Targeting of tumor radioiodine therapy by expression of the sodium iodide symporter under control of the survivin promoter

To test the feasibility of using the survivin promoter to induce specific expression of sodium/iodide symporter (NIS) in cancer cell lines and tumors for targeted use of radionuclide therapy, a recombinant adenovirus, Ad-SUR-NIS, that expressed the NIS gene under control of the survivin promoter was constructed. Ad-SUR-NIS mediating iodide uptake and cytotoxicity was performed in vitro. Scintigraphic, biodistribution and radioiodine therapy studies were performed in vivo. PC-3 (prostate); HepG2 (hepatoma) and A375 (melanoma) cancer cells all exhibited perchlorate-sensitive iodide uptake after infection with Ad-SUR-NIS, ∼50 times higher than that of negative control Ad-CMV-GFP-infected cells. No significant iodide uptake was observed in normal human dental pulp fibroblast (DPF) cells after infection with Ad-SUR-NIS. Clonogenic assays demonstrated that Ad-SUR-NIS-infected cancer cells were selectively killed by exposure to 131I. Ad-SUR-NIS-infected tumors show significant radioiodine accumulation (13.3±2.85% ID per g at 2 h post-injection), and the effective half-life was 3.1 h. Moreover, infection with Ad-SUR-NIS in combination with 131I suppressed tumor growth. These results indicate that expression of NIS under control of the survivin promoter can likely be used to achieve cancer-specific expression of NIS in many types of cancers. In combination with radioiodine therapy, this strategy is a possible method of cancer gene therapy

Activin signaling as an emerging target for therapeutic interventions

After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-β (TGF-β) ligands such as myostatin, growth and differentiation factor-11 and nodal. Thus, although the activity of each ligand is distinct, they are also redundant, both physiologically and pathologically in vivo. Activin receptors activated by ligands phosphorylate the receptor-regulated Smads for TGF-β, Smad2 and 3. The Smad proteins then undergo multimerization with the co-mediator Smad4, and translocate into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. Signaling through receptors and Smads is controlled by multiple mechanisms including phosphorylation and other posttranslational modifications such as sumoylation, which affect potein localization, stability and transcriptional activity. Non-Smad signaling also plays an important role in activin signaling. Extracellularly, follistatin and related proteins bind to activins and related TGF-β ligands, and control the signaling and availability of ligands

Synthesis and spectroscopic study of mesoporous aluminum methylphosphonate foam templated by dibutyl methylphosphonate

New types of templates and novel interactive mechanisms between template and framework are very important for creating porous materials. In this work, by using neutral dibutyl methylphosphonate as a template, an inorganic-organic hybrid mesoporous material, aluminum methylphosphonate, was prepared. The as-synthesized material was studied by P-31 magnetic angle spinning nuclear magnetic resonance (MAS NMR), Al-27 MAS NMR, C-13 CP/MAS, FT-IR spectroscopy, thermogravimetry (TG), differential thermal analysis (DTA), and transmission electron microscopy. After thermal treatment at 673 K and 10 mmHg for 2 h, hybrid mesoporous foam was obtained. The transformation process was investigated by FT-IR. TG-DTA results indicate that the methyl group bonded to the framework keeps intact up to 792 K under air and 823 K under nitrogen. The characterization results from nitrogen gas adsorption-desorption measurements show that the BET surface area and the Barrett-Joyner-Halenda desorption cumulative pore volume of the foam are 90 m(2) g(-1) and 0.32 cm(3) g(-1) respectively. (C) 2003 Elsevier Inc. All rights reserved

Syntheses and structures of sodium aluminodiphosphonates with different morphologies (diphosphonate=1-hydroxyethylidenediphosphonate)

A new family of sodium aluminodiphosphonates (diphosphonate = 1-hydroxyethylidenediphosphonate) has been synthesised hydrothermally at 433 K for 15 days. By altering the aluminium source, two different morphologies, namely hexagonal tubular and solid morphology, have been obtained, and the corresponding crystals were named as DLES-Alt and DLES-Als, respectively. Under the synthesis condition for DLES-Alt, if the reaction time was changed to 7 days, a small amount of crystals with the solid morphology accompanying DLES-Alt were observed, and designated as DLES-Alts. Meanwhile, crystals with a plate-like morphology (designated as DLES-Alp) were always the accompanying phase of the main phase of DLES-Alt or DLES-As. All of the crystals were isostructures. A hexagonal ring containing a propeller-like chiral motif along [0 0 1] is a common characteristic of these crystals. Being a representative case, the crystallographic data of DLES-Alt is trigonal (space group P-3), with cell parameters at 293 K as follows: a = 17.853(4), b = 17.853(4), c = 8.823(4)Angstrom, V = 2435.3(14) Angstrom(3), and Z = 6. (C) 2004 Elsevier B.V. All rights reserved

The Arabidopsis small G protein ROP2 is activated by light in guard cells and inhibits light-induced stomatal opening

ROP small G proteins function as molecular switches in diverse signaling processes. Here, we investigated signals that activate ROP2 in guard cells. In guard cells of Vicia faba expressing Arabidopsis thaliana constitutively active (CA) ROP2 fused to red fluorescent protein (RFP-CA-ROP2), fluorescence localized exclusively at the plasma membrane, whereas a dominant negative version of RFP-ROP2 (DN-ROP2) localized in the cytoplasm. In guard cells expressing green fluorescent protein-ROP2, the relative fluorescence intensity at the plasma membrane increased upon illumination, suggesting that light activates ROP2. Unlike previously reported light-activated factors, light-activated ROP2 inhibits rather than accelerates light-induced stomatal opening; stomata bordered by guard cells transformed with CA-rop2 opened less than controls upon light irradiation. When introduced into guard cells together with CA-ROP2, At RhoGDI1, which encodes a guanine nucleotide dissociation inhibitor, inhibited plasma membrane localization of CA-ROP2 and abolished the inhibitory effect of CA-ROP2 on light-induced stomatal opening, supporting the negative effect of active ROP2 on stomatal opening. Mutant rop2 Arabidopsis guard cells showed phenotypes similar to those of transformed V. faba guard cells; CA-rop2 stomata opened more slowly and to a lesser extent, and DN-rop2 stomata opened faster than wild-type stomata in response to light. Moreover, in rop2 knockout plants, stomata opened faster and to a greater extent than wild-type stomata in response to light. Thus, ROP2 is a light-activated negative factor that attenuates the extent of light-induced changes in stomatal aperture. The inhibition of light-induced stomatal opening by light-activated ROP2 suggests the existence of feedback regulatory mechanisms through which stomatal apertures may be finely controlled.X1133sciescopu