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Background The recruitment of a sufficient number of immune cells to induce an inflamed tumor microenvironment (TME) is a prerequisite for effective response to cancer immunotherapy. The immunological phenotypes in the TME of EGFR–mutated lung cancer were characterized as non-inflamed, for which immunotherapy is largely ineffective. Methods Global proteomic and phosphoproteomic data from lung cancer tissues were analyzed aiming to map proteins related to non-inflamed TME. The ex vivo and in vivo studies were carried out to evaluate the anti-tumor effect. Proteomics was applied to identify the potential target and signaling pathways. CRISPR-Cas9 was used to knock out target genes. The changes of immune cells were monitored by flow cytometry. The correlation between PKCδ and PD-L1 was verified by clinical samples. Results We proposed that PKCδ, a gatekeeper of immune homeostasis with kinase activity, is responsible for the un-inflamed phenotype in EGFR-mutated lung tumors. It promotes tumor progression by stimulating extracellular matrix (ECM) and PD-L1 expression which leads to immune exclusion and assists cancer cell escape from T cell surveillance. Ablation of PKCδ enhances the intratumoral penetration of T cells and suppresses the growth of tumors. Furthermore, blocking PKCδ significantly sensitizes the tumor to immune checkpoint blockade (ICB) therapy (αPD-1) in vitro and in vivo model. Conclusions These findings revealed that PKCδ is a critical switch to induce inflamed tumors and consequently enhances the efficacy of ICB therapy in EGFR-mutated lung cancer. This opens a new avenue for applying immunotherapy against recalcitrant tumors. Graphical Abstract

The combination between biphasic calcium phosphate (BCP) and the osteomimetic porous micro-structure obtained via freeze casting is hoped to achieve excellent bone regeneration, while the effects of HA and β-TCP ratio changes on the degradation and biological performance of the BCP scaffolds with this unique micro-structure need to be determined. Here, we prepared the osteomimetic BCP scaffolds with different HA/β-TCP ratios (HA30/β-TCP70, HA50/β-TCP50, HA70/β-TCP30) and the effects of different HA/β-TCPHA/β-TCP ratios on the degradation and biological performance were studied in vitro and vivo. These BCP scaffolds with different HA/β-TCP ratios exhibited similar microstructure, mechanical performance, and protein absorption capability, while HA70/β-TCP30 BCP scaffolds showed an advisable degradation rate. Study in vitro confirmed the bio-compatibility and promotion on the proliferation, differentiation of MG63 cells in the porous osteomimetic BCP scaffolds with a HA/β-TCP ratio at 30:70. Implantation experiments also showed that the porous osteomimetic BCP scaffolds with a HA/β-TCP ratio at 30:70 had excellent bone regeneration capacity and proper degradation rate compatible with bone growth. These results reveal that the porous osteomimetic BCP scaffold with a HA/β-TCP ratio at 30:70 is a potential candidate of biodegradable bone substitutes used for bone repair.

The porous HA/BaTiO3 ceramics have the potential to exhibit superior capabilities to promote bone in-growth. However, there are few reports on in vivo studies. Here, we fabricated bio-inspired porous HA/BaTiO3 composites for bone repair via freeze-casting. These composites had a unique microstructure composed of the central canal and radically distributed lamellae, similar to the structure of nature cortical bone unite, the Haversian system. Polarized and non-polarized bio-inspired porous HA/BaTiO3 samples were implanted into the femoral condyle of the New Zealand rabbits. It was demonstrated that the polarization of the porous HA/BaTiO3 played a favorable part in bone regeneration. Moreover, the combination between the osteoconductivity of the microstructure and augmented osteogenic cell behavior induced by charges on surfaces of polarized porous HA/BaTiO3 facilitated bone penetration through the implants. The bio-inspired porous HA/BaTiO3 composites are demonstrated to be promising scaffolds for bone repair. 多孔HA/BaTiO3陶瓷具有促进骨再生的潜在能力。本研究通过冷冻冰模法制备了一种仿生多孔HA/BaTiO3复合骨支架材料,这种仿生多孔结构由中央管和呈放射状分布的层板组成,这与天然致密骨结构单位—哈弗系统相似。在植入实验中,极化和非极化的多孔HA/BaTiO3样本被植入新西兰兔的股骨髁。结果显示:多孔HA/BaTiO3的电极化处理促进了骨再生;极化多孔HA/BaTiO3表面的电荷增强了成骨细胞的成骨活动,这与具有良好骨传导性的仿生多孔结构共同实现了骨组织对支架材料的穿透。本研究证明了仿生多孔HA/BaTiO3复合材料有希望用作骨修复支架。

Background Acute Myeloid Leukemia (AML) is a hematological cancer characterized by heterogeneous hematopoietic cells. Through the use of multidimensional sequencing technologies, we previously identified a distinct myeloblast population, CD34+CD117dim, the proportion of which was strongly associated with the clinical outcome in t (8;21) AML. In this study, we explored the potential value of the CD34+CD117dim population signature (117DPS) in AML stratification. Methods Based on the CD34+CD117dim gene signature, the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to construct the 117DPS model using the gene expression data from Gene Expression Omnibus (GEO) database (GSE37642-GPL96 was used as training cohort; GSE37642-GPL570, GSE12417-GPL96, GSE12417-GPL570 and GSE106291 were used as validation cohorts). In addition, the RNA-seq data from The Cancer Genome Atlas (TCGA)-LAML and Beat AML projects of de-novo AML patients were also analyzed as validation cohorts. The differences of clinical features and tumor-infiltrating lymphocytes were further explored between the high-risk score group and low-risk score group. Results The high-risk group of the 117DPS model exhibited worse overall survival than the low-risk group in both training and validation cohorts. Immune signaling pathways were significantly activated in the high-risk group. Patients with high-risk score had a distinct pattern of infiltrating immune cells, which were closely related to clinical outcome. Conclusion The 117DPS model established in our study may serve as a potentially valuable tool for predicting clinical outcome of patients with AML.

Maintaining the balance of intestinal microbiota is vital for the growth and health of crustaceans. The current study explored the influences of the surface layer proteins (SLPs) of Pediococcus pentosaceus on the growth performance, disease resistance, and gut microbial community of the freshwater prawn Macrobrachium rosenbergii. After 28 days of feeding, obvious enhancements in the growth performance were found in the PF (a commercial basic diet + intact P. pentosaceus) group compared to the CF (a commercial basic diet, control) and RF (a commercial basic diet + LiCl-treated P. pentosaceus) groups. Meanwhile, the relative percent survival (RPS) of the PF group was found to be 82.1%, higher than the RF group (RPS = 63.2%) in the challenge test. There were noteworthy differences in the relative richness of Aeromonas among different treatments, and the PF group was the lowest. Whereas the relative abundance of Lactococcus between the CF and RF group did not markedly differences, which was obviously lower than the PF group. The prediction of bacterial phenotype indicated that the pathogenic potential of intestinal microbiota was decreased by increasing dietary SLPs-carrying P. pentosaceus. The results suggested that SLPs-carrying P. pentosaceus can improve growth, modulate intestinal microbiota, and increase the resistance of prawns against Aeromonas hydrophila infection.