Chemical genomics with pyrvinium identifies C1orf115 as a regulator of drug efflux.

Pyrvinium is a quinoline-derived cyanine dye and an approved anti-helminthic drug reported to inhibit WNT signaling and have anti-proliferative effects in various cancer cell lines. To further understand the mechanism by which pyrvinium is cytotoxic, we conducted a pooled genome-wide CRISPR loss-of-function screen in the human HAP1 cell model. The top drug-gene sensitizer interactions implicated the malate-aspartate and glycerol-3-phosphate shuttles as mediators of cytotoxicity to mitochondrial complex I inhibition including pyrvinium.

Publisher Correction: Targeting hepatic glutaminase activity to ameliorate hyperglycemia.

In the version of this article initially published, the "[13C2]α-ketoglutarate" label on Fig. 1g is incorrect. It should be "[13C5]α-ketoglutarate".

Targeting hepatic glutaminase activity to ameliorate hyperglycemia.

Glucagon levels increase under homeostatic, fasting conditions, promoting the release of glucose from the liver by accelerating the breakdown of glycogen (also known as glycogenolysis). Glucagon also enhances gluconeogenic flux, including from an increase in the hepatic consumption of amino acids. In type 2 diabetes, dysregulated glucagon signaling contributes to the elevated hepatic glucose output and fasting hyperglycemia that occur in this condition.

EGFR signaling promotes inflammation and cancer stem-like activity in inflammatory breast cancer.

Inflammatory breast cancer (IBC) is the most lethal and aggressive type of breast cancer, with a strong proclivity to metastasize, and IBC-specific targeted therapies have not yet been developed. Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in IBC. However, the mechanism behind the therapeutic effect of EGFR targeted therapy is not well defined.

Phenotyping hepatocellular metabolism using uniformly labeled carbon-13 molecular probes and LC-HRMS stable isotope tracing.

Metabolite stable isotope tracing is a powerful bioanalytical strategy that has the potential to unravel phenotypic markers of early pharmaceutical efficacy by monitoring enzymatic incorporation of carbon-13 atoms into targeted pathways over time. The practice of probing biological systems with carbon-13 labeled molecules using broad MS-based screens has been utilized for many years in academic laboratories but has had limited application in the pharmaceutical R&D environment. The goal of this work was to establish a LCMS analytical workflow that was capable of monitoring carbon-13 isotope changes in glycolysis, the TCA and urea cycles, and non-essential amino acid metabolism.

Changes in cancer cell metabolism revealed by direct sample analysis with MALDI mass spectrometry.

Biomarker discovery using mass spectrometry (MS) has recently seen a significant increase in applications, mainly driven by the rapidly advancing field of metabolomics. Instrumental and data handling advancements have allowed for untargeted metabolite analyses which simultaneously interrogate multiple biochemical pathways to elucidate disease phenotypes and therapeutic mechanisms. Although most MS-based metabolomic approaches are coupled with liquid chromatography, a few recently published studies used matrix-assisted laser desorption (MALDI), allowing for rapid and direct sample analysis with minimal sample preparation.

Quantitative MALDI tandem mass spectrometric imaging of cocaine from brain tissue with a deuterated internal standard.

Mass spectrometric imaging (MSI) is an analytical technique used to determine the distribution of individual analytes within a given sample. A wide array of analytes and samples can be investigated by MSI, including drug distribution in rats, lipid analysis from brain tissue, protein differentiation in tumors, and plant metabolite distributions. Matrix-assisted laser desorption/ionization (MALDI) is a soft ionization technique capable of desorbing and ionizing a large range of compounds, and it is the most common ionization source used in MSI.

Identifying tissue-specific signal variation in MALDI mass spectrometric imaging by use of an internal standard.

Generating analyte-specific distribution maps of compounds in a tissue sample by matrix-assisted laser desorption/ionization (MALDI) mass spectrometric imaging (MSI) has become a useful tool in numerous areas across the biological sciences. Direct analysis of the tissue sample provides MS images of an analyte's distribution with minimal sample pretreatment. The technique, however, suffers from the inability to account for tissue-specific variations in ion signal.

Quantitative tandem mass spectrometric imaging of endogenous acetyl-L-carnitine from piglet brain tissue using an internal standard.

Matrix-assisted laser desorption/ionization (MALDI) based mass spectrometric imaging (MSI) is increasingly being used as an analytical tool to evaluate the molecular makeup of tissue samples. From the direct analysis of a tissue section, the physical integrity of sample is preserved; thus, spatial information of a compound's distribution may be determined. One limitation of the technique, however, has been the inability to determine the absolute concentration from a tissue sample.

Plasma concentration and local anesthetic activity of procaine hydrochloride following subcutaneous administration to horses.

Objective: To determine the durations of the local anesthetic effect and plasma procaine concentrations associated with 5- and 10-mg doses of procaine hydrochloride (with or without 100 microg of epinephrine) administered SC over the lateral palmar digital nerves of horses.

Animals: 6 healthy adult horses.

Procedures: The hoof withdrawal reflex latency (HWRL) period was determined by use of a focused heat lamp before and after administration of procaine with and without epinephrine.