Synthesis and cytotoxicity of potential tumor-inhibitory analogues of trimelamol (2,4,6-tris[(hydroxymethyl)methylamino]-1,3,5-triazine) having electron-withdrawing groups in place of methyl

In exploring the structural features which determine the antitumor activity of 2,4,6-tris-[(hydroxymethyl)methylamino]-1,3,5-triazine (trimelamol, 1), we have synthesized analogues in which the methyl groups have been replaced by the electron-withdrawing substituents 2,2,2-trifluoroethyl (5), propargyl (13), and cyanomethyl (15) via the respective tris(alkylamino)triazines 3, 12, and 14. Three mono[(hydroxymethyl)amino]triazines (4, 7, and 10) were also prepared. All the new tris(hydroxymethyl) derivatives showed cytotoxicities toward a variety of experimental rodent and human ovarian tumor cell lines similar to those shown by 1, the cyanomethyl analogue (15) having the most favorable profile. Mono(hydroxymethyl) derivatives (4 and 7) were ca. one-third as toxic. The new tris(hydroxymethyl) analogues were more stable to aqueous hydrolysis than was 1. Half-life (pH 7.5) values were, for 1, 120 min, for 5, 690 min, for 13, 450 min, and for 15, 275 min, but at pH 2.0, 15 (t1/2 350 min) was the most stable. This cyanomethyl analogue was also the most water-soluble, being comparable to 1 whereas 5 and 13 were poorly soluble.     

Frequent clones of p53-mutated keratinocytes in normal human skin

The multiple genetic hit model of cancer predicts that normal individuals should have stable populations of cancer-prone, but noncancerous, mutant cells awaiting further genetic hits. We report that whole-mount preparations of human skin contain clonal patches of p53-mutated keratinocytes, arising from the dermal-epidermal junction and from hair follicles. These clones, 60-3000 cells in size, are present at frequencies exceeding 40 cells per cm2 and together involve as much as 4% of the epidermis. In sun-exposed skin, clones are both more frequent and larger than in sun-shielded skin. We conclude that, in addition to being a tumorigenic mutagen, sunlight acts as a tumor promoter by favoring the clonal expansion of p53-mutated cells. These combined actions of sunlight result in normal individuals carrying a substantial burden of keratinocytes predisposed to cancer.     

Protoporphyrin-IX as a Substitute for Nitrite in Cured-Meat Color Production

The iron-free heme derivative protoporphyrin-IX, was added to a cooked emulsified beef product to mimic the typical cured-color obtained with nitrite. Although the pigment was stable and could be recovered from the emulsion it imparted a purple hue as noted by visual observation and Hunterlab color values (L,a,b). The possible implications of this pigment as a meat colorant are discussed.     

Self-learning inductive inference machines

Self-knowledge is a concept that is present in several philosophies. In this article, we consider the issue of whether or not a learning algorithm can in some sense possess self-knowledge. The question is answered affirmatively. Self-learning inductive inference algorithms are taken to be those that learn programs for their own algorithms, in addition to other functions.
La connaissance de soi est un concept qui se retrouve dans plusieurs philosophies. Dans cet article, les auteurs s'interrogent à savoir si un algorithme d' apprentissage peut dans une certaine mesure posséder la connaissance de soi. lis apportent une reponse positive a cette question. Les algorithmes d'inference inductive autodidactes sont ceux qui font l'apprentissage de programmes pour leurs propres algorithmes, en plus d' autres fonctions.     

The wheel–rail interface—some recent accidents

The importance of the wheel–rail interface to the safe operation of railways is discussed. Some aspects of the history of rails and wheels are introduced. Several recent accidents involving the wheel–rail interface are described. The great importance of operating both vehicles and track as a system is emphasized, together with the necessity of maintaining both in good condition.     

Nitrone spin-traps block calcium channels and induce pulmonary artery relaxation independent of free radicals

Free radicals react with nitrones to form stable nitroxides which can be identified by ESR spectroscopy. Unfortunately, little is known regarding the pharmacological properties of these compounds. In this study, three commonly used nitrones, 5,5-dimethylpyrroline-N-oxide (DMPO), alpha-phenyl-tert-butylnitrone (PBN), and alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (POBN), were found to induce relaxation of preconstricted isolated rat pulmonary artery rings. Additional experiments with PBN indicated that vasorelaxation could not be attributed to production of endothelial derived factors, prostaglandins, or free radicals. Patch-clamp techniques revealed reversible calcium channel blockade with PBN at a concentration below that needed to detect free radicals. Calcium channel blockade probably accounts for the vasorelaxation observed in the isolated ring preparations described here, and should be considered when using nitrone spin-traps both in in vivo and clinical studies.     

CHALLENGE STUDIES WITH CLOSTRIDIUM BOTULINUM TYPE E IN A VALUE-ADDED SURIMI PRODUCT STORED UNDER A MODIFIED ATMOSPHERE

Challenge studies were carried out on raw, cooked, and sterilized surimi nuggets, inoculated with 10⁴ spores/g of C. botulinum type E spores. All products were packaged in air and air with an Ageless SS oxygen absorbent and stored at 4, 12 and 25C. Toxin was not detected in any raw product throughout storage (28 days). The absence of toxigenesis was attributed to the low pH (4.1–4.3) due mainly to the growth of lactic acid bacteria (10⁷CFU/g). Toxin was also not detected in any cooked product after 28 days. Product pH did not decrease as previously (due to the absence of LAB), but counts of C. botulinum still decreased throughout storage.
In sterile nuggets , C. botulinum counts increased to 10⁶ cfu/g at both 12 and 25C, respectively, by 28 days. Lactic acid bacteria and Bacillus spp. were not detected throughout the 28 days storage period. Toxin was detected by days 28 and 14 at 12 and 25C, respectively, and toxigenesis preceded spoilage. The absence of toxin in cooked nuggets was attributed to the anti-botulinal role by Bacillus species, the predominant spoilage bacteria in cooked nuggets.