce ischemic neuroprotection in mice by modulating the brain infiltration of leukocytes and, specifically polymorphonuclear neutrophils. So far, effects of MSC-sEVs were only studied in young ischemic rodents. We herein examined the effects of MSC-sEVs in aged mice.Male and female C57Bl6/j mice (8-10 weeks or 15-24 months) were exposed to transient intraluminal middle cerebral artery occlusion. Vehicle or sEVs (equivalent of 2×106 MSCs) were intravenously administered. Neurological deficits, ischemic injury, blood-brain barrier integrity, brain leukocyte infiltration, and blood leukocyte responses were evaluated over up to 7 days.MSC-sEV delivery reduced neurological deficits, infarct volume, brain edema, and neuronal injury in young and aged mice of both sexes, when delivered immediately postreperfusion or with 6 hours delay. MSC-sEVs decreased leukocyte and specifically polymorphonuclear neutrophil, monocyte, and macrophage infiltrates in ischemic brains of aged mice. In peripheral blood, the number of monocytes and activated T cells was significantly reduced by MSC-sEVs.MSC-sEVs induce postischemic neuroprotection and anti-inflammation in aged mice.

Investigation of vermiculite infiltration effect on microstructural properties of thermal barrier coatings (TBCs) produced by electron beam physical vapor deposition method (EB-PVD)

Abstract: Thermal barrier coatings (TBCs) are protective coating systems that are mostly utilized to improve the thermal insulation and functional performance of gas turbine engines and other aircraft components that are both stable and movable. These coatings protect materials operating in harsh conditions from structural damage caused by corrosion, oxidation, the CaO-MgO-Al 2 O 3 -SiO 2 effect (CMAS), thermal shock , volcanic ash, and vermiculite deposits at high temperatures. In this study, CoNiCrAIY metallic bond coatings were coated on Inconel 718 super alloy using a high velocity oxygen-fuel (HVOF) deposition technique. Then, single YSZ, Gd 2 Zr 2 O 7 (GZ), and double YSZ/GZ based ceramic topcoats were applied to the bond coats by using the electron beam physical vapor deposition (EB-PVD) method. The produced TBC samples and the uncoated Inconel 718 superalloy substrate were subjected to vermiculite (VM) deposition at 1250 °C for 4 h, and then the coatings were characterized. To determine the phase structures, microstructural and mechanical properties of the TBCs, X-ray diffractometer (XRD), scanning electron microscopy (SEM), energy dispersive spectrometer elemental mapping analysis (EDS), stereo microscopy analyses, porosity, and hardness measurements were used. The obtained results were comparatively evaluated with the recent related studies in the literature. • The aim of this study is to investigate the VM behavior of innovative single- and double-layer TBC systems. • The VM infiltration has occurred through the surface of the Inconel 718 superalloy substrate and all other TBC systems. • HVOF-bond coating and EB-PVD GZ coating were used for deposition of the TBCs. • On the Inconel 718 super alloy surface, YSZ, Gd 2 Zr 2 O 7 , and YSZ/Gd 2 Zr 2 O 7 coatings were deposited. • The TBC systems' initial porosity percentages decreased, but the top coating hardnesses increased. • The TGO structure formed at the interface with the effect of high temperature.

IDH–wild-type glioblastoma cell density and infiltration distribution influence on supramarginal resection and its impact on overall survival: a mathematical model

Abstract: Recent studies have proposed resection of the T2 FLAIR hyperintensity beyond the T1 contrast enhancement (supramarginal resection [SMR]) for IDH-wild-type glioblastoma (GBM) to further improve patients' overall survival (OS). GBMs have significant variability in tumor cell density, distribution, and infiltration. Advanced mathematical models based on patient-specific radiographic features have provided new insights into GBM growth kinetics on two important parameters of tumor aggressiveness: proliferation rate (ρ) and diffusion rate (D). The aim of this study was to investigate OS of patients with IDH-wild-type GBM who underwent SMR based on a mathematical model of cell distribution and infiltration profile (tumor invasiveness profile).Volumetric measurements were obtained from the selected regions of interest from pre- and postoperative MRI studies of included patients. The tumor invasiveness profile (proliferation/diffusion [ρ/D] ratio) was calculated using the following formula: ρ/D ratio = (4π/3)2/3 × (6.106/[VT21/1 - VT11/1])2, where VT2 and VT1 are the preoperative FLAIR and contrast-enhancing volumes, respectively. Patients were split into subgroups based on their tumor invasiveness profiles. In this analysis, tumors were classified as nodular, moderately diffuse, or highly diffuse.A total of 101 patients were included. Tumors were classified as nodular (n = 34), moderately diffuse (n = 34), and highly diffuse (n = 33). On multivariate analysis, increasing SMR had a significant positive correlation with OS for moderately and highly diffuse tumors (HR 0.99, 95% CI 0.98-0.99; p = 0.02; and HR 0.98, 95% CI 0.96-0.99; p = 0.04, respectively). On threshold analysis, OS benefit was seen with SMR from 10% to 29%, 10% to 59%, and 30% to 90%, for nodular, moderately diffuse, and highly diffuse, respectively.The impact of SMR on OS for patients with IDH-wild-type GBM is influenced by the degree of tumor invasiveness. The authors' results show that increasing SMR is associated with increased OS in patients with moderate and highly diffuse IDH-wild-type GBMs. When grouping SMR into 10% intervals, this benefit was seen for all tumor subgroups, although for nodular tumors, the maximum beneficial SMR percentage was considerably lower than in moderate and highly diffuse tumors.

HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors

Abstract: Abstract The lack of tumor infiltration by CD8 + T cells is associated with poor patient response to anti-PD-1 therapy. Understanding how tumor infiltration is regulated is key to improving treatment efficacy. Here, we report that phosphorylation of HRS, a pivotal component of the ESCRT complex involved in exosome biogenesis, restricts tumor infiltration of cytolytic CD8 + T cells. Following ERK-mediated phosphorylation, HRS interacts with and mediates the selective loading of PD-L1 to exosomes, which inhibits the migration of CD8 + T cells into tumors. In tissue samples from patients with melanoma, CD8 + T cells are excluded from the regions where tumor cells contain high levels of phosphorylated HRS. In murine tumor models, overexpression of phosphorylated HRS increases resistance to anti-PD-1 treatment, whereas inhibition of HRS phosphorylation enhances treatment efficacy. Our study reveals a mechanism by which phosphorylation of HRS in tumor cells regulates anti-tumor immunity by inducing PD-L1 + immunosuppressive exosomes, and suggests HRS phosphorylation blockade as a potential strategy to improve the efficacy of cancer immunotherapy.

Mg gas infiltration for the fabrication of MgB2 pellets using nanosized and microsized B powders

Abstract: MgB2 superconductor pellets were synthesized through Mg gas infiltration method using nanosized- and microsized B powders. There was a marked difference in the superconducting properties of the two samples, particularly in the pinning force and dominant pinning mechanism. The microstructures of the samples were observed using HR-TEM and STEM-HAADF, and the results showed that the primary reason for the difference in the superconducting properties is the distribution of the nanosized second-phase particle MgO. Additionally, a feasible reaction model for the Mg gas infiltration method was established. Compared to the Mg liquid infiltration method, the gas infiltration showed better penetrability ability with a small amount of residual Mg. This study presents a novel synthesis process to fabricate an MgB2 pellet with superior density and superconducting properties. This method can be used in multiple applications such as superconducting bearings, compact superconductor magnets, and magnetic shielding.

Cell division in tissues enables macrophage infiltration

Abstract: Cells migrate through crowded microenvironments within tissues during normal development, immune response, and cancer metastasis. Although migration through pores and tracks in the extracellular matrix (ECM) has been well studied, little is known about cellular traversal into confining cell-dense tissues. We find that embryonic tissue invasion by Drosophila macrophages requires division of an epithelial ectodermal cell at the site of entry. Dividing ectodermal cells disassemble ECM attachment formed by integrin-mediated focal adhesions next to mesodermal cells, allowing macrophages to move their nuclei ahead and invade between two immediately adjacent tissues. Invasion efficiency depends on division frequency, but reduction of adhesion strength allows macrophage entry independently of division. This work demonstrates that tissue dynamics can regulate cellular infiltration.

The Economic Effects of Mafia: Firm Level Evidence

Abstract: We analyze the effects of Mafia infiltration in the legal economy. Combining information from investigative records with panel data on firms’ governance and balance sheets, we build an indicator of infiltration in firms located in an area with no tradition of Mafia. We show that Mafia targets young and less efficient firms and that infiltration generates a significant rise in firms’ revenues, with no proportionate growth in production inputs and a deterioration of the firm’s financial situation leading to market exit. These findings are consistent with a story of predatory behavior in which infiltration is used for money laundering or rent extraction. (JEL D22, G32, G34, K42, L25)

Reduced Neutrophil Extracellular Trap Formation During Ischemia Reperfusion Injury in C3 KO Mice: C3 Requirement for NETs Release

