Dendritic Type Research Articles

Different In Vitro-Generated MUTZ-3-Derived Dendritic Cell Types Secrete Dexosomes with Distinct Phenotypes and Antigen Presentation Potencies.

Human dendritic cell (DC) dexosomes were evaluated for their function and preclinical validation for vaccines. Dexosomes are small DC-secreted vesicles that contain absorbing immune signals. Vaccine manufacturing requires a significant number of monocyte-derived DCs (Mo-DCs) from donor blood; thus, Mo-DC dexosomes are expected to serve as novel materials for cancer vaccination. In this study, we characterized a potential dexosome model using immature and mature MUTZ3-derived DCs (M-imIL-4-DC, M-imIFN-DC, M-mIL-4-DC, and M-mIFN-DC) and their dexosomes (M-imIL-4-Dex, M-imIFN-Dex, M-mIL4-Dex, and M-mIFN-Dex). Despite the lack of significant differences in viability, M-mIFN-DC showed a significantly higher level of yield and higher levels of maturation surface markers, such as CD86 and HLA-ABC, than M-mIL-4-DC. In addition, M-mIFN-Dex expressed a higher level of markers, such as HLA-ABC, than M-mIL-4-Dex. Furthermore, M-mIFN-Dex exhibited a higher level of antigen presentation potency, as evaluated using a MART-1 system, than either M-imIFN-Dex or M-mIL-4-Dex. We found that M-mIFN-Dex is one of the four types of MUTZ3-derived DCs that harbor potential immunogenicity, suggesting that DC dexosomes could be useful resources in cancer immunotherapy.

Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC

Despite the promise of immune checkpoint inhibition (ICI), therapeutic responses remain limited. This raises the possibility that standard of care treatments delivered in concert may compromise the tumor response. To address this, we employ tobacco-signature head and neck squamous cell carcinoma murine models in which we map tumor-draining lymphatics and develop models for regional lymphablation with surgery or radiation. We find that lymphablation eliminates the tumor ICI response, worsening overall survival and repolarizing the tumor- and peripheral-immune compartments. Mechanistically, within tumor-draining lymphatics, we observe an upregulation of conventional type I dendritic cells and type I interferon signaling and show that both are necessary for the ICI response and lost with lymphablation. Ultimately, we provide a mechanistic understanding of how standard oncologic therapies targeting regional lymphatics impact the tumor response to immune-oncology therapy in order to define rational, lymphatic-preserving treatment sequences that mobilize systemic antitumor immunity, achieve optimal tumor responses, control regional metastatic disease, and confer durable antitumor immunity.

Morphology and Structure of Electrolytically Synthesized Tin Dendritic Nanostructures

The formation of tin dendritic nanostructures by electrolysis from the alkaline electrolyte has been investigated. Morphology and structure of Sn dendrites produced applying both potentiostatic and galvanostatic regimes of the electrolysis are characterized by SEM and XRD, respectively. Depending on the applied cathodic potentials, three types of Sn dendrites were obtained: (a) needle-like and spear-like, (b) fern-like, and (c) stem-like dendrites. The very branchy dendrites with branches of the prismatic shape obtained by the galvanostatic regime of electrolysis represented a novel type of Sn dendrites, not previously reported in the literature. To explain the formation of various dendritic forms, correlation with the polarization characteristics for this electrodeposition system is considered. The needle-like and the spear-like dendrites represented monocrystals of (200),(400) preferred orientation, the fern-like dendrites exhibited the predominant (220),(440) preferred orientation, while in the stem-like particles Sn crystallites were oriented to a greater extent in the (440) crystal plane than in other planes. The galvanostatically synthesized Sn particles possessed the strong (200),(400) preferred orientation. The strong influence of parameters and regimes of electrodeposition on structural characteristics of Sn dendrites is explained by the fundamental laws of electrocrystallization taking into consideration the concept of slow-growing and fast-growing crystal planes.

