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Splitting from a lump: harmonizing ALCL classification
Pegcetacoplan in C3 Glomerulopathy and Immune-Complex MPGN
A genetic toolkit for the human gut bacterium Mediterraneibacter gnavus identifies capsular polysaccharides as a competitive colonization factor
Abstract Mediterraneibacter gnavus is a human symbiotic gut bacterium whose abundance often increases in patients with various diseases, such as active inflammatory bowel disease (IBD). However, the genetic factors governing its gut colonization and pathogenicity remain elusive due to the lack of genetic modification systems. In this study, we developed several genetic tools for M. gnavu s, including a shuttle vector, an inducible promoter, fluorescent reporters, and systems for gene disruption and deletion. Using these genetic tools, we constructed mutants for six of the eight sortase-encoding genes in M. gnavus ATCC 29149 and identified those involved in the surface presentation of capsular polysaccharide (CPS) and superantigen-like proteins. We also identified a CPS biosynthetic gene cluster adjacent to the sortase gene and demonstrated that CPS production is crucial for competitive colonization in germ-free mouse intestines. Notably, CPS production was inversely correlated with inflammatory activity, and CPS cluster-positive strains were more prevalent in healthy individuals than in Crohn’s disease patients. These findings suggest that CPS contributes to the modulation of inflammation and pathogenesis. This study highlights the potential of precise gene-modification systems to uncover genetic determinants of intestinal colonization and pathogenesis in gut bacteria.
The glycosaminoglycan oncofetal chondroitin sulfate is a novel target for antibody-drug conjugate therapy for AML
Abstract Antibody-drug conjugates (ADCs) have emerged as promising targeted therapies for acute myeloid leukemia (AML). However, most ADCs exhibit off-target binding to normal hematopoietic stem and myeloid progenitor cells, resulting in adverse hematotoxicity and narrow therapeutic windows, thereby limiting their clinical application to young and fit patients with AML who are eligible for intensive curative therapies. Proteoglycans with high levels of the glycosaminoglycan oncofetal chondroitin sulfate (ofCS) are abundantly expressed in solid cancers but are absent or expressed at low levels in normal adult tissues. Here, we report high ofCS levels on bone marrow (BM) cells from patients with AML and patient-derived xenografts (PDXs) from these patients, whereas BM cells from healthy individuals showed low or undetectable ofCS levels. Consistently, an anti-ofCS antibody demonstrated binding to and internalization into AML cells, and anti-ofCS ADCs effectively killed AML cells in vitro. Moreover, anti-ofCS ADC treatment significantly prolonged survival of AML PDXs compared with controls and was associated with low toxicity. Thus, anti-ofCS ADCs could represent an effective therapy with acceptable toxicity for patients with AML, including those who are ineligible for or unresponsive to current intensive curative therapies. In conclusion, this study demonstrates, to our knowledge for the first time, that a glycosaminoglycan-like ofCS is a druggable target for the development of effective antibody-based AML therapies.