Abstract: Complement C3 plays a prominent role in inflammatory processes, and its increase exacerbates ischemia reperfusion injury (IRI)-induced acute kidney injury (AKI). Infiltrated neutrophils can be stimulated to form neutrophil extracellular traps (NETs), leading to renal injury. However, the relationship between the increase of C3 and the release of NETs in AKI was not clear. Here we found that IRI in the mouse kidney leads to increased neutrophils infiltration and NET formation. Furthermore, neutrophils depletion by anti-Ly6G IgG (1A8) did not reduce C3 activation but reduced kidney injury and inflammation, indicating a link between neutrophils infiltration and renal tissue damage. Pretreatment with 1A8 suppressed ischemia-induced NET formation, proving that extracellular traps (ETs) in renal tissue were mainly derived from neutrophils. Renal ischemia injury also leads to increased expression of C3. Moreover, C3 KO mice (C3 KO) with IRI exhibited attenuated kidney damage and decreased neutrophils and NETs. In vitro, C3a primed neutrophils to form NETs, reflected by amorphous extracellular DNA structures that colocalized with CitH3 and MPO. These data reveal that C3 deficiency can ameliorate AKI by reducing the infiltration of neutrophils and the formation of NETs. Targeting C3 activation may be a new therapeutic strategy for alleviating the necroinflammation of NETs in AKI.

Dendritic Cells and Macrophages in the Pathogenesis of Psoriasis

Abstract: Psoriasis is a chronic inflammatory skin disease characterized by scaly indurated erythema. This disease impairs patients’ quality of life enormously. Pathological findings demonstrate proliferation and abnormal differentiation of keratinocytes and massive infiltration of inflammatory immune cells. The pathogenesis of psoriasis is complicated. Among immune cells, dendritic cells play a pivotal role in the development of psoriasis in both the initiation and the maintenance phases. In addition, it has been indicated that macrophages contribute to the pathogenesis of psoriasis especially in the initiation phase, although studies on macrophages are limited. In this article, we review the roles of dendritic cells and macrophages in the pathogenesis of psoriasis.

Persistent post-COVID-19 smell loss is associated with inflammatory infiltration and altered olfactory epithelial gene expression

Abstract: Most human subjects infected by SARS-CoV-2 report an acute alteration in their sense of smell, and more than 25% of COVID patients report lasting olfactory dysfunction. While animal studies and human autopsy tissues have suggested mechanisms underlying acute loss of smell, the pathophysiology that underlies persistent smell loss remains unclear. Here we combine objective measurements of smell loss in patients suffering from post-acute sequelae of SARS-CoV-2 infection (PASC) with single cell sequencing and histology of the olfactory epithelium (OE). This approach reveals that the OE of patients with persistent smell loss harbors a diffuse infiltrate of T cells expressing interferon-gamma; gene expression in sustentacular cells appears to reflect a response to inflammatory signaling, which is accompanied by a reduction in the number of olfactory sensory neurons relative to support cells. These data identify a persistent epithelial inflammatory process associated with PASC, and suggests mechanisms through which this T cell-mediated inflammation alters the sense of smell.

Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches

Abstract: The immune cell compartment of the mammalian brain changes dramatically and peripheral T cells infiltrate the brain parenchyma during normal aging. However, the mechanisms underlying age-related T cell infiltration in the central nervous system remain unclear.Chronic inflammation and peripheral T cell infiltration were observed in the subventricular zone of aged mice. Cell-cell interaction analysis revealed that aged microglia released CCL3 to recruit peripheral CD8+ memory T cells. Moreover, the aged microglia shifted towards a pro-inflammation state and released TNF-α to upregulate the expression of VCAM1 and ICAM1 in brain venous endothelial cells, which promoted the transendothelial migration of peripheral T cells. In vitro experiment reveals that human microglia would also transit to a chemotactic phenotype when treated with CSF from the elderly.Our research demonstrated that microglia play an important role in the aging process of brain by shifting towards a pro-inflammation and chemotactic state. Aged microglia promote T cell infiltration by releasing chemokines and upregulating adhesion molecules on venous brain endothelial cells.

Sensitivity of headwater streamflow to thawing permafrost and vegetation change in a warming Arctic

Abstract: Climate change has the potential to impact headwater streams in the Arctic by thawing permafrost and subsequently altering hydrologic regimes and vegetation distribution, physiognomy and productivity. Permafrost thaw and increased subsurface flow have been inferred from the chemistry of large rivers, but there is limited empirical evidence of the impacts to headwater streams. Here we demonstrate how changing vegetation cover and soil thaw may alter headwater catchment hydrology using water budgets, stream discharge trends, and chemistry across a gradient of ground temperature in northwestern Alaska. Colder, tundra-dominated catchments shed precipitation through stream discharge, whereas in warmer catchments with greater forest extent, evapotranspiration (ET) and infiltration are substantial fluxes. Forest soils thaw earlier, remain thawed longer, and display seasonal water content declines, consistent with greater ET and infiltration. Streambed infiltration and water chemistry indicate that even minor warming can lead to increased infiltration and subsurface flow. Additional warming, permafrost loss, and vegetation shifts in the Arctic will deliver water back to the atmosphere and to subsurface aquifers in many regions, with the potential to substantially reduce discharge in headwater streams, if not compensated by increasing precipitation. Decreasing discharge in headwater streams will have important implications for aquatic and riparian ecosystems.