The effect of chemotherapeutic agents on telomere length maintenance in breast cancer cell lines

Copyright @ 2014 the authors. This article is made available through the Brunel Open Access Publishing Fund. It is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Mammalian telomeric DNA consists of tandem repeats of the sequence TTAGGG associated with a specialized set of proteins, known collectively as Shelterin. These telosomal proteins protect the ends of chromosomes against end-to-end fusion and degradation. Short telomeres in breast cancer cells confer telomere dysfunction and this can be related to Shelterin proteins and their level of expression in breast cancer cell lines. This study investigates whether expression of Shelterin and Shelterin-associated proteins are altered, and influence the protection and maintenance of telomeres, in breast cancer cells. 5-aza-2'-deoxycytidine (5-aza-CdR) and trichostatin A (TSA) were used in an attempt to reactivate the expression of silenced genes. Our studies have shown that Shelterin and Shelterin-associated genes were down-regulated in breast cancer cell lines; this may be due to epigenetic modification of DNA as the promoter region of POT1 was found to be partially methylated. Shelterin genes expression was up-regulated upon treatment of 21NT breast cancer cells with 5-aza-CdR and TSA. The telomere length of treated 21NT cells was measured by q-PCR showed an increase in telomere length at different time points. Our studies have shown that down-regulation of Shelterin genes is partially due to methylation in some epithelial breast cancer cell lines. Removal of epigenetic silencing results in up-regulation of Shelterin and Shelterin-associated genes which can then lead to telomere length elongation and stability

Telomere elongation in the breast cancer cell line 21NT after treatment with an epigenetic modifying drug

Background: Telomere length dysregulation plays a major role in cancer development and aging. Telomeres are maintained by a group of specialized genes known as shelterin and shelterin-associated proteins. In breast cancer lines it has been shown that shelterin proteins are dysregulated thereby affecting the telomere stability and contributing to the neoplastic conversion of the mammary epithelial cells. Interestingly, the regulation of some of the shelterin genes is thought to be controlled epigenetically. Methods and Results: In this study, we set out to measure the effect of increased shelterin gene expression on telomere length in breast cancer cell line 21NT treated with 5-aza-2-deoxycytidine (5-aza-CdR) using known telomere length assays. We measured telomere lengths using: Telomere Restriction Fragment length (TRF), absolute quantitative-PCR and cytogenetic Interphase Quantitative Fluorescent in situ Hybridization (iQ-FISH). We found that non-cytotoxic levels of 5-aza-CdR affect telomere lengths by causing a significant and stable increase in telomere lengths of the breast cancer cell line. The increase in telomere lengths was consistently observed when various telomere length methods were used. Conclusions: Further investigation is required to understand the underlying mechanism involved, and the significance of telomere length elongation in relation to clinical outcome when epigenetic modifying drugs are utilized.We thank Professor Robert Newbold for his support and for providing the opportunity to carry out this work within the Institute of Cancer Genetics and Pharmacogenomics, Brunel University London. HY was supported by a triennial project grant (Strategic Award) from the National Centre for Replacement, Refinement, and Reduction (NC3Rs) of animals in research (NC. K500045.1 and G0800697)

Holographic Superconductors from Einstein-Maxwell-Dilaton Gravity

We construct holographic superconductors from Einstein-Maxwell-dilaton gravity in 3+1 dimensions with two adjustable couplings $\alpha$ and the charge $q$ carried by the scalar field. For the values of $\alpha$ and $q$ we consider, there is always a critical temperature at which a second order phase transition occurs between a hairy black hole and the AdS RN black hole in the canonical ensemble, which can be identified with the superconducting phase transition of the dual field theory. We calculate the electric conductivity of the dual superconductor and find that for the values of $\alpha$ and $q$ where $\alpha/q$ is small the dual superconductor has similar properties to the minimal model, while for the values of $\alpha$ and $q$ where $\alpha/q$ is large enough, the electric conductivity of the dual superconductor exhibits novel properties at low frequencies where it shows a "Drude Peak" in the real part of the conductivity.Comment: 25 pages, 13 figures; v2, typos corrected; v3, refs added, to appear in JHE

Maxwell-Chern-Simons Vortices and Holographic Superconductors

We investigate probe limit vortex solutions of a charged scalar field in Einstein-Maxwell theory in 3+1 dimensions, for an asymptotically AdS Schwarzschild black hole metric with the addition of an axionic coupling to the Maxwell field. We show that the inclusion of such a term, together with a suitable potential for the axion field, can induce an effective Chern-Simons term on the 2+1 dimensional boundary. We obtain numerical solutions of the equations of motion and find Maxwell-Chern-Simons like magnetic vortex configurations, where the magnetic field profile varies with the size of the effective Chern-Simons coupling. The axion field has a non-trivial profile inside the AdS bulk but does not condense at spatial infinity.Comment: 17 pages, 5 figures, version accepted for publication in JHE

Preserving the impossible: conservation of soft-sediment hominin footprint sites and strategies for three-dimensional digital data capture.

