Open-Source Throttling of CD8+ T Cells in Brain with Low-Intensity Focused Ultrasound-Guided Sequential Delivery of CXCL10, IL-2, and aPD-L1 for Glioblastoma Immunotherapy.

Improving clinical immunotherapy for glioblastoma (GBM) relies on addressing the immunosuppressive tumor microenvironment (TME). Enhancing CD8+ T cell infiltration and preventing its exhaustion holds promise for effective GBM immunotherapy. Here, a low-intensity focused ultrasound (LIFU)-guided sequential delivery strategy is developed to enhance CD8+ T cells infiltration and activity in the GBM region. The sequential delivery of CXC chemokine ligand 10 (CXCL10) to recruit CD8+ T cells and interleukin-2 (IL-2) to reduce their exhaustion is termed an "open-source throttling" strategy. Consequently, up to 3.39-fold of CD8+ T cells are observed with LIFU-guided sequential delivery of CXCL10, IL-2, and anti-programmed cell death 1 ligand 1 (aPD-L1), compared to the free aPD-L1 group. The immune checkpoint inhibitors (ICIs) therapeutic efficacy is substantially enhanced by the reversed immunosuppressive TME due to the expansion of CD8+ T cells, resulting in the elimination of tumor, prolonged survival time, and long-term immune memory establishment in orthotopic GBM mice. Overall, LIFU-guided sequential cytokine and ICIs delivery offers an "open-source throttling" strategy of CD8+ T cells, which may present a promising strategy for brain-tumor immunotherapy.

DNA Methyltransferase 3A: a Significant Target for the Discovery of Inhibitors as Potent Anticancer Drugs.

DNA methyltransferase (DNMT) is a conserved family of Cytosine methylases, which plays a crucial role in the regulation of Epigenetics. They have been considered promising therapeutic targets for cancer. Among the DNMT family, mutations in the DNMT3A subtype are particularly important in hematologic malignancies. The development of specific DNMT3A subtype inhibitors to validate the therapeutic potential of DNMT3A in certain diseases is a significant task. In this review, we summarized the small molecule inhibitors of DNMT3A discovered in recent years and their inhibitory activities, and classified them based on their inhibitory mechanisms.

The Effect of Co Content and Annealing Temperatures on the Resistivity in Ag-Co Films.

Ag-Co films with ultra-high resistivity were prepared on polyimide by magnetron sputtering. The effect of Co content and annealing temperatures on the resistivity and microstructure of Ag-Co films has been thoroughly investigated and the relation between resistivity and microstructure has been discussed. Results show that thicker Ag-Co films without annealing present lower resistivity due to better crystallinity. However, thin Ag-Co films (≤21 nm) annealed at 360 °C present ultra-high film resistivity because of the formation of diffusion pits on the film surface which blocks the transmission of electrons in films to increase film resistivity. Inversely, the resistivity of thick Ag-Co films (≥45 nm) annealed at 360 °C is much less than that annealed at lower than 260 °C owing to no diffusion pits. Furthermore, the addition of Co inhibits the growth of Ag grains and limits the migration of electrons in Ag-Co films further, also resulting in the increase of Ag-Co films' resistivity.