We studied miRNA profiles in 4419 human samples (3312 neoplastic, 1107 nonmalignant), corresponding to 50 normal tissues and 51 cancer types. The complexity of our database enabled us to perform a detailed analysis of microRNA (miRNA) activities. We inferred genetic networks from miRNA expression in normal tissues and cancer. We also built, for the first time, specialized miRNA networks for solid tumors and leukemias. Nonmalignant tissues and cancer networks displayed a change in hubs, the most connected miRNAs. hsa-miR-103/106 were downgraded in cancer, whereas hsa-miR-30 became most prominent. Cancer networks appeared as built from disjointed subnetworks, as opposed to normal tissues. A comparison of these nets allowed us to identify key miRNA cliques in cancer. We also investigated miRNA copy number alterations in 744 cancer samples, at a resolution of 150 kb. Members of miRNA families should be similarly deleted or amplified, since they repress the same cellular targets and are thus expected to have similar impacts on oncogenesis. We correctly identified hsa-miR-17/92 family as amplified and the hsa-miR-143/145 cluster as deleted. Other miRNAs, such as hsa-miR-30 and hsa-miR-204, were found to be physically altered at the DNA copy number level as well. By combining differential expression, genetic networks, and DNA copy number alterations, we confirmed, or discovered, miRNAs with comprehensive roles in cancer. Finally, we experimentally validated the miRNA network with acute lymphocytic leukemia originated in Mir155 transgenic mice. Most of miRNAs deregulated in these transgenic mice were located close to hsa-miR-155 in the cancer network
Ethene/propene copolymerizations were performed with catalytic systems composed of a
stereorigid racemic isospecific metallocene and polymethylalumoxane. A number of complexes were used
as representatives of three different classes of metallocenes. r-Me2C(3-t-Bu-Cp)2ZrCl2, r-Me2C(3-t-Bu-Ind)2ZrCl2, r-EBDMIZrCl2, r-EBDMTHIZrCl2, and r-Me2Si(2-Me-4-Ph-Ind)2ZrCl2 were chosen as sterically
hindered complexes. The parent metallocenes, r-Me2C(Ind)2ZrCl2, r-EBIZrCl2, and r-Me2Si(Ind)2ZrCl2 were
also employed as well as other compounds bearing different substituents on the indenyl ligands such as
r-Me2C(3-Me3Si-Ind)2ZrCl2, r/m-Me2C(3-Me-Ind)2ZrCl2, and r-Me2Si(2-Me-Ind)2ZrCl2. The reactivity ratios
of copolymerization (r
E and r
P) were determined and examined in the light of the metallocene structure.
The complexes that were particularly demanding from the steric point of view were identified as suitable
candidates for promoting copolymerizations with a high product of reactivity ratios, giving r
E
r
P in a range
from 1.7 to 3.0. The other two classes of metallocenes gave rise to r
E
r
P clearly lower than 1. A more
complex situation was observed as far as the reactivity ratios r
E and r
P are concerned. The enhancement
of the steric hindrance brought about in most cases an increase of r
E but not a substantial decrease of r
P.
In some cases, r
E was found to remain almost unchanged and r
P dramatically increased. A correlation
between the reactivity ratios and the metallocene structure is attempted.
Indenyl silyl amido titanium complexes based on indenoindoles, indenopyrrole, and 2-methylindenothiophene have been prepared and tested in propylene polymerization. The indenoindole ligand precursors were prepared in high yields by the acid-catalyzed Fischer condensation of indan-2-one and arylhydrazines. The Ti complexes dimethylsilyl(tertbutylamido 6) were prepared by reacting the ligand, a 2-fold excess of MeLi, and TiCl 4 . The molecular structures of the amidosilylindenyl titanium complexes 2 and 6 have been determined by single-crystal X-ray diffraction analysis: the indenoindole moiety in 2 and the indenothiophene moiety in 6 are perfectly planar, implying a certain degree of delocalization of the heteroatom lone pairs into the aromatic moiety coordinated to the metal atom. Catalysts 1, 2, and 5 produce syndiotactic amorphous polypropylenes (sam-PP) of very high molecular weights, even at polymerization temperatures as high as 80 °C. Syndiotactic pentad contents range between 48 and 57% rrrr, and regioerrors are close to or below the detection limit of the 13 C NMR analysis (at 100 MHz). In toluene solution, [Ph 3 C][B(C 6 F 5 ) 4 ] is a more efficient activator than MAO, [HNMe 2 Ph][B(C 6 F 5 ) 4 ], or B(C 6 F 5 ) 3 . The catalytic activity of 5/[Ph 3 C][B(C 6 F 5 ) 4 ] shows an approximate first-order dependence on propylene concentration, while the tacticity and the molecular weight do not seem to change noticeably with the monomer concentration. The obtained activation energy barrier for chain release with this catalyst is ∆∆E r q ) 7.7 kcal/mol. The influence of cyclopentadienyl ligand substituents on polymerization activity has been rationalized by means of the group electronegativity of the [Me 2 Si(Cp′)(t-Bu-N)TiMe] fragment, as defined within the framework of density functional theory.
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