Dendritic Research Articles

Spermine Synthase : A Potential Prognostic Marker for Lower-Grade Gliomas.

The objective of this study was to assess the relationship between spermine synthase (SMS) expression, tumor occurrence, and prognosis in lower-grade gliomas (LGGs). A total of 523 LGG patients and 1152 normal brain tissues were included as controls. Mann-Whitney U test was performed to evaluate SMS expression in the LGG group. Functional annotation analysis was conducted to explore the biological processes associated with high SMS expression. Immune cell infiltration analysis was performed to examine the correlation between SMS expression and immune cell types. The association between SMS expression and clinical and pathological features was assessed using Spearman correlation analysis. In vitro experiments were conducted to investigate the effects of overexpressing or downregulating SMS on cell proliferation, apoptosis, migration, invasion, and key proteins in the protein kinase B (AKT)/epithelialmesenchymal transition signaling pathway. The study revealed a significant upregulation of SMS expression in LGGs compared to normal brain tissues. High SMS expression was associated with certain clinical and pathological features, including older age, astrocytoma, higher World Health Organization grade, poor disease-specific survival, disease progression, non-1p/19q codeletion, and wild-type isocitrate dehydrogenase. Cox regression analysis identified SMS as a risk factor for overall survival. Bioinformatics analysis showed enrichment of eosinophils, T cells, and macrophages in LGG samples, while proportions of dendritic (DC) cells, plasmacytoid DC (pDC) cells, and CD8+ T cells were decreased. High SMS expression in LGGs may promote tumor occurrence through cellular proliferation and modulation of immune cell infiltration. These findings suggest the prognostic value of SMS in predicting clinical outcomes for LGG patients.

Exploring ambient and elevated temperature fretting wear behavior of laser-cladding (FeCrCoNi)84AlxNby high-entropy alloy coatings

In this work, (FeCrCoNi)84AlxNby (x = 12, 8, 4 and y = 4, 8, 12 (at. %)) high-entropy alloy (HEA) coatings were successfully deposited on 316 stainless steel via laser cladding (LC). FCC/BCC + Laves structure was introduced into FeCrCoNi HEA system by designing different Al/Nb ratios, aiming to improve the fretting wear resistance. The phase constituents, microstructure, and fretting wear resistance of (FeCrCoNi)84AlxNby HEA coatings at ambient temperature and 285 °C were respectively analyzed. Results confirmed that the microstructure of three HEA coatings displayed the interdendritic (IR) - dendritic (DR) structure. With the Al/Nb ratio decreased from 3/1 to 1/3, the phase constituents of HEA coatings transformed from the BCC solution to FCC solution and Laves phase, and the content of the Laves phase gradually increased. Moreover, the average grain size decreased from 16.9 μm to 4.6 μm, while the average geometrically necessary dislocations (GNDs) density increased from 1.842 × 1010 m−2 to 2.821 × 1010 m−2. The microhardness of the HEA coatings was improved from 210 HV0.2 to 361–647 HV0.2 compared with that of the substrate. The decrement of Al/Nb ratio improved the fretting wear resistance of HEA coatings both at ambient temperature and 285 °C, especially at 285 °C. The wear volume decreased from 0.8 × 105 μm3 to 0.39 × 105 μm3 and the fretting wear mechanism changed from severe fatigue wear to slight abrasive wear at 285 °C. In the Al4Nb12 HEA coating, the soft structure (FCC) and the hard structure (Laves) were combined into a wear-resistant skeleton, and the Laves structure was massively distributed along the FCC phase to prevent the FCC phase from further slipping in the fretting wear process, which in turn minimizes the fretting damage. The present work provides a theoretical basis for the related research on the fretting wear characteristics of laser cladding HEA coatings.

Tribological behavior and characteristics of TIG surface cladded AlCoCrFeNi high-entropy alloy on 304L stainless steel

