Enhanced Fatty Acid Scavenging and Glycerophospholipid Metabolism Accompany Melanocyte Neoplasia Progression in Zebrafish.

Alterations in lipid metabolism in cancer cells impact cell structure, signaling, and energy metabolism, making lipid metabolism a potential diagnostic marker and therapeutic target. In this study, we combined PET, desorption electrospray ionization-mass spectrometry (DESI-MS), nonimaging MS, and transcriptomic analyses to interrogate changes in lipid metabolism in a transgenic zebrafish model of oncogenic RAS-driven melanocyte neoplasia progression. Exogenous fatty acid uptake was detected in melanoma tumor nodules by PET using the palmitic acid surrogate tracer 14(R,S)-18F-fluoro-6-thia-heptadecanoic acid ([18F]-FTHA), consistent with upregulation of genes associated with fatty acid uptake found through microarray analysis. DESI-MS imaging revealed that FTHA uptake in tumors was heterogeneous. Transcriptome and lipidome analyses further highlighted dysregulation of glycerophospholipid pathways in melanoma tumor nodules, including increased abundance of phosphatidyl ethanolamine and phosphatidyl choline species, corroborated by DESI-MS, which again revealed heterogeneous phospholipid composition in tumors. Overexpression of the gene encoding lipoprotein lipase (LPL), which was upregulated in zebrafish melanocyte tumor nodules and expressed in the majority of human melanomas, accelerated progression of oncogenic RAS-driven melanocyte neoplasia in zebrafish. Depletion or antagonism of LPL suppressed human melanoma cell growth; this required simultaneous fatty acid synthase (FASN) inhibition when FASN expression was also elevated. Collectively, our findings implicate fatty acid acquisition as a possible therapeutic target in melanoma, and the methods we developed for monitoring fatty acid uptake have potential for diagnosis, patient stratification, and monitoring pharmacologic response. SIGNIFICANCE: These findings demonstrate the translational potential of monitoring fatty acid uptake and identify lipoprotein lipase as a potential therapeutic target in melanoma.

Pre- and postsynaptic serotonergic differences in males with extreme levels of impulsive aggression without callous unemotional traits: a positron emission tomography study using (11)C-DASB and (11)C-MDL100907.

BACKGROUND: Impulsive aggression (IA) in adults is associated with brain serotonin (5-HT) system abnormalities and is more common following childhood adversity. Within aggressive behavior, IA and callous unemotional (CU) traits are core components of differentiable factors with opposing 5-HT abnormalities. We aimed to investigate 5-HT abnormalities in IA and potential correlations with severity of childhood adversity while controlling for confounding 5-HT effects of high CU traits and mental disorders. METHODS: Healthy male subjects (mean age 34 ± 9 years) without high CU traits were recruited with IA ratings in the high (n = 14) and low (n = 13) population extremes. Serotonin transporter (SERT) and 5-HT(2A) receptor availability was measured in multiple brain regions using positron emission tomography with (11)C-DASB and (11)C-MDL100907, respectively, and compared between high-IA and low-IA groups. Correlations were measured between SERT and 5-HT(2A) receptor availability, impulsivity and aggression, and childhood adversity. RESULTS: Compared with the low-IA group, SERT were significantly higher in brainstem regions in the high-IA group (by 29.0% ± 11.4%) and modestly lower across cortical regions (by 11.1% ± 6.0%), whereas 5-HT(2A) receptors were also modestly lower (by 8.6% ± 4.0%). Across all subjects, brainstem SERT were significantly positively correlated with impulsivity, aggression, and childhood trauma ratings. Within the high-IA group, higher brainstem SERT was most strongly predicted by severity of childhood trauma (r = .76 in midbrain). CONCLUSIONS: Pre-and postsynaptic 5-HT differences are present in men with high levels of IA and are strongly suggestive of a persisting effect of childhood adversity on serotonergic neurodevelopment and emotional-behavioral control.

An investigation of paint from a mural in the church of Sainte Madeleine, Manas, France.

The pigment in brown paint samples taken from a church in the Drôme region of France has been shown to be almost pure 6-bromoindigo and 6,6'-dibromoindigo. The composition of the pigment was established by comparison with 6-bromoindigo and 6,6'-dibromoindigo standards using atmospheric pressure photoionization combined with liquid chromatography and tandem mass spectrometry. The brown paint samples were taken from a frieze of ca 20 brown images having symmetric tree-like forms composed of five overlapping filled circles representing foliage. The tree-like images, simple rather than artistic, had a metallic luster. The molar ratio of 6-bromoindigo and 6,6'-dibromoindigo in the brown paint pigment (98:2) is remarkably similar to that of shellfish purple from the Mediterranean Murex brandaris (96.5:3.5) thus, it is possible that the origin of the indigoid compounds in the brown paint pigment is the eastern coast of the Mediterranean Sea. As the production of Tyrian purple ended with the fall of Byzantium in 1453, purple pigment had to have been produced prior to this time. We have conjectured about the circumstances that may account for the use of 'purple' in this manner in the Drôme region and how the pigment was transported there from the eastern coast of the Mediterranean Sea during the time of the Crusades.

Brain serotonin transporter occupancy by oral sibutramine dosed to steady state: a PET study using (11)C-DASB in healthy humans.

Sibutramine is a centrally acting monoamine reuptake inhibitor prescribed as an appetite suppressant in the management of obesity. Its effects are mostly attributable to serotonin and norepinephrine transporter (SERT and NET, respectively) inhibition by its potent metabolites mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2). However, there is a paucity of in vivo data in humans about mechanisms underlying both clinical efficacy and the dose-independent non-response observed in a minority of patients. Twelve healthy male patients (mean age 41 years) completed a double-blind, placebo-controlled, within-subject crossover investigation of brain SERT occupancy by sibutramine 15 mg daily at steady state. Correlations were measured between occupancy and (i) plasma concentrations of sibutramine, M1 and M2; (ii) appetite suppression. (11)C-DASB PET scans were performed on the HRRT camera. Binding potentials (BP(ND)) were calculated by the Logan reference tissue (cerebellum) method. SERT occupancy was modest (mean 30+/-10%), was similar across brain regions, but varied widely across subjects (15-46%). Occupancy was correlated positively (p=0.09) with M2 concentration, but not with sibutramine or M1. No significant appetite suppression was seen at <25% occupancy and greatest suppression was associated with highest occupancy (25-46%). However, several subjects with occupancy (36-39%) in the higher range had no appetite suppression. SERT occupancy by clinical doses of sibutramine is of modest magnitude and may be mediated predominantly by M2 in humans. 5-HT reuptake inhibition may be necessary but is not sufficient for sibutramine's efficacy in humans, supporting preclinical data suggesting that the hypophagic effect requires the co-inhibition of both SERT and NET.

Characterisation of heterogeneous solid surfaces by multiple probe, temperature-programmed inverse gas chromatography (IGC). A feasibility study.

A method is described for the characterisation of the surfaces of powdered solids by temperature programmed, multiple-probe, inverse gas chromatography. This modification of "traditional" inverse gas chromatography (IGC) allows rapid screening of solid surfaces to compare the adsorptive behaviour of pairs or sets of surfaces. This feasibility study examined the criteria for selection of a suitable probe set and approaches to the analysis and interpretation of the data generated. The technique was used to compare carbon black samples, chosen for their surface heterogeneity and the difficulty of surface characterisation using other techniques. The choice of a low surface area, methylated silica solid diluent and the elimination of its influence on the measurements is discussed. The probe set selected readily distinguished the carbon black samples and allowed tentative conclusions to be drawn regarding steric and electronic influences on probe-solid interactions.