Direct Visualization of Live Zebrafish Glycans via Single-Step Metabolic Labeling with Fluorophore-Tagged Nucleotide Sugars
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Authors: Hong, Senlian; Sahai-Hernandez, Pankaj; Chapla, Digantkumar Gopaldas; Moremen, Kelley W.; Traver, David; Wu, Peng
Abstract
Dynamic turnover of cell-surface glycans is involved in a myriad of biological events, making this process an attractive target for in vivo molecular imaging. Metabolic glycan labeling coupled with bioorthogonal chemistry has paved the way for visualizing glycans in living organisms. However, a two-step labeling sequence is required, which suffers from the tissue-penetration difficulties of the imaging probes. Here, by exploring the substrate promiscuity of endogenous glycosyltransferases, we developed a single-step fluorescent glycan labeling strategy by using fluorophore-tagged analogues of the nucleotide sugars. Injecting fluorophore-tagged sialic acid and fucose into the yolk of zebrafish embryos at the one-cell stage enables systematic imaging of sialylation and fucosylation in live zebrafish embryos at distinct developmental stages. From these studies, we obtained insights into the role of sialylated and fucosylated glycans in zebrafish hematopoiesis.
Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia
LEUKEMIA
Authors: Bhojwani, Deepa; Sposto, Richard; Shah, Nirali N.; Rodriguez, Vilmarie; Yuan, Constance; Stetler-Stevenson, Maryalice; O'Brien, Maureen M.; McNeer, Jennifer L.; Quereshi, Amrana; Cabannes, Aurelie; Schlegel, Paul; Rossig, Claudia; Dalla-Pozza, Luciano; August, Keith; Alexander, Sarah; Bourquin, Jean-Pierre; Zwaan, Michel; Raetz, Elizabeth A.; Loh, Mignon L.; Rheingold, Susan R.
Abstract
Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/ refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted in 6 (12%) and grade 3/ 4 infections in 11 (22%) patients. No patient developed sinusoidal obstruction syndrome (SOS) during InO therapy; however, 11 of 21 (52%) patients who underwent hematopoietic stem cell transplantation (HSCT) following InO developed SOS. Downregulation of surface CD22 was detected as a possible escape mechanism in three patients who developed a subsequent relapse after InO. We conclude that InO is a well-tolerated, effective therapy for children with relapsed ALL and prospective studies are warranted. Identification of risk factors for developing post-HSCT SOS and strategies to mitigate this risk are ongoing.