The present study examines the tribological properties of AlCoCrFeNi high-entropy alloy (HEA) surface cladded on 304L stainless steel via a Tungsten Inert Gas (TIG) heat source. Commercially pure powders of aluminum, cobalt, chromium, and nickel were ball-milled, mixed in specific ratios, and applied onto the substrate with polyvinyl alcohol as a binder. Cladding was performed with optimized parameters to create layers of HEA. Microstructural and EDS analysis revealed equiaxial dendrites rich in aluminum and nickel in dendritic (DI) areas, and rich in iron, chromium, and cobalt in interdendritic (ID) areas. Mixing entropy was calculated by consideration of EDS analysis of the cladding and based on the initial definition of a high-entropy alloy, the high-entropy nature of the cladding was confirmed. XRD analysis showed the presence of FCC, A2/B2, and hard σ phases. Surface alloyed material exhibited higher hardness compared to the base material, with an average of 540 HV versus 200 HV. A pin-on-disc wear test machine was used to assess tribological properties under different loads of 10, 20, and 40 N. The wear rates of the high-entropy cladded material were 36 and 50 % less than those of the 304L stainless steel under applied loads of 10 and 40 N, respectively, while their wear rates were almost similar at 20 N. Friction coefficients of HEA pins were notably lower than 304L at 10 and 20 N, with smoother profiles. Wear mechanisms of the HEA material varied with load: oxidative wear at 10 and 20 N due to the formation of an oxide layer, and abrasion and spallation at 40 N, resulting in a threefold increase in wear rate at this load. Overall, the study highlights the effectiveness of HEA cladding in improving tribological properties, especially under high applied load.

Microstructure and hardness of CoNiCrFeTix high-entropy alloy coatings prepared by laser cladding: Combining experimental and molecular dynamics simulation

Laser cladding technology offers several advantages over alternative coating methods, including rapid cooling, low dilution rate, and effective metallurgical bonding between the coating and matrix. However, there is limited understanding regarding the microstructures and properties of laser-cladded high-entropy alloy (HEA) coatings. Thus, our research aims to investigate the characteristics and performance of CoNiCrFeTix (x = 0.1, 0.3, 0.5, 0.7) HEA coatings, produced through laser cladding, on Q235 steel substrates We employ molecular dynamics (MD) simulation and experimental techniques to examine the impact of Ti element content on the structure and hardness of the cladding layer. The MD simulation accurately reproduces the melting and nucleation processes of crystal structures, providing insights beyond what is observable through experiments alone. Our results reveal that the cladding layer is predominantly composed of an FCC phase, with an increasing presence of a BCC phase as the Ti content rises. Correspondingly, experimental observations confirm that the CoNiCrFeTix HEA coating primarily consists of the FCC phase, while FeCr, Ni2Ti, and Co2Ti phases emerge with higher Ti content.The cladding layer exhibits a characteristic dendritic (DR) structure, where the interdendritic (ID) region expands as Ti content increases. Additionally, we conducted surface hardness testing on the cladding layer. The hardness of the cladding layer increases with the increase of Ti content, and the increase in Ti content enhances the stability of the dislocation density in the cladding layer.

Study on the microstructure and wear resistance of AlCrCuFeNiTix high entropy alloys for surfacing welding

In order to investigate the effect of Ti element content on the microstructure and wear resistance of AlCrCuFeNiTix (x = 0, 0.3, 0.6, 0.9) high entropy surfacing alloy, a melting electrode gas shielded welding technology was used to prepare AlCrCuFeNiTix high entropy surfacing alloy on the surface of carbon steel plates. The microstructure, phase composition, and wear resistance of the alloy were analyzed. The results show that the phase composition of the surfacing alloy becomes a BCC+FCC solid solution phase, with a much higher content of BCC phase than FCC phase. The microstructure consists of disordered BCC phase rich in Fe and Cr, ordered BCC phase rich in Al and Ni, and FCC phase rich in Cu. The microstructure exhibits typical dendritic (DR) and interdendritic (ID) structures. With the increase of Ti element, hard Fe2Ti phase precipitates in the interdendritic zone, and the micro hardness of the alloy shows an increasing trend. The maximum hardness can reach 636 HV, which is 2.4 times that of the base material. With the increase of Ti element, the friction coefficient of the alloy shows a trend of first decreasing and then increasing, and the wear amount first decreases and then increases. When Ti is 0.6, the wear resistance of the high entropy surfacing alloy reaches its best.

Genetically engineered probiotics for an optical imaging-guided tumor photothermal therapy/immunotherapy.

