Biomedical subjects

Atul Deshpande

Publications and source records attributed to Atul Deshpande.

4 recordsLinked to original sources

PubMed2025

Neoadjuvant Immunotherapy Promotes the Formation of Mature Tertiary Lymphoid Structures in a Remodeled Pancreatic Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. In this study, we report the generation of a spatial multiomic atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that are significantly associated with improved survival in patients with PDAC. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.

Humans↗

PubMed2025

BIWT: a bioinformatics walkthrough for embedding spatial multiomics in agent-based models for virtual cells.

SUMMARY: Whereas transcriptomic and spatial profiling offer static snapshots of tissue structure, mechanistic models use biological rules to predict how tissues evolve. We present the BioInformatics WalkThrough (BIWT) software to directly initialize spatial agent-based models from single-cell and spatial molecular data. We demonstrate how initialization strategies affect tumor-immune dynamics and spatial clustering, positioning BIWT as a software suite to generate data-driven virtual cells representing both experimental and clinical contexts. AVAILABILITY AND IMPLEMENTATION: The BIWT software is available at https://github.com/PhysiCell-Tools/PhysiCell-Studio. The sample dataset for running the BIWT is available at https://zenodo.org/records/16365625. The code and instructions for reproducing the use case example is available at https://github.com/drbergman/BIWT-Paper.

Software↗

PubMed2006

Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons.

Characterization of soluble oligomeric amyloid beta (Abeta) species in the brains of Alzheimer's disease (AD) patients and transgenic models has raised the possibility that different conformations of Abeta may contribute to AD pathology via different mechanisms. To characterize the toxic effect of different Abeta conformations, we tested side by side the effect of well characterized Abeta oligomers (AbetaOs), Abeta-derived diffusible ligands (ADDLs), and fibrillar Abeta (Abetaf) preparations in human cortical neurons (HCNs). Both AbetaOs and ADDLs bind rapidly and with high affinity to synaptic contacts and cellular membranes. AbetaOs (5 microm) induced rapid and massive neuronal death. Calcium influx accelerated, but was not required for, AbetaO toxicity. AbetaOs elicited a stereotyped succession of cellular changes consistent with the activation of a mitochondrial death apoptotic pathway. At low concentrations AbetaOs caused chronic and subtler mitochondrial alterations but minimal cell death. ADDLs induced similar toxic changes as AbetaOs but on a fivefold longer time scale. Higher concentrations of Abetaf and longer incubation times were required to produce widespread neuritic dystrophy but modest HCN cell death. Thus various Abeta species may play relevant roles in AD, causing neurotoxicity by distinct non-overlapping mechanisms affecting neuronal function and viability over multiple time courses.

Alzheimer Disease↗

PubMed2003

Telomere maintenance in fission yeast requires an Est1 ortholog.

Telomerase regulation is critical to genome maintenance yet remains poorly understood. Without telomerase's ability to synthesize telomere repeats, chromosome ends shorten progressively, as conventional DNA polymerases cannot fully replicate the ends of linear molecules. In Saccharomyces cerevisiae, telomerase activity in vivo absolutely depends on a set of telomerase accessory proteins that includes Est1p, which appears to recruit or activate telomerase at the site of polymerization. Thus, est1Delta cells have the same cellular senescence phenotype as cells lacking either the catalytic protein subunit of telomerase or its template-containing RNA subunit. While the telomerase protein is highly conserved among eukaryotes, the apparent lack of Est1p homologs has frustrated efforts to describe a common mechanism of telomerase recruitment and activation. Here, we describe SpEst1p, a homolog of Est1p from the evolutionarily distant Schizosaccharomyces pombe. Like ScEst1p, SpEst1p is required for telomerase activity in vivo. Coupled with the identification of an orthologous Est1 protein in humans [10], this suggests a much wider conservation of telomerase regulation than was previously known. Strikingly, in cells with compromised telomere function (taz1Delta), SpEst1p loss confers a lethal germination phenotype, while telomerase loss does not, indicating that SpEst1p plays an unexpected additional role in chromosome end protection.

Animals↗