Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted.

Tumours ferment glucose to lactate even in the presence of oxygen (aerobic glycolysis; Warburg effect). The pentose phosphate pathway (PPP) allows glucose conversion to ribose for nucleic acid synthesis and glucose degradation to lactate. The nonoxidative part of the PPP is controlled by transketolase enzyme reactions. We have detected upregulation of a mutated transketolase transcript (TKTL1) in human malignancies, whereas transketolase (TKT) and transketolase-like-2 (TKTL2) transcripts were not upregulated. Strong TKTL1 protein expression was correlated to invasive colon and urothelial tumours and to poor patients outcome. TKTL1 encodes a transketolase with unusual enzymatic properties, which are likely to be caused by the internal deletion of conserved residues. We propose that TKTL1 upregulation in tumours leads to enhanced, oxygen-independent glucose usage and a lactate-based matrix degradation. As inhibition of transketolase enzyme reactions suppresses tumour growth and metastasis, TKTL1 could be the relevant target for novel anti-transketolase cancer therapies. We suggest an individualised cancer therapy based on the determination of metabolic changes in tumours that might enable the targeted inhibition of invasion and metastasis.

Single-step gas chromatography-mass spectrometry analysis of glycolipid constituents as heptafluorobutyrate derivatives with a special reference to the lipid portion.

In a previous work (Zanetta et al. Glycobiology 9, 255-266 (1999)), it was reported that all constituents of gangliosides could be obtained as heptafluorobutyrate derivatives after methanolysis in a single gas chromatography analysis. This report demonstrates that gas chromatography coupled with mass spectrometry in the electron impact mode allows identification and quantification of long-chain bases and fatty acids without interference from monosaccharides. On the basis of ions specific for families and for individual compounds, sphingosines, sphinganines, and phytosphingosines (including ramified, unsaturated, hydroxylated, and etherified compounds) can be identified. Fatty acid methyl esters, including linear, ramified, unsaturated, and hydroxylated species, are identified and quantified in the same way. Possible extensions of this method to the fatty moiety of other lipids (alkylacylglycerol and dimethyl acetal) are discussed.

Kinetics of nerve impulse blocking by protein cross-linking aldehydes. Apparent critical thermal points.

The effect of formaldehyde, crotonaldehyde, butyraldehyde, glutaraldehyde and cinnamaldehyde on the compound action potential of frog sciatic nerve was studied in the temperature domain 20-35 degrees C at various aldehyde concentrations. All these reagents gradually decrease the amplitude of nerve action potential, up to the complete block, the order of effectiveness being: crotonaldehyde greater than cinnamaldehyde greater than butyraldehyde greater than formaldehyde greater than glutaraldehyde. The effect of cinnamaldehyde is almost completely reversible, while all others have irreversible action. The dependence of the blocking time on temperature and concentration is well expressed in all cases by the same empirical equation. This dependence points to the existence of critical temperatures, specific for each aldehyde, at which impulse blocking would be instantaneous, regardless of concentration. These temperatures (obtained by extrapolation) lie between 43 degrees C (for crotonaldehyde) and 57.5 degrees C (for butyraldehyde). The existence of free amino groups within ionic channels, as main sites of aldehyde attack, is inferred.

Effect of protein cross-linking aldehydes on nerve activity.

The changes in excitability and conduction properties of frog sciatic nerve under the influence of glutaraldehyde (GA), formaldehyde (FA), butyric aldehyde (BA) and crotonic aldehyde (CA) were examined in the concentration domain 0.01-1.00% (w/v) and at 20, 25, 30 and 35 degrees C. All these reagents irreversibly reduce the amplitude of the compound action potential of the nerve and decrease the conduction velocity up to the complete block. These changes occur as approximately exponential time decays. The decreasing order of efficiency is : CA greater than BA greater than FA greater than GA, showing no obvious correlation with the molecular weight of the aldehydes. The rise in temperature activates the decrease of amplitude but has a compensatory affect on the decrease of conduction velocity. The rising phase of the nervogram apparently remains unchanged, while the duration of the falling phase is up to threefold lengthened--more but slower at low temperatures and concentrations. These changes in the electrical response of the nerve are analysed as expressing the diffusion of aldehydes within the tissue, and their specific reactions with the proteins of the ionic channels.