A study on hydogeomorphological status of kadalundi river basin in kerala using geospatial technology

Detailed hydro geomorphologic study has been carried out for Kadalundi River Basin in Kerala to understand the drainage pattern, spatial and temporal water availability using secondary data collected from different Departments. Geomorphological parameters have been estimated as a part of this study and it is found that Kadalundi river basin is a sixth order stream. The drainage pattern is complex with considerable variation in spatial arrangements, which are controlled by topography, slope, rock type and structural deformations. The basin is characterized by dendritic type of drainage pattern with variable density. The densest dendritic pattern is developed on the hard Charnockite and Gneissic rocks. In some areas, the drainage pattern is sub dendritic reflecting structural control. The existing land use pattern is derived from Indian Remote Sensing Satellite (IRS – LISS II1, P6) using ERDAS software. Using hydrological toolset of Spatial Analyst, an extension of ArcGIS software, slope map, aspect map and Digital Elevation Model (DEM) have been derived. In addition, the basic thematic map on geology and soil also been derived.. For annual period, the rainfall varies from 1800- 4100 mm, 1400- 2600 mm for South –West monsoon period and 600-1100 mm for the North-East monsoon period.

Nitrogen Metabolism Disorder Accelerates Occurrence and Development of Lung Adenocarcinoma: A Bioinformatic Analysis and In Vitro Experiments.

BackgroundNitrogen metabolism (NM) plays a pivotal role in immune regulation and the occurrence and development of cancers. The aim of this study was to construct a prognostic model and nomogram using NM-related genes for the evaluation of patients with lung adenocarcinoma (LUAD).MethodsThe differentially expressed genes (DEGs) related to NM were acquired from The Cancer Genome Atlas (TCGA) database. Consistent clustering analysis was used to divide them into different modules, and differentially expressed genes and survival analysis were performed. The survival information of patients was combined with the expressing levels of NM-related genes that extracted from TCGA and Gene Expression Omnibus (GEO) databases. Subsequently, univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) regression were used to build a prognostic model. GO and KEGG analysis were elaborated in relation with the mechanisms of NM disorder (NMD). Meanwhile, immune cells and immune functions related to NMD were discussed. A nomogram was built according to the univariate and multivariate Cox analysis to identify independent risk factors. Finally, real-time fluorescent quantitative PCR (RT-PCR) and Western bolt (WB) were used to verify the expression level of hub genes.ResultsThere were 138 differential NM-related genes that were divided into two gene modules. Sixteen NM-related genes were used to build a prognostic model and the receiver operating characteristic curve (ROC) showed that the efficiency was reliable. GO and KEGG analysis suggested that NMD accelerated development of LUAD through the Wnt signaling pathway. The level of activated dendritic cells (aDCs) and type II interferon response in the low-risk group was higher than that of the high-risk group. A nomogram was constructed based on ABCC2, HMGA2, and TN stages, which was identified as four independent risk factors. Finally, RT-PCR and WB showed that CDH17, IGF2BP1, IGFBP1, ABCC2, and HMGA2 were differently expressed between human lung fibroblast (HLF) cells and cancer cells.ConclusionsHigh NM levels were revealed as a poor prognosis of LUAD. NMD regulates immune system through affecting aDCs and type II interferon response. The prognostic model with NM-related genes could be used to effectively evaluate the outcomes of patients.

Tổ chức và tính chất của lớp phủ hợp kim entropy cao chế tạo bằng phương pháp phun phủ laser

FeMnNiCrCu0.5high-entropy alloy (HEA) coating was prepared on the C45 steel by laser cladding. Constituent phase, microstructure and chemical composition of the coating was investigated usingX-ray diffraction (XRD), scanning electron microscopy (SEM) with energy dispersive spectroscopy (EDS), respectively. The microhardness and corrosion resistance of the coating are also studied. Results showed that the HEA coating reveals a good metallurgical bonding to the substrate, and they consist of the heat-affected zone, bonding zone and cladding zone. The microstructure of the coating showed a typical dendrite crystal growing from the substrate. FeMnNiCrCu0.5 coating was composed a single face-center cubic (FCC) phase, and the surface hardness of the coating is 195 HV0.2. In 0.5M H2SO4solution, the coating has better corrosion resistance than the substrate, which allows the HEAcoating to be used as an anti-corrosion coating in engineering applications.

