Is there a role for epigenetic therapies in modulating dna damage repair pathways to enhance chemotherapy and overcome drug resistance?

Epigenetic therapies describe drug molecules such as DNA methyltransferase, histone methyltransferase and histone acetylase/deacetylase inhibitors, which target epigenetic mechanisms such as DNA methylation and histone modifications. Many DNA damage response (DDR) genes are epigenetically regulated in cancer leading to transcriptional silencing and the loss of DNA repair capacity. Epigenetic marks at DDR genes, such as DNA methylation at gene promoters, have the potential to be used as stratification biomarkers, identifying which patients may benefit from particular chemotherapy treatments. For genes such as MGMT and BRCA1, promoter DNA methylation is associated with chemosensitivity to alkylating agents and platinum coordination complexes, respectively, and they have use as biomarkers directing patient treatment options. In contrast to epigenetic change leading to chemosensitivity, DNA methylation of DDR genes involved in engaging cell death responses, such as MLH1, are associated with chemoresistance. This contrasting functional effect of epigenetic modification on chemosensitivity raises challenges in using DNA-demethylating agents, and other epigenetic approaches, to sensitise tumours to DNA-damaging chemotherapies and molecularly targeted agents. Demethylation of MGMT/BRCA1 could lead to drug resistance whereas demethylation of MLH1 could sensitise cells to chemotherapy. Patient selection based on a solid understanding of the disease pathway will be one means to tackle these challenges. The role of epigenetic modification of DDR genes during tumour development, such as causing a mutator phenotype, has different selective pressures and outcomes compared to epigenetic adaptation during treatment. The prevention of epigenetic adaptation during the acquisition of drug resistance will be a potential strategy to improve the treatment of patients using epigenetic therapies

Growth factor restriction impedes progression of wound healing following cataract surgery: identification of VEGF as a putative therapeutic target

Secondary visual loss occurs in millions of patients due to a wound-healing response, known as posterior capsule opacification (PCO), following cataract surgery. An intraocular lens (IOL) is implanted into residual lens tissue, known as the capsular bag, following cataract removal. Standard IOLs allow the anterior and posterior capsules to become physically connected. This places pressure on the IOL and improves contact with the underlying posterior capsule. New open bag IOL designs separate the anterior capsule and posterior capsules and further reduce PCO incidence. It is hypothesised that this results from reduced cytokine availability due to greater irrigation of the bag. We therefore explored the role of growth factor restriction on PCO using human lens cell and tissue culture models. We demonstrate that cytokine dilution, by increasing medium volume, significantly reduced cell coverage in both closed and open capsular bag models. This coincided with reduced cell density and myofibroblast formation. A screen of 27 cytokines identified nine candidates whose expression profile correlated with growth. In particular, VEGF was found to regulate cell survival, growth and myofibroblast formation. VEGF provides a therapeutic target to further manage PCO development and will yield best results when used in conjunction with open bag IOL designs

The effect of windspeed on sea surface temperature retrieval from space

The effect of windspeed on water emissivity, whilst being negligible around normal incidence, becomes significant above angles of about 50-degrees. We calculate the effect of windspeed On retrieved sea surface temperature and show that errors become significant for the potentially very accurate Along Track Scanning Radiometer (ATSR, carried on board ESA's first remote sensing satellite, ERS-1) since brightness temperatures measured at almost-equal-to 56-degrees, as well as those measured at nadir, are used to provide improved atmospheric correction. We show that when an SST retrieval algorithm generated assuming zero windspeed is applied to brightness temperatures calculated for windspeeds of 5, 10 and 15 m/s, a potential error of up to 0.4 K is introduced. Since coincident windspeed data can be obtained from the ERS-1 radar altimeter, accurate correction can be made for this effect and we Provide a Preliminary algorithm for the correction of ATSR SST data

Witnessing the active assembly phase of massive galaxies since z = 1

We present an analysis of ~60 000 massive (stellar mass M_star > 10^{11} M_sun) galaxies out to z = 1 drawn from 55.2 deg2 of the United Kingdom Infrared Telescope (UKIRT) Infrared Deep Sky Survey (UKIDSS) and the Sloan Digital Sky Survey (SDSS) II Supernova Survey. This is by far the largest survey of massive galaxies with robust mass estimates, based on infrared (K-band) photometry, reaching to the Universe at about half its present age. We find that the most massive (M_star > 10^{11.5} M_sun) galaxies have experienced rapid growth in number since z = 1, while the number densities of the less massive systems show rather mild evolution. Such a hierarchical trend of evolution is consistent with the predictions of the current semi-analytic galaxy formation model based on Lambda CDM theory. While the majority of massive galaxies are red-sequence populations, we find that a considerable fraction of galaxies are blue star-forming galaxies. The blue fraction is smaller in more massive systems and decreases toward the local Universe, leaving the red, most massive galaxies at low redshifts, which would support the idea of active 'bottom-up' formation of these populations during 0 < z < 1.Comment: Accepted for publication in MNRAS; replaced with revised version (minor changes in results and wordings); MNRAS online early version availabl

Mediastinal Lymphangioma and Chylothorax: Thoracic Involvement of Gorham's Disease

