Decoding the tumor microenvironment with spatial technologies

Nature Immunology, Journal Year: 2023, Volume and Issue: 24(12), P. 1982 - 1993

Published: Nov. 27, 2023

Language: Английский

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Lumican, a Multifunctional Cell Instructive Biomarker Proteoglycan Has Novel Roles as a Marker of the Hypercoagulative State of Long Covid Disease

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2825 - 2825

Published: Feb. 29, 2024

This study has reviewed the many roles of lumican as a biomarker tissue pathology in health and disease. Lumican is structure regulatory proteoglycan collagen-rich tissues, with cell instructive properties through interactions number surface receptors repair, thereby regulating proliferation, differentiation, inflammation innate humoral immune systems to combat infection. The exponential increase publications last decade dealing testify its role pleiotropic protein. Recent findings show novel hypercoagulative state that occurs SARS CoV-2 infections; thus, it may also prove useful delineation complex changes characterize COVID-19 be prognostic diagnostic long COVID disease sequelae.

Language: Английский

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Integrating cryo-OrbiSIMS with computational modelling and metadynamics simulations enhances RNA structure prediction at atomic resolution

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 22, 2024

Abstract The 3D architecture of RNAs governs their molecular interactions, chemical reactions, and biological functions. However, a large number protein complexes remain poorly understood due to the limitations conventional structural biology techniques in deciphering complex structures dynamic interactions. To address this limitation, we have benchmarked an integrated approach that combines cryogenic OrbiSIMS, state-of-the-art solid-state mass spectrometry technique, with computational methods for modelling RNA at atomic resolution enhanced precision. Furthermore, using 7SK RNP as test case, successfully determined full structure native its apo, disease-remodelled states, which offers insights into interactions plasticity within these states. Overall, our study establishes cryo-OrbiSIMS valuable tool field it enables challenging, systems.

Language: Английский

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Metabolomic and Proteomic Analysis of ApoE4-Carrying H4 Neuroglioma Cells in Alzheimer’s Disease Using OrbiSIMS and LC-MS/MS

Analytical Chemistry, Journal Year: 2024, Volume and Issue: 96(29), P. 11760 - 11770

Published: July 11, 2024

Growing clinical evidence reveals that systematic molecular alterations in the brain occur 20 years before onset of AD pathological features. Apolipoprotein E4 (ApoE4) is one most significant genetic risk factors for Alzheimer's disease (AD), which not only associated with features such as amyloid-β deposition, phosphorylation tau proteins, and neuroinflammation but also involved metabolism, neuron growth, synaptic plasticity. Multiomics, metabolomics proteomics, are applied widely identifying key disease-related disease-progression-related changes. Despite recent advances development analytical technologies, screening entire profile metabolites remains challenging due to numerous classes compounds diverse chemical properties require different extraction processes mass spectrometry. In this study, we utilized Orbitrap Secondary Ion Mass Spectrometry (OrbiSIMS) a filtering tool examine ApoE4-carried neuroglioma cells compared wild-type H4 cells. The findings were using liquid chromatography (LC)-MS/MS targeted analysis confirmation specific metabolite classes. Detected peptide fragments by OrbiSIMS provided preliminary indications protein These extensively analyzed through proteomics explore ApoE4's impact on proteins. Our approach, combining LC-MS/MS, revealed disruptions lipid including glycerophospholipids sphingolipids, well amino acid encompassing alanine, aspartate, glutamate metabolism; aminoacyl-tRNA biosynthesis; glutamine taurine hypotaurine metabolism. Further LC-MS/MS studies confirmed dysfunction tRNA aminoacylation metabolic processes, highlighted RNA splicing influenced ApoE4.

Language: Английский

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Development of a high-throughput screening platform to identify new therapeutic agents for Medulloblastoma Group 3

SLAS DISCOVERY, Journal Year: 2024, Volume and Issue: 29(2), P. 100147 - 100147

Published: Feb. 12, 2024

Pediatric brain tumors (PBTs) represent about 25% of all pediatric cancers and are the most common solid in children adolescents. Medulloblastoma (MB) is frequently occurring malignant PBT, accounting for almost 10% cancer deaths. MB Group 3 (MB G3) accounts 25-30% cases has worst outcome, particularly when associated with MYC amplification. However, no targeted treatments this group have been developed so far.Here we describe a unique high throughput screening (HTS) platform specifically designed to identify new therapies G3. The incorporates optimized validated 2D 3D efficacy toxicity models, that account tumor heterogenicity, limited unacceptable from very early stage drug discovery. by conducting pilot HTS campaign 1280 lead-like compound library. Results showed 8 active compounds, targeting reported targets several currently approved or clinical trials patients PBTs, including MB. Moreover, hits were combined avoid resistance, identifying synergistic pairs, one which under study recurrent other PBTs.