Drainage Patterns and River Sinuosity in Padang, West Sumatra

Padang City is the capital of West Sumatra Province. This city has several rivers, each of which is a watershed. Watershed management can be done through geomorphological analysis by taking a landscape approach to finding out the tectonics working in the area. The morphotectonic analysis carried out in this study was an analysis of the drainage pattern and the river's sinuosity. The purpose of this study was to determine the characteristics of the watershed in the Padang City associated with tectonic activity based on morphometric analysis. The parameters used are the drainage pattern and the river sinuosity index. The results of the research that has been carried out, it is found that the genetic types of rivers found in the Padang City, West Sumatra are dendritic, trellis, and parallel types. Meanwhile, after analyzing the average value of the sinuosity index on river flows in Padang City, it was obtained a value of 1.56 or categorized as a meandering river type with active tectonics. The results of this study can be used as new information in watershed management in Padang City, West Sumatra Province.

The Neonatal Fc Receptor Is Elevated in Monocyte-Derived Immune Cells in Pancreatic Cancer.

The neonatal Fc receptor (FcRn) is responsible for recycling of IgG antibodies and albumin throughout the body. This mechanism has been exploited for pharmaceutic delivery across an array of diseases to either enhance or diminish this function. Monoclonal antibodies and albumin-bound nanoparticles are examples of FcRn-dependent anti-cancer therapeutics. Despite its importance in drug delivery, little is known about FcRn expression in circulating immune cells. Through time-of-flight mass cytometry (CyTOF) we were able to characterize FcRn expression in peripheral blood mononuclear cell (PBMC) populations of pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer donors. Furthermore, we were able to replicate these findings in an orthotopic murine model of PDAC. Altogether, we found that in both patients and mice with PDAC, FcRn was elevated in migratory and resident classical dendritic cell type 2 (cDC2) as well as monocytic and granulocytic myeloid-derived suppressor cell (MDSC) populations compared to tumor-free controls. Furthermore, PBMCs from PDAC patients had elevated monocyte, dendritic cells and MDSCs relative to non-cancer donor PBMCs. Future investigations into FcRn activity may further elucidate possible mechanisms of poor efficacy of antibody immunotherapies in patients with PDAC.

Abstract 984: Dissecting the ecosystem of treatment-naïve melanoma brain metastasis using multi-modal single-cell analysis

Abstract Brain metastases are the most frequent malignancies in the brain and are associated with significant morbidity and mortality. Melanoma brain metastases (MBM) occur in most patients with advanced melanoma and are challenging to treat. Our understanding of the treatment-naïve landscape of MBM is still rudimentary, and there are no site-specific molecular therapies available. To gain comprehensive insights into the niche-specific biology of MBM, we performed multi-modal profiling of fresh and frozen samples using single-cell RNA-seq, single-cell TCR-seq, single-nuclei RNA-seq, and spatial transcriptional profiling. We evolved single-nucleus RNA-seq processing methods to enable profiling of minute amounts of archival, frozen specimens and compared data quality and structure between matched fresh and frozen MBM. We curated a treatment-naïve single-transcriptome atlas of MBM, collected either fresh samples over 1 year or profiled frozen samples dating back more than 15 years, and compared these samples to extracranial melanoma metastases (ECMM). In total, we profiled 25 samples with more than 114,000 transcriptomes. We identified more than 20 different cell types, including diverse tumor-infiltrating T-cell subsets and rare dendritic cell types, and tissue-specific cell types, such as activated microglia. Tumor cells in MBM showed an increase in copy number alterations (CNAs) compared to ECMM, which we validated using an external dataset of whole exome sequencing (WES) data including both MBM and ECMM. MBM-derived tumor cells show enrichment of genes involved in neuronal development and function, and site-specific metabolic programs (e.g., oxidative phosphorylation). Comparison with an external bulk RNA-seq dataset validated enriched key genes in MBM and ECMM as putative dependencies. We recovered cell-cell interactions between tumor and brain-resident cells involved in brain development, homeostasis, and disease. Similar to ECMM, the tumor microenvironment of MBM contained CD8+ T cells across a spectrum of differentiation, exhaustion and expansion, which was associated with loss of TCF7 expression and adoption of a TOX+ cell state. CD4+ T cells included T regulatory, T helper and T follicular-helper-like expression profiles. Plasma cells showed spatially localized expansion and limited heterogeneity. Myeloid cells largely adopted pro-tumorigenic cell states, including microglia, the brain-resident myeloid cells, which showed an activation trajectory characterized by expression of SPP1 (osteopontin). Spatial transcriptional analysis revealed restricted expression of antigen presentation genes with only a subset of these locations showing a type I interferon response. In summary, this work presents a multi-modal single-cell approach to dissect and compare the landscape of treatment-naïve MBM and ECMM. Citation Format: Johannes C. Melms, Jana Biermann, Amit Dipak Amin, Yiping Wang, Somnath Tagore, Massimo Andreatta, Ajay Nair, Meri Rogava, Patricia Ho, Lindsay A. Caprio, Zachary H. Walsh, Shivem Shah, Daniel H. Vacarro, Blake Caldwell, Adrienne M. Luoma, Joseph Driver, Matthew Ingham, Suthee Rapisuwon, Jennifer Wargo, Craig L. Slinguff, Evan Z. Macosco, Fei Chen, Richard Carvajal, Michael B. Atkins, Michael A. Davies, Elham Azizi, Santiago J. Carmona, Hanina Hibshoosh, Peter D. Canoll, Jeffrey N. Bruce, Wenya L. Bi, Gary K. Schwartz, Benjamin Izar. Dissecting the ecosystem of treatment-naïve melanoma brain metastasis using multi-modal single-cell analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 984.