Human footprints provide some of the most publically emotive and tangible evidence of our ancestors. To the scientific community they provide evidence of stature, presence, behaviour and in the case of early hominins potential evidence with respect to the evolution of gait. While rare in the geological record the number of footprint sites has increased in recent years along with the analytical tools available for their study. Many of these sites are at risk from rapid erosion, including the Ileret footprints in northern Kenya which are second only in age to those at Laetoli (Tanzania). Unlithified, soft-sediment footprint sites such these pose a significant geoconservation challenge. In the first part of this paper conservation and preservation options are explored leading to the conclusion that to 'record and digitally rescue' provides the only viable approach. Key to such strategies is the increasing availability of three-dimensional data capture either via optical laser scanning and/or digital photogrammetry. Within the discipline there is a developing schism between those that favour one approach over the other and a requirement from geoconservationists and the scientific community for some form of objective appraisal of these alternatives is necessary. Consequently in the second part of this paper we evaluate these alternative approaches and the role they can play in a 'record and digitally rescue' conservation strategy. Using modern footprint data, digital models created via optical laser scanning are compared to those generated by state-of-the-art photogrammetry. Both methods give comparable although subtly different results. This data is evaluated alongside a review of field deployment issues to provide guidance to the community with respect to the factors which need to be considered in digital conservation of human/hominin footprints

Can HRCT be used as a marker of airway remodelling in children with difficult asthma?

BACKGROUND: Whole airway wall thickening on high resolution computed tomography (HRCT) is reported to parallel thickening of the bronchial epithelial reticular basement membrane (RBM) in adult asthmatics. A similar relationship in children with difficult asthma (DA), in whom RBM thickening is a known feature, may allow the use of HRCT as a non-invasive marker of airway remodelling. We evaluated this relationship in children with DA. METHODS: 27 children (median age 10.5 [range 4.1-16.7] years) with DA, underwent endobronchial biopsy from the right lower lobe and HRCT less than 4 months apart. HRCTs were assessed for bronchial wall thickening (BWT) of the right lower lobe using semi-quantitative and quantitative scoring techniques. The semi-quantitative score (grade 0-4) was an overall assessment of BWT of all clearly identifiable airways in HRCT scans. The quantitative score (BWT %; defined as [airway outer diameter - airway lumen diameter]/airway outer diameter x100) was the average score of all airways visible and calculated using electronic endpoint callipers. RBM thickness in endobronchial biopsies was measured using image analysis. 23/27 subjects performed spirometry and the relationships between RBM thickness and BWT with airflow obstruction evaluated. RESULTS: Median RBM thickness in endobronchial biopsies was 6.7(range 4.6-10.0) microm. Median qualitative score for BWT of the right lower lobe was 1(range 0-1.5) and quantitative score was 54.3 (range 48.2-65.6)%. There was no relationship between RBM thickness and BWT in the right lower lobe using either scoring technique. No relationship was found between FEV1 and BWT or RBM thickness. CONCLUSION: Although a relationship between RBM thickness and BWT on HRCT has been found in adults with asthma, this relationship does not appear to hold true in children with D

Thermodynamics of Holographic Defects

Using the AdS/CFT correspondence, we study the thermodynamic properties and the phase diagram of matter fields on (2+1)-dimensional defects coupled to a (3+1)-dimensional N=4 SYM "heat bath". Considering a background magnetic field, (net) quark density, defect "magnitude" $\delta N_c$ and the mass of the matter, we study the defect contribution to the thermodynamic potentials and their first and second derivatives to map the phases and study their physical properties. We find some features that are qualitatively similar to other systems e.g. in (3+1) dimensions and a number of features that are particular to the defect nature, such as its magnetic properties, unexpected properties at T->0 and finite density; and the finite $\delta N_c$ effects, e.g. a diverging susceptibility and vanishing density of states at small temperatures, a physically consistent negative heat capacity and new types of consistent phases.Comment: 33 pages, 16 figures (jpg and pdf), typos fixed and references added, final version published in JHE

d+idd+id Holographic Superconductors

A holographic model of $d+id$ superconductors based on the action proposed by Benini, Herzog, and Yarom [arXiv:1006.0731] is studied. This model has a charged spin two field in an AdS black hole spacetime. Working in the probe limit, the normalizable solution of the spin two field in the bulk gives rise to a $d+id$ superconducting order parameter at the boundary of the AdS. We calculate the fermion spectral function in this\ superconducting background and confirm the existence of fermi arcs for non-vanishing Majorana couplings. By changing the relative strength $\gamma$ of the $d$ and $id$ condensations, the position and the size of the fermi arcs are changed. When $\gamma =1$, the spectrum becomes isotropic and the spectral function is s-wave like. By changing the fermion mass, the fermi momentum is changed. We also calculate the conductivity for these holographic $d+id$ superconductors where time reversal symmetry has been broken spontaneously. A non-vanishing Hall conductivity is obtained even without an external magnetic field.Comment: 24 pages,17 figures, Add more discussions on hall conductivity, two new figures, Matched with published versio

Analytic study of properties of holographic p-wave superconductors

In this paper, we analytically investigate the properties of p-wave holographic superconductors in $AdS_{4}$-Schwarzschild background by two approaches, one based on the Sturm-Liouville eigenvalue problem and the other based on the matching of the solutions to the field equations near the horizon and near the asymptotic $AdS$ region. The relation between the critical temperature and the charge density has been obtained and the dependence of the expectation value of the condensation operator on the temperature has been found. Our results are in very good agreement with the existing numerical results. The critical exponent of the condensation also comes out to be 1/2 which is the universal value in the mean field theory.Comment: Latex, To appear in JHE

Fermion correlators in non-abelian holographic superconductors

We consider fermion correlators in non-abelian holographic superconductors. The spectral function of the fermions exhibits several interesting features such as support in displaced Dirac cones and an asymmetric distribution of normal modes. These features are compared to similar ones observed in angle resolved photoemission experiments on high T_c superconductors. Along the way we elucidate some properties of p-wave superconductors in AdS_4 and discuss the construction of SO(4) superconductors.Comment: 49 pages, 11 figure