DNA microarray profiling of genes differentially regulated by the histone deacetylase inhibitors vorinostat and LBH589 in colon cancer cell lines

BACKGROUND: Despite the significant progress made in colon cancer chemotherapy, advanced disease remains largely incurable and novel efficacious chemotherapies are urgently needed. Histone deacetylase inhibitors (HDACi) represent a novel class of agents which have demonstrated promising preclinical activity and are undergoing clinical evaluation in colon cancer. The goal of this study was to identify genes in colon cancer cells that are differentially regulated by two clinically advanced hydroxamic acid HDACi, vorinostat and LBH589 to provide rationale for novel drug combination partners and identify a core set of HDACi-regulated genes.

METHODS: HCT116 and HT29 colon cancer cells were treated with LBH589 or vorinostat and growth inhibition, acetylation status and apoptosis were analyzed in response to treatment using MTS, Western blotting and flow cytometric analyses. In addition, gene expression was analyzed using the Illumina Human-6 V2 BeadChip array and Ingenuity Pathway Analysis.

RESULTS: Treatment with either vorinostat or LBH589 rapidly induced histone acetylation, cell cycle arrest and inhibited the growth of both HCT116 and HT29 cells. Bioinformatic analysis of the microarray profiling revealed significant similarity in the genes altered in expression following treatment with the two HDACi tested within each cell line. However, analysis of genes that were altered in expression in the HCT116 and HT29 cells revealed cell-line-specific responses to HDACi treatment. In addition a core cassette of 11 genes modulated by both vorinostat and LBH589 were identified in both colon cancer cell lines analyzed.

CONCLUSION: This study identified HDACi-induced alterations in critical genes involved in nucleotide metabolism, angiogenesis, mitosis and cell survival which may represent potential intervention points for novel therapeutic combinations in colon cancer. This information will assist in the identification of novel pathways and targets that are modulated by HDACi, providing much-needed information on HDACi mechanism of action and providing rationale for novel drug combination partners. We identified a core signature of 11 genes which were modulated by both vorinostat and LBH589 in a similar manner in both cell lines. These core genes will assist in the development and validation of a common gene set which may represent a molecular signature of HDAC inhibition in colon cancer.

Vacuum birefringence in strong inhomogeneous electromagnetic fields

Birefringence is one of the fascinating properties of the vacuum of quantum electrodynamics (QED) in strong electromagnetic fields. The scattering of linearly polarized incident probe photons into a perpendicularly polarized mode provides a distinct signature of the optical activity of the quantum vacuum and thus offers an excellent opportunity for a precision test of nonlinear QED. Precision tests require accurate predictions and thus a theoretical framework that is capable of taking the detailed experimental geometry into account. We derive analytical solutions for vacuum birefringence which include the spatio-temporal field structure of a strong optical pump laser field and an x-ray probe. We show that the angular distribution of the scattered photons depends strongly on the interaction geometry and find that scattering of the perpendicularly polarized scattered photons out of the cone of the incident probe x-ray beam is the key to making the phenomenon experimentally accessible with the current generation of FEL/high-field laser facilities.

Proton acceleration enhanced by a plasma jet in expanding foils undergoing relativistic transparency

Ion acceleration driven by the interaction of an ultraintense (2 × 10²⁰ W cm^-2) laser pulse with an ultrathin ( nm) foil target is experimentally and numerically investigated. Protons accelerated by sheath fields and via laser radiation pressure are angularly separated and identified based on their directionality and signature features (e.g. transverse instabilities) in the measured spatial-intensity distribution. A low divergence, high energy proton component is also detected when the heated target electrons expand and the target becomes relativistically transparent during the interaction. 2D and 3D particle-in-cell simulations indicate that under these conditions a plasma jet is formed at the target rear, supported by a self-generated azimuthal magnetic field, which extends into the expanded layer of sheath-accelerated protons. Electrons trapped within this jet are directly accelerated to super-thermal energies by the portion of the laser pulse transmitted through the target. The resulting streaming of the electrons into the ion layers enhances the energy of protons in the vicinity of the jet. Through the addition of a controlled prepulse, the maximum energy of these protons is demonstrated experimentally and numerically to be sensitive to the picosecond rising edge profile of the laser pulse.