To Study the Hydrological System and Watershed by Using Remote Sensing (RS) and Geographic Information System (GIS) in Kannad Taluka, Aurangabad District, MS, India

The current study in this research focuses on the importance of the digital elevation model (DEM) and satellite images to evaluate and interpret the relative parameters of watersheds in Kannad taluka, Aurangabad district, India. Watersheds in the area were identified and calculated using the SRTM DEM through ARCGIS 10.8 software. Kannad shows a first to fourth-order drainage network which is of dendritic type, which indicates a sign of the structural lack of control and homogeneity of the watersheds in Kannad taluka. The basin’s mean bifurcation ratio is found to be 1.47 which indicates that the drainage network pattern is not much influenced by geological structures. Based on the hydrological assessment on the watershed scale, the present study reveals that the SRTM DEM is the most accurate application compared to other techniques. As visual or manual identification and evaluation are difficult and may not provide a holistic view of watersheds, modern tools of RS and GIS were used to study the watershed of Kannad taluka. There was lack of published reports on watersheds by using the RS and GIS and work undertaken.

Triggering receptor expressed on myeloid cells (Trem)-1 plays important roles in UVB induced immune suppression and cutaneous carcinogenesis

Abstract American Cancer Society acknowledges that most skin cancers result from exposure to ultraviolet (UV) rays in sunlight. UVB radiation induces mutant cells as well as immune suppression. Tumors only occur when mutant cells are in an immune suppressive environment. The mechanisms for UVB induced immune suppression are yet to be fully elucidated. The goal of this work is to explore new mechanisms for UVB induced immune suppression and skin carcinogenesis by using advanced technology. Analysis of UVB exposed mouse (Nanostring) and human (RNAseq) skin shows that triggering receptor expressed on myeloid cells (TREM)-1 signal pathway is the top canonic pathway increased by UVB. TREM-1 has roles in inflammatory diseases and cancers. However, its role in UVB induced immune suppression and skin cancers is not understood. We have found by using multi-color flow cytometry that UVB induces TREM-1 expression in a subset of conventional dendritic cell type 2 (cDC2) in the draining lymph nodes (LN). TREM-1+ cDC2 cells are barely detected in normal LN and express a high level of the co-inhibitory molecule PD-L1. In functional assays, treatment of mice with a specific TREM-1 blocking peptide LP-17 significantly diminishes UVB-induced suppression of contact hypersensitivity responses that are mediated by T cells. Further, mice treated with this peptide show decreased incidence of photocarcinogenesis and reduced number of tumors. In summary, our findings demonstrate that UVB induces the development of a novel TREM-1+ cDC2 cell subset and that TREM-1 has an important role in UVB induced immune suppression and skin carcinogenesis. Importantly, our study implies new strategies for targeting TREM-1 in the prevention and treatment of UVB induced skin cancers. Supported by grants from NIH (R01AR072213 and R01AI154842)

Investigations on microstructure and properties of Ti-Nb-Zr medium-entropy alloys for metallic biomaterials