Bacteria-based cancer therapy (BCT) has been extensively investigated because of the tumor targeting and antitumor immunity activating abilities of bacteria over traditional nanodrugs, but their potential systemic toxicity poses a challenge. Therefore, it is important to visualize the precise localization and real-time distribution of bacteria in vivo to guide the treatment. Herein, biogenetically engineered Escherichia coli Nissle 1917 (EcN) were constructed to highly express tyrosinase to intracellularly generate cyanine 5-labeled melanin-like polymers (Cy5-Mel), thus endowing them with a bright fluorescence and an excellent photothermal performance upon NIR laser irradiation, thereby inducing the intense immunogenic death of tumor cells and release of tumor-associated antigens. Acting as adjuvants, bacteria can greatly stimulate the maturation of dendritic (DC) cells. The in vivo behaviors of these bacteria was monitored via noninvasive optical imaging when they were intravenously administrated to tumor-bearing mice. From this, NIR exposure on tumor sites was carried out at an appropriate time point to induce the damage to tumor cells and for the modulation of tumor immune microenvironments. Thus, via a simple bioengineering strategy, a promising bacteria-based theranostic platform was constructed for tumor treatment.

Combining Bulk RNA-seq and scRNA-seq data to identify RNA m5C methyltransferases NSUN1: a rising star as a biomarker for cancer diagnosis, prognosis and therapy.

RNA 5-methylcytosine (m5C) methyltransferases NSUN1 is a member of the NOP2/SUN (NSUN) RNA methyltransferase family. Studies have found that the expression of NSUN1 is elevated in breast and colon cancer and can predict poor prognosis. However, the NSUN1 gene has only been studied in a few tumors. Single-cell RNA sequencing (scRNA-seq) and Bulk RNA-seq data were used for comprehensive analysis of NSUN1 in cancers. The Human Protein Atlas (HPA) database was used to identify the gene location. Immunofluorescence staining was used to detect NSUN1 subcellular distribution within the nucleus, endoplasmic reticulum (ER), and microtubules of A-431, U-2, U-251 cells. The cBioPortal tool was used to analyze the alteration frequency and mutation type. The epigenetic profile of NSUN1 also was analyzed by using the University of Alabama at Birmingham CANcer data analysis Portal (UCLCAN). Tumor mutation burden (TMB), microsatellite instability (MSI), and immune checkpoint expression in cancers were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to perform enrichment and visualization. The study was based on online resources and public databases. Elevated NSUN1 expression had been observed in most human cancers. Analysis of scRNA-seq data showed that NSUN1 was highly expressed in immune cells such as T cells, B cells, and dendritic (DC) cells. High NSUN1 expression indicated poor overall survival (OS) and disease-free survival (DFS). The characteristics of genetic alteration, methylation and phosphorylation of NSUN1 were analyzed and higher levels of phosphorylation in tumor tissues were found. In addition, the expression of NSUN1 was closely related to tumor-infiltrating immune cells. At the same time, the expression of NSUN1 was positively correlated with the expression of multiple immune checkpoints. The gene expression profile, survival status, genetic alteration, methylation, phosphorylation and infiltrating immune cells of NSUN1 in human cancers were comprehensively analyzed. The results herein implied that NSUN1 may be an effective biomarker for early cancer diagnosis, prognosis and therapy.

Microstructure and mechanical properties of functional gradient materials of high entropy alloys prepared by direct energy deposition

In this study, FeCrCoNiMo0.5W0.75 HEAs functional gradient materials were prepared by the direct energy deposition (DED) technique, and the phase transition, microstructure and mechanical properties of the materials along the building direction were investigated. The material realizes a transition from a single FCC phase to an FCC + TCP phase from the bottom to the top. The bottom and middle of the material are typical dendritic (DR)-interdendritic (ID) structures, and at the top, due to the precipitation of the eutectic structure σ phase and μ phase, the material transforms into a hypoeutectic structure of FCC + eutectic. According to the EBSD results, the interior of the material is mainly columnar crystals that grow vertically to the molten pool. This unidirectional columnar growth makes the material have a strong texture in the <100> direction. In addition, a large degree of grain refinement is exhibited from the bottom to the top, with the grain size reduced from 19 μm to 6.5 μm. According to the TEM results, the density of dislocations is much higher near the phase and grain boundaries than in other regions, and dislocation entanglement is formed by the continuous accumulation of loose dislocations. The micro-hardness of the material increased along the construction direction up to 892.5HV0.5, and the material has good compressive strength up to 2041 ± 45 MPa. The material has excellent wear resistance and high-temperature wear resistance, forming a continuous oxide layer at 800 °C, which greatly reduces the friction coefficient and wear rate.

Vitamin A deficiency and vitamin A supplementation affect innate and T cell immune responses to rotavirus A infection in a conventional sow model.

