Synthesis and biological evaluation of non-peptide alpha(v)beta(3)/alpha(5)beta(1) integrin dual antagonists containing 5,6-dihydropyridin-2-one scaffolds

Small constrained non-peptidic molecules consisting of a polyfunctionalized rigid core, carrying appendages corresponding to arginine and aspartic acid side chains, have been recently reported to be promising for drug development. In this work, the 5,6-dihydropyridin-2-one was envisaged as a scaffold to turn into potential integrin ligands, introducing a carboxylic acid and a basic appendage. The synthesis and the antiadhesion activity of a small library of peptidomimetics capable to recognize alpha(v)beta(3) and alpha(5)beta(1) integrins has been herein reported.     

EGFR through STAT3 modulates ΔN63α expression to sustain tumor‐initiating cell proliferation in squamous cell carcinomas

Many squamous cell carcinomas (SCCs) are characterized by high levels of EGFR and by overexpression of the ΔNp63α isoform. Here, we investigated the regulation of ΔNp63α expression upon EGFR activation and the role of the EGFR–ΔNp63α axis in proliferation of SCC tumor‐initiating cells (TICs). SCC cell lines A‐431, Cal‐27, and SCC‐25 treated with EGF showed a time‐dependent increase in ΔNp63α expression at the protein and mRNA levels, which was blocked by the tyrosine kinase inhibitor (TKI) Lapatinib. RNA interference experiments suggested the role of STAT3 in regulating ΔNp63α expression downstream of EGFR. Inactivation of EGFR by the monoclonal antibody Cetuximab and RNA interference against STAT3 or ΔNp63α impaired the TICs ability to grow under non‐differentiating conditions. Radiation treatment, which triggers EGFR activation, induced ΔNp63α accumulation without affecting TICs proliferation, whereas the combination Cetuximab plus radiation significantly reduced TICs growth under non‐differentiating conditions. Together, our findings provide evidence that ΔNp63α expression is regulated by EGFR activation through STAT3 and that the EGFR–ΔNp63α axis is crucial for proliferation of TICs present in SCCs. J. Cell. Physiol. 228: 871–878, 2013. © 2012 Wiley Periodicals, Inc.     

The Holocene treeline in the northern Andes (Ecuador): First evidence from soil charcoal

Indications for the speed and timing of past altitudinal treeline shifts are often contradictory. Partly, this may be due to interpretation difficulties of pollen records, which are generally regional rather than local proxies. We used pedoanthracology, the identification and dating of macroscopic soil charcoal, to study vegetation history around the treeline in the northern Ecuadorian Andes. Pedoanthracology offers a complementary method to pollen-based vegetation reconstructions by providing records with high spatial detail on a local scale. The modern vegetation is tussock grass páramo (tropical alpine vegetation) and upper montane cloud forest, and the treeline is located at ca. 3600 m. Charcoal was collected from soils in the páramo (at 3890 and 3810 m) and in the forest (at 3540 m), and represents a sequence for the entire Holocene.The presence of páramo taxa throughout all three soil profiles, especially in combination with the absence of forest taxa, shows that the treeline in the study area has moved up to its present position only late in the Holocene (after ca. 5850 cal years BP). The treeline may have been situated between 3600 m and 3800 m at some time after ca. 4900 cal years BP, or it may never have been higher than it is today. The presence of charcoal throughout the profiles also shows that fires have occurred in this area at least since the beginning of the Holocene.These results contradict interpretations of palaeological data from Colombia, which suggest a rapid treeline rise at the Pleistocene–Holocene transition. They also contradict the hypothesis that man-made fires have destroyed large extents of forest above the modern treeline. Instead, páramo fires have probably contributed to the slowness of treeline rise during the Holocene.     

Osservazioni Sulle Foglie del Genere Alstroemria

Riassunto

Le foglie giovani di Alstroemeria sono guainanti, con guaina fenduta avvolgente il nono; i nomofilli invece ne mancano perchè essa confusasi colla corteccia primaria. La torsione dei filli è dovuta alla loro crescenza asimmetrica spiralata. La fillotassi, dapprima distica, diviene tristica.     

Synthesis,characterization and immunochemical evaluation of cephalosporin antigenic determinants

Lack of knowledge of the exact chemical structure of cephalosporin antigenic determinants has hindered clinical interpretation of adverse reactions to these drugs and delayed understanding of the mechanisms involved in the specific recognition and binding of IgE molecules to these antigenic determinants. We further resolve the relationship between structure and activity of proposed antigenic chemicals, including the rational design and synthesis of these haptenic structures. Comparative RAST inhibition studies of the synthesized molecules revealed that they were recognized by IgE antibodies induced by cephalosporin antibiotics. Thus, these data indicate that recognition is mainly directed to the acyl side chain and to the beta-lactam fragment that remains linked to the carrier protein in the cephalosporin conjugation course.     

Antiproliferative effects on human tumor cells and rat aortic smooth muscular cells of 2,3-heteroarylmaleimides and heterofused imides

A series of 2,3-heteroarylmaleimides 9 and polyheterocondensed imides 12 were prepared in good yields and short reaction time using a very efficient procedure consisting in the condensation of the corresponding anhydrides and N,N-diethylethylenediamine and microwave heating. The antiproliferative activity of the novel molecules was tested against human tumor cells (NCI-H460 lung carcinoma) and rat aortic smooth muscle cells (SMCs). The IC50 values for the novel molecules ranged from 0.08 to 13.9 microM in SMCs, and from 0.84 to 9 microM in the tumor cell line. The activity profile for compounds 9 and 12 is comparable to that obtained for amonafide in NCI-H460, except for fused imides 12b,i which proved to be about 10-fold more potent. Whereas, in rat SMCs, only the compound 12b was shown to be 10-fold more potent than amonafide. Instead 12c is equipotent to amonafide. These results suggest that the extended pi-system and the kind of heteroatom are essential in the binding with the molecular target.