Gene expression data from microdissected p53 restored adenocarcinomas.

Metal / dielectric nanostructures, such as metal nanoparticles of different shape (spheres, rods, stars) capped with organic adsorbates, have a strong potential for the development of new materials for nanotechnology. Among these structures, those including monolayer protected clusters of noble metal nanoparticles modified with organic fluorophores are of great interest for the fabrication of new fluorescent bio- and chemical sensors, and for optical devices as well. The nature of the interactions between metals and organic fluorophores is still not totally understood. These interactions, which depend on various factors, including the geometry of the systems, the physicochemical properties of the interacting materials and their environment, often result in an enhancement or a quenching of the emission. The performed investigations comprise design, preparation, characterization and photophysical study of monolayer protected clusters of noble metal nanoparticles modified with newly synthesized organic fluorophore.

Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumor-suppressor pathways. The quest to personalize cancer medicine based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumor suppressors and activation of oncogenes are required for tumor maintenance. Mutations in the p53 tumor-suppressor pathway are a hallmark of cancer and significant efforts toward pharmaceutical reactivation of mutant p53 pathways are underway1-3. Here we show that restoration of p53 in established murine lung tumors leads to significant but incomplete tumor cell loss specifically in malignant adenocarcinomas but not in adenomas. Also, we define amplification of MAPK signaling as a critical determinant of malignant progression. The differential response to p53 restoration depends on activation of the Arf tumor suppressor downstream of hyperactive MAPK signaling. We propose that p53 naturally limits malignant progression by responding to increased oncogenic signaling, but is unresponsive to low levels of oncogene activity that are sufficient for early stages of lung tumor development. These data suggest that restoration of pathways important in tumor progression, as opposed to initiation, may lead to incomplete tumor regression due to the stage-heterogeneity of tumor cell populations. 3 cell lines each treated with Tamoxifen or EtOH vehicle. Tamoxifen treatment results in reactivation of p53 expression

Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumor-suppressor pathways. The quest to personalize cancer medicine based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumor suppressors and activation of oncogenes are required for tumor maintenance. Mutations in the p53 tumor-suppressor pathway are a hallmark of cancer and significant efforts toward pharmaceutical reactivation of mutant p53 pathways are underway1-3. Here we show that restoration of p53 in established murine lung tumors leads to significant but incomplete tumor cell loss specifically in malignant adenocarcinomas but not in adenomas. Also, we define amplification of MAPK signaling as a critical determinant of malignant progression. The differential response to p53 restoration depends on activation of the Arf tumor suppressor downstream of hyperactive MAPK signaling. We propose that p53 naturally limits malignant progression by responding to increased oncogenic signaling, but is unresponsive to low levels of oncogene activity that are sufficient for early stages of lung tumor development. These data suggest that restoration of pathways important in tumor progression, as opposed to initiation, may lead to incomplete tumor regression due to the stage-heterogeneity of tumor cell populations. 18 tumors of different grade and treatment status. 6 treated grade 3, 4 treated grade2, 4 untreated grade3, 4 untreated grade2

Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway(1-3). Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas, but not in adenomas. We define amplification of MAPK signalling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signalling to mediate tumour regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.

Dihydroxy naphthalenes have been applied in Betti-type solventless condensation between aldehydes and (S)-phenylethylamine as a chiral auxiliary. A series of chiral 1,3-aminonaphthols has been synthesized and isolated in diastereoisomerically pure form. The absolute configurations of the aminonaphthols synthesized have been determined by means of advanced NMR experiments and confirmed by X-ray crystallography. The new chiral aminonaphthols have been tested as pre-catalysts for the addition of diethyl zinc and alkynyl-Zn-reagents to aldehydes with enantioselectivities of up to 98% ee. (C) 2013 Elsevier Ltd. All rights reserved.

The efficiency of the alkaloids quinine, cinchonine, cinchonidine and ephedrine, the aminoalcohols prolinol, and alaninol, as well as the aminoacids proline, and phenylalanine as catalysts for the enantioselective addition of diethylzinc to ferrocene carbaldehyde and benzaldehyde has been studied. The addition reactions proceeded with acceptable yields and low to moderate enantioselectivities. The side products ferrocenyl methanol and 1 -ferrocenyl-1-propanone, observed during the additions to ferrocene carbaldehyde were isolated and characterized.

Herein, we report on the synthesis, spectral, crystallographic and electrochemical properties of a small library of N-substituted 2-ferrocenyl-1,3-thiazolidin-4-ones, designed as novel GABA(A) benzodiazepine-binding site ligands. The anxiolytic properties of the title compounds were evaluated in several different in vivo models, whereas the involvement of the GABAA receptor complex in the activity of the most potent compound, 2-ferrocenyl-3-(4-methoxyphenylethyl)-1,3-thiazolidin-4-one, was inferred from experiments with known GABA(A)-targeting agents. Ligand docking experiments revealed that the high, dose-dependent, anxiolytic activity of the new compounds might be due to their favorable interactions with the benzodiazepine-binding site of the GABA(A) receptor complex. The incorporation of the ferrocene core and fine tuning of the distance between the thiazolidinone core and an additional aromatic ring were judged to be crucial structural requirements for the observed anxiolytic effect. (C) 2014 Elsevier Masson SAS. All rights reserved.