CDK4 down-regulation induced by paclitaxel is associated with G1 arrest in gastric cancer cells

Paclitaxel induces a cell cycle block at G2-M phase by preventing the depolymerization of microtubules and induces p53-independent apoptosis in many cancer cells. We observed that gastric cancer cells treated with paclitaxel have shown a cyclin-dependent kinase (CDK)4 down-regulation. This paclitaxel-induced CDK4 down-regulation resulted in a cell cycle arrest at G1-S phase. To confirm this observation, we prepared stable transfectants that overexpressed CDK4 and analyzed the cell cycle progression. Ectopic expression of CDK4 in SNU cells resulted in a release of paclitaxel-induced G1 arrest. The release of G1 arrest by enforced expression of CDK4 seems to make the cells more sensitive to paclitaxel-induced apoptosis. From this finding, we could then suggest that paclitaxel treatment induces both G1-S and G2-M blocks in the cell cycle progression of gastric cancer cells.     

Synthesis and antiplatelet, antiinflammatory, and antiallergic activities of substituted 3-chloro-5,8-dimethoxy-1,4-naphthoquinone and related compounds

2-Amino (6), 2-alkylamino (7-8), 2-methoxy (9), 2-acetamido (10), and 5,8-diacetoxy (11) derivatives of the lead compound 2,3-dichloro-5,8-dimethoxy-1,4-naphthoquinone (4) were synthesized, together with 6,7-dichloro-5,8dimethoxy-1,4-naphthoquinone (5), a positional isomer of 4. Antiplatelet, antiinflammatory, and antiallergic activities were evaluated, and most compounds were quite potent in all assays. Compounds 5 and 9-11 were especially active; however, 5 was ineffective against neutrophil superoxide formation, and 10 was ineffective against mast cell degranulation.     

The prognostic significance of tumor cell detection in intraoperative pleural lavage and lung tissue cultures for patients with lung cancer

METHODS: Three hundred forty-two patients with lung cancer and 99 patients with nonneoplastic lung diseases (control group) underwent intraoperative pleural lavage with 300 ml physiologic saline solution before (lavage I) and after resection (lavage II). RESULTS: Studies of the lavage fluid in all control patients were negative, that is, there were no false positive findings. Tumor cells were found in lavage I in 132 patients (38.6%) and also in lavage II in 99 of them. In stage I (pT1 N0, pT2 N0) lung cancer, tumor cell detection was possible in 47 patients (28.6%). The 4-year survival of patients with resected non-small-cell lung cancer was 24% (95% confidence interval, 16% to 32%) if lavage I results were positive and 52% (95% confidence interval, 45% to 59%) if lavage I results were negative (all stages, p = 0.007). For patients with stage I disease (n = 164) the 4-year survival was 35% (95% confidence interval, 18% to 52%) if lavage I results were positive (n = 47), and 69% (95% confidence interval, 60% to 78%) if lavage I results were negative (n = 117) (p = 0.037). On multivariate analysis the positive cytologic result in intraoperative pleural lavage was an additional prognostic factor for our patients. To prove how the tumor cells enter the pleural cavity, we performed tissue cultures of tumor-free parenchyma in 23 cases of lung cancer. Tumor cell detection by histology and immunohistology was possible in 16 cases (69.6%). Detection of tumor cells in pleural lavage fluid before resection proves that tumor cells have spread into the pleural cavity. CONCLUSION: The positive result in pleural lavage seems to be a prognostic predictor for patients with lung cancer.     

A ¹⁸F-labeled fluorobutyl-substituted spirocyclic piperidine derivative as a selective radioligand for PET Imaging of sigma₁ receptors

In this study, we synthesized and evaluated a new spirocyclic piperidine derivative 3 , containing a 4‐fluorobutyl side chain, as a PET radioligand for neuroimaging of σ₁ receptors. In vitro, compound 3 displayed high affinity for σ₁ receptors (K_i=1.2 nM ) as well as high selectivity. [¹⁸F] 3 radiosynthesis was performed from the corresponding tosylate precursor, with high radiochemical yield (45–51 %), purity (>98 %), and specific activity (>201 GBq μmol^?1). Metabolic stability of [¹⁸F] 3 in the brain of CD‐1 mice was verified, and no penetration of peripheral radiometabolites into the cerebral tissue was observed. Results of ex vivo autoradiography revealed that the distribution of [¹⁸F] 3 in the brain corresponded to regions with high σ₁ receptor density. The highest region‐specific total‐to‐nonspecific ratio was determined in the facial nucleus (4.00). Biodistribution studies indicated rapid and high levels in brain uptake of [¹⁸F] 3 (2.2 % ID per gram at 5 min p.i.). Pre‐administration of haloperidol significantly inhibited [¹⁸F] 3 uptake into the brain and σ₁ receptor‐expressing organs, further confirming in vivo target specificity.     

