Neuronal GPCR NMUR-1 regulates energy homeostasis in response to pathogen infection.

A key question in current immunology is how the innate immune system generates high levels of specificity. Our previous study in revealed that NMUR-1, a neuronal G protein-coupled receptor homologous to mammalian receptors for the neuropeptide neuromedin U (NMU), regulates distinct innate immune responses to different bacterial pathogens. Here, by using quantitative proteomics and functional assays, we discovered that NMUR-1 regulates FF ATP synthase and ATP production in response to pathogen infection, and that such regulation contributes to NMUR-1-mediated specificity of innate immunity.

Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer.

Mutant KRAS (KM), the most common oncogene in lung cancer (LC), regulates fatty acid (FA) metabolism. However, the role of FA in LC tumorigenesis is still not sufficiently characterized. Here, we show that KMLC has a specific lipid profile, with high triacylglycerides and phosphatidylcholines (PC).

Oleic acid is an endogenous ligand of TLX/NR2E1 that triggers hippocampal neurogenesis.

Neural stem cells, the source of newborn neurons in the adult hippocampus, are intimately involved in learning and memory, mood, and stress response. Despite considerable progress in understanding the biology of neural stem cells and neurogenesis, regulating the neural stem cell population precisely has remained elusive because we have lacked the specific targets to stimulate their proliferation and neurogenesis. The orphan nuclear receptor TLX/NR2E1 governs neural stem and progenitor cell self-renewal and proliferation, but the precise mechanism by which it accomplishes this is not well understood because its endogenous ligand is not known.

CES2 sustains HNF4α expression to promote pancreatic adenocarcinoma progression through an epoxide hydrolase-dependent regulatory loop.

Objective: Intra-tumoral expression of the serine hydrolase carboxylesterase 2 (CES2) contributes to the activation of the pro-drug irinotecan in pancreatic ductal adenocarcinoma (PDAC). Given other potential roles of CES2, we assessed its regulation, downstream effects, and contribution to tumor development in PDAC.

Methods: Association between the mRNA expression of CES2 in pancreatic tumors and overall survival was assessed using The Cancer Genome Atlas.

CES2 Expression in Pancreatic Adenocarcinoma Is Predictive of Response to Irinotecan and Is Associated With Type 2 Diabetes.

Purpose: The combination chemotherapy of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has provided clinically meaningful improvement for pancreatic ductal adenocarcinoma (PDAC). We previously uncovered a role for the serine hydrolase carboxylesterase 2 (CES2) in mediating intratumoral activation of the prodrug irinotecan, a constituent of FOLFIRINOX. We aimed to further test the predictive value of CES2 for response to irinotecan using patient-derived xenograft (PDX) models and to elucidate the determinants of CES2 expression and response to FOLFIRINOX treatment among patients with PDAC.

ITLN1 modulates invasive potential and metabolic reprogramming of ovarian cancer cells in omental microenvironment.

Advanced ovarian cancer usually spreads to the omentum. However, the omental cell-derived molecular determinants modulating its progression have not been thoroughly characterized. Here, we show that circulating ITLN1 has prognostic significance in patients with advanced ovarian cancer.

Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress.

: Cisplatin (CDDP) is commonly utilized in the treatment of advanced solid tumors including head and neck squamous cell carcinoma (HNSCC). Cisplatin response remains highly variable among individual tumors and development of cisplatin resistance is common. We hypothesized that development of cisplatin resistance is partially driven by metabolic reprogramming.

Correlation of molecular and morphologic effects of thermoembolization in a swine model using mass spectrometry imaging.

Hepatocellular carcinoma is a growing worldwide problem with a high mortality rate. This malignancy does not respond well to chemotherapy, and most patients present late in their disease at which time surgery is no longer an option. Over the past three decades, minimally invasive methods have evolved to treat unresectable disease and prolong survival.

Imaging Mass Spectrometry: A New Tool to Assess Molecular Underpinnings of Neurodegeneration.

Neurodegenerative diseases are prevalent and devastating. While extensive research has been done over the past decades, we are still far from comprehensively understanding what causes neurodegeneration and how we can prevent it or reverse it. Recently, systems biology approaches have led to a holistic examination of the interactions between genome, metabolome, and the environment, in order to shed new light on neurodegenerative pathogenesis.

