Halogenated chalcones with high-affinity binding to P-glycoprotein: potential modulators of multidrug resistance

Previous studies have shown that flavonoids are modulators of the transmembrane P-glycoprotein (P-gp) which mediates cell multidrug resistance. Some structural elements have been identified which seem to contribute to these compounds' activity. In the present study, a series of halogenated chalcones was prepared to further explore the structural requirements for the P-gp modulation. Four halogenated chalcones have been synthesized and evaluated as potential modulators of P-gp-mediated multidrug resistance of cancer cells by in vitro assays using a purified recombinant domain of the transporter containing the modulator binding site. Halogenated chalcones exhibited high-affinity binding, the 2',4', 6'-trihydroxy-4-iodochalcone behaving as the most potent compound with a KD value in the nanomolar range.     

Refactoring: Current Research and Future Trends

In this paper we provide an detailed overview of existing research in the field of software restructuring and refactoring, from a formal as well as a practical point of view. Next, we propose an extensive list of open questions that indicate future research directions, and we provide some partial answers to these questions.     

Intravascular ultrasound in endovascular stent-grafts for peripheral aneurysm: a clinical study

The present series of experiments was performed to investigate the influence of acute intracranial hypertension on the upper limit (UL) of cerebral blood flow (CBF) autoregulation. Three groups of eight rats each--one with normal intracranial pressure (ICP) (2 mmHg), one with ICP = 30 mmHg, and one with ICP = 50 mmHg--were investigated. Intracranial hypertension was maintained by continuous infusion of lactated Ringer's solution into the cisterna magna, where the pressure was used as ICP. Cerebral perfusion pressure (CPP), calculated as mean arterial blood pressure (MABP)-ICP, was increased stepwise by continuous intravenous infusion of norepinephrine. CBF was calculated by the intracarotid 133Xe method. In all three groups the corresponding CBF/CPP curve included a plateau where CBF was independent of changes in CPP, showing intact autoregulation. At normal ICP the UL was found at a CPP of 141 +/-2 mmHg, at ICP = 30 mmHg the UL was 103+/-5 mmHg, and at ICP = 50 mmHg the UL was found at 88+/-7 mmHg. This shift of the UL was more pronounced than the shift of the lower limit (LL) of the CBF autoregulation found previously. We conclude that intracranial hypertension is followed by both a shift toward lower CPP values and a narrowing of the autoregulated interval between the LL and the UL.     

High Acceleration for Video Processing Applications Using Specialized Instruction Set Based on Parallelism and Data Reuse

This paper describes an application-specific instruction set for a configurable processor to accelerate motion-compensated frame rate conversion (MC-FRC) algorithms based on block motion estimation (BME). The paper shows that the key to achieve very high performance when creating new instructions is to leverage, at the same time, parallel computations, data reuse, and efficient cache use. This is supported by concrete examples that demonstrate how it can be done in the case of the two algorithms considered. The new instructions are used to implement two BME algorithms: one implements the full search (FS) block matching algorithm (BMA), while the other implements the One-Dimensional Full Search (ODFS) BMA. The obtained acceleration factors exceed one hundred for the MC-FRC algorithm embedding the FS algorithm and twenty for the ODFS algorithm. The results show that getting such global acceleration is the consequence of combining parallel computations, data reuse, and efficient cache use, not of only one of them.     

Social insurance cost of standard discectomy and percutaneous nucleotomy. A retrospective study of 87 social insurance claim files of male blue collar workers

To evaluate the effect of cadmium intoxication on renal transport systems for organic anions and cations, transport of p-aminohippurate (PAH) and tetraethylammonium (TEA) were studied in renal cortical plasma membrane vesicles isolated from cadmium-intoxicated rats. Cadmium intoxication was induced by daily injections of CdCl2 (2 mg Cd/kg.day sc) for 2-3 weeks. Renal plasma membrane vesicles were prepared by Percoll gradient centrifugation and magnesium precipitation method. Vesicular uptake of substrate was determined by rapid filtration technique using Millipore filter. The cadmium treatment resulted in a marked attenuation of Na(+)-dependent, alpha-ketoglutarate (alpha KG)-driven PAH uptake in the basolateral membrane vesicle (BLMV), and this was due to a reduction in Vmax and not K(m). The Na(+)-alpha KG symport activity of the BLMV was not affected by 2-week cadmium treatment, but it was significantly inhibited by 3-week cadmium treatment. On the other hand, the alpha KG-PAH antiport activity of the BLMV appeared to be markedly suppressed in 2-week as well as 3-week cadmium-treated animals. The cadmium treatment inhibited the proton gradient-dependent TEA transport in the brush-border membrane vesicle (BBMV), and this was associated with a reduction in Vmax with no change in K(m). These results indicate that cadmium exposures may impair the capacities for organic anion transport in the proximal tubular basolateral membrane and organic cation transport in the luminal membrane. The cadmium effect on organic anion transport is attributed mainly to an inhibition of dicarboxylate-organic anion antiport system.     

Crystal structure of MTCP-1: implications for role of TCL-1 and MTCP-1 in T cell malignancies

Two related oncogenes, TCL-1 and MTCP-1, are overexpressed in T cell prolymphocytic leukemias as a result of chromosomal rearrangements that involve the translocation of one T cell receptor gene to either chromosome 14q32 or Xq28. The crystal structure of human recombinant MTCP-1 protein has been determined at 2.0 A resolution by using multiwavelength anomalous dispersion data from selenomethionine-enriched protein and refined to an R factor of 0.21. MTCP-1 folds into a compact eight-stranded beta barrel structure with a short helix between the fourth and fifth strands. The topology is unique. The structure of TCL-1 has been predicted by molecular modeling based on 40% amino acid sequence identity with MTCP-1. The identical residues are clustered inside the barrel and on the surface at one side of the barrel. The overall structure of MTCP-1 superficially resembles the structures of proteins in the lipocalin family and calycin superfamily. These proteins have diverse functions, including transport of retinol, fatty acids, chromophores, pheromones, synthesis of prostaglandin, immune modulation, and cell regulation. However, MTCP-1 differs in the topology of the beta strands. The structural similarity suggests that MTCP-1 and TCL-1 form a unique family of beta barrel proteins that is predicted to bind small hydrophobic ligands and function in cell regulation.     

Comparison of interface state density in MIS structure deduced from DLTS and Terman measurements

Interface state impedance has been theoretically predicted to introduce spurious detailed structures in the trap density curves when determined by high-frequency C/V measurements (Terman method). This is experimentally demonstrated on irradiated MOS structures. Terman analysis of these MOS capacitors presents a peak in the trap density near the conduction band, while a flat continuum is found by deep level transient spectroscopy (DLTS). A numerical simulation shows that this discrepancy can be taken into account by the only interface state impedance effect.     

99mTc human immunoglobulin scintigraphy--a reliable method to detect joint activity in rheumatoid arthritis

The ability of 99mtechnetium labelled nonspecific, polyclonal human immunoglobulin G (99mTc-IgG) scintigraphy to depict and quantify synovial inflammation was studied in 30 patients with rheumatoid arthritis (RA). All patients were injected with 350 MBq 99mTc-IgG and imaging was performed 4 h later. This resulted in excellent images of inflamed synovium. Scores for 99mTc-IgG joint scintigraphy correlated highly with scores for joint swelling and C-reactive protein levels, weakly with pain scores and not with radiographic scores of joint destruction. These results suggest that 99mTc-IgG joint scintigraphy may provide an objective test to detect synovitis and measure the activity of the disease.