Rotavirus A (RVA) causes ~200,000 diarrheal deaths annually in children <5yrs, mostly in low- and middle-income countries. Risk factors include nutritional status, social factors, breastfeeding status, and immunodeficiency. We evaluated the effects of vitamin A (VA) deficiency/VA supplementation and RVA exposure (anamnestic) on innate and T cell immune responses in RVA seropositive pregnant and lactating sows and passive protection of their piglets post-RVA challenge. Sows were fed VA deficient (VAD) or sufficient (VAS) diets starting at gestation day (GD)30. A subset of VAD sows received VA supplementation from GD|76 (30,000IU/day, VAD+VA). Sows (6 groups) were inoculated with porcine RVA G5P[7] (OSU strain) or Minimal Essential Medium (mock) at GD~90: VAD+RVA; VAS+RVA; VAD+VA+RVA; VAD-mock; VAS-mock; and VAD+VA-mock. Blood, milk, and gut-associated tissues were collected from sows at several time points to examine innate [natural killer (NK), dendritic (DC) cells], T cell responses and changes in genes involved in the gut-mammary gland (MG)-immunological axis trafficking. Clinical signs of RVA were evaluated post inoculation of sows and post-challenge of piglets. We observed decreased frequencies of NK cells, total and MHCII+ plasmacytoid DCs, conventional DCs, CD103+ DCs and CD4+/CD8+ and T regulatory cells (Tregs) and NK cell activity in VAD+RVA sows. Polymeric Ig receptor and retinoic acid receptor alpha (RARα) genes were downregulated in mesenteric lymph nodes and ileum of VAD+RVA sows. Interestingly, RVA-specific IFN-γ producing CD4+/CD8+ T cells were increased in VAD-Mock sows, coinciding with increased IL-22 suggesting inflammation in these sows. VA supplementation to VAD+RVA sows restored frequencies of NK cells and pDCs, and NK activity, but not tissue cDCs and blood Tregs. In conclusion, similar to our recent observations of decreased B cell responses in VAD sows that led to decreased passive immune protection of their piglets, VAD impaired innate and T cell responses in sows, while VA supplementation to VAD sows restored some, but not all responses. Our data reiterate the importance of maintaining adequate VA levels and RVA immunization in pregnant and lactating mothers to achieve optimal immune responses, efficient function of the gut-MG-immune cell-axis and to improve passive protection of their piglets.

Abstract 6785: Dendritic cell/myeloma fusion vaccine with lenalidomide maintenance following autologous hematopoietic cell transplant induced T cell activation and expansion

Abstract Introduction: Multiple myeloma (MM), a clonal disorder of terminally differentiated plasma cells, is the second most common hematologic malignancy with ~57.9% 5-year survival rate. Current MM therapies are not curative and in most patients MM relapse. Aiming to restore antitumor immunity and counteract MM evolution, we have developed a personalized dendritic(DC)/MM cell fusion vaccine, whereby several tumor antigens are presented in the context of DC mediated co-stimulation. BMT CTN 1401 is a multicenter randomized phase II clinical trial (NCT02728102) evaluating the efficacy of the DC/MM vaccine combined with lenalidomide maintenance (Len) after autoHCT. 203 patients were enrolled from 18 centers. Aim: To evaluate the impact of the DC/MM vaccine on the establishment of anti-MM immune response we profiled the peripheral blood (PB) immune landscape at the single-cell level, with particular focus on the T cell compartment. Method: We performed single-cell immunoprofiling (gene expression + V(D)J sequencing) on 40 patients (3xDC/MM vaccine/Len/GM-CSF: N=20; Len/GM-CSF: N=10; Len: N=10). 160 PB mononuclear cells (PBMC) samples were collected at enrollment, prior to Len, after 1 and 3 vaccines and were processed using the 10x Genomics single cell 5' assay. Here we present the analysis relative to 52 PBMC samples from 13 vaccinated patients included in the initial study cohort. The remaining 108 PBMC samples have already been subjected to single-cell immunoprofiling and the analysis is ongoing. Results: 309,423 cells passed quality-check identifying 47 cell populations, corresponding to 20 major compartments. The T cell compartment (146,373 cells) was divided into 14 different cell populations including activated CD8, CD4, and NKT cells that exhibited a gradual increase during the course of the study. Relatively, TCR sequencing demonstrated a recovery of T cell clonal diversity and a progressive rise in the frequency of expanded clonotypes within the activated CD4 and cytotoxic T cell populations after vaccination. Consistently, we observed a progressively raised number of shared TCR clonotypes within the activated CD8 and CD4 T cell subsets. The identification of common epitope/paratope hotspots among the expanded clonotypes and the different patients revealed a higher proportion of shared TCR clonotype groups across patients after vaccination compared to the early post-transplant period, predominantly after 3 vaccinations. Conclusions: Assessment of PBMC samples from 13 vaccinated patients provided a detailed picture of the PBMC landscape. The constant T cell expansion in patients following vaccination coupled with the shared paratope/epitope hotspots and TCR signatures among patients indicated the TCR cross-reactivity and suggested for the establishment of an anti-MM immune response. Citation Format: Giulia Cheloni, Dimitra Karagkouni, Daniela Torres, David J. Chung, Nina Shah, Natalie S. Callander, Thinle Chodon, Yvonne Efebera, Nancy Geller, Peiman Hematti, Hillard Lazarus, Ehsan Malek, Philip L. McCarthy, Ajay K. Nooka, Jacalyn Rosenblatt, Aaron P. Rapoport, Robert J. Soiffer, Dina Stroopinsky, Edmund K. Waller, Marcelo C. Pasquini, Ioannis Vlachos, David Avigan. Dendritic cell/myeloma fusion vaccine with lenalidomide maintenance following autologous hematopoietic cell transplant induced T cell activation and expansion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6785.

