Adoptive immunotherapy (AI) with pathogen-specific T cells is a promising alternative to pharmacotherapy for the treatment of opportunistic infections after allogeneic hematopoietic cell ...transplantation or solid organ transplantation. However, clinical implementation of AI is limited to patients not receiving high-dose steroids, a prerequisite for optimal T-cell function, practically excluding the most susceptible to infections patients from the benefits of AI. To address this issue, we here rapidly generated, clinical doses of a steroid-resistant T-cell product, simultaneously targeting four viruses (adenovirus, cytomegalovirus, Epstein Barr virus, and BK virus) and the fungus
, by genetic disruption of the glucocorticoid receptor (GR) gene using CRISPR/CAS9 ribonucleoprotein delivery. The product, "Cerberus" T cells (Cb-STs), was called after the monstrous three-headed dog of Greek mythology, due to its triple potential; specificity against viruses, specificity against fungi and resistance to glucocorticoids. Following efficient on-target GR disruption and minimal off-target editing, the generated Cb-STs maintained the characteristics of pentavalent-STs, their unedited counterparts, including polyclonality, memory immunophenotype, specificity, and cytotoxicity while they presented functional resistance to dexamethasone. Cb-STs may become a powerful, one-time treatment for severely immunosuppressed patients under glucocorticoids who suffer from multiple, life-threatening infections post-transplant, and for whom therapeutic choices are limited.
Growth of covalently bonded Sierpiński triangles (CB-STs) on metal surfaces was investigated by scanning tunneling microscopy (STM). Three synthetic strategies (namely, dehydration condensation, ...cyclotrimerization coupling and Schiff-base reactions) were used to fabricate CB-STs. Second-generation CB-STs were obtained at the solid–vacuum interface utilizing the Schiff-base reaction between 4,4′′-dialdehyde-1,1′:3′,1′′-terphenyl (TPDAL) and 1,3,5-tris(4-aminophenyl)benzene (TAPB) on Au(111). The CB-ST patterns persist at annealing temperatures as high as 500 K. Homotactic three-fold motifs, insufficient migration and irreversible covalent reaction are the main limitations for growing higher-generation STs. The present results provide new insights on the growth of STs on metal surfaces.
Growth of covalently bonded Sierpi ski triangles (CB-STs) on metal surfaces was investigated by scanning tunneling microscopy (STM). Three synthetic strategies (namely, dehydration condensation, ...cyclotrimerization coupling and Schiff-base reactions) were used to fabricate CB-STs. Second-generation CB-STs were obtained at the solid-vacuum interface utilizing the Schiff-base reaction between 4,4′′-dialdehyde-1,1′:3′,1′′-terphenyl (TPDAL) and 1,3,5-tris(4-aminophenyl)benzene (TAPB) on Au(111). The CB-ST patterns persist at annealing temperatures as high as 500 K. Homotactic three-fold motifs, insufficient migration and irreversible covalent reaction are the main limitations for growing higher-generation STs. The present results provide new insights on the growth of STs on metal surfaces.
Growth of covalently bonded Sierpi ski triangles (CB-STs) on metal surfaces was investigated by scanning tunneling microscopy (STM).
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