Antiproliferative and pro-apoptotic effects afforded by novel Src-kinase inhibitors in human neuroblastoma cells

<p>Abstract</p> <p>Background</p> <p>Neuroblastoma (NB) is the second most common solid malignancy of childhood that usually undergoes rapid progression with a poor prognosis upon metastasis. The Src-family tyrosine kinases (SFKs) are a group of proteins involved in cancer development and invasiveness that seem to play an important role in the NB carcinogenesis.</p> <p>Methods</p> <p>To determine cell proliferation, the growth rate was evaluated by both MTT test and cells counted. Analysis of DNA content was performed for the evaluation of the cell cycle and apoptosis. To characterize the mechanisms underlying the antiproliferative effects induced by SI 34, a novel pyrazolo-pyrimidine derivative provided with Src inhibitory activity, the involvement of some cellular pathways that are important for cell proliferation and survival was investigated by western blot assays. In particular, the contribution of cyclins, Src and ERK were examined. Finally, experiments of cell adhesion and invasiveness were performed.</p> <p>Results</p> <p>Treatment of SH-SY5Y human NB cells and CHP100 human neuroepithelioma (NE) cultures with three novel pyrazolo[3,4-<it>d</it>]pyrimidine derivatives, namely SI 34, SI 35 and SI 83, inhibits the cell proliferation in a time and concentration-dependent manner. The maximal effect was obtained after 72 hours incubation with SI 34 10 μM. Fluorescence microscopy experiments, flow cytometry analysis and determination of caspase-3 activity by fluorimetric assays showed that SI 34 induced SH-SY5Y apoptosis. Moreover, SI 34 determined cell cycle arrest at the G0/G1 phase, paralleled by a decreased expression of cyclin D1. Furthermore, our data indicate that SI 34 reduces the SH-SY5Y cells adhesion and invasiveness. Evidence that SI 34 inhibits the Src and the ERK-phosphorylation, suggests the mechanism through which it exerts its effects in SH-SY5Y cells.</p> <p>Conclusions</p> <p>Our study shows the ability of this pyrazolo-pyrimidine Src inhibitor in reducing the growth and the invasiveness of human NB cells, suggesting a promising role as novel drug in the treatment of neuroblastoma.</p

A statistical interpretation of the correlation between intermediate mass fragment multiplicity and transverse energy

Multifragment emission following Xe+Au collisions at 30, 40, 50 and 60 AMeV has been studied with multidetector systems covering nearly 4-pi in solid angle. The correlations of both the intermediate mass fragment and light charged particle multiplicities with the transverse energy are explored. A comparison is made with results from a similar system, Xe+Bi at 28 AMeV. The experimental trends are compared to statistical model predictions.Comment: 7 pages, submitted to Phys. Rev.

The Role of Time and Frequency in Future Systems

Over the past twenty years, the Global Positioning System (GPS) has revolutionized the performance and the geographical availability of time and frequency discrimination, while at the same time reducing the cost to the individual user. This paper examines the question of what comes next for time and frequency dissemination. The question has two motivations: How can improved performance be achieved in the future, and how can redundant sources of time and frequency be provided to critical systems? A model is developed for time and frequency dissemination based on the time management performed in GPS. Several candidate systems for future time and frequency distribution are identified. One system - SONET telecommunications - is discussed in detail. Performance requirements and hardware implementation are presented

Statistical Multifragmentation in Central Au+Au Collisions at 35 MeV/u

Multifragment disintegrations, measured for central Au + Au collisions at E/A = 35 MeV, are analyzed with the Statistical Multifragmentation Model. Charge distributions, mean fragment energies, and two-fragment correlation functions are well reproduced by the statistical breakup of a large, diluted and thermalized system slightly above the multifragmentation threshold.Comment: Latex file, 8 pages + 4 postscript figures available upon request from [email protected]

Multifragment production in Au+Au at 35 MeV/u

Multifragment disintegration has been measured with a high efficiency detection system for the reaction $Au + Au$ at $E/A = 35\ MeV$. From the event shape analysis and the comparison with the predictions of a many-body trajectories calculation the data, for central collisions, are compatible with a fast emission from a unique fragment source.Comment: 9 pages, LaTex file, 4 postscript figures available upon request from [email protected]. - to appear in Phys. Lett.

Bioprocessing of barley and lentil grains to obtain in situ synthesis of exopolysaccharides and composite wheat bread with improved texture and health properties

A comprehensive study into the potential of bioprocessing techniques (sprouting and sourdough fermentation) for improving the technological and nutritional properties of wheat breads produced using barley and lentil grains was undertaken. Dextran biosynthesis in situ during fermentation of native or sprouted barley flour (B or SB) alone or by mixing SB flour with native or sprouted lentil flour (SB-L or SB-SL) by Weissella paramesenteroides SLA5, Weissella confusa SLA4, Leuconostoc pseudomesenteroides DSM 20193 or Weissella confusa DSM 20194 was assessed. The acidi-fication and the viscosity increase during 24 h of fermentation with and without 16% sucrose (on flour weight), to promote the dextran synthesis, were followed. After the selection of the fermentation parameters, the bioprocessing was carried out by using Leuconostoc pseudomesenteroides DSM 20193 (the best LAB dextran producer, up to 2.7% of flour weight) and a mixture of SB-SL (30:70% w/w) grains, enabling also the decrease in the raffinose family oligosaccharides. Then, the SB-SL sourdoughs containing dextran or control were mixed with the wheat flour (30% of the final dough) and leavened with baker’s yeast before baking. The use of dextran-containing sourdough allowed the production of bread with structural improvements, compared to the control sourdough bread. Compared to a baker’s yeast bread, it also markedly reduced the predicted glycemic index, in-creased the soluble (1.26% of dry matter) and total fibers (3.76% of dry matter) content, giving pe-culiar and appreciable sensory attributes