In this study, three medium entropy alloys (MEAs), TiNbZr, Ti1.5Nb1.5Zr and Ti1.5NbZr1.5 were designed and investigated to be applied as biomedical materials. The results showed that the alloys prepared by arc melting have a typical dendrite microstructure, caused by elemental segregation during solidification. With composition changes, the partition of the constituting elements behaves differently. The microstructure inhomogeneity and chemical segregation could be greatly reduced by homogenization treatment. The MEAs show good compressive ductility (>40%) and yield strength comparable to or even superior to those of the commercially used biomedical alloys (e.g., 316 stainless steel and pure titanium), which are mainly contributed from the solid-solution strengthening effect. In addition, these MEAs exhibit acceptable Young's modulus ranging from 80 to 93 GPa by nano-indentation tests. The alloys also show excellent corrosion resistance in the phosphate buffer saline (PBS) solution and favorable cyto-compatibility, which are comparable to or even superior to pure titanium and/or Ti-6Al-4V alloys. Based on these properties, the Ti-Nb-Zr MEAs show a promising potential in biomedical applications. The results in this study could be instructive for further alloy design of such biomedical MEAs.

Strength-ductility synergy of Al-bearing low-density refractory TiNbMo0.5AlX medium entropy alloys via precipitation

A series of TiNbMo0.5AlX (x = 0.125, 0.15, 0.175, 0.2, 0.225, 0.25) refractory medium entropy alloys with low density (6.82–7.01 g/cm3) was developed in this work, which should synchronously meet the requirement of mechanical properties at both ambient and high temperature conditions. We found excess Al-addition was conducive to the formation of precipitates with FCC structure; with increasing Al content, the microstructure of alloys evolved from single BCC phase (Al0.125) to BCC matrix + FCC-Ti dual-phase characteristics. Meanwhile, most of these alloys exhibited typical dendrite morphology, except for equiaxed Al0.225. Controlled by elastic strain energy, the precipitates were mainly distributed in interdendrite as clusters of flake-like. All developed alloys presented excellent comprehensive mechanical properties, such as 1022 MPa yield strength and 31% fracture strain could be realized in room-temperature. Al0.225, which also retained 710 MPa strength and 39% strain at 800 °C. The dislocation-dominated deformation mechanism plays an important role in achieving excellent properties. The dislocation pile-up effectively increases compressive strength, and the magnificent compressive ductility is attributed to the dislocation-slip mechanism. The typical Kurdjumov-Sachs (K–S) coherent relationship between BCC matrix and FCC-Ti was investigated, which effectively possessed a significant enhancement in the strength-ductility synergy. In addition, no apparent softening was observed in the stress-strain curves, which made it possible for the alloy to work stably at 800 °C. This work opens new perspectives for the design and application of RMEAs with high strength-ductility synergy.

Role of interfacial energy anisotropy in dendrite orientation in Al-Zn alloys: A phase field study

The influence of interfacial energy anisotropy on dendrite morphology is still not well understood. We investigated the dendrite morphology and solute segregation in Al-Zn alloys using the phase-field method. We observed typical and atypical dendrite orientation transition and three types of dendrite morphology “Christmas tree dendrite”, “seaweed dendrite” and “butterfly dendrite” depending on the anisotropic interfacial energy. Two types of dendrite may undergo the so called-“smooth dendrite orientation transition”, which produces a large amount of solute segregation holes in 〈100〉 dendrites, and liquid grooves in 〈110〉 seaweed and butterfly patterns, thus may significantly impact the mechanical properties of castings. We identified a strong correlation between supersaturation and the formation of liquid holes and liquid grooves as well as the degree of solute segregation. We also proposed that the interfacial energy anisotropy can be related with Zn content by discussing the anisotropic Young’s modulus and experimental pattern of Al-Zn alloys. The inducement of anisotropy and the quantitative relationship between interfacial energy anisotropy, Zn concentration, elastic anisotropy and dendrite orientation deserves attention.

Comprehensive Assessment of Selected Immune Cell Subpopulations Changes in Chemotherapy-Naïve Germ Cell Tumor Patients.

