Inducers of Friend leukaemic cell differentiation in vitro--effects of in vivo administration.

Studies were conducted of the in vivo therapeutic potential of compounds which induce the differentiation of Friend leukaemia cells (FLC) in vitro. DBA2/J mice were inoculated with Friend leukaemia cells grown in tissue culture and at various times thereafter were treated with either N-methylacetamide, dimethylacetamide, or tetramethylurea. While survival was only occasionally prolonged, in every study these agents significantly inhibited leukaemia cell proliferation in the spleen and to a lesser extent in the marrow. These agents had no effect on the rate of proliferation of FLC growing subcutaneously nor on the proliferation of myeloid leukaemia in RFMS mice. These studies indicate that the administration of inducing agents to mice bearing Friend leukaemia can alter the proliferation characteristics of the leukaemia cells and hence suggest that these agents may have therapeutic potential

Design Rules for Self-Assembly of 2D Nanocrystal/Metal-Organic Framework Superstructures.

We demonstrate the guiding principles behind simple two dimensional self-assembly of MOF nanoparticles (NPs) and oleic acid capped iron oxide (Fe3 O4 ) NCs into a uniform two-dimensional bi-layered superstructure. This self-assembly process can be controlled by the energy of ligand-ligand interactions between surface ligands on Fe3 O4 NCs and Zr6 O4 (OH)4 (fumarate)6 MOF NPs. Scanning transmission electron microscopy (TEM)/energy-dispersive X-ray spectroscopy and TEM tomography confirm the hierarchical co-assembly of Fe3 O4 NCs with MOF NPs as ligand energies are manipulated to promote facile diffusion of the smaller NCs. First-principles calculations and event-driven molecular dynamics simulations indicate that the observed patterns are dictated by combination of ligand-surface and ligand-ligand interactions. This study opens a new avenue for design and self-assembly of MOFs and NCs into high surface area assemblies, mimicking the structure of supported catalyst architectures, and provides a thorough fundamental understanding of the self-assembly process, which could be a guide for designing functional materials with desired structure

Shielding efficiency and E(J) characteristics measured on large melt cast Bi-2212 hollow cylinders in axial magnetic fields

We show that tubes of melt cast Bi-2212 used as current leads for LTS magnets can also act as efficient magnetic shields. The magnetic screening properties under an axial DC magnetic field are characterized at several temperatures below the liquid nitrogen temperature (77 K). Two main shielding properties are studied and compared with those of Bi-2223, a material that has been considered in the past for bulk magnetic shields. The first property is related to the maximum magnetic flux density that can be screened, Blim; it is defined as the applied magnetic flux density below which the field attenuation measured at the centre of the shield exceeds 1000. For a cylinder of Bi-2212 with a wall thickness of 5 mm and a large ratio of length over radius, Blim is evaluated to 1 T at T = 10 K. This value largely exceeds the Blim value measured at the same temperature on similar tubes of Bi-2223. The second shielding property that is characterized is the dependence of Blim with respect to variations of the sweep rate of the applied field, dBapp/dt. This dependence is interpreted in terms of the power law E = Ec(J/Jc)^n and allows us to determine the exponent n of this E(J) characteristics for Bi-2212. The characterization of the magnetic field relaxation involves very small values of the electric field. This gives us the opportunity to experimentally determine the E(J) law in an unexplored region of small electric fields. Combining these results with transport and AC shielding measurements, we construct a piecewise E(J) law that spans over 8 orders of magnitude of the electric field.Comment: 16 pages, 7 figure

COPE-ICD: A randomised clinical trial studying the effects and meaning of a comprehensive rehabilitation programme for ICD recipients -design, intervention and population

<p>Abstract</p> <p>Background</p> <p>Growing evidence exists that living with an ICD can lead to fear and avoidance behaviour including the avoidance of physical activity. It has been suggested that psychological stress can increase the risk of shock and predict death. Small studies have indicated a beneficial effect arising from exercise training and psychological intervention, therefore a large-scale rehabilitation programme was set up.</p> <p>Methods/Design</p> <p>A mixed methods embedded experimental design was chosen to include both quantitative and qualitative measures. A randomised clinical trial is its primary component. 196 patients (power-calculated) were block randomised to either a control group or intervention group at a single centre. The intervention consists of a 1-year psycho-educational component provided by two nurses and a 12-week exercise training component provided by two physiotherapists. Our hypothesis is that the COPE-ICD programme will reduce avoidance behaviour, sexual dysfunction and increase quality of life, increase physical capability, reduce the number of treatment-demanding arrhythmias, reduce mortality and acute re-hospitalisation, reduce sickness leading to absence from work and be cost-effective. A blinded investigator will perform all physical tests and data collection.</p> <p>Discussion</p> <p>Most participants are men (79%) with a mean age of 58 (range 20-85). Most ICD implantations are on primary prophylactic indication (66%). 44% is NYHA II. Mean walk capacity (6MWT) is 417 m. Mean perception of General Health (SF-36) is PCS 42.6 and MCS 47.1.</p> <p>A large-scale ICD rehabilitation trial including psycho-educational intervention and exercise training has been initiated and will report findings starting in 2011.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00569478">NCT00569478</a></p

