Purpose: Genomic complexity is present in approximately 15% to 30% of all chronic lymphocytic leukemia (CLL) and has emerged as a strong independent predictor of rapid disease progression and short remission duration in CLL. We conducted this study to advance our understanding of the causes of genomic complexity in CLL.Experimental Design: We have obtained quantitative measurements of radiation-induced apoptosis and radiation-induced ATM autophosphorylation in purified CLL cells from 158 and 140 patients, respectively, and have used multivariate analysis to identify independent contributions of various biological variables on genomic complexity in CLL.Results: Here, we identify a strong independent effect of radiation resistance on elevated genomic complexity in CLL and describe radiation resistance as a predictor for shortened CLL survival. Furthermore, using multivariate analysis, we identify del17p/p53 aberrations, del11q, del13q14 type II (invariably resulting in Rb loss), and CD38 expression as independent predictors of genomic complexity in CLL, with aberrant p53 as a predictor of ∼50% of genomic complexity in CLL. Focusing on del11q, we determined that normalized ATM activity was a modest predictor of genomic complexity but was not independent of del11q. Through single nucleotide polymorphism array-based fine mapping of del11q, we identified frequent monoallelic loss of Mre11 and H2AFX in addition to ATM, indicative of compound del11q-resident gene defects in the DNA double-strand break response.Conclusions: Our quantitative analysis links multiple molecular defects, including for the first time del11q and large 13q14 deletions (type II), to elevated genomic complexity in CLL, thereby suggesting mechanisms for the observed clinical aggressiveness of CLL in patients with unstable genomes. Clin Cancer Res; 16(3); 835-47. ©2010 AACR.Genomic aberrations substantially influence the biology and clinical outcome of patients with chronic lymphocytic leukemia (CLL; refs. 1-3). The presence of specific chromosomal deletions, in particular del17p and del11q, allows for the identification of a subset of patients with shortened overall survival. Furthermore, CLL patients with chromosomal translocations, complex aberrant karyotypes, or elevated genomic complexity, as measured through single nucleotide polymorphism (SNP) arrays, have recently been shown to have aggressive CLL that is characterized by rapid disease progression and short remission duration (4-9). An ad hoc summary analysis of these published reports suggests that CLL cases with these latter genomic complexity characteristics are substantially more common than CLL with del17p or p53 mutations and that the overlap between these two groups of CLL is partial, thus implying the existence of additional unidentified factors that cause genomic complexity in CLL.Subchromosomal deletions, which are the quantitatively dominant genomic aberration in CLL, must have involved DNA double-strand breaks as intermediates. Given that the cellular response to DNA doub...

No abstract

For the reaction of a,b-unsaturated ketones with electron-rich arenes catalyzed by gold(III) chloride both, a Friedel±Crafts-type mechanism and an initial metallation, are evaluated. Gold(III) chloride has proven to be an efficient catalyst under very moderate reaction conditions, however, in the case of sterically demanding products HBF 4 turned out to be the superior catalyst.

A glucose-responsive nanogel that can undergo reversible and rapid volume phase transitions is made of ConA interpenetrated in a poly(NIPAM) network.

No abstract

G-quadruplexes are higher-order DNA and RNA structures formed from guanine-rich sequences. These structures have recently emerged as a new class of potential molecular targets for anticancer drugs. An understanding of the three-dimensional interactions between small molecular ligands and their G-quadruplex targets in solution is crucial for rational drug design and the effective optimization of G-quadruplex ligands. Thus far, rational ligand design has been focused mainly on the G-quartet platform. It should be noted that small molecules can also bind to loop nucleotides, as observed in crystallography studies. Hence, it would be interesting to elucidate the mechanism underlying how ligands in distinct binding modes influence the flexibility of G-quadruplex. In the present study, based on a crystal structure analysis, the models of a tetra-substituted naphthalene diimide ligand bound to a telomeric G-quadruplex with different modes were built and simulated with a molecular dynamics simulation method. Based on a series of computational analyses, the structures, dynamics, and interactions of ligand-quadruplex complexes were studied. Our results suggest that the binding of the ligand to the loop is viable in aqueous solutions but dependent on the particular arrangement of the loop. The binding of the ligand to the loop enhances the flexibility of the G-quadruplex, while the binding of the ligand simultaneously to both the quartet and the loop diminishes its flexibility. These results add to our understanding of the effect of a ligand with different binding modes on G-quadruplex flexibility. Such an understanding will aid in the rational design of more selective and effective G-quadruplex binding ligands.

Starting from 2-methylfuran and crotonaldehyde, both jungianol and epi-jungianol were prepared by a six-step sequence including a gold-catalyzed arene synthesis and a photochemical S(N)2-like reduction with lithium aluminum hydride. Not a single protective group was needed in the entire synthesis. With both diastereomers in hand, the stereochemical assignment in the literature could be corrected by means of a thorough (1)H NMR spectroscopic analysis and an X-ray diffraction study on an epi-jungianol derivative.

Mycoplasma gallisepticum and Escherichia coli are well known respiratory disease-inducing pathogens. Previous studies have reported that co-infection by MG and E.coli causes significant economic loss in the poultry industry. In order to assess the respiratory toxicity of co-infection in chicken lung, we established a co-infection model to investigate changes in the inflammatory cytokines, lung tissue structure, and transcriptome profiles of chicken lung. The results showed that co-infection caused a wider range of immune damage and more severe tissue lesions than single-pathogen infection. Differentially expressed gene (DEG) analysis indicated that 3,115/1,498/1,075 genes were significantly expressed among the three infection groups, respectively. Gene ontology and KEGG analysis showed genes enriched in response to immune response, cytokine-cytokine receptor interaction, and inflammation-related signaling pathways. Among these pathways, IL-17 signaling was found to be significantly enriched only in co-infection. The expression of IL-17C, CIKS, TRAF6, NFκB, C/EBPβ, and inflammatory chemokines were significantly up-regulated in response to co-infection. Taken together, we concluded that co-infection increased the expression of inflammatory chemokines in lungs through IL-17 signaling, leading to cilia loss and excessive mucus secretion. These results provide new insights into co-infection and reveal target proteins for drug therapy.