The pattern of immune cell distribution in testicular germ cell tumors (GCT) significantly differs from the immune environment in normal testicular tissues. The present study aimed to evaluate the role of different leukocyte subpopulation in GCTs. A cohort of 84 chemotherapy-naïve GCT patients was analyzed. Immunophenotyping of peripheral blood leukocyte subpopulations was carried out by flow cytometry. In addition, the data assessing the immunophenotypes and the baseline clinicopathological characteristics of the included subjects were statistically evaluated. Their prognostic value for the assessment of progression-free survival (PFS) and overall survival (OS) was estimated. The percentage of different innate/adaptive immune cell subpopulations was significantly associated with poor risk-related clinical features, including the number of metastatic sites, presence of retroperitoneal, mediastinal, lung, brain and non-pulmonary visceral metastases as well as with the S-stage and International Germ Cell Consensus Classification Group (IGCCCG) risk groups. In univariate analysis, the percentages of neutrophils, eosinophils, dendritic cells type 2, lymphocytes and T cytotoxic cells were significantly associated with PFS, while the neutrophil, non-classical monocyte and lymphocyte percentage were associated with OS. However, all these outcome correlations were not independent of IGCCCG in multivariate analysis. The data indicated a link among different innate/adaptive peripheral immune cell subpopulations in GCT patients. In addition, the association between these subpopulations and tumor characteristics was also investigated. The findings of the present study may contribute to a deeper understanding of the interactions between cancer and innate/adaptive immune response in GCT patients.

Mechanical and chemical properties of CoCrFeNiMo0.2 high entropy alloy coating fabricated on Ti6Al4V by laser cladding

CoCrFeNiMo0.2 high entropy alloy (HEA) coating was successfully synthesized on Ti6Al4V sheet by laser cladding. Microstructural characteristics of the HEA coating were investigated by the combined use of multiple characterization techniques. The results indicate that the coating consists of body-centered cubic (BCC) and σ phases with a typical uniform dendrite microstructure. The hardness of the coating is ∼900 HV0.1, about 2.3 times that of the substrate. The coated Ti6Al4V alloy presents better oxidation resistance than Ti6Al4V at 600 °C due to a compact oxide layer rich in Cr element. Compared to the Ti6Al4V substrate, a lower wear rate is noted for the coating, demonstrating greatly improved wear resistance, especially at 600 °C. The wear mechanisms of the coating are dominated by abrasive wear and oxidative wear. A more positive corrosion potential value and lower corrosion current density value are found for the coating, indicating a better corrosion resistance than the Ti6Al4V alloy. In-depth analyses suggest that the improved surface performance is associated with combined contributions from the solid-solution strengthening and grain refinement hardening, as well as the addition of Cr element.

Microneedle-mediated Intratumoral Delivery of Anti-CTLA-4 Promotes cDC1-dependent Eradication of Oral Squamous Cell Carcinoma with Limited irAEs.

Head and neck squamous cell carcinoma (HNSCC) ranks sixth in cancer incidence worldwide and has a 5-year survival rate of only 63%. Immunotherapies-principally immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies that restore endogenous antitumor T-cell immunity-offer the greatest promise for HNSCC treatment. Anti-PD-1 has been recently approved for first-line treatment of recurrent and metastatic HNSCC; however, less than 20% of patients show clinical benefit and durable responses. In addition, the clinical application of ICI has been limited by immune-related adverse events (irAE) consequent to compromised peripheral immune tolerance. Although irAEs are often reversible, they can become severe, prompting premature therapy termination or becoming life threatening. To address the irAEs inherent to systemic ICI therapy, we developed a novel, local delivery strategy based upon an array of soluble microneedles (MN). Using our recently reported syngeneic, tobacco-signature murine HNSCC model, we found that both systemic and local-MN anti-CTLA-4 therapy lead to >90% tumor response, which is dependent on CD8 T cells and conventional dendritic cell type 1 (cDC1). However, local-MN delivery limited the distribution of anti-CTLA-4 antibody from areas distal to draining lymphatic basins. Employing Foxp3-GFPDTR transgenic mice to interrogate irAEs in vivo, we found that local-MN delivery of anti-CTLA-4 protects animals from irAEs observed with systemic therapy. Taken together, our findings support the exploration of MN-intratumoral ICI delivery as a viable strategy for HNSCC treatment with reduced irAEs, and the opportunity to target cDC1s as part of multimodal treatment options to boost ICI therapy.

