scholarly journals Large-scale and high-resolution mass spectrometry-based proteomics profiling defines molecular subtypes of esophageal cancer for therapeutic targeting

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wei Liu ◽  
Lei Xie ◽  
Yao-Hui He ◽  
Zhi-Yong Wu ◽  
Lu-Xin Liu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Esophageal Cancer ◽  
Proteomic Analysis ◽  
Ribosomal Proteins ◽  
Large Scale ◽  
Molecular Subtypes ◽  
High Resolution Mass Spectrometry ◽  
Model Potential ◽  
Effective Strategies ◽  
Aggressive Cancer

AbstractEsophageal cancer (EC) is a type of aggressive cancer without clinically relevant molecular subtypes, hindering the development of effective strategies for treatment. To define molecular subtypes of EC, we perform mass spectrometry-based proteomic and phosphoproteomics profiling of EC tumors and adjacent non-tumor tissues, revealing a catalog of proteins and phosphosites that are dysregulated in ECs. The EC cohort is stratified into two molecular subtypes—S1 and S2—based on proteomic analysis, with the S2 subtype characterized by the upregulation of spliceosomal and ribosomal proteins, and being more aggressive. Moreover, we identify a subtype signature composed of ELOA and SCAF4, and construct a subtype diagnostic and prognostic model. Potential drugs are predicted for treating patients of S2 subtype, and three candidate drugs are validated to inhibit EC. Taken together, our proteomic analysis define molecular subtypes of EC, thus providing a potential therapeutic outlook for improving disease outcomes in patients with EC.

scholarly journals AlphaTims: Indexing trapped ion mobility spectrometry - time of flight data for fast and easy accession and visualization

2021 ◽  
Author(s):  
Sander Willems ◽  
Eugenia Voytik ◽  
Patricia Skowronek ◽  
Maximilian T Strauss ◽  
Matthias Mann
Keyword(s):  
Mass Spectrometry ◽  
Open Source ◽  
Ion Mobility Spectrometry ◽  
Ion Mobility ◽  
Large Scale ◽  
High Resolution Mass Spectrometry ◽  
Time Of Flight ◽  
Arrival Times ◽  
Trapped Ion ◽  
Trapped Ion Mobility Spectrometry

High resolution mass spectrometry-based proteomics generates large amounts of data, even in the standard liquid chromatography (LC) - tandem mass spectrometry configuration. Adding an ion mobility dimension vastly increases the acquired data volume, challenging both analytical processing pipelines and especially data exploration by scientists. This has necessitated data aggregation, effectively discarding much of the information present in these rich data sets. Taking trapped ion mobility spectrometry (TIMS) on a quadrupole time-of-flight platform (Q-TOF) as an example, we developed an efficient indexing scheme that represents all data points as detector arrival times on scales of minutes (LC), milliseconds (TIMS) and microseconds (TOF). In our open source AlphaTims package, data are indexed, accessed and visualized by a combination of tools of the scientific Python ecosystem. We interpret unprocessed data as a sparse 4D matrix and use just-in-time compilation to machine code with Numba, accelerating our computational procedures by several orders of magnitude while keeping to familiar indexing and slicing notations. For samples with more than six billion detector events, a modern laptop can load and index raw data in about a minute. Loading is even faster when AlphaTims has already saved indexed data in a HDF5 file, a portable scientific standard used in extremely large-scale data acquisition. Subsequently, data accession along any dimension and interactive visualization happen in milliseconds. We have found AlphaTims to be a key enabling tool to explore high dimensional LC-TIMS-QTOF data and have made it freely available as an open-source Python package with a stand-alone graphical user interface at https://github.com/MannLabs/alphatims or as part of the AlphaPept ecosystem.

scholarly journals Large-scale, enzyme-based xenobiotic identification for exposomics

2020 ◽  
Author(s):  
Ken Liu ◽  
Choon Lee ◽  
Grant Singer ◽  
Michael Woodworth ◽  
Thomas Ziegler ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Resolution ◽  
Retention Time ◽  
Human Disease ◽  
Large Scale ◽  
High Resolution Mass Spectrometry ◽  
Chemical Identification ◽  
Mass Spectrometry Identification ◽  
Level Of Understanding ◽  
Resolution Mass