Dual-Energy CT: Lower Limits of Iodine Detection and Quantification.

Background Assessments of the quantitative limitations among the six commercially available dual-energy (DE) CT acquisition schemes used by major CT manufacturers could aid researchers looking to use iodine quantification as an imaging biomarker. Purpose To determine the limits of detection and quantification of DE CT in phantoms by comparing rapid peak kilovoltage switching, dual-source, split-filter, and dual-layer detector systems in six different scanners. Materials and Methods Seven 50-mL iohexol solutions were used, with concentrations of 0.

Analytical Platforms and Techniques to Study Stem Cell Metabolism.

Over the past decade, advances in systems biology or 'omics techniques have enabled unprecedented insights into the biological processes that occur in cells, tissues, and on the organism level. One of these technologies is the metabolomics, which examines the whole content of the metabolites in a given sample. In a biological system, a stem cell for instance, there are thousands of single components, such as genes, RNA, proteins, and metabolites.

Cisplatin generates oxidative stress which is accompanied by rapid shifts in central carbon metabolism.

Cisplatin is commonly utilized in the treatment of solid tumors. Its mechanism of action is complex and multiple mechanisms of resistance have been described. We sought to determine the impact of cisplatin-generated oxidative stress on head and neck squamous cell carcinoma (HNSCC) proliferation, survival and metabolic activity in order to identify a potential metabolic signature associated with cisplatin response.

Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy.

Unlabelled: Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis.

Pharmacokinetic determinants of virological response to raltegravir in the in vitro pharmacodynamic hollow-fiber infection model system.

Daily administration (q24h) of raltegravir has been shown to be as efficacious as twice-daily administration (q12h) in the hollow-fiber infection model (HFIM) system. However, q24h regimens were not noninferior to q12h dosing in a clinical trial. We hypothesized that between-patient variability in raltegravir pharmacokinetics (PK) was responsible for the discordance in conclusions between the in vitro and in vivo studies.

Pharmacodynamic evaluation of the activities of six parenteral vancomycin products available in the United States.

A recent report found that generic parenteral vancomycin products may not have in vivo efficacies equivalent to those of the innovator in a neutropenic murine thigh infection model despite having similar in vitro microbiological activities and murine serum pharmacokinetics. We compared the in vitro and in vivo activities of six of the parenteral vancomycin products available in the United States. The in vitro assessments for the potencies of the vancomycin products included MIC/minimal bactericidal concentration (MBC) determinations, quantifying the impact of human and murine serum on the MIC values, and time-kill studies.

Combination treatment with meropenem plus levofloxacin is synergistic against Pseudomonas aeruginosa infection in a murine model of pneumonia.

Background: Meropenem plus levofloxacin treatment was shown to be a promising combination in our in vitro hollow fiber infection model. We strove to validate this finding in a murine Pseudomonas pneumonia model.

Methods: A dose-ranging study with meropenem and levofloxacin alone and in combination against Pseudomonas aeruginosa was performed in a granulocytopenic murine pneumonia model.

Interaction of drug- and granulocyte-mediated killing of Pseudomonas aeruginosa in a murine pneumonia model.

Background: Killing of bacterial pathogens by granulocytes is a saturable process, as previously demonstrated. There is virtually no quantitative information about how granulocytes interact with antimicrobial chemotherapy to kill bacterial cells.

Methods: We performed a dose-ranging study with the aminoglycoside plazomicin against Pseudomonas aeruginosa ATCC27853 in a granulocyte-replete murine pneumonia model.

Automated MALDI matrix deposition method with inkjet printing for imaging mass spectrometry.

Careful matrix deposition on tissue samples for matrix-assisted laser desorption/ionization (MALDI) is critical for producing reproducible analyte ion signals. Traditional methods for matrix deposition are often considered an art rather than a science, with significant sample-to-sample variability. Here we report an automated method for matrix deposition, employing a desktop inkjet printer (<$200) with 5760 x 1440 dpi resolution and a six-channel piezoelectric head that delivers 3 pL/drop.