Microstructure and mechanical properties of WNbMoTaZrx (x = 0.1, 0.3, 0.5, 1.0) refractory high entropy alloys

WNbMoTa refractory high entropy alloy (RHEA) with single BCC phase has high strength, high hardness and excellent high-temperature mechanical properties. However, the limited plasticity greatly affects its engineering applications. In this work, WNbMoTaZrx (x = 0.1, 0.3, 0.5, 1.0) RHEAs were prepared by vacuum arc melting. The microstructure, hardness, compressive properties and fracture behavior were characterized. The results have shown that WNbMoTaZrx RHEAs have a single BCC1 solid solution phase at low Zr content, and a second BCC2 phase appeared in the RHEAs with a higher Zr content. With the increase of Zr content, the microstructure of WNbMoTaZrx RHEAs changed to a typical dendrite structure, and simultaneously increase of strength, hardness and compressive plasticity was observed. The improvement of the mechanical properties was mainly attributed to the solid solution strengthening of Zr elements, the formation of more interdendritic regions, and the refinement of dendrite structures. The deformation mechanisms of the RHEAs with increased compressive plasticity were examined using step-by-step observations and discussed related to the evolution of microstructures. The results have shown that under applied loadings, deformation bands were initiated within the dendrite regions, while the propagation of deformation bands was impeded by interdendritic regions, resulting in significantly increased compressive plasticity. The fracture mode also changed from the intergranular fracture in WNbMoTa RHEA to the transgranular fracture in WNbMoTaZr1.0 RHEA. The present work not only gives more insight into the strengthening and deformation mechanisms of the WNbMoTaZrx (x = 0.1, 0.3, 0.5, 1.0) RHEAs, but also explores the application potential of WNbMoTa-based RHEAs.

Targeting psychological stress-steroid-MARCH1 signaling pathway promotes the efficacy of specific allergen immunotherapy.

Background: The therapeutic efficacy of allergen specific immunotherapy (SIT) is recognized, but needs improved. Psychological stress influences the immune system's function. The objective of this study is to elucidate the effects of psychological stress on compromising the effectiveness of SIT. Methods: A murine model with the airway allergic disorder (AAD) was established. Mice were treated with SIT with or without restraint stress (Rs). Results: Rs was found to significantly hamper the efficacy of SIT in mice with AAD. Induction of IL-10+ dendritic cells and type 1 regulatory T cells were reduced by Rs in the airway tissues. Rs-induced cortisol release subverted immune tolerance generation. Expression of MARCH1 was elevated in dendritic cells of the allergic lesion sites. The Rs-induced MARCH1 mediated the immune impairment in AAD mice. Genetic ablation of MARCH1 in dendritic cells efficiently blocked the Rs-compromised the therapeutic efficacy of SIT. Conclusion: Rs can increase the expression of MARCH1 in DCs of the allergic lesion sites. MARCH1 interferes with the immune regulatory properties in DCs, and impairs the immune regulatory capacity. Blocking MARCH1 can counteract the Rs-affected SIT efficacy.

Immune Regulatory Functions of IgG in the Ontogeny of Human Natural Regulatory T Cells

The heavy constant region of IgG (Fc) is highly immunogenic for human natural regulatory T cells (nTreg). Mature IgG+ B cells prime Fc-specific Treg via recycling of surface immunoglobulin with an antigen-processing pathway that is very efficient in presenting immunodominant Fc peptides to Treg. Some of these peptides are pan-HLA binders, explaining the presence of Fc-specific Treg in circulation in healthy pediatric and adult subjects. Following IgG+ B cell priming, further Treg expansion occurs with the presentation of Fc peptides following IgG uptake and processing by CD14+ myeloid dendritic cells type 2 (cDC2) and CD4+ immunoglobulin-like transcript 4 (ILT-4+) tolerogenic DC that secretes IL-10 when stimulated by the Fc that enters cells prevalently via Fcg receptor II. Fc-specific Treg are important in regulating naive T cell differentiation and account for a key mechanism of success for intravenous immunoglobulin therapy (IVIG) in several inflammatory conditions, including Kawasaki disease (KD) a pediatric acute vasculitis of the coronary arteries.