A new multifunctional di-topic tetrazolate-based ligand, 2,3-di-1H-tetrazol-5-ylpyrazine (H(2)dtp) has been designed and synthesized. The solvothermal reaction of this ligand with ZnCl(2) gave a robust guest-free three-dimensional zeolite-like chiral metal-organic framework (MOF) complex, [Zn(dtp)], which crystallized in chiral space group P6(1) and possessed chiral open channels with nitrogen-rich walls and the diameter of approximately 4.1 A. This framework presents a unique uniform etd (8,3) topology, is the first example of its type in MOFs, and exhibits high thermal stability with the decomposition temperature above 380 degrees C and permanent porosity. It is interesting that this material is able to selectively adsorb O(2) and CO(2) over N(2) gas, being a rare example in MOFs. In addition, C(2)H(2) and MeOH adsorption results show that although the framework channel holds nitrogen-rich walls that may provide H-bonding sites, no NH H-bond effect between the guest molecules and microporous surface was observed.

Purpose: To determine the possibility of synergistic antileukemic activity and the underlying molecular mechanisms associated with cytarabine combined with valproic acid (VPA; a histone deacetylase inhibitor and a Food and Drug Administration-licensed drug for treating both children and adults with epilepsy) in pediatric acute myeloid leukemia (AML).Experimental Design: The type and extent of antileukemic interactions between cytarabine and VPA in clinically relevant pediatric AML cell lines and diagnostic blasts from children with AML were determined by MTT assays and standard isobologram analyses. The effects of cytarabine and VPA on apoptosis and cell cycle distributions were determined by flow cytometry analysis and caspase enzymatic assays. The effects of the two agents on DNA damage and Bcl-2 family proteins were determined by Western blotting.Results: We showed synergistic antileukemic activities between cytarabine and VPA in four pediatric AML cell lines and nine diagnostic AML blast samples. t(8;21) AML blasts were significantly more sensitive to VPA and showed far greater sensitivities to combined cytarabine and VPA than non-t(8;21) AML cases. Cytarabine and VPA cooperatively induced DNA double-strand breaks, reflected in induction of γH2AX and apoptosis, accompanied by activation of caspase-9 and caspase-3. Further, VPA induced Bim expression and short hairpin RNA knockdown of Bim resulted in significantly decreased apoptosis induced by cytarabine and by cytarabine plus VPA.Conclusions: Our results establish global synergistic antileukemic activity of combined VPA and cytarabine in pediatric AML and provide compelling evidence to support the use of VPA in the treatment of children with this deadly disease. Clin Cancer Res; 16(22); 5499-510. ©2010 AACR.

The eukaryotic genome is divided into chromosomal domains of distinct gene activities. Transcriptionally silent chromatin tends to encroach upon active chromatin. Barrier elements that can block the spread of silent chromatin have been documented, but the mechanisms of their function are not resolved. We show that the prokaryotic LexA protein can function as a barrier to the propagation of transcriptionally silent chromatin in yeast. The barrier function of LexA correlates with its ability to disrupt local chromatin structure. In accord with this, (CCGNN) n and poly(dA-dT), both of which do not favor nucleosome formation, can also act as efficient boundaries of silent chromatin. Moreover, we show that a Rap1p-binding barrier element also disrupts chromatin structure. These results demonstrate that nucleosome exclusion is one of the mechanisms for the establishment of boundaries of silent chromatin domains.Eukaryotic DNA is compacted into chromatin. The first level of packaging is the formation of nucleosomes, each consisting of a protein core of histones H2A, H2B, H3, and H4, around which 146 bp of DNA is wrapped. Higher levels of compaction involve histone H1 and/or other proteins that associate with nucleosomes (38). Based on its cytological and molecular properties, chromatin is roughly divided into condensed heterochromatin and decondensed euchromatin, which are interspersed in the genome. In general, heterochromatin inhibits gene expression whereas euchromatin allows it, leading to a position effect on gene activity. Heterochromatin formed in one part of the genome may propagate along the chromosome, consuming euchromatin in its path. This is accomplished by the spreading of heterochromatin-specific complexes that interact with nucleosomes and condense chromatin to a higher level (20,35). In addition, various covalent modifications of histones (e.g., acetylation and methylation) also play pivotal roles in establishing the state of chromatin at a particular locus (27). For instance, heterochromatin is associated with characteristic hypoacetylation of histones.In Saccharomyces cerevisiae, transcriptionally silent chromatin at HMR, HML, or telomeres is the yeast equivalent of metazoan heterochromatin that is formed through coordinated actions of cis-acting elements and trans-acting factors (41). The cis-acting elements include telomeric repeats and sites flanking each HM locus that are known as silencers, and the trans-acting proteins include Sir2p-Sir4p and silencer-or telomere-binding proteins. Silencer-or telomere-binding proteins recruit the SIR complex (Sir2p/Sir3p/Sir4p), which then propagates sequentially along an array of nucleosomes. The SIR complex is an integral part of silent chromatin, and interactions between Sir3p/Sir4p and histones H3 and H4 are key to the establishment and maintenance of silenced chromatin (41). There is evidence that Sir3p has higher affinity to unacetylated histone H4 (10). Sir2p is an NAD-dependent protein deacetylase that is likely involved in reducing histone acetylation ...

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The in situ solvothermal reaction of 9,10-dicyanoanthracene and ZnCl(2)/NaN(3) gave the complex, {[Zn(7)(OH)(8)(DTA)(3)].H(2)O}(n) () (DTA(2-) = 9,10-ditetrazolateanthracene), which presents a pcu-type topological framework formed by DTA(2-) bridging unprecedented heptanuclear spindle [Zn(7)(OH)(8)](6+) clusters as SBUs, and exhibits strong luminescent emission with long lifetime.

An azido-metal-1,2,4-triazolate coordination polymer, [Cu(trz)(N(3))](n) (trz = 1,2,4-triazolate) was synthesized using hydrothermal methods; the complex has a rare three-dimensional non-interpenetrated utp or (10,3)-d topological network structure and exhibits spin-canted antiferromagnetism at low temperature.

Accumulated studies have provided controversial evidences of the association between Forkhead Box M1 (FOXM1) expression and survival of human solid tumors. To address this inconsistency, we performed a meta-analysis with 23 studies identified from PubMed and Medline. We found elevated FOXM1-protein expression was significantly associated with worse 3-year overall survival (OS) (OR = 3.30, 95% CI = 2.56 to 4.25, P < 0.00001) 5-year OS (OR =3.35, 95% CI = 2.64 to 4.26, P < 0.00001) and 10-year OS (OR = 5.24, 95% CI = 2.61 to 10.52, P < 0.00001) of human solid tumors. Similar results were observed when disease free survival (DFS) were analyzed. Subgroup analysis showed that FOXM1 overexpression was associated with poor prognosis of colorectal cancer, gastric cancer, hepatic cancer, lung cancer and ovarian cancer. High expression level of FOXM1 was also associated with advanced tumor stage. In conclusion, elevated FOXM1 expression is associated with poor survival in most solid tumors. FOXM1 is a potential biomarker for prognosis prediction and a promising therapeutic target in human solid tumors.

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