Biology subjects

Astorkia, M.

Publications and source records attributed to Astorkia, M..

3 recordsLinked to original sources

bioRxiv2025

Total body irradiation primes CD19-directed CAR T cells against large B-cell lymphoma

CD19-targeting chimeric antigen receptor T cells (CART19) have demonstrated significant effectiveness in treating relapsed or refractory large B-cell lymphoma (LBCL). However, they often fail to sustain durable remissions in more than half of all treated patients. Therefore, there is an urgent need to identify approaches to enhance CART19 efficacy. Here, we studied the impact of low-dose radiation on CART19 activity in vitro and find that radiation enhances the cytotoxicity of CART19 against LBCL by upregulating death receptors. Disrupting the FAS receptor diminishes this benefit, indicating that this pathway plays an important role in enhancing the cytotoxic effects of CAR T cells. To further validate these findings, we conducted in vivo studies using a lymphoma syngeneic mouse model delivering total body irradiation (TBI). We observed that delivering TBI at a single dose of 1Gy prior to CAR T cell infusion significantly improved CART19-mediated tumor elimination and increased overall survival rates. Importantly, we characterized several important effects of TBI, including enhanced lymphodepletion, improved T cell expansion and persistence, better intra-tumoral migration, and a more favorable, anti-tumor phenotypic composition of the T cells. In summary, for the first time, we have demonstrated preclinically that administering TBI before CART19 infusion significantly accelerates tumor elimination and improves overall survival. This approach holds promise for translation into clinical practice and serves as a valuable foundation for further research to enhance outcomes for patients receiving CART19 treatment.

cancer biology↗

bioRxiv2023

Molecular and network disruptions in neurodevelopment uncovered by single cell transcriptomics analysis of CHD8 heterozygous cerebral organoids

About 100 genes have been associated with significantly increased risks of autism spectrum disorders (ASD) with an estimate of [~]1000 genes that may be involved. The new challenge now is to investigate the molecular and cellular functions of these genes during neural and brain development, and then even more challenging, to link the altered molecular and cellular phenotypes to the ASD clinical manifestations. In this study, we use single cell RNA-seq analysis to study one of the top risk gene, CHD8, in cerebral organoids, which models early neural development. We identify 21 cell clusters in the organoid samples, representing non-neuronal cells, neural progenitors, and early differentiating neurons at the start of neural cell fate commitment. Comparisons of the cells with one copy of the CHD8 knockout and their isogenic controls uncover thousands of differentially expressed genes, which are enriched with function related to neural and brain development, with genes and pathways previously implicated in ASD, but surprisingly not for Schizophrenia and intellectual disability risk genes. The comparisons also find cell composition changes, indicating potential altered neural differential trajectories upon CHD8 reduction. Moreover, we find that cell-cell communications are affected in the CHD8 knockout organoids, including the interactions between neural and glial cells. Taken together, our results provide new data for understanding CHD8 functions in the early stages of neural lineage development and interaction.

genomics↗

bioRxiv2021

Characterization of Cell-cell Communication in Autistic Brains with Single Cell Transcriptomes

Autism spectrum disorder is a neurodevelopmental disorder, affecting 1-2% of children. Studies have revealed genetic and cellular abnormalities in the brains of affected individuals, leading to both regional and distal cell communication deficits. Recent application of single cell technologies, especially single cell transcriptomics, has significantly expanded our understanding of brain cell heterogeneity and further demonstrated that multiple cell types and brain layers or regions are perturbed in autism. The underlying high-dimensional single cell data provides opportunities for multi-level computational analysis that collectively can better deconvolute the molecular and cellular events altered in autism. Here, we apply advanced computation and pattern recognition approaches on single cell RNA-seq data to infer and compare inter-cell-type signaling communications in autism brains and controls. Our results indicate that at a global level there are cell-cell communication differences in autism in comparison to controls, largely involving neurons as both signaling senders and receivers, but glia also contribute to the communication disruption. Although the magnitude of change is moderate, we find that excitatory and inhibitor neurons are involved in multiple intercellular signaling that exhibit increased strengths in autism, such as NRXN and CNTN signaling. Not all genes in the intercellular signaling pathways are differentially expressed, but genes in the pathways are enriched for axon guidance, synapse organization, neuron migration, and other critical cellular functions. Furthermore, those genes are highly connected to and enriched for genes previously associated with autism risks. Overall, our proof-of-principle computational study using single cell data uncovers key intercellular signaling pathways that are potentially disrupted in the autism brains, suggesting that more studies examining cross-cell type affects can be valuable for understanding autism pathogenesis.

bioinformatics↗