Magnetic resonance detects metabolic changes associated with chemotherapy-induced apoptosis

Apoptosis was induced by treating L1210 leukaemia cells with mechlorethamine, and SW620 colorectal cells with doxorubicin. The onset and progression of apoptosis were monitored by assessing caspase activation, mitochondrial transmembrane potential, phosphatidylserine externalization, DNA fragmentation and cell morphology. In parallel, 31P magnetic resonance (MR) spectra of cell extracts were recorded. In L1210 cells, caspase activation was detected at 4 h. By 3 h, the MR spectra showed a steady decrease in NTP and NAD, and a significant build-up of fructose 1,6-bisphosphate (F-1,6-P) dihydroxyacetonephosphate and glycerol-3-phosphate, indicating modulation of glycolysis. Treatment with iodoacetate also induced a build-up of F-1,6-P, while preincubation with two poly(ADP-ribose) polymerase inhibitors, 3-aminobenzamide and nicotinamide, prevented the drop in NAD and the build-up of glycolytic intermediates. This suggested that our results were due to inhibition of glyceraldehyde-3-phosphate dehydrogenase, possibly as a consequence of NAD depletion following poly(ADP-ribose) polymerase activation. Doxorubicin treatment of the adherent SW620 cells caused cells committed to apoptosis to detach. F-1,6-P was observed in detached cells, but not in treated cells that remained attached. This indicated that our observations were not cell line- or treatment-specific, but were correlated with the appearance of apoptotic cells following drug treatment. The 31P MR spectrum of tumours responding to chemotherapy could be modulated by similar effects

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research

Silver(I) nitrate adducts with bidentate 2-, 3- and 4-pyridyl phosphines. Solution P-31 and [P-31-Ag-109] NMR studies of 1 : 2 complexes and crystal structure of dimeric [{Ag(d2pype)(mu-d2pype)}(2)]-[NO3](2)center dot 2CH(2)Cl(2) [d2pype = 1,2-bis(di-2-pyridylphosphino)ethane]

The 1 : 2 complexes of silver(I) nitrate with 1,2-bis(di-n-pyridylphosphino)ethane (dnpype) for n = 2, 3 and 4 have been synthesized and solution properties characterized by NMR spectroscopy, including variable-temperature one-dimensional P-31-{H-1}, two-dimensional [P-31-P-31] COSY and [P-31-Ag-109] HMQC NMR experiments. The 3-pyridyl (d3pype) and 4-pyridyl (d4pype) complexes exist as bis-chelated monomeric [Ag(d3pype)(2)](+) and [Ag(d4pype)(2)](+) while the 2-pyridyl (d2pype) complex forms an equilibrium mixture of monomeric [Ag(d2pype)(2)](+), dimeric [{Ag(d2pype)(2)}(2)](2+) and trimeric [{Ag(d2pype)(2)}(3)](3+) species in which the d2pype ligands co-ordinate in both bridging and chelated modes via the phosphorus atoms, The relative percentages of the species present are dependent on both temperature and solvent, Crystals of the 2-pyridyl complex obtained from CH2Cl2-Et2O solution have been shown by crystal structure determination to be the dimer [{Ag(d2pype)(mu-d2pype)}(2)]-[NO3](2) .2CH(2)Cl(2). Each silver ion is co-ordinated by one chelated and two bridging d2pype ligands forming a ten-membered ring in a double boat conformation. The pyridyl nitrogen atoms do not co-ordinate to the silver. The differences in solution behaviour of the three systems and the potential significance of these complexes to th antitumour properties of chelated 1:2 silver(I) diphosphine complexes are discussed

Reactions of cisplatin hydrolytes with methionine, cysteine, and plasma ultrafiltrate studied by a combination of HPLC and NMR techniques

The reactions of cis-[PtCl(NH3)(2)(H2O)](+) with L-methionine have been studied by 1D Pt-195 and N-15 NMR, and by 2D[H-1, N-15] NMR, When the platinum complex is in excess, the initial product, cis-[PtCl(NH3),(Hmet-S)](+) undergoes slow ring closure to [Pt(NH3)(2)(Hmet-N,S)](2+) . Slow ammine loss then occurs to give the isomer of [PtCl(NH3) (Hmet-N,S)](+) with chloride hans to sulfur. When methionine is in excess, a reaction sequence is proposed in which trans-[PtCl(NH3) (Hmet-S)(2)](+) isomerises to the cis-isomer, with subsequent ring closure reactions leading to cis-[Pt(Hmet-N,S)(2)](2+). Near pH 7, methionine is unreactive toward cis-[PtCl(OH) (NH3)(2)]. By contrast, L-cysteine reacts readily with cis- [PtCl(OH) (NH3)(2)] at pH7, but there were many reaction products, including bridged species. Cis-[PtCl(OH) (NH3)(2)] reacts with reduced thiols in ultrafiltered plasma but these are oxidized if the plasma is not fresh or appropriately stored. With very low concentrations of the platinum complexes (35.5 mu M), HPLC experiments (UV detection at 305 nm) indicate that the thiolate (probably cysteine) reactions become simpler as bridging becomes less important. (C) 1999 Elsevier Science Inc. All rights reserved