Pancreatic cancer has the worst prognosis among all cancers. Cancer screening of body fluids may improve the survival time prognosis of patients, who are often diagnosed too late at an incurable stage. Several studies report the dysregulation of lipid metabolism in tumor cells, suggesting that changes in the blood lipidome may accompany tumor growth. Here we show that the comprehensive mass spectrometric determination of a wide range of serum lipids reveals statistically significant differences between pancreatic cancer patients and healthy controls, as visualized by multivariate data analysis. Three phases of biomarker discovery research (discovery, qualification, and verification) are applied for 830 samples in total, which shows the dysregulation of some very long chain sphingomyelins, ceramides, and (lyso)phosphatidylcholines. The sensitivity and specificity to diagnose pancreatic cancer are over 90%, which outperforms CA 19-9, especially at an early stage, and is comparable to established diagnostic imaging methods. Furthermore, selected lipid species indicate a potential as prognostic biomarkers.

26Alzheimer's disease (AD) is the most common neurodegenerative disease affecting 27 the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in 28 the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced 29 mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by 30 expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on a 31 deeper analysis of these metabolic changes associated with A-induced mitochondrial 32 dysfunction. Integrating metabolomics, transcriptomics, biochemical studies and 33 computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle 34 metabolism following even low-level Aβ expression. In particular, GRU102 show 35 reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate 36 dehydrogenase. These defects are associated with elevation of protein carbonyl 37 content specifically in mitochondria. Importantly, metabolic failure occurs before any 38 significant increase in global protein aggregate is detectable. Treatment with an anti-39 diabetes drug, Metformin, reverses A-induced metabolic defects, reduces protein 40 aggregation and normalizes the lifespan of GRU102. Our results point to metabolic 41 dysfunction as an early and causative event in AD pathology and a promising target 42 for intervention. 43 44 45 46 47 48 49 50 51 Introduction 52Alzheimer's disease (AD) is a debilitating neurodegenerative disease, that is clinically 53 characterized by the formation of amyloid-beta (A) plaques and aggregates of 54 hyperphosphorylated tau protein in the brain 1 . Even though AD is primarily a 55 neuronal disorder, perturbations in mitochondrial functions including energy 56 metabolism have consistently been observed not only in the brain 2-4 but also in non-57 neuronal cells derived from AD subjects, including in fibroblasts and platelets [5][6][7][8][9][10] . 58These findings form part of an emerging story that there is an important metabolic 59 component to the etiology of AD 11 , and that these metabolic defects may precede A 60 aggregate formation 12,13 . The metabolism-related hypothesis of AD therefore posits 61 that AD is, in part, mediated by impairments to the brain's insulin response, which 62 promotes oxidative stress and inflammation, similar to that seen in diabetes 11,14 . 63Intranasal insulin treatment has been shown to ameliorate AD pathology in a 64 transgenic rat model and to improve mild cognitive impairment (MCI) in patients [15][16][17][18] . 65 66Several animal studies have confirmed that oxidative stress, mitochondrial 67 dysfunction and metabolic alterations are early events in the pathophysiological 68 progression of AD. Energy deficits, reduction in mitochondrial membrane potential, 69 abnormal mitochondrial gene expression and increased oxidative stress have been 70 observed early in transgenic AD mice (2-3 months of age) well before the appearance 71 of A plaques 19,20 . The A-induced oxidative stress hypothesis further posits that A, 72 predomi...

