Dose-related immunomodulatory effects of recombinant TRAIL in the tumor immune microenvironment

Abstract Background In addition to specifically inducing tumor cell apoptosis, recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has also been reported to influence the cancer immune microenvironment; however, its underlying effects and mechanisms remain unclear. Investigating the immunomodulatory effects and mechanisms of recombinant TRAIL in the tumor microenvironment (TME) may provide an important perspective and facilitate the exploration of novel TRAIL strategies for tumor therapy. Methods Immunocompetent mice with different tumors were treated with three doses of recombinant TRAIL, and then the tumors were collected for immunological detection and mechanistic investigation. Methodological approaches include flow cytometry analysis and single-cell sequencing. Results In an immunocompetent mouse model, recombinant soluble mouse TRAIL (smTRAIL) had dose-related immunomodulatory effects. The optimal dose of smTRAIL (2 mg/kg) activated innate immune cells and CD8+ T cells, whereas higher doses of smTRAIL (8 mg/kg) promoted the formation of a tumor-promoting immune microenvironment to counteract the apoptotic effects on tumor cells. The higher doses of smTRAIL treatment promoted M2-like macrophage recruitment and polarization and increased the production of protumor inflammatory cytokines, such as IL-10, which deepened the suppression of natural killer (NK) cells and CD8+ T cells in the tumor microenvironment. By constructing an HU-HSC-NPG.GM3 humanized immune system mouse model, we further verified the immunomodulatory effects induced by recombinant soluble human TRAIL (shTRAIL) and found that combinational administration of shTRAIL and trabectedin, a macrophage-targeting drug, could remodel the tumor immune microenvironment, further enhance antitumor immunity, and strikingly improve antitumor effects. Conclusion Our results highlight the immunomodulatory role of recombinant TRAIL and suggest promising therapeutic strategies for clinical application. Graphical Abstrac

Association of Polymorphisms in Vitamin D-Metabolizing Enzymes DHCR7 and CYP2R1 with Cancer Susceptibility: A Systematic Review and Meta-Analysis

The deficiency of vitamin D has been reported to be relevant to cancer risk. DHCR7 and CYP2R1 are crucial components of vitamin D-metabolizing enzymes. Thus, accumulating researchers are concerned with the correlation between polymorphisms of DHCR7 and CYP2R1 genes and cancer susceptibility. Nevertheless, the conclusions of literatures are inconsistent. We conducted an integrated review for the correlation of DHCR7 and CYP2R1 SNPs with cancer susceptibility. In the meanwhile, a meta-analysis was performed using accessible data to clarify the association between DHCR7 and CYP2R1 SNPs and overall cancer risk. Literatures which meet the rigid inclusion and exclusion criteria were involved. The association of each SNP with cancer risk was calculated by odds ratios (ORs). 12 case-control designed studies covering 23780 cases and 27307 controls were ultimately evolved in the present meta-analysis of five SNPs (DHCR7 rs12785878 and rs1790349 SNP; CYP2R1 rs10741657, rs12794714, and rs2060793 SNP). We found that DHCR7 rs12785878 SNP was significantly related to cancer risk in the whole population, Caucasian subgroup, and hospital-based (HB) subgroup. DHCR7 rs1790349 SNP was analyzed to increase cancer risk in Caucasians. Moreover, CYP2R1 rs12794714-A allele had correlation with a lower risk of colorectal cancer. Our findings indicated that rs12785878, rs1790349, and rs12794714 SNPs might potentially be biomarkers for cancer susceptibility

Micro-fractional epidermal powder delivery for skin vaccination

Skin is a highly immunogenic site for vaccine delivery due to its richness of antigen-presenting cells. Several vaccines have been approved for skin delivery and in particular intradermal delivery in the last two decades. Yet intradermal delivery often causes frequent and severe local reactions, preventing the incorporation of adjuvants to further boost skin vaccination. Here we describe a novel skin delivery technology, called micro-fractional epidermal powder delivery or EPD, with minimized local reactions for improved skin vaccination. EPD is based on laser or microneedle treatment to generate microchannel arrays in the epidermis followed by topical application of powder vaccine-coated array patches to deliver vaccines into the skin via microchannels. Due to the fractional delivery, EPD significantly reduces vaccine/adjuvant-induced local reactions without compromising vaccine immunogenicity and adjuvant potency. EPD also eliminates needle injection-associated pain and is promising to improve vaccine stability due to the direct powder delivery. This chapter describes detailed methods for the advantageous EPD in preclinical animal models

Earth observation in archaeology: A brief review

Observing archaeological objects of interest (AOI) is pivotal to our understanding of past human-environment interactions, eco-social dynamics, and even the evolution of the ancient civilization. This has required development of advanced observational approaches to image and identify AOI at various circumstances and conditions. In the past decades, it has become very popular to employ passive and active sensing-based Earth observation (EO) technology to observe and analyse AOI all over the world. This has been promoted and highlighted by the surge of the observational data from different EO systems as well as the advances in digital image processing and analysis. Specifically, the employment of conventional single EO platform and transition to multi-platform integrated EO network provides significant improvement in the efficiency and accuracy of AOI prospecting together with diverse sensors and/or instruments. This paper aims to present a brief review on the use of EO-based solutions in AOI prospecting, with focus on the progress, application, advantage and limitations. Advances in EO science and technology have empowered archaeologists and EO specialists to explore the past in greater detail. Remote, proximal and in-situ networked and software-defined sensors that rely on the acquisition, processing and analysis of big EO data are more powerful than ever and continue to let us see the unseen - that is, new knowledge about the past and who are we

Pseudo-Leidenfrost phenomenon of low surface tension droplet induced by external aerodynamic field

Droplet regulation has significant application potential in many fields; however, conventional controlling methods make it difficult to effectively control low surface tension droplets. Inspired by the Leidenfrost phenomenon, a pseudo-Leidenfrost system was established innovatively through micro-airflow rather than evaporated vapor to lift a droplet. Both experimental and numerical studies were carried out to investigate the pseudo-Leidenfrost effect of the FC3283 (perfluorotripropylamine) droplet. By FC3283, it is an extremely low surface tension working medium with thermal stability at room temperature. The oscillation of the droplet in the vertical direction was analyzed by tracking the position of the droplet centroid. The velocity of micro-airflow and pressure distributions at the bottom surface of the droplet, which were similar to the Leidenfrost phenomenon, were revealed. The mechanical analysis of the FC3283 droplet in a pseudo-Leidenfrost period was analyzed. Besides, the pseudo-Leidenfrost phenomenon of FC40 [FC-40 FluorinertTM Electronic Liquid] droplets with various Weber number was investigated. Weber number conditions for droplets triggering the pseudo-Leidenfrost phenomenon were revealed. The results showed that the motion of pseudo-Leidenfrost droplets in a period could be divided into three stages: falling, hovering, and rising. In the hovering stage, the Laplace force played an important role, which was the main reason for the rebound of the droplet, while the role of the aerodynamic force was to keep the droplet on the surface of the gas film. The Weber number had a significant influence on the pseudo-Leidenfrost phenomenon: droplets with a small Weber number tended to be absorbed by the micropores, while a too large Weber number would cause droplets to suspend or even leave. This study is helpful for controlling low surface tension droplets and laying a foundation for the transportation of low surface tension droplets