We report a case of mediastinal lymphangioma associated with Gorham's disease in a 38-year-old man who had suffered recurrent clavicular fractures during a seven-year period. Mediastinal widening associated with osteolysis of the clavicles and the sternal manubrium was revealed by chest radiography, while computed tomography demonstrated a cystic anterior mediastinal mass infiltrating mediastinal fat and associated with osseous destruction of the clavicles and manubrium. Chylothorax recurred during the course of the disease

Differential Impact of a Dutch Alcohol Prevention Program Targeting Adolescents and Parents Separately and Simultaneously: Low Self-Control and Lenient Parenting at Baseline Predict Effectiveness

To test whether baseline levels of the factors accountable for the impact of the Prevention of Alcohol use in Students (PAS) intervention (self-control, perceived rules about alcohol and parental attitudes about alcohol), moderate the effect of the intervention. A cluster randomized trial including 3,490 Dutch early adolescents (M age = 12.66, SD = 0.49) and their parents randomized over four conditions: 1) parent intervention, 2) student intervention, 3) combined intervention and 4) control group. Moderators at baseline were used to examine the differential effects of the interventions on onset of (heavy) weekly drinking at 34-month follow-up. The combined intervention was only effective in preventing weekly drinking among those adolescents who reported to have lower self-control and more lenient parents at baseline. No differential effect was found for the onset of heavy weekly drinking. No moderating roles of self-control and lenient parenting were found for the separate student and parent interventions regarding the onset of drinking. The combined intervention is more effective among adolescents with low-self control and lenient parents at baseline, both factors that were a specific target of the intervention. The relevance of targeting self-control in adolescents and restrictive parenting is underlined

Physio-chemical assessment of beauty leaf (Calophyllum inophyllum) as second-generation biodiesel feedstock

Recently, biodiesels from non-edible vegetable oil, known as second generation biodiesel, are receiving more attention because it can overcome food versus fuel crisis related to edible oils. The Beauty Leaf tree (Calophyllum Inophyllum) is a potential source of non-edible vegetable oil for producing future generation biodiesel because of its sustainability in a wide range of climate conditions, easy cultivation, high fruit production rate, and the high oil content in the seed. In this study, bio-oil was extracted from beauty leaf tree seeds through three different oil extraction methods. The important physical and chemical properties of produced beauty leaf oils were experimentally analysed and compared with commercial edible vegetable oils. Biodiesel was produced using a two-stage esterification process consisting of acid catalysed pre-esterification and alkali catalysed Transesterification. Fatty acid methyl ester (FAME) profile and physicochemical properties including kinematic viscosity, density, higher heating value and acid value were measured using laboratory standard testing equipment following internationally recognized testing procedures. Other fuel properties including oxidation stability, iodine value, cetane number, flash point, cold filter plugging point, cloud point and pour point temperature were estimated using Fatty acid methyl ester (FAME) of biodiesel. Physicochemical properties of beauty leaf oil biodiesels are described briefly and compared with recognised biodiesel standards and commercially available biodiesels produced from edible oil feedstock. Quality of produced biodiesel was assessed based 13 important chemical and physical properties through Preference Ranking Organisation Method for Enrichment Evaluation (PROMETHEE) and Graphical Analysis for Interactive Assistance (GAIA) analysis. This study found that Mechanical extraction using the screw press can produce oil from correctly prepared product at a low cost, however overall this method is ineffective with relatively low oil yields. The study found that seed preparation has a significant impact on oil yields, especially in the mechanical oil extraction method. High temperature and pressure in extraction process increases the performance of oil extraction. On the contrary, this process increases the free fatty acid content in the oil. Clear difference was found in physical properties of beauty leaf oils that eventually affected the oil to biodiesel conversion process. However, beauty leaf oils methyl esters (biodiesel) were very consistent and able to meet almost all indicators of biodiesel standards. Furthermore, it showed as a better automobile fuel compared to most of the commercially available biodiesels produced from edible oil sources. Result of this study indicated that, Beauty Leaf oil seed is readily available feedstock to commence the commercial production of 2nd generation biodiesel. The findings of this study are expected to serve as the basis from which industrial scale biodiesel production from Beauty Leaf can be made

The Cosmic Lens All-Sky Survey: statistical strong lensing, cosmological parameters, and global properties of galaxy populations

Extensive analyses of statistical strong gravitational lensing are performed based on the final Cosmic Lens All Sky Survey (CLASS) well-defined statistical sample of flat spectrum radio sources and current estimates of galaxy luminosity functions per morphological type. The analyses are done under the assumption that galactic lenses are well-approximated by singular isothermal ellipsoids and early-type galaxies evolved passively since redshift $z \sim 1$. Depending on how the late-type galaxy population is treated (i.e., whether its characteristic velocity dispersion is constrained or not), we find for a flat universe with a cosmological constant that the present matter fraction of the present critical density $\Omega_{\rm m} = 0.31^{+0.27}_{-0.14}$ (68%) for the unconstrained case or $0.40^{+0.28}_{-0.16}$ (68%) for the constrained case, with an additional systematic uncertainty of $\approx 0.11$ arising from the present uncertainty in the distribution of CLASS sources in redshift and flux density. