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Results From First-in-Human Phase I Study of a Novel CD19-1XX Chimeric Antigen Receptor With Calibrated Signaling in Large B-Cell Lymphoma.
J Clin Oncol
January 2025
Center for Cell Engineering, Sloan Kettering Institute, New York, NY.
Purpose: We designed a CD19-targeted chimeric antigen receptor (CAR) comprising a calibrated signaling module, termed 1XX, that differs from that of conventional CD28/CD3ζ and 4-1BB/CD3ζ CARs. Preclinical data demonstrated that 1XX CARs generated potent effector function without undermining T-cell persistence. We hypothesized that 1XX CAR T cells may be effective at low doses and elicit minimal toxicities.
View Article and Find Full Text PDFReactions of SleC, Its Structure and Inhibition in Mitigation of Spore Germination in .
J Am Chem Soc
January 2025
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
Spore germination in is initiated by a cascade of activities of several proteins that culminates in the activation of SleC, a cell-wall-processing enzyme. We report herein the details of the enzymatic activities of SleC by the use of synthetic peptidoglycan fragments and of spore sacculi. The reactions include the formation of 1,6-anhydromuramate─a hallmark of lytic transglycosylase activity─as well as a muramate hydrolytic product, both of which proceed through the same transient oxocarbenium species.
View Article and Find Full Text PDFImpaired spatial coding of the hippocampus in a dentate gyrus hypoplasia mouse model.
Proc Natl Acad Sci U S A
February 2025
Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, MD 21218.
The hippocampal dentate gyrus (DG) is thought to orthogonalize inputs from the entorhinal cortex (pattern separation) and relay this information to the CA3 region. In turn, attractor dynamics in CA3 perform a pattern completion or error correction operation before sending its output to CA1. In a mouse model of congenital hypoplasia of the DG, a deficiency in the (Wls) gene, specifically in cells expressing , which targets neuronal progenitors, led to an almost total absence of dentate granule cells and modestly impaired performance in spatial tasks.
View Article and Find Full Text PDFEstablishment and application of a zebrafish model of Werner syndrome identifies sapanisertib as a potential antiaging drug.
Proc Natl Acad Sci U S A
February 2025
State Key Laboratory of Genetic Engineering, School of Life Sciences, Liver Cancer Institute of Zhongshan Hospital, Fudan University, Shanghai 200438, China.
Aging is a complex process that affects multiple organs, and the discovery of a pharmacological approach to ameliorate aging is considered the Holy Grail of medicine. Here, we performed an N-ethyl-N-nitrosourea forward genetic screening in zebrafish and identified an accelerated aging mutant named (), harboring a mutation in the - () gene. Loss of leads to a short lifespan and age-related characteristics in the intestine of zebrafish embryos, such as cellular senescence, genomic instability, and epigenetic alteration.
View Article and Find Full Text PDFMultiplex generation and single-cell analysis of structural variants in mammalian genomes.
Science
January 2025
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
Studying the functional consequences of structural variants (SVs) in mammalian genomes is challenging because (i) SVs arise much less commonly than single-nucleotide variants or small indels and (ii) methods to generate, map, and characterize SVs in model systems are underdeveloped. To address these challenges, we developed Genome-Shuffle-seq, a method that enables the multiplex generation and mapping of thousands of SVs (deletions, inversions, translocations, and extrachromosomal circles) throughout mammalian genomes. We also demonstrate the co-capture of SV identity with single-cell transcriptomes, facilitating the measurement of SV impact on gene expression.
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