Apoptosis and therapy of malignant diseases of the hematopoietic system

Apoptosis is essential in the pathogenesis of hematological diseases. A tumor develops, if the balance between cell division and cell death is disturbed. In recent years many genes involved either in blocking or inducing this process have been identified. Additionally, several cytokines which influence apoptosis have been found. Some of these cytokines could also play a role in the development of resistance to chemotherapeutic agents. Many anticancer drugs exert their action via apoptosis. A strategy to selectively induce apoptosis of tumor cells without altering healthy cells and thus reducing the side effects of therapeutic regimens is a major goal for future development of new therapeutic techniques. Blocking the factors which are responsible for resistance is another promising therapeutic approach and could further improve the clinical outcome and finally prolong the life of patients.     

Identification and characterization of a novel member of the fibroblast growth factor family

A new member of the fibroblast growth factor (FGF) family, FGF-13, has been molecularly cloned as a result of high throughput sequencing of a human ovarian cancer cell library. The open reading frame of the novel human gene (1419 bp) encodes for a protein of 216 a.a. with a molecular weight of 22 kDa. The FGF-13 sequence contains an amino-terminal hydrophobic region of 23 a.a. characteristic of a signal secretion sequence. FGF-13 is most homologous, 70% similarity at the amino acid level, to FGF-8. Northern hybridization analysis demonstrated prominent expression of FGF-13 in human foetal and adult brain, particularly in the cerebellum and cortex. In proliferation studies with BaF3 cells, FGF-13 preferentially activates cell clones expressing either FGF receptor variant, 3-IIIc or 4. The signal transduction pathways of FGF-13 and FGF-2 were compared in rat hippocampal astrocytes. The two FGFs induce an equivalent level of tyrosine phosphorylation of mitogen-activated protein kinase (MAPK) and c-raf activation. However, FGF-13 is more effective than FGF-2 in inducing the phosphorylation of phospholipase C-gamma (PLC-gamma). Treatment of neuronal cultures from rat embryonic cortex with FGF-13 increases the number of glutamic acid decarboxylase immunopositive neurons, the level of high-affinity gamma-aminobutyric acid (GABA) uptake, and choline acetyltransferase enzyme activity. The GABAergic neuronal response to FGF-13 treatment is rapid with a significant increase occurring within 72 h. We have identified a novel member of the FGF family that is expressed in the central nervous system (CNS) and increases the number as well as the level of phenotypic differentiation of cortical neurons in vitro.     

Colorectal cancer detection and screening

Colon cancer is a leading cause of death in the United States and is estimated to cause 56,500 deaths during 1998. Most cancers evolve from adenomatous polyps. Screening asymptomatic average-risk individuals is recommended to reduce colorectal cancer mortality by detection and removal of adenomatous polyps.     

Simulation of Concrete Paving Operations on Interstate-74

The objective of this paper was to study and optimize the concrete paving operations taking place in the reconstruction project of Interstate-74 using computer simulation. To achieve this objective, field data were collected during construction, and were then used to determine adequate probabilistic density functions for the activities’ duration and to test a developed simulation model. Upon testing, the developed model was used to study the impacts of resources on the flow of operations and on the cost effectiveness of the construction process. In general, application of simulation methods to concrete paving operations was successful and its accuracy was acceptable as compared to field measurements. Based on the results of a sensitivity analysis of the critical resources, multiple factors were considered in the decision-making process to ensure that all aspects of the operation are evaluated. This includes total operation time, productivity, costs of the operation, average truck delay, and idle times for the paver and the spreader. For the conditions pertinent to this construction site, ten trucks, one paver and one spreader, and three finishing and plastic-covering crews are recommended. Using this set of resources would result in a prompt and effective execution of the operation. Practical implementation and limitations of the developed model in similar construction operations is discussed.     