Abstract 2875: Evidence of immunosuppression in patients with breast ductal carcinoma in situ

Abstract Introduction: Ductal carcinoma in situ (DCIS) is a noninvasive precursor to invasive breast cancer. Although not all DCISlesions progress to cancer, most DCIS are treated as early breast cancer, given the uncertainty of which lesions will progress. The current increase in the incidence of DCIS has sparked interest in the immune contexture of the DCIS lesions as well as the immune status of DCIS patients, as a means to predict which DCIS lesions will progress to cancer. Studies done so far in invasive breast cancer showed that the immune system can mediate both tumor-promoting influence (via T regulatory (Treg) cells, M2 macrophages, myeloid-derived suppressor cells (MDSCs)), as well as tumor-suppressing influences (via CD8+ and CD4+ effector T cells, natural killer cells (NK), M1 macrophages, tissue-resident memory T (Trm) cells, B cell and dendritic (DCs) cells). Similar studies are still lacking in DCIS. Our aim was to start closing the gap in our understanding of the DCIS immune microenvironment, which will pave the way for novel preventative and therapeutic strategy. Methods: We analyzed by flow cytometry peripheral blood mononuclear cells (PBMCs) from newly diagnosed DCIS patients for the presence of various immune cell types expressing specific phenotypic markers of immune effectors or immune suppressors and compared them with PBMC from age-matched healthy individuals. Results: We found a statistically significant increase in the frequency of FoxP3+ regulatory T cells in DCIS PBMC compared with healthy controls. There was also a significant increase in Tim-3+CD8+ T effector memory cells (P= 0.035) and Tim-3+ CD8+ NKT cells (P = 0.033) in the PBMCs of patients with DCIS compared with healthy controls. T cells expressing other exhaustion markers, such as PD-1+ and LAG-3+ were present at very low levels in both groups. Conclusion: Our results suggest that some of the many immunosuppressive mechanisms seen in patients with invasive breast cancer, such as regulatory T cells, are already present in pre-cancer DCIS. Evidence of the beginning of immune suppression is also reflected in the increased frequency of CD4+ and CD8+ T cells expressing the exhaustion marker Tim-3. Citation Format: Sedigheh Taghinezhad-S, Amir Hossein Mohseni, Pamela L. Beatty, Leisha A. Emens, Olivera J. Finn. Evidence of immunosuppression in patients with breast ductal carcinoma in situ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2875.

Electrochemical corrosion behavior in sulfuric acid solution and dry sliding friction and wear properties of laser-cladded CoCrFeNiNbx high entropy alloy coatings

