The p53 tumor suppressor is a transcription factor that mediates varied cellular responses. The C terminus of p53 is subjected to multiple and diverse post-translational modifications. An attractive hypothesis is that differing sets of combinatorial modifications therein determine distinct cellular outcomes. To address this in vivo, a Trp53ΔCTD/ΔCTD mouse was generated in which the endogenous p53 is targeted and replaced with a truncated mutant lacking the C-terminal 24 amino acids. These Trp53ΔCTD/ΔCTD mice die within 2 wk post-partum with hematopoietic failure and impaired cerebellar development. Intriguingly, the C terminus acts via three distinct mechanisms to control p53-dependent gene expression depending on the tissue. First, in the bone marrow and thymus, the C terminus dampens p53 activity. Increased senescence in the Trp53ΔCTD/ΔCTD bone marrow is accompanied by up-regulation of Cdkn1 (p21). In the thymus, the C-terminal domain negatively regulates p53-dependent gene expression by inhibiting promoter occupancy. Here, the hyperactive p53ΔCTD induces apoptosis via enhanced expression of the proapoptotic Bbc3 (Puma) and Pmaip1 (Noxa). In the liver, a second mechanism prevails, since p53ΔCTD has wild-type DNA binding but impaired gene expression. Thus, the C terminus of p53 is needed in liver cells at a step subsequent to DNA binding. Finally, in the spleen, the C terminus controls p53 protein levels, with the overexpressed p53ΔCTD showing hyperactivity for gene expression. Thus, the C terminus of p53 regulates gene expression via multiple mechanisms depending on the tissue and target, and this leads to specific phenotypic effects in vivo.

Alzheimer's disease is a progressive degenerative disease of the brain marked by gradual and irreversible declines in cognitive functions. Acetylcholinesterase (AChE) plays a biological role in the termination of nerve impulse transmissions at cholinergic synapses by rapid hydrolysis of its substrate, "acetylcholine". The deficit level of acetylcholine leads to deprived nerve impulse transmission. Thus the cholinesterase inhibitors would reverse the deficit in acetylcholine level and consequently may reverse the memory impairments, which is characteristic of the Alzheimer's disease. The molecular interactions between AChE and Carnosic acid, a well known antioxidant substance found in the leaves of the rosemary plant has always been an area of interest. Here in this study we have performed in silico approach to identify carnosic acid derivatives having the potential of being a possible drug candidate against AChE. The best candidates were selected on the basis of the results of different scoring functions.

The polluted water, mixture of chemicals and dyes, discharged by various textile and paper industries, is a serious problem for the environment, peculiarly the water. Dyes are stable to light, heat and oxidizing agents and are usually biologically non-degradable, which makes them complicated environmental pollutants. To examine the removal of dye from water, a three-dimensional poly (2-hydroxyethyl methacrylate) (PHEMA) and eosin Y were used, respectively, as a dye retention support and pollutant. The study of the interaction between dye and a hydrophilic polymer networks by the conformational modeling using computer software represents the goal of the present work. Both the swelling and ultraviolet-visible spectrophotometry studies show that the pollutant was well retained by the porous polymer network PHEMA. The conformational study of the system composed of polymer network/dye shows that the interaction of the oxygen (O) and bromine (Br) of eosin Y with the hydrogen (H) of the PHEMA depends on the polymer porosity that was varied by the cross-linking rate of the three-dimensional polymer networks. The results obtained by this work can be applied to improve the retention efficiency of such material for use in wastewater application.

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5569 Background: Muscle (MT) and adipose tissue (AT) share common intra cellular pathways with tumor, thus it is not surprising to observe metabolic consequences with targeted therapies. The aim of the study was to assess the effects of vandetanib, a tyrosine kinase inhibitor (TKI) which demonstrated efficacy for the treatment of advanced medullary thyroid carcinoma (MTC), on MT and AT. Methods: 33 patients (25 men and 8 women, mean age of 54 years) with metastatic MTC received vandetanib 300 mg/d (n=23) or placebo (n=10) in the setting of the ZETA study. Cross-sectional areas (cm2) of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and MT were assessed by computed tomography imaging at 3rd lumbar vertebra and were indexed for height (cm2/m2). Comparisons between treatment and placebo were made at 3 months, and long-term evolution was evaluated over 12 months. Results: At 3 months, compared to baseline, patients treated with vandetanib gained 1.5 kg, 1.3 cm2/m2 of MT, 5.1 cm2/m2 of VAT and 4.5 cm2/m2 of SAT. In contrast, patients under placebo lost 1.5 kg (p=0.02), 1.0 cm2/m2 of MT (p=0.009), 5.5 cm2/m2 of SAT (p=0.004) and gained significantly less VAT (0.6 cm2/m2) (p=0.02). At 12 months, compared to baseline, patients treated with vandetanib gained 2 kg (NS), lost 0.3 cm2/m2 MT (NS), gained 3.4 cm2/m2 of VAT (NS) and 8.7 cm2/m2 of SAT (95% CI, 1.1 to 16.2). A significant decrease of calcitonin (defined as ≤50% compared to baseline) was associated with higher weight (p=0.01), VAT (p=0.01), and total adipose tissue (p=0.02). Conclusions: Beyond its proved efficacy in MTC treatment, and despite common intracellular pathways, vandetanib is the only studied TKI to preserve MT and to restore AT. Further research is needed to explore whether the relationship between changes of VAT and vandetanib treatment results from a direct metabolic action of vandetanib or is a consequence of biochemical tumor control.