Thermophilic xylanase from Thermomyces lanuginosus: high-resolution X-ray structure and modeling studies

The crystal structure of the thermostable xylanase from Thermomyces lanuginosus was determined by single-crystal X-ray diffraction. The protein crystallizes in space group P21, a = 40.96(4) A, b = 52. 57(5) A, c = 50.47 (5) A, beta = 100.43(5) degrees, Z = 2. Diffraction data were collected at room temperature for a resolution range of 25-1.55 A, and the structure was solved by molecular replacement with the coordinates of xylanase II from Trichoderma reesei as a search model and refined to a crystallographic R-factor of 0.155 for all observed reflections. The enzyme belongs to the family 11 of glycosyl hydrolases [Henrissat, B., and Bairoch, A. (1993) Biochem. J. 293, 781-788]. pKa calculations were performed to assess the protonation state of residues relevant for catalysis and enzyme stability, and a heptaxylan was fitted into the active-site groove by homology modeling, using the published crystal structure of a complex between the Bacillus circulans xylanase and a xylotetraose. Molecular dynamics indicated the central three sugar rings to be tightly bound, whereas the peripheral ones can assume different orientations and conformations, suggesting that the enzyme might also accept xylan chains which are branched at these positions. The reasons for the thermostability of the T. lanuginosus xylanase were analyzed by comparing its crystal structure with known structures of mesophilic family 11 xylanases. It appears that the thermostability is due to the presence of an extra disulfide bridge, as well as to an increase in the density of charged residues throughout the protein.     

Do interpersonal traits predict affect? A comparison of three models.

Predictions from interpersonal traits to affect were examined in the context of 3 models. In the global trait model, traits were used to predict affect aggregated over a 20-day period. In the situational congruence model, traits were used to predict affect in trait-relevant situations. In the behavioral concordance model, the co-occurrence between behaviors and affect was examined for individual participants, and then traits were used to predict the degree to which behavior and affect co-occurred. No support was found for the global trait and situational congruence models. Support was found for the behavioral concordance model for 3 of the 4 traits. Individuals high on agreeableness and quarrelsomeness experienced pleasant affect when they engaged in behaviors concordant with their traits. Individuals high on agreeableness, quarrelsomeness, and dominance experienced unpleasant affect when they engaged in behaviors opposite to their traits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Estimation of quasiperiodic signal parameters by means of dynamicsignal models

The problem of estimating the parameters of a quasiperiodic signal consisting of a sum of a given number of sinusoidal signals with known frequencies but unknown time-varying amplitudes and phases superimposed by some additive noise sources is treated in this paper. Different estimation techniques that solve the problem are presented in this paper. The reason to do that is twofold: (1) to present the derivation of a new estimator for quasiperiodic signals, which is based on Kalman filtering theory and a random walk model, and to illustrate its structure and parametrization; and (2) to compare the new estimator with another Kalman filter-based estimator that uses an “oscillator model” and with the more classical running recursive discrete Fourier series method     

Intracellular concentrations of mitoxantrone in leukemic cells in vitro vs in vivo

The aim of this study was to determine the intracellular pharmacokinetics of mitoxantrone in vivo and to use these results to establish how leukemic cells should be incubated to perform clinically relevant in vitro studies of this drug. Blood samples were obtained from 11 patients with acute nonlymphoblastic leukemia at certain intervals up to 20 h after the infusion of mitoxantrone 12 mg/m2. Plasma and leukemic cells were separated and the drug concentrations were determined with HPLC. Before treatment, leukemic cells from 12 patients were incubated with 0.02, 0.05, 0.1, 0.2 and 1.0 microM mitoxantrone for 1-4 h and thereafter cultured in suspension culture for 20 h; during this time cell samples were taken at certain intervals for drug determination. In cells incubated with 0.05 and 0.2 microM mitoxantrone the cytotoxic effect was measured with the DiSC assay after cultivation for 4-5 days. In vivo, the intracellular levels exceeded the plasma concentrations already at the end of infusion and after 2 h the intracellular concentrations were 200-300 times higher than in plasma. In vitro, the intracellular steady state level of mitoxantrone was reached after 1-2 h and there was a pronounced intracellular retention even after 20 h culture in drug-free medium. Incubation with 0.05 microM during 1 h gave intracellular concentrations of mitoxantrone similar to those achieved in vivo. This incubation concentration gave a mean cytotoxic effect of 53% living cells measured with the DiSC assay, which gives good possibilities to discriminate between mitoxantrone-sensitive and unsensitive cells. We believe that exposing leukemic cells in vitro for in vivo mimicking mitoxantrone concentrations could increase the clinical relevance of predictive assays.