Dietary n-3 Fatty Acids Significantly Suppress Lipogenesis in Bovine Muscle and Adipose Tissue: A Functional Genomics Approach

Changes in fatty acid composition of longissimus muscle and subcutaneous adipose tissue of German Holstein bulls induced by a grass-silage/n-3 fatty acid based intervention diet versus a maize-silage/n-6 fatty acid based control diet were analyzed and related to shifts in lipogenic gene expression, protein expression, and enzyme activity patterns. Significantly higher amounts of n-3 fatty acids and by mean factors of 2.2–2.5 decreased n-6/n-3 fatty acid ratios in both tissues were obtained upon n-3 fatty acid intervention. In longissimus muscle, these changes of fatty acid profiles were associated with reduced SREBP1c (p = 0.02), ACC (p = 0.00), FAS (p = 0.10) and SCD (p = 0.03) gene expression, Δ6D (p = 0.03) and SCD (p = 0.03) protein expression as well as SCD enzyme activity (p = 0.03). In subcutaneous adipose tissue, significantly reduced ACC (p = 0.00) and FAS (p = 0.01) gene expression, SCD protein expression (p = 0.02) and SCD enzyme activity (p = 0.03) were detected upon n-3 fatty acid intervention, although lower degrees of correlation between gene and corresponding gene products were obtained in relation to longissimus muscle. The study elucidates tissue-specific functional genomic responses to dietary fatty acid manipulation in regard to fatty acid profile tailoring of animal tissues.     

Modeling and in-depth analysis of the start-up of dividing-wall columns

Saving potentials of up to 30% in capital and operating costs are the driving forces behind the increase in the application of dividing-wall columns in industry. However, a lack of knowledge still exists when dealing with the start-up of dividing-wall columns, which is inherently a strongly nonlinear process. Here, for the first time the start-up of dividing-wall columns is explored, where the starting point is an empty column at ambient conditions. A model is presented which is capable of predicting the dynamic discrete-continuous changes which are characteristic of dividing-wall columns. The proposed process model takes into account the heat transfer across the dividing wall as well as the vapor distribution below the dividing wall. The degree of accuracy of the model is clearly determined by comparing different simplifications, e.g. a constant vapor distribution ratio equal to the steady-state value. The detailed studies were carried out with strict product specifications so that the influence of process parameters could be quantified. The rigorous process model and the obtained simulation results presented in this study provide a promising basis for developing and applying optimal start-up policies for dividing-wall columns.     

Applying Model Predictive Control to Dividing Wall Columns

The technology of dividing wall columns can offer enormous energy savings compared to common distillation columns and configurations. The technology of model predictive control is also advantageous since such a controller minimizes the future deviation of the predicted controlled variable from the reference point. The practical application of model predictive controllers for dividing wall columns is still limited due to limited experience with high interactions among the process variables. The scope of this work is the development and analysis of a method for the design of model predictive controllers for dividing wall columns. An experimental investigation verifies the practicability of the applied approach. The methods generated are transferable to other applications. Thus, the industrial acceptance of model predictive controllers for dividing wall columns is enhanced.     

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins

Molecules containing an (cyanovinyl)arene moiety are known as tyrphostins because of their ability to inhibit proteins from the tyrosine kinase family, an interesting target for the development of anticancer and trypanocidal drugs. In the present work, (E)‐(cyanovinyl)benzeneboronic acids were synthesized by Knoevenagel condensations without the use of any catalysts in water through a simple protocol that completely avoided the use of organic solvents in the synthesis and workup process. The in vitro anticancer and trypanocidal activities of the synthesized boronic acids were also evaluated, and it was discovered that the introduction of the boronic acid functionality improved the activity of the boronic tyrphostins. In silico target fishing with the use of a chemogenomic approach suggested that tyrosine‐phosphorylation‐regulated kinase 1a (DYRK1A) was a potential target for some of the designed compounds.     

Influence of Compaction Conditions on the Foamability of AlSi8Mg4 Alloy

Aluminum AlSi8Mg4 alloy foams were produced by the powder compact foaming route using different parameters for the uniaxial powder compaction step. Compaction time, pressure, and temperature were varied and were found to influence both the density of the foamable precursor and the peak expansion reached during foaming. While peak expansion cannot be related to any single pressing parameter alone in a simple way, a clear dependence of expansion on the precursor density was found. Densification to a relative density between 97.5 and 99 pct yielded volume expansions of the foam up to 880 pct. Lower densities result in weaker foaming, due to insufficient encapsulation of the blowing agent; in addition, we were surprised to find that higher densification also has an adverse effect on peak expansion, most likely due to the elimination of nucleation centers or the effect of entrapped compressed air. Precursor microstructures were analyzed to identify the mechanisms leading to the observed density dependence of expansion.     

Reversibly erasable nanoporous anti-reflection coatings from polyelectrolyte multilayers

For nearly two centuries, researchers have sought novel methods to increase light transmission in optical systems, as well as to eliminate unwanted reflections and glare. Anti-reflection coatings and surfaces have enabled the increasing performance demands of optical components fabricated from glass-based optical materials. With the current trend of technology moving towards optically transparent polymeric media and coatings, the need for anti-reflection technology and environmentally benign processing methods for polymeric materials independent of shape or size has become quite apparent. We describe an economical, aqueous-based process controlled at the molecular level that simultaneously coats all surfaces of almost any material. Systematically designed nanoporous polymer films are used, which are suitable for optical applications operating at both visible and near-infrared wavelengths. These high-efficiency anti-reflection coatings are created from phase-separated polyelectrolyte multilayer films that undergo a reversible pH-induced swelling transition. Furthermore, such films, easily patterned by an inkjet printing technique, possess potential for pH-responsive biomaterial and membrane applications.