Autotaxin (ATX) was originally identified as a potent tumor cell motility-stimulating factor that displays multiple enzymatic activities including ATPase, Type I nucleotide ...pyrophosphatase/phosphodiesterase, and lysophospholipase D, depending on its substrates. We demonstrate herein that ATX is a key regulator of extracellular lysophosphatidic acid (LPA) that can act as survival factor, in addition to its mitogenic activity in mouse fibroblasts. Introduction of
atx gene into NIH3T3 cells resulted in resistance to conditional apoptosis induced by serum-deprivation, and exogenous ATX protein prevented cells from death by starvation. Flow cytometric analysis showed that co-treatment of ATX with lysophosphatidylcholine as substrate rescued NIH3T3 cells from cellular apoptosis, and this survival activity of ATX was also demonstrated by caspase-3 degradation and PARP cleavage resulting from the enzymatic activity of extracellular ATX. Furthermore, the effect of ATX in preventing apoptosis appears to be mediated through the G-protein-coupled receptor pathway followed by the activation of phosphoinositide 3-kinase and Akt pathway leading to enhanced cell survival. These findings provide novel insights into understanding the functions of ATX as a key regulator of bioactive phospholipids and suggest interventions to correct dysfunction in conditions of tumor cell growth and metastasis.
Tumor necrosis factor-related apoptosis-inducing ligand-receptor 1 (TRAIL-R1) and tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) are cell-surface receptors involved in ...tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell-death signaling. TRAIL-R1 and TRAIL-R2 genes have recently been mapped to chromosome 8p21-22, which is a frequent site of allelic deletions in many types of human tumors, including non-Hodgkin's lymphoma (NHL). Because TRAIL/TRAIL receptor system plays an important role in lymphocyte homeostasis, we hypothesized that the mutations of TRAIL-R1 and TRAIL-R2 may be involved in the development of NHL and that such mutations may be responsible for the allelic losses of 8p21-22 in NHL. In this study, we analysed the entire coding region of TRAIL-R2 gene and the death domain region of TRAIL-R1 gene for the detection of the somatic mutations in a series of 117 human NHLs using polymerase chain reaction (PCR)-based single strand conformation polymorphism (SSCP) analysis. Overall, eight tumors (6.8%) were found to have two TRAIL-R1 gene mutations or six TRAIL-R2 gene mutations. Interestingly, of the eight mutations, six missense mutations (two TRAIL-R1 and four TRAIL-R2) were detected in the death domains and one nonsense mutation of TRAIL-R2 was detected just before the death domain. Our data suggest that somatic mutations of TRAIL-R1 and TRAIL-R2 genes may play a role in the pathogenesis of some NHLs and that TRAIL-R1 and TRAIL-R2 genes might be the relevant genes to the frequent loss of chromosome 8p21-22 in human NHL.
Unilateral temporoparietal injury may result in an attentional deficit for stimuli presented in contralesional space. Thus, bilateral temporoparietal degeneration associated with Alzheimer disease ...(AD) might result in a bilateral attentional disturbance. Tests for hemispatial neglect, however, primarily assess spatial attentional asymmetries, and a bilateral attentional disorder might not be detected with these tests. The goal of this study was to learn whether optokinetic stimulation (OKS) would perturb the balanced attentional deficits of AD patients and alter their spatial allocation of attention.
In Experiment I, 10 AD patients with bilateral temporoparietal glucose hypometabolism on PET and 10 controls bisected lines in two conditions: stationary solid lines superimposed on a moving background and "striped lines" where the whole line was stationary but the stripes within the line moved. The background OKS or the stripes within the line moved leftward or rightward or were stationary. In Experiment II, to investigate whether the influence of background movements would increase with AD severity, we conducted a similar experiment in 56 patients with various stages of AD.
In Experiment I, the line bisection errors (LBEs) of AD subjects, but not of the controls, were markedly influenced by both background and within line stripe motions, deviations occurring in the same direction of movement. In Experiment II, LBEs also occurred in the same direction as background movement and increased with dementia severity.
These results demonstrate that patients with Alzheimer disease are spatially distracted by moving stimuli.
Two types of ultracapacitor modules have been developed for use as energy-storage devices for 42-V systems in automobiles. The modules show high performance and good reliability in terms of discharge ...and recharge capability, long-term endurance, and high energy and power. During a 42-V system simulation test of 6-kW power boosting/regenerative braking, the modules demonstrate very good performance. In high-power applications such as 42-V and hybrid vehicle systems, ultracapacitors have many merits compared with batteries, especially with respect to specific power at high rate, thermal stability, charge–discharge efficiency, and cycle-life. Ultracapacitors are also very safe, reliable and environmentally friendly. The cost of ultracapacitors is still high compared with batteries because of the low production scale, but is decreasing very rapidly. It is estimated that the cost of ultracapacitors will decrease to US$ 300 per 42-V module in the near future. Also, the maintenance cost of the ultracapacitor is nearly zero because of its high cycle-life. Therefore, the combined cost of the capacitor and maintenance will be lower than that of batteries in the near future. Overall, comparing performance, price and other parameters of ultracapacitors with batteries, ultracapacitors are the most likely candidate for energy-storage in 42-V systems.
Both epidermal growth factor receptor (EGFR) and RAS gene mutations contribute to the development of non-small cell lung cancer (NSCLC). Because RAS is one of the downstream molecules in the EGFR ...signal transduction, the association between the somatic mutations of EGFR and RAS may be important in the pathogenesis of NSCLC . However, to date, such data are lacking. In this study, we analyzed the hotspot regions of K-RAS gene (codons 12, 13, 59 and 61) and EGFR gene (exons 18, 19 and 21) in 153 NSCLC tissue samples including 69 adenocarcinomas. Overall, we detected 30 EGFR mutations (19.6%) and 6 K-RAS mutations (3.9%) in the 153 NSCLCs. In the 69 adenocarcinomas, 26 EGFR mutations (37.7%) and six K-RAS mutations (8.7%) were detected. Of note, the 26 tumors with EGFR mutations did not harbor any K-RAS mutations, and the six tumors with K-RAS mutations did not harbor any EGFR mutations. Inverse relationship between K-RAS and EGFR mutations in the lung adenocarcinoma was statistically significant (P=0.046, chi2 test). As regards smoking history, EGFR mutation was significantly associated with never-smoking history, whereas K-RAS mutation was significantly associated with smoking history. Our data suggest that mutations of EGFR and K-RAS genes might separately, but not cooperatively, contribute to lung adenocarcinoma pathogenesis, and that EGFR and K-RAS mutants could separately be anti-neoplastic targets in lung adenocarcinomas.
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