Bivariate stochastic modeling of functional response with natural mortality

A correction due to Abbott (1925) is the standard method of dealing with control mortality in insect bioassay to estimate the mortality of an insect conditional on control mortality not having occurred. In this article a bivariate stochastic process for overall mortality is developed in which natural mortality and predation are jointly modeled to take account of the competing-risks associated with prey loss. The total mortality estimate from this model is essentially identical with that from more classical modeling. However, when predation loss is estimated in the absence of control mortality the results are somewhat different, with the estimate from the bivariate model being lower than that from using Abbott’s formula in conjunction with the classical model. It is argued that overdispersion in observed mortality data corresponds to correlated outcomes (death or survival) for the prey initially present, while Abbott’s correction relies implicitly on independence

Oxaliplatin induces drug resistance more rapidly than cisplatin in H69 small cell lung cancer cells

Cisplatin produces good responses in solid tumours including small cell lung cancer (SCLC) but this is limited by the development of resistance. Oxaliplatin is reported to show activity against some cisplatin-resistant cancers but there is little known about oxaliplatin in SCLC and there are no reports of oxaliplatin resistant SCLC cell lines. Studies of drug resistance mainly focus on the cellular resistance mechanisms rather than how the cells develop resistance. This study examines the development of cisplatin and oxaliplatin resistance in H69 human SCLC cells in response to repeated treatment with clinically relevant doses of cisplatin or oxaliplatin for either 4 days or 2h. Treatments with 200ng/ml cisplatin or 400ng/ml oxaliplatin for 4 days produced sublines (H69CIS200 and H69OX400 respectively) that showed low level (approximately 2-fold) resistance after 8 treatments. Treatments with 1000ng/ml cisplatin or 2000ng/ml oxaliplatin for 2h also produced sublines, however these were not stably resistant suggesting shorter treatment pulses of drug may be more effective. Cells survived the first five treatments without any increase in resistance, by arresting their growth for a period and then regrowing. The period of growth arrest was reduced after the sixth treatment and the H69CIS200 and H69OX400 sublines showed a reduced growth arrest in response to cisplatin and oxaliplatin treatment suggesting that "regrowth resistance" initially protected against drug treatment and this was further upregulated and became part of the resistance phenotype of these sublines. Oxaliplatin dose escalation produced more surviving sublines than cisplatin dose escalation but neither set of sublines were associated with increased resistance as determined by 5-day cytotoxicity assays, also suggesting the involvement of regrowth resistance. The resistant sublines showed no change in platinum accumulation or glutathione levels even though the H69OX400 subline was more sensitive to buthionine sulfoximine treatment. The H69CIS200 cells were cross-resistant to oxaliplatin demonstrating that oxaliplatin does not have activity against low level cisplatin resistance. Relative to the H69 cells, the H69CIS200 and H69OX400 sublines were more sensitive to paclitaxel and taxotere suggests the taxanes may be useful in the treatment of platinum resistant SCLC. These novel cellular models of cisplatin and oxaliplatin resistant SCLC will be useful in developing strategies to treat platinum-resistant SCLC

ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair

Background: The H69CIS200 and H69OX400 cell lines are novel models of low-level platinum-drug resistance. Resistance was not associated with increased cellular glutathione or decreased accumulation of platinum, rather the resistant cell lines have a cell cycle alteration allowing them to rapidly proliferate post drug treatment. Results: A decrease in ERCC1 protein expression and an increase in RAD51B foci activity was observed in association with the platinum induced cell cycle arrest but these changes did not correlate with resistance or altered DNA repair capacity. The H69 cells and resistant cell lines have a p53 mutation and consequently decrease expression of p21 in response to platinum drug treatment, promoting progression of the cell cycle instead of increasing p21 to maintain the arrest. Conclusion: Decreased ERCC1 protein and increased RAD51B foci may in part be mediating the maintenance of the cell cycle arrest in the sensitive cells. Resistance in the H69CIS200 and H69OX400 cells may therefore involve the regulation of ERCC1 and RAD51B independent of their roles in DNA repair. The novel mechanism of platinum resistance in the H69CIS200 and H69OX400 cells demonstrates the multifactorial nature of platinum resistance which can occur independently of alterations in DNA repair capacity and changes in ERCC1