MORC2/ß-catenin signaling axis promotes proliferation and migration of breast cancer cells.

Although Microrchidia 2 (MORC2) is overexpressed in many types of human cancer, its role in breast cancer progression remains unknown. Here, we report that the chromatin remodeler MORC2 expression positively correlates with ß-catenin expression in breast cancer cell lines and patients. Overexpression of MORC2 augmented the expression of ß-catenin and its target genes, cyclin D1 and c-Myc. Consistent with these results, we found MORC2 knockdown resulted in decreased expression of ß-catenin and its target genes. Surprisingly, we observed that c-Myc, the target gene of ß-catenin, regulated the MORC2-ß-catenin signaling axis through a feedback mechanism. We demonstrated that MORC2 regulates ß-catenin expression and function by modulating the phosphorylation of AKT. In addition, we observed reduced proliferation and migration of MORC2 overexpressing breast cancer cells upon ß-catenin inhibition. Overall, our results demonstrate that MORC2 promotes breast cancer cell proliferation and migration by regulating ß-catenin signaling.

Activation-Induced Cytidine Deaminase Links Ovulation-Induced Inflammation and Serous Carcinogenesis.

In recent years, the notion that ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs) has gained evidence. However, the mechanistic pathway for this process has not been revealed yet. In the current study, we propose the mutator protein activation-induced cytidine deaminase (AID) as a link between ovulation-induced inflammation in FTECs and genotoxic damage leading to ovarian carcinogenesis. We show that AID, previously shown to be functional only in B lymphocytes, is expressed in FTECs under physiological conditions, and is induced in vitro upon ovulatory-like stimulation and in vivo in carcinoma-associated FTECs. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs. Overall, our data provides new insights into the etiology of ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early detection.

Identification of genomic aberrations in hemangioblastoma by droplet digital PCR and SNP microarray highlights novel candidate genes and pathways for pathogenesis.

BACKGROUND: The genetic mechanisms underlying hemangioblastoma development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays and droplet digital PCR analysis to detect copy number variations (CNVs) in total of 45 hemangioblastoma tumors. RESULTS: We identified 94 CNVs with a median of 18 CNVs per sample. The most frequently gained regions were on chromosomes 1 (p36.32) and 7 (p11.2). These regions contain the EGFR and PRDM16 genes. Recurrent losses were located at chromosome 12 (q24.13), which includes the gene PTPN11. CONCLUSIONS: Our findings provide the first high-resolution genome-wide view of chromosomal changes in hemangioblastoma and identify 23 candidate genes: EGFR, PRDM16, PTPN11, HOXD11, HOXD13, FLT3, PTCH, FGFR1, FOXP1, GPC3, HOXC13, HOXC11, MKL1, CHEK2, IRF4, GPHN, IKZF1, RB1, HOXA9, and micro RNA, such as hsa-mir-196a-2 for hemangioblastoma pathogenesis. Furthermore, our data implicate that cell proliferation and angiogenesis promoting pathways may be involved in the molecular pathogenesis of hemangioblastoma.

Wilms' tumor blastemal stem cells dedifferentiate to propagate the tumor bulk.

An open question remains in cancer stem cell (CSC) biology whether CSCs are by definition at the top of the differentiation hierarchy of the tumor. Wilms' tumor (WT), composed of blastema and differentiated renal elements resembling the nephrogenic zone of the developing kidney, is a valuable model for studying this question because early kidney differentiation is well characterized. WT neural cell adhesion molecule 1-positive (NCAM1(+)) aldehyde dehydrogenase 1-positive (ALDH1(+)) CSCs have been recently isolated and shown to harbor early renal progenitor traits. Herein, by generating pure blastema WT xenografts, composed solely of cells expressing the renal developmental markers SIX2 and NCAM1, we surprisingly show that sorted ALDH1(+) WT CSCs do not correspond to earliest renal stem cells. Rather, gene expression and proteomic comparative analyses disclose a cell type skewed more toward epithelial differentiation than the bulk of the blastema. Thus, WT CSCs are likely to dedifferentiate to propagate WT blastema.

The long non-coding RNA ERIC is regulated by E2F and modulates the cellular response to DNA damage.