Language: Английский

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Orbi‐SIMS Mediated Metabolomics Analysis of Pathogenic Tissue up to Cellular Resolution

Chemistry - Methods, Journal Year: 2024, Volume and Issue: 4(7-8)

Published: July 12, 2024

Abstract Tumors have a complex metabolism that differs from most metabolic processes in healthy tissues. It is highly dynamic and driven by the tumor cells themselves, as well non‐transformed stromal infiltrates immune components. Each of these cell populations has distinct depends on both their cellular state availability nutrients. Consequently, to fully understand individual states all tumor‐forming cells, correlative mass spectrometric imaging (MSI) up resolution with minimal metabolite shift needs be achieved. By using secondary ion spectrometer (SIMS) equipped an Orbitrap analyzer, we present workflow image primary murine tissues correlate images post acquisition immunofluorescence or histological staining. In breast cancer model, could identify profiles clearly distinguish tissue infiltrates. We demonstrate robustness classification applying same independent model lung cancer, which accurately segmented traits. Our pipeline allows segmentation simultaneous identification, future will enable design subpopulation‐targeted interventions for therapeutic purposes.

Language: Английский

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Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing

Neuro-Oncology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 9, 2024

Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current preclinical vivo model systems for MB have increased our understanding molecular mechanisms regulating development. However, they may not be suitable large-scale studies. The aim this study was to investigate if a zebrafish-based xenograft can recapitulate growth and enable rapid drug testing.

Language: Английский

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Discriminant Principal Component Analysis of ToF‐SIMS Spectra for Deciphering Compositional Differences of MSC‐Secreted Extracellular Matrices

Small Methods, Journal Year: 2023, Volume and Issue: 7(6)

Published: March 28, 2023

Identifying characteristic extracellular matrix (ECM) variants is a key challenge in mechanistic biology, bioengineering, and medical diagnostics. The reported study demonstrates the potential of time-of-flight secondary ion mass spectrometry (ToF-SIMS) to detect subtle differences between human mesenchymal stromal cell (MSC)-secreted ECM types as induced by exogenous stimulation or emerging pathology. ToF-SIMS spectra decellularized samples are evaluated discriminant principal component analysis (DPCA), an advanced multivariate technique, decipher compositional features. To establish approach, signatures major proteins determined from pre-defined mixtures. Based on that, sets produced MSCs vitro analyzed. Differences content collagen, fibronectin, laminin resulting combined supplementation MSC cultures with polymers that induce macromolecular crowding ascorbic acid detected DPCA spectra. results verified immunostaining. Finally, comparative healthy donors patients suffering myelodysplastic syndrome display novel methodology reveal disease-associated alterations composition.

Language: Английский

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Advanced progress of spatial metabolomics in head and neck cancer research

Neoplasia, Journal Year: 2023, Volume and Issue: 47, P. 100958 - 100958

Published: Dec. 23, 2023

Head and neck cancer ranks as the sixth most prevalent malignancy, constituting 5 % of all cases. Its inconspicuous onset often leads to advanced stage diagnoses, prompting need for early detection enhance patient prognosis. Currently, research into diagnostic markers relies predominantly on genomics, proteomics, transcriptomics, other methods, which, unfortunately, necessitate tumor tissue homogenization, resulting in loss temporal spatial information. Emerging a recent addition omics toolkit, metabolomics stands out. This method conducts situ mass spectrometry analyses fresh specimens while effectively preserving their spatiotemporal The utilization life science offers distinct advantages. article comprehensively reviews progress head research, encompassing insights cell metabolic reprogramming. Various imaging techniques, such secondary ion spectrometry, stroma-assisted laser desorption/ionization, desorption electrospray ionization, enable metabolite analysis cancer. Finally, significant emphasis is placed application presently available techniques diagnosis, margin assessment, prognosis

Language: Английский

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Surviving the hunger games: Metabolic reprogramming in medulloblastoma

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 215, P. 115697 - 115697

Published: July 20, 2023

Medulloblastoma is a highly malignant pediatric brain tumor characterized by its aggressive nature and limited treatment options. Metabolic changes have recently emerged as key factors in the development, progression, response to therapy various types of cancer. Cancer cells exhibit remarkable adaptability modulating glucose, lipids, amino acids, nucleotide metabolism survive nutrient- oxygen-deprived environments. Although medulloblastoma has been extensively studied from genomic perspective, leading identification four subgroups their respective subcategories, investigation metabolic phenotype remained relatively understudied. This review focus on available literature, aiming summarize current knowledge about main pathways that are deregulated tumors, while emphasizing controversial aspects progress yet be made. Furthermore, we underscored insights gained so far regarding impact development drug resistance therapeutic strategies employed target specific pathways.

Language: Английский

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