Background Fetal docosahexaenoic acid (DHA) supply relies on preferential transplacental transfer, which is regulated by placental DHA lipid metabolism. Maternal hyperglycemia and obesity associate with higher birthweight and fetal DHA insufficiency but the role of placental DHA metabolism is unclear. Methods Explants from 17 term placenta were incubated with 13C-labeled DHA for 48 h, at 5 or 10 mmol/L glucose treatment, and the production of 17 individual newly synthesized 13C-DHA labeled lipids quantified by liquid chromatography mass spectrometry. Results Maternal BMI positively associated with 13C-DHA-labeled diacylglycerols, triacylglycerols, lysophospholipids, phosphatidylcholine and phosphatidylethanolamine plasmalogens, while maternal fasting glycemia positively associated with five 13C-DHA triacylglycerols. In turn, 13C-DHA-labeled phospholipids and triacylglycerols positively associated with birthweight centile. In-vitro glucose treatment increased most 13C-DHA-lipids, but decreased 13C-DHA phosphatidylethanolamine plasmalogens. However, with increasing maternal BMI, the magnitude of the glucose treatment induced increase in 13C-DHA phosphatidylcholine and 13C-DHA lysophospholipids was curtailed, with further decline in 13C-DHA phosphatidylethanolamine plasmalogens. Conversely, with increasing birthweight centile glucose treatment induced increases in 13C-DHA triacylglycerols were exaggerated, while glucose treatment induced decreases in 13C-DHA phosphatidylethanolamine plasmalogens were diminished. Conclusions Maternal BMI and glycemia increased the production of different placental DHA lipids implying impact on different metabolic pathways. Glucose-induced elevation in placental DHA metabolism is moderated with higher maternal BMI. In turn, findings of associations between many DHA lipids with birthweight suggest that BMI and glycemia promote fetal growth partly through changes in placental DHA metabolism.

Nuclear envelope (NE) expansion must be controlled to maintain nuclear shape and function. The nuclear membrane expands massively during ‘closed’ mitosis, enabling chromosome segregation within an intact NE. Phosphatidic acid (PA) and diacylglycerol (DG) can both serve as biosynthetic precursors for membrane lipid synthesis. How they are regulated in time and space and what are the implications of changes in their flux for mitotic fidelity is largely unknown. Using genetically encoded PA and DG probes, we show that DG is depleted from the inner nuclear membrane during mitosis in the fission yeast Schizosaccharomyces pombe, but PA does not accumulate, indicating that it is rerouted to membrane synthesis. We demonstrate that DG-to-PA conversion catalysed by the diacylglycerol kinase Dgk1 and direct glycerophospholipid synthesis from DG by diacylglycerol cholinephosphotransferase / ethanolaminephosphotransferase Ept1 reinforce NE expansion. We conclude that DG consumption through both de novo and the Kennedy pathways fuels a spike in glycerophospholipid biosynthesis, controlling NE expansion, and ultimately, mitotic fidelity.

Pancreatic cancer has the worst prognosis among all cancers1. Cancer screening programs based on the analysis of body fluids can improve the survival time of patients, who are often diagnosed too late at an incurable stage2. Several studies have reported the dysregulation of lipid metabolism in tumor cells and tissues3, suggesting that the changes of blood lipidome may accompany tumor growth and progression. Analytical methods based on mass spectrometry (MS) using either direct infusion or chromatographic separation4 are convenient for high-throughput lipidomic profiling. Here we show that the comprehensive quantitation of a wide range of serum lipids reveals statistically significant differences between pancreatic cancer patients and healthy controls visualized by multivariate data analysis. Initial results for 364 human serum samples in the discovery phase were subsequently verified in the qualification phase on 554 samples measured by three independent laboratories, and finally on 830 samples from four blood collection sites in the verification phase. Concentrations suggestive of dysregulation of some very long chain sphingomyelins (SM 42:1, SM 41:1, SM 39:1, and SM 40:1), ceramides (Cer 41:1, and Cer 42:1), and (lyso)phosphatidylcholines (LPC 18:2) were recorded. Some lipid species indicated a potential as biomarkers of survival. The sensitivity and specificity to diagnose pancreatic cancer is over 90%, which outperforms CA 19-9, especially in early stage, and is comparable to established imaging diagnostic methods. The accuracy of lipidomic approach is not influenced by the cancer stage, analytical method, or blood collection site.