Publications by authors named "James Sawicki"

Article Synopsis
  • Native mass spectrometry (MS) is a crucial technique for studying noncovalent interactions between proteins and ligands, but not all MS methods maintain proteins' natural shapes.
  • The demand for quick analysis methods is particularly important in the early phases of drug discovery since most approved and developing drugs interact with targets through these noncovalent interactions.
  • This study outlines a rapid approach using IR-MALDESI-MS, achieving approximately 13-second analysis times for noncovalent protein-ligand complexes, specifically testing known binders with carbonic anhydrase and Bruton's tyrosine kinase.
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Introduction: Ultra-high-throughput mass spectrometry, uHT-MS, is a technology that utilizes ionization and sample delivery technologies optimized to enable sampling from well plates at > 1 sample per second. These technologies do not need a chromatographic separation step and can be utilized in a wide variety of assays to detect a broad range of analytes including small molecules, lipids, and proteins.

Areas Covered: This manuscript provides a brief historical review of high-throughput mass spectrometry and the recently developed technologies that have enabled uHT-MS.

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The complexity of new therapeutics continues to increase and the timeline for the discovery of these therapeutics continues to shrink. This creates demand for new analytical techniques to facilitate quicker discovery and development of novel drugs. Mass spectrometry is one of the most prolific analytical techniques that has been applied across the entire drug discovery pipeline.

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Introduction: Secondary pharmacology profiling is routinely applied in pharmaceutical drug discovery to investigate the pharmaceutical effects of a drug at molecular targets distinct from (off-target) the intended therapeutic molecular target (on-target). Data from a randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on VIOXX, rofecoxib) trial, raised significant concerns about COX-2 inhibition as a primary or secondary target, shaping the screening and decision-making processes of some pharmaceutical companies. COX-2 is often included in off-target screens due to cardiovascular (CV) safety concerns about secondary interactions with this target.

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The utility of zebrafish is becoming more frequent due to lower costs and high similarities to humans. Zebrafish larvae are attractive subjects for drug screening and drug metabolism research. However, obtaining good quality zebrafish larvae sections for batch samples at designated planes, angles, and locations for comparison purposes is a challenging task.

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(1) Imaging of pharmaceutical compounds in tissue is an increasingly important subsection of Mass Spectrometry Imaging (MSI). Identifying proper target engagement requires MS platforms with high sensitivity and spatial resolution. Three prominent categories of drugs are small molecule drugs, antibody-drug conjugate payloads, and protein degraders.

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Mass spectrometry (MS) is the primary analytical tool used to characterize proteins within the biopharmaceutical industry. Electrospray ionization (ESI) coupled to liquid chromatography (LC) is the current gold standard for intact protein analysis. However, inherent speed limitations of LC/MS prevent analysis of large sample numbers (>1000) in a day.

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Infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry is an ambient-direct sampling method that is being developed for high-throughput, label-free, biochemical screening of large-scale compound libraries. Here, we report the development of an ultra-high-throughput continuous motion IR-MALDESI sampling approach capable of acquiring data at rates up to 22.7 samples per second in a 384-well microtiter plate.

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Mass spectrometry (MS) can provide high sensitivity and specificity for biochemical assays without the requirement of labels, eliminating the risk of assay interference. However, its use had been limited to lower-throughput assays due to the need for chromatography to overcome ion suppression from the sample matrix. Direct analysis without chromatography has the potential for high throughput if sensitivity is sufficient despite the presence of a matrix.

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Percutaneous microwave ablation (MWA) is a promising technology for patients with breast cancer, as it may help treat individuals who have less aggressive cancers or do not respond to targeted therapies in the neoadjuvant or pre-surgical setting. In this study, we investigate changes to the microwave dielectric properties of breast tissue that are induced by MWA. While similar changes have been characterized for relatively homogeneous tissues, such as liver, those prior results are not directly translatable to breast tissue because of the extreme tissue heterogeneity present in the breast.

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Objective: In this paper, we investigate the impact of perfusion on the performance of microwave ablation across a large frequency range.

Methods: We designed multiple microwave ablation antennas to operate in liver tissue at discrete frequencies in the range 1.9-18 GHz.

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Article Synopsis
  • - Venetoclax (ABT-199) is a B-cell lymphoma-2 (Bcl-2) inhibitor being developed for blood cancers, with studies showing that after a single oral dose in humans, the complete radioactive dose was recovered, mainly through feces, while very little was excreted in urine.
  • - Around 65% of venetoclax is absorbed, with about 66% of the dose processed by the liver, resulting in several metabolites, including the unchanged drug and its nitro reduction metabolite M30, which was mostly found in feces.
  • - One significant metabolite, M27, accounts for 12% of the drug-related material and is formed mainly through the cyto
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Purpose: The use of higher frequencies in percutaneous microwave ablation (MWA) may offer compelling interstitial antenna design advantages over the 915 MHz and 2.45 GHz frequencies typically employed in current systems. To evaluate the impact of higher frequencies on ablation performance, we conducted a comprehensive computational and experimental study of microwave absorption and tissue heating as a function of frequency.

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There has been a recent surge of interest in the use of transition metal polypyridyl complexes as visible light-absorbing photocatalysts for synthetic applications. Among the most attractive features of this approach is the availability of many known complexes with well-characterized photophysical and electrochemical properties. In particular, Ru(bpz)3 (2+) is a powerful photooxidant that has proven to be uniquely suited for oxidatively induced photoredox transformations.

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A synthetic strategy to access 2,6-disubstituted pyridines from triazolopyridines through a regioselective nickel-catalyzed alkenylation reaction of the C7-H bond is described. The N2 fragment embedded in the resulting C-H functionalized triazolopyridine can be readily excised using acidic or oxidative conditions to unmask the pyridine.

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