BACKGROUND: The human genome encodes thousands of unique long non-coding RNAs (lncRNAs), and these transcripts are emerging as critical regulators of gene expression and cell fate. However, the transcriptional regulation of their expression is not fully understood. The pivotal transcription factor E2F1 which can induce both proliferation and cell death, is a critical downstream target of the tumor suppressor, RB. The retinoblastoma pathway is often inactivated in human tumors resulting in deregulated E2F activity. RESULTS: Here, we report that lncRNA XLOC 006942, which we named ERIC, is regulated by E2F1 and, most probably, also E2F3. We show that expression levels of ERIC were elevated upon activation of exogenous E2F1, E2F3 or endogenous E2Fs. Moreover, knockdown of either E2F1 or E2F3 reduced ERIC levels and endogenous E2F1 binds ERIC's promoter. Expression of ERIC was cell cycle regulated and peaked in G1 in an E2F1-dependent manner. Inhibition of ERIC expression increased E2F1-mediated apoptosis, suggesting that E2F1 and ERIC constitute a negative feedback loop that modulates E2F1 activity. Furthermore, ERIC levels were increased following DNA damage by the chemotherapeutic drug Etoposide, and inhibition of ERIC expression enhanced Etoposide -induced apoptosis. CONCLUSIONS: Our data identify ERIC as a novel lncRNA that is transcriptionally regulated by E2Fs, and restricts apoptosis induced by E2F1, as well as by DNA damage.

DFT and surface-enhanced Raman scattering study of tryptophan-silver complex.

Surface-enhanced Raman scattering (SERS) study of tryptophan was carried out in silver hydrosol. The surface adsorption properties of tryptophan were investigated due to its biological importance. Tryptophan is an essential amino acid needed for the normal growth in infants and for nitrogen balance in adults. DFT calculations using B3LYP functional with LANL2DZ basis set was carried out to support the experimental Raman and SERS data. The strong enhancement of 1343 cm(-1) band, assigned to the CO(2) sym. stretching vibration in the SERS spectrum along with a red shift of 63 cm(-1), manifests that chemical mechanism contributes to the SERS activity. Moreover, the observed features in the SERS spectrum as well as theoretical calculations infer that tryptophan is chemisorbed to the silver surface directly through the oxygen and nitrogen atoms of the carboxylate and amino groups with an edge-on orientation with the indole ring lying nearly perpendicular to the silver surface. The SERS enhancement factors for various Raman vibrations of tryptophan were found to be of the order of 10(5)-10(6).

Intervenous tubercle of Lower: true tubercle or normal interatrial fold?

Richard Lower, in 1669, first described the tubercle that now bears his name, calling it the intervenous tubercle located between the fossa ovalis and the superior vena cava. The aim of the study was to confirm the existence of the tubercle as described initially by Lower, adding details of its location, dimensions, and prevalence. We examined 100 formalin-fixed human hearts. In no heart did we find any discrete tubercle or elevation of the right atrial wall superior to the superior limbus (rim) of the fossa ovalis. In addition, we could find no morphometric differences in the thickness of the area superior to the superior limbus of the fossa. Dissections revealed that very little of the extensive musculature can be removed without opening the right atrial wall and arriving outside the heart. This is the essential criterion in distinguishing folds from "true" septal structures. When viewed in this light, it is only the flap valve of the fossa ovalis, and its immediate muscular infero-anterior rim, the so-called lower limbus, that can be removed so as to create communications between the cavities of the atrial chambers, and not exiting at the same time from the cavities of the heart. This is because the larger part of the muscular borders of the fossa ovalis is no more than an infolding of the atrial walls, which incorporates extracardiac adipose tissue within the fold. Although this process of folding unequivocally produces an intracardiac buttress, namely, the limbuses (rims) of the fossa, the buttress, being an infolding, does not constitute, according to our definition, a true septum. On this basis, we suggest that it is the superior limbus of the fossa ovalis, or the superior interatrial fold, that previously has been considered to represent the intervenous tubercle of Lower.

A simple approach for facile synthesis of Ag, anisotropic Au and bimetallic (Ag/Au) nanoparticles using cruciferous vegetable extracts.