Identification and validation of the dopamine agonist bromocriptine as a novel therapy for high-risk myelodysplastic syndromes and secondary acute myeloid leukemia

Myelodysplastic syndromes (MDS) represent a broad spectrum of diseases characterized by their clinical manifestation as one or more cytopenias, or a reduction in circulating blood cells. MDS is predominantly a disease of the elderly, with a median age in the UK of around 75. Approximately one third of MDS patients will develop secondary acute myeloid leukemia (sAML) that has a very poor prognosis. Unfortunately, most standard cytotoxic agents are often too toxic for older patients. This means there is a pressing unmet need for novel therapies that have fewer side effects to assist this vulnerable group. This challenge was tackled using bioinformatic analysis of available transcriptomic data to establish a gene-based signature of the development and progression of MDS. This signature was then used to identify novel therapeutic compounds via statistically-significant connectivity mapping. This approach suggested re-purposing an existing and widely-prescribed drug, bromocriptine as a novel potential therapy in these disease settings. This drug has shown selectivity for leukemic cells as well as synergy with current therapies.

Tri-axial accelerometers quantify behaviour in the Eurasian badger (Meles meles): towards an automated interpretation of field data

The popularity of tri-axial accelerometer data loggers to quantify animal activity through the analysis of signature traces is increasing. However, there is no consensus on how to process the large data sets that these devices generate when recording at the necessary high sample rates. In addition, there have been few attempts to validate accelerometer traces with specific behaviours in non-domesticated terrestrial mammals.

Transverse Spreading of Electrons in High-Intensity Laser Fields

We show that for collisions of electrons with a high-intensity laser, discrete photon emissions introduce a transverse beam spread that is distinct from that due to classical (or beam shape) effects. Via numerical simulations, we show that this quantum induced transverse momentum gain of the electron is manifest in collisions with a realistic laser pulse of intensity within reach of current technology, and we propose it as a measurable signature of strong-field quantum electrodynamics.

Probing confinement resonances by photoionizing Xe inside a C60+ molecular cage

Double photoionization accompanied by loss of n C atoms (n=0, 2, 4, 6) was investigated by merging beams of Xe@C60+ ions and synchrotron radiation and measuring the yields of product ions. The giant 4d dipole resonance of the caged Xe atom has a prominent signature in the cross section for these product channels, which together account for 6.2 ± 1.4 of the total Xe 4d oscillator strength of 10. Compared to that for a free Xe atom, the oscillator strength is redistributed in photon energy due to multipath interference of outgoing Xe 4d photoelectron waves that may be transmitted or reflected by the spherical C60+ molecular cage, yielding so-called confinement resonances. The data are compared with an earlier measurement and with theoretical predictions for this single-molecule photoelectron interferometer system. Relativistic R-matrix calculations for the Xe atom in a spherical potential shell representing the fullerene cage show the sensitivity of the interference pattern to the molecular geometry. © 2013 American Physical Society.

Modeling the Rossiter-McLaughlin Effect: Impact of the Convective Center-to-limb Variations in the Stellar Photosphere

bservations of the Rossiter–McLaughlin (RM) effect provide information on star–planet alignments, which can inform planetary migration and evolution theories. Here, we go beyond the classical RM modeling and explore the impact of a convective blueshift that varies across the stellar disk and non-Gaussian stellar photospheric profiles. We simulated an aligned hot Jupiter with a four-day orbit about a Sun-like star and injected center-to-limb velocity (and profile shape) variations based on radiative 3D magnetohydrodynamic simulations of solar surface convection. The residuals between our modeling and classical RM modeling were dependent on the intrinsic profile width and v sin i; the amplitude of the residuals increased with increasing v sin i and with decreasing intrinsic profile width. For slowly rotating stars the center-to-limb convective variation dominated the residuals (with amplitudes of 10 s of cm s−1 to ~1 m s−1); however, for faster rotating stars the dominant residual signature was due a non-Gaussian intrinsic profile (with amplitudes from 0.5 to 9 m s−1). When the impact factor was 0, neglecting to account for the convective center-to-limb variation led to an uncertainty in the obliquity of ~10°–20°, even though the true v sin i was known. Additionally, neglecting to properly model an asymmetric intrinsic profile had a greater impact for more rapidly rotating stars (e.g., v sin i = 6 km s−1) and caused systematic errors on the order of ~20° in the measured obliquities. Hence, neglecting the impact of stellar surface convection may bias star–planet alignment measurements and consequently theories on planetary migration and evolution.

Addiction to Runx1 is partially attenuated by loss of p53 in the Eµ-Myc lymphoma model

The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eµ-Myc model of Burkitt's lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eµ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eµ-Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status.