Abstract Advances in genomics have revealed many of the genetic underpinnings of human disease, but exposomics methods are currently inadequate to obtain a similar level of understanding of environmental contributions to human disease. Exposomics methods are limited by low abundance of xenobiotic metabolites and lack of authentic standards, which precludes identification using solely mass spectrometry-based criteria. Here, we develop and validate a method for enzymatic generation of xenobiotic metabolites for use with high-resolution mass spectrometry (HRMS) for chemical identification. Generated xenobiotic metabolites were used to confirm identities of respective metabolites in mice and human samples based upon accurate mass, retention time and co-occurrence with related xenobiotic metabolites. The results establish a generally applicable enzyme-based identification (EBI) for mass spectrometry identification of xenobiotic metabolites.

scholarly journals Acute pancreatitis promotes the generation of two different exosome populations

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
A. Jiménez-Alesanco ◽  
M. Marcuello ◽  
M. Pastor-Jiménez ◽  
L. López-Puerto ◽  
L. Bonjoch ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Acute Pancreatitis ◽  
Proteomic Analysis ◽  
Ribosomal Proteins ◽  
Deep Understanding ◽  
Physiological Effects ◽  
Cell Distribution ◽  
Different Populations ◽  
Low Levels ◽  
Alveolar Compartment

AbstractExosomes are small extracellular vesicles that act as intercellular messengers. Previous studies revealed that, during acute pancreatitis, circulating exosomes could reach the alveolar compartment and activate macrophages. However, proteomic analysis suggested that the most likely origin of these exosomes could be the liver instead of the pancreas. The present study aimed to characterize the exosomes released by pancreas to pancreatitis-associated ascitic fluid (PAAF) as well as those circulating in plasma in an experimental model of taurocholate-induced acute pancreatitis in rats. We provide evidence that during acute pancreatitis two different populations of exosomes are generated with relevant differences in cell distribution, protein and microRNA content as well as different implications in their physiological effects. During pancreatitis plasma exosomes, but not PAAF exosomes, are enriched in the inflammatory miR-155 and show low levels of miR-21 and miR-122. Mass spectrometry-based proteomic analysis showed that PAAF exosomes contains 10–30 fold higher loading of histones and ribosomal proteins compared to plasma exosomes. Finally, plasma exosomes have higher pro-inflammatory activity on macrophages than PAAF exosomes. These results confirm the generation of two different populations of exosomes during acute pancreatitis. Deep understanding of their specific functions will be necessary to use them as therapeutic targets at different stages of the disease.

scholarly journals Precursor-Directed Biosynthesis of Aminofulvenes: New Chalanilines from Endophytic Fungus Chalara sp.

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4418
Author(s):  
Mahsa Khoshbakht ◽  
Jason Srey ◽  
Donovon A. Adpressa ◽  
Annika Jagels ◽  
Sandra Loesgen
Keyword(s):  
Mass Spectrometry ◽  
Structure Elucidation ◽  
Large Scale ◽  
High Resolution Mass Spectrometry ◽  
2D Nmr ◽  
Chemical Diversity ◽  
Epigenetic Modifier ◽  
Nmr Techniques ◽  
Directed Biosynthesis ◽  
Resolution Mass

The plant endophyte Chalara sp. is able to biotransform the epigenetic modifier vorinostat to form unique, aniline-containing polyketides named chalanilines. Here, we sought to expand the chemical diversity of chalaniline A-type molecules by changing the aniline moiety in the precursor vorinostat. In total, twenty-three different vorinostat analogs were prepared via two-step synthesis, and nineteen were incorporated by the fungus into polyketides. The highest yielding substrates were selected for large-scale precursor-directed biosynthesis and five novel compounds, including two fluorinated chalanilines, were isolated, purified, and structurally characterized. Structure elucidation relied on 1D and 2D NMR techniques and was supported by low- and high-resolution mass spectrometry. All compounds were tested for their bioactivity but were not active in antimicrobial or cell viability assays. Aminofulvene-containing natural products are rare, and this high-yielding, precursor-directed process allows for the diversification of this class of compounds.

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