We present a simple and straightforward approach for the synthesis and stabilization of relatively monodisperse Ag, Au and bimetallic (Ag/Au) nanoparticles by using cruciferous vegetable (green/red) extracts by simply adjusting the pH environment in the aqueous medium. The vegetable extracts act both as reducing and capping agents. The monometallic and bimetallic nanoparticles of Ag and Au so obtained were characterized by UV-visible spectroscopy, X-ray diffraction (XRD), dynamic light scattering (DLS) and transmission electron microscopy (TEM). It is shown that red cabbage extract can be used for the preparation of anisotropic Au nanoparticles. The formation of Au anisotropic nanoparticles was found to depend on a number of environmental factors, such as the pH of the reaction medium, reaction time, and initial reactant concentrations. Additionally, it is shown that these extract-stabilized Au and Ag nanoparticles can be used as a seed for preparation of bimetallic Au/Ag nanoparticles. For bimetallic alloy nanoparticles the absorption peak was observed between the two maxima of the corresponding metallic particles. The surface plasmon absorption maxima for bimetallic nanoparticles changed linearly with increasing Au mole ratio content in various alloy compositions. It has been shown that the formation of hollow Au spheres depends on the experimental conditions.

Preparation, characterization, surface modification and redox reactions of silver nanoparticles in the presence of tryptophan.

The synthesis and characterization of water-soluble dispersions of Ag nanoparticles by the reduction of AgNO(3) using tryptophan under alkaline synthesis conditions are reported. The Ag nanoparticle formation was very slow at low concentration and rapid at extremes. For surface modification and redox reactions, manipulating the interparticles interaction controlled the size of Ag nanoparticles aggregates. Our results suggest that the replacement of the BH(4)(-) ions adsorbed on the nanoparticle surface by tryptophan destabilizes the particles and further caused aggregation. A mechanism is proposed for the formation of silver nanoparticles by tryptophan. The experimental results are supported by theoretical calculations. The Ag nanoparticles were characterized by UV-vis absorption, dynamic light scattering and transmission electron microscopy techniques.

Effect of plant-based phenol derivatives on the formation of Cu and Ag nanoparticles.

The complexes formed on the reaction of various metal ions viz., Cu(II) and Cu(I) with phenol derivatives viz. catechol, chlorogenic acid (CGA), hydroquinone and n-propyl gallate (nPG) were established by UV-visible spectroscopy. The metal/ligand complexing ratio and complexation constants have been determined. Further, we showed that nanoparticles of Cu can be prepared from metal-phenol complexes in the presence of a protein (gelatin) by γ-irradiation showing that the reduction is metal ion centered. Formation of Ag nanoparticles was also observed on photo-irradiation with xenon lamp in the presence of dihydroxy benzene. The Ag and Cu nanoparticles were characterized by transmission electron microscopy (TEM) and UV-visible absorption spectroscopy. TEM technique showed the presence of Cu and Ag nanoparticles with average size of 20 and 30 nm, respectively.

Free radical reactions with the extract of brassica family.

Using different extraction protocols, the antioxidant properties of green and red cabbage extracts were evaluated in terms of the total antioxidant capacities using the 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulphonic acid) (ABTS) radical scavenging method. The results demonstrate that the total antioxidant capacity of green and red cabbages correlated well with the total phenolics and total flavonoids content present in the extracts. The ABTS radical scavenging capacity of red cabbage was much higher than that of green cabbage extract. Using time resolved absorption kinetic spectrophotometry, free radical reactions with the extracts of green and red cabbages were established. The reactions of extracts were examined using a pulse radiolysis technique. Kinetic studies indicated that extracts may act as free radical scavengers for O2(-), OH radicals and as an antioxidant to repair free-radical damage to biologically important guanosine radical.

Role of phenol derivatives in the formation of silver nanoparticles.

We demonstrate that dihydroxy benzenes are excellent reducing agents and may be used to reduce silver ions to synthesize stable silver nanoparticles in air-saturated aqueous solutions. The formation of Ag nanoparticles in deaerated aqueous solution at high pH values suggests that the reduction of silver ions occurs due to oxidation of dihydroxy benzenes and probably on the surface of Ag2O. Pulse radiolysis studies show that the semi-quinone radical does not participate in the reduction of silver ions at short time scales. Nevertheless, results show that primary intermediates undergo slower transformation in the presence of dihydroxy benzenes than in their absence. This slow transformation eventually leads to the formation of silver nanoparticles. The Ag nanoparticles were characterized by UV-vis absorption spectroscopy, X-ray diffraction (XRD), and transmission electron microscopy (TEM). XRD and TEM techniques showed the presence of Ag nanoparticles with an average size of 30 nm.