Hamiltonian structure of 2+1 dimensional gravity

A summary is given of some results and perspectives of the hamiltonian ADM approach to 2+1 dimensional gravity. After recalling the classical results for closed universes in absence of matter we go over the the case in which matter is present in the form of point spinless particles. Here the maximally slicing gauge proves most effective by relating 2+1 dimensional gravity to the Riemann- Hilbert problem. It is possible to solve the gravitational field in terms of the particle degrees of freedom thus reaching a reduced dynamics which involves only the particle positions and momenta. Such a dynamics is proven to be hamiltonian and the hamiltonian is given by the boundary term in the gravitational action. As an illustration the two body hamiltonian is used to provide the canonical quantization of the two particle system.Comment: 13 pages,2 figures,latex, Plenary talk at SIGRAV2000 Conferenc

Identification of sulfation sites of metabolites and prediction of the compounds’ biological effects

Characterizing the biological effects of metabolic transformations (or biotransformation) is one of the key steps in developing safe and effective pharmaceuticals. Sulfate conjugation, one of the major phase II biotransformations, is the focus of this study. While this biotransformation typically facilitates excretion of metabolites by making the compounds more water soluble, sulfation may also lead to bioactivation, producing carcinogenic products. The end result, excretion or bioactivation, depends on the structural features of the sulfation sites, so obtaining the structure of the sulfated metabolites is critically important. We describe herein a very simple, high-throughput procedure for using mass spectrometry to identify the structure—and thus the biological fate—of sulfated metabolites. We have chemically synthesized and analyzed libraries of compounds representing all the biologically relevant types of sulfation products, and using the mass spectral data, the structural features present in these analytes can be reliably determined, with a 97% success rate. This work represents the first example of a high-throughput analysis that can identify the structure of sulfated metabolites and predict their biological effects

A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor Selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors

<p><b>Purpose:</b> This Phase I study assessed whether food influences the rate and extent of selumetinib absorption in patients with advanced solid malignancies and determined the safety, tolerability, and pharmacokinetic (PK) profile of selumetinib and its active metabolite N-desmethyl-selumetinib in fed and fasted states.</p> <p><b>Methods:</b> A single dose of 75 mg selumetinib was to be taken with food on Day 1 followed by a single dose of 75 mg after fasting for at least 10 h on Day 8, or vice versa, followed by twice daily dosing of 75 mg selumetinib from Day 10. Plasma concentrations and PK parameters were determined on Days 1 and 8. Patients could continue to receive selumetinib for as long as they benefitted from treatment.</p> <p><b>Results:</b> In total, 31 patients were randomized to receive selumetinib; 15 to fed/fasted sequence and 16 to fasted/fed sequence. Comprehensive PK sampling was performed on 11 and 10 patients, respectively. The geometric least-squares means of C<sub>max</sub> and AUC for selumetinib were reduced by 62% (ratio 0.38 90% CI 0.29, 0.50) and 19% (ratio 0.81 90% CI 0.74, 0.88), respectively, under fed compared with fasting conditions. The rate of absorption (t<sub>max</sub>) of selumetinib (fed) was delayed by approximately 2.5 h (median). The food effect was also observed for the active metabolite N-desmethyl-selumetinib. Selumetinib was well tolerated.</p> <p><b>Conclusions:</b> The presence of food decreased the extent of absorption of selumetinib. It is recommended that for further clinical studies, selumetinib be taken on an empty stomach. Selumetinib demonstrated an acceptable safety profile in the advanced cancer population.</p&gt

Specific prebiotics modulate gut microbiota and immune activation in HAART-naive HIV-infected adults: results of the “COPA” pilot randomized trial

Intestinal mucosal immune system is an early target for human immunodeficiency virus type 1 (HIV-1) infection, resulting in CD4+ T-cell depletion, deterioration of gut lining, and fecal microbiota composition. We evaluated the effects of a prebiotic oligosaccharide mixture in highly active antiretroviral therapy (HAART)-naive HIV-1-infected adults. In a pilot double-blind, randomized, placebo-controlled study, 57 HAART-naive HIV-1-infected patients received a unique oligosaccharide mixture (15 or 30 g short chain galactooligosaccharides/long chain fructooligosaccharides/pectin hydrolysate-derived acidic oligosaccharides (scGOS/lcFOS/pAOS) daily) or a placebo for 12 weeks. Microbiota composition improved significantly with increased bifidobacteria, decreased Clostridium coccoides/Eubacterium rectale cluster, and decreased pathogenic Clostridium lituseburense/Clostridium histolyticum group levels upon prebiotic supplementation. In addition, a reduction of soluble CD14 (sCD14), activated CD4+/CD25+ T cells, and significantly increased natural killer (NK) cell activity when compared with control group were seen in the treatment group. The results of this pilot trial highly significantly show that dietary supplementation with a prebiotic oligosaccharide mixture results in improvement of the gut microbiota composition, reduction of sCD14, CD4+ T-cell activation (CD25), and improved NK cell activity in HAART-naive HIV-infected individuals