Organic pollutants in sea-surface microlayer and aerosol in thecoastal environment of Leghorn—(Tyrrhenian Sea)

The levels of dissolved and particle-associated n-alkanes, alkylbenzenes, phthalates, PAHs, anionic surfactants and surfactant fluorescent organic matter ŽSFOM. were measured in sea-surface microlayer ŽSML. and sub-surface water ŽSSL. samples collected in the Leghorn marine environment in September and October 1999. Nine stations, located in the Leghorn harbour and at increasing distances from the Port, were sampled three times on the same day. At all the stations, SML concentrations of the selected organic compounds were significantly higher than SSL values and the enrichment factors ŽEFsSML concentrationrSSL concentration. were greater in the particulate phase than in the dissolved phase. SML concentrations varied greatly among the sampling sites, the highest levels Žn-alkanes 3674 mgrl, phthalates 177 mgrl, total PAHs 226 mgrl. being found in the particulate phase in the Leghorn harbour. To improve the knowledge on pollutant exchanges between sea-surface waters and atmosphere, the validity of spray drop adsorption model ŽSDAM. was verified for SFOM, surface-active agents, such as phthalates, and compounds which can interact with SFOM, such as n-alkanes and PAHs. q2001 Elsevier Science B.V. All rights reserved

Optimizing anticancer therapy in metastatic non-castrate prostate cancer: American society of clinical oncology clinical practice guideline

Purpose This clinical practice guideline addresses abiraterone or docetaxel with androgen-deprivation therapy (ADT) for metastatic prostate cancer that has not been treated (or has been minimally treated) with testosterone-lowering agents. Methods Standard therapy for newly diagnosed metastatic prostate cancer has been ADT alone. Three studies have compared ADT alone with ADT and docetaxel, and two studies have compared ADT alone with ADT and abiraterone. Results Three prospective randomized studies (GETUG-AFU 15, STAMPEDE, and CHAARTED) examined overall survival (OS) with adding docetaxel to ADT. STAMPEDE and CHAARTED favored docetaxel (hazard ratio [HR], 0.78; 95% CI, 0.66 to 0.93; n = 2,962 and HR, 0.73; 95% CI, 0.59 to 0.89; n = 790, respectively). GETUG-AFU 15 was negative. LATITUDE and STAMPEDE examined the impact on OS of adding abiraterone (with prednisone or prednisolone) to ADT. LATITUDE and STAMPEDE favored abiraterone (HR, 0.62; 95% CI, 0.51 to 0.76; n = 1,199 and HR, 0.63; 95% CI, 0.52 to 0.76; n = 1,917, respectively). Recommendations ADT plus docetaxel or abiraterone in newly diagnosed metastatic non-castrate prostate cancer offers a survival benefit as compared with ADT alone. The strongest evidence of benefit with docetaxel is in men with de novo high-volume (CHAARTED criteria) metastatic disease. Similar survival benefits are seen using abiraterone acetate in high-risk patients (LATITUDE criteria) and in the metastatic population in STAMPEDE. ADT plus abiraterone and ADT plus docetaxel have not been compared, and it is not known if some men benefit more from one regimen as opposed to the other. Fitness for chemotherapy, patient comorbidities, toxicity profiles, quality of life, drug availability, and cost should be considered in this decision. Additional information is available at www.asco.org/genitourinary-cancer-guidelines

Agreeability and gastrointestinal motility responses to fully characterized experimental pasta enriched in wheat by-products

Pasta, a Mediterranean diet staple, enhances well-being when enriched with healthy ingredients like durum wheat-germ (WG) and wheat-bran (WB). We studied the nutritional and clinical responses to four experimental pastas (EP1-EP4) made with de-oiled WG, WB, and microencapsulated durum wheat-oil (mWO), compared to a control pasta of water and semolina dough. WG addition significantly boosted total phenols and radical scavenging activity. Simulated colonic fermentation showed WG-enriched pasta enhanced short-chain fatty acids production. The clinical response to pasta was studied in 70 healthy subjects by semiquantitative scales of sensory perception, functional ultrasonography of gastric and gallbladder kinetics, and breath test for orocecal transit time. Sensory analysis revealed differences in odor, aftertaste, and overall pleasantness, especially in EP2. Gastrointestinal motility was similar across pastas, but EP3 had a shorter transit time and higher colonic fermentation. This study suggests that wheat by-products enriched pastas offer nutraceutical benefits, agreeability, digestibility, and sustainability