316 stainless steel (SS) was coated with CoCrFeNiNbx (x: atomic ratio, x = 0, 0.1, 0.2, and 0.3) high entropy alloy coatings (HEACs) by laser cladding (LC). The impacts of Nb content on the phase composition, microstructure, microhardness, wear resistance and corrosion properties of CoCrFeNi based HEACs were examined. Different from the canonical dendritic (DR) - interdendritic (ID) microstructure presented by the other three HEACs, the ID of Nb0.3 HEACs also existed nanoscale Nb-rich Laves phase composed of NbNi and NbCo. The inclusion of Nb significantly reduced the average grain size of CoCrFeNi based HEACs from 59.43 μm to 11.38 μm. It also greatly diminished the formation of high angle grain boundaries (HAGBs), increasing the percentage of low angle grain boundaries (LAGBs) from 31 % to 61 %. The microhardness of Nb-containing HEACs was significantly promoted due to the solid solution strengthening and fine grain strengthening caused by large size Nb atoms. Affected by Laves phase with high coordination number and space filling ratio and higher proportion of LAGBs, the microhardness of Nb0.3 HEAC was even as high as 530 HV. The increase in Nb concentration also strengthened the HEACs' resistance to wear. Nb0, Nb0.1, Nb0.2, and Nb0.3 HEACs had corresponding specific wear rates of 0.36, 0.32, 0.23, and 0.20 mm3/Nm. Unlike 316 SS, Nb0 and Nb0.1 HEACs, which had both adhesive wear and abrasive wear, Nb0.2 and Nb0.3 HEACs were mainly wear by abrasive wear. The corrosion behavior of CoCrFeNiNbx HEACs in 0.5 M H2SO4 solution was similar to 316 SS, but the corrosion resistance was stronger than 316 SS. Nb0.3 HEAC with the Ecorr of −164 mV and Icorr of 6.40 × 10−7 A/cm2 showed the best acid corrosion resistance, which could be attributed to the stable and dense passivation film on its surface. Distinct from the intergranular corrosion of other coatings, the corrosion of Nb0.3 HEAC mainly occurred in DR, because the FCC phase acted as the anode site in it when FCC and Laves phase co-existed.

Shock compression and spall damage of dendritic high-entropy alloy CoCrFeNiCu

Plate impact experiments are conducted on a dendritic dual face-center cubic phase high-entropy alloy (HEA) CoCrFeNiCu, consisting of Cu-lean dendritic (DR) and Cu-rich interdendritic regions (ID). Free surface velocity histories are obtained along with microstructure characterizations. The Hugoniot equation of state and spall strength at different shock stresses are determined. Dislocation slip is the main deformation mode for CoCrFeNiCu HEA, and the dislocation density of the Cu-rich interdendritic regions increases more significantly during shock compression. Both ductile and brittle damage modes are observed. With increasing impact velocity, the Cu-rich interdendritic regions with severe strain localizations and more defects provide more damage nucleation sites. The spall strength increases firstly, reaches its maximum at a peak shock stress of 5.8 GPa, and then decreases. Molecular dynamics simulations reveal that the abnormal dependence of spall strength on peak shock stress is a result of strain localization and thermal softening in the Cu-rich regions.

Effect of Heat Treatment on Microstructure, Tensile Properties and High-Temperature Corrosion Resistance of the FeCrMnNi High Entropy Alloy

FeCrMnNi high-entropy alloys prepared by vacuum induction melting were tested and characterized using an X-ray diffractometer, a scanning electron microscope, a micro hardness tester and a universal tensile tester to investigate the effects of the heat treatment temperature on the microstructure and mechanical properties of the alloys and the heat-resistant corrosion properties of FeCrMnNi alloy after annealing at 800 °C. It is a high-entropy alloy with a typical dendritic (DR) morphology. With the increase in the heat-treatment temperature, the amount of ultrafine precipitates with the BCC structure in the matrix increased; furthermore, the amount of ultrafine precipitates started to decrease at temperatures above 900 °C, and the DR structure gradually weakened. After heat treatment at temperatures above 800 °C, the alloy showed a tensile strength of 721.1 MPa and an elongation at break of 26.7%, which indicates improved strength of the alloy while maintaining good plasticity, mainly because a large amount of nanoscale particles precipitated between the DR structures and enabled fine grain strengthening. Therefore, an appropriate heat-treatment temperature helps to improve the overall mechanical properties of the high-entropy alloy.

Rebooting Regulatory T Cell and Dendritic Cell Function in Immune-Mediated Inflammatory Diseases: Biomarker and Therapy Discovery under a Multi-Omics Lens.

Immune-mediated inflammatory diseases (IMIDs) are a group of autoimmune and chronic inflammatory disorders with constantly increasing prevalence in the modern world. The vast majority of IMIDs develop as a consequence of complex mechanisms dependent on genetic, epigenetic, molecular, cellular, and environmental elements, that lead to defects in immune regulatory guardians of tolerance, such as dendritic (DCs) and regulatory T (Tregs) cells. As a result of this dysfunction, immune tolerance collapses and pathogenesis emerges. Deeper understanding of such disease driving mechanisms remains a major challenge for the prevention of inflammatory disorders. The recent renaissance in high throughput technologies has enabled the increase in the amount of data collected through multiple omics layers, while additionally narrowing the resolution down to the single cell level. In light of the aforementioned, this review focuses on DCs and Tregs and discusses how multi-omics approaches can be harnessed to create robust cell-based IMID biomarkers in hope of leading to more efficient and patient-tailored therapeutic interventions.

Induction of Heme Oxygenase-1 Modifies the Systemic Immunity and Reduces Atherosclerotic Lesion Development in ApoE Deficient Mice.

Heme oxygenase-1 (HO-1) has been reported to protect against oxidation and inflammation in atherosclerosis. It remains unclear how the immune system participates in the cytoprotective function of HO-1 in the context of atherosclerosis. In this study, we attempted to investigate the potential effect of a HO-1 inducer, hemin, and a HO-1 inhibitor, Tin-protoporphyrin IX (SnPP), on the progression of atherosclerosis in ApoE deficient mice. Using mass cytometry, 15 immune cell populations and 29 T cell sub-clusters in spleen and peripheral blood were thoroughly analyzed after hemin or SnPP treatment. SnPP elevated risk factors of atherosclerosis, whereas hemin reduced them. In-depth analysis showed that hemin significantly modified the immune system in both spleen and peripheral blood. Hemin increased dendritic (DC) and myeloid-derived suppressor cells (MDSCs), but decreased natural killer (NK) cells. An opposite effect was observed with SnPP treatment in terms of NK cells. NK cells and MDSCs were positively and negatively correlated with total cholesterol and low-density lipoprotein, respectively. Moreover, the T cell profiles were significantly reshaped by hemin, whereas only minor changes were observed with SnPP. Several hemin-modulated T cell clusters associated with atherosclerosis were also identified. In summary, we have unraveled an important regulatory role for HO-1 pathway in immune cell regulation and atherosclerosis. Our finding suggests that modulating HO-1 signaling represents a potential therapeutic strategy against atherosclerosis.

Exogenous interleukin-33 promotes hepatocellular carcinoma growth by remodelling the tumour microenvironment

BackgroundInterleukin-33 (IL-33) is an effective inducer of pro-inflammatory cytokines regulating innate and adaptive immunity. Inflammation could be a double-edged sword, promoting or inhibiting tumour growth. To date, the roles and mechanisms of IL-33 in tumours remain controversial. Here, we examined the effect of exogenous IL-33 on the biological characteristics of hepatocellular carcinoma (HCC) and the possible mechanism of action.MethodsIn this study, IL-33 expression in the tissues of 69 HCC patients was detected and its relationship with prognosis was evaluated. After establishing a mouse HCC model and IL-33 treatment operation, the infiltration of splenic myeloid-derived suppressor (MDSCs), dendritic (DCs), regulatory T, and natural killer (NK) cells was detected by flow cytometry analysis, and the vascular density of the tumour tissues was detected by immunohistochemistry to reveal the mechanism of IL-33 in HCC proliferation. Finally, the Cancer Genome Atlas database was used to analyse Gene Ontology terms the and Kyoto Encyclopaedia of Genes and Genomes pathway. Moreover, the chi-square test, two-tailed unpaired Student’s t-test, and multiple t-tests were performed using SPSS version 23.0 and GraphPad Prism 8.0 software.ResultsThe IL-33 expression level was negatively correlated with the overall survival of HCC patients, suggesting its potential clinical significance in the prognosis of HCC. We found that systemic IL-33 administration significantly promoted the tumour size in vivo. Furthermore, the IL-33-treated mice presented decreased frequencies of tumouricidal NK and CD69+ CD8+ T cells. After IL-33 treatment, the incidence of monocytic MDSCs and conventional DCs increased, while that of granulocytic MDSCs decreased. Moreover, IL-33 promoted the formation of intracellular neovascularization. Therefore, IL-33 accelerated HCC progression by increasing the accumulation of immunosuppressive cells and neovascularization formation. Finally, we found that the transcription of IL-33 was closely related to the PI3K-Akt and MAPK pathways in Gene Set Enrichment Analysis plots, which were involved in the tumourigenesis and pathogenesis of HCC.ConclusionsTaken together, IL-33 may be a key tumour promoter of HCC proliferation and tumourigenicity, an important mediator, and a potential therapeutic target for regulating HCC progression.

Investigation on structural stability of as-cast Al0.5CrCuFeMnTi high entropy alloy

To reveal the bonding effect of alloying elements in high entropy alloys and the source of structural stability of alloys, an as-cast Al0·5CrCuFeMnTi high entropy alloy was synthesized by arc melting under argon protection. The results show that the as-cast alloy is composed of a hexagonal close-packed (HCP) and a body-centered cubic (BCC) structure, and there is a distinct phase interface with a disordered arrangement of atoms between the dendritic (DR) and interdendritic (ID) regions. The calibrated (002), (110), and (112) crystal faces determined through high-resolution transmission electron microscopy confirm that DR phase has the HCP structure, while the ID phase forms solid solutions with the BCC structure by calibrated (110), (01-1), and (12-1) crystal faces. The results from first principles calculations show that the structural stability of the alloy is improved by the strong covalent bonding between Fe and Al, Cr, Fe, Ti atoms in the DR region, and between Al and Cu, Mn atoms in the ID region. The calculated results of solid solution parameters show that the atomic size difference and the mixing enthalpy of this alloy satisfy the criteria for stable solid solutions.

The regulatory role of PGC1α-related coactivator in response to drug-induced liver injury.

PGC1α‐Related Coactivator (PRC) is a transcriptional coactivator promoting cytokine expression in vitro in response to mitochondrial injury and oxidative stress, however, its physiological role has remained elusive. Herein we investigate aspects of the immune response function of PRC, first in an in vivo thioacetamide (TAA)‐induced mouse model of drug‐induced liver injury (DILI), and subsequently in vitro in human monocytes, HepG2, and dendritic (DC) cells. TAA treatment resulted in the dose‐dependent induction of PRC mRNA and protein, both of which were shown to correlate with liver injury markers. Conversely, an adenovirus‐mediated knockdown of PRC attenuated this response, thereby reducing hepatic cytokine mRNA expression and monocyte infiltration. Subsequent in vitro studies with conditioned media from HepG2 cells overexpressing PRC, activated human monocytes and monocyte‐derived DC, demonstrated up to 20% elevated expression of CD86, CD40, and HLA‐DR. Similarly, siRNA‐mediated knockdown of PRC abolished this response in oligomycin stressed HepG2 cells. A putative mechanism was suggested by the co‐immunoprecipitation of Signal Transducer and Activator of Transcription 1 (STAT1) with PRC, and induction of a STAT‐dependent reporter. Furthermore, PRC co‐activated an NF‐κB‐dependent reporter, indicating interaction with known major inflammatory factors. In summary, our study indicates PRC as a novel factor modulating inflammation in DILI.

Amelioration of sepsis-induced acute kidney injury through inhibition of inflammatory cytokines and oxidative stress in dendritic cells and neutrophils respectively in mice: Role of spleen tyrosine kinase signaling

Sepsis often leads to complications such as acute kidney injury (AKI) which is reported to range from 30 to 50% in critically ill patients. Dendritic (DCs) and neutrophils play a decisive role in the advancement of AKI through release of inflammatory cytokines and reactive oxygen species (ROS) respectively. Both of these processes are assumed to be controlled by spleen tyrosine kinase (Syk) signaling in DCs and neutrophils. However, the role of Syk signaling in these immune cells in sepsis-induced AKI has not been investigated. Therefore, the purpose of this study was to evaluate the effect of a Syk inhibitor, R406 on sepsis-induced AKI in a mouse model. Renal function (creatinine/blood urea nitrogen), inflammatory cytokines (IL-6/MCP-1) in CD11c + DCs and oxidant parameters in neutrophils [inducible nitric oxide synthase (iNOS), NADPH oxidase (NOX2), nitrotyrosine] were assessed. Our results showed elevated expression of Syk in neutrophils and CD11c + DC which was linked with increased IL-6/MCP-1 in CD11c + DCs, and iNOS, NOX2 and nitrotyrosine in neutrophils during sepsis-induced AKI. Inhibitor of Syk signaling, R406 led to improvement of sepsis-induced AKI as depicted by an attenuation of creatinine/blood urea nitrogen in serum, renal myeloperoxidase activity, and repair of tubular structures in kidney. Further, R406 led to a decrease in IL-6/MCP-1 in CD11c + DCs, and iNOS, NOX2 and nitrotyrosine in neutrophils during sepsis-induced AKI. In conclusion, our study proposes that Syk signaling in DCs and neutrophils plays a critical role during sepsis-induced AKI. Therefore, Syk inhibition in innate immune cells might serve as an effective strategy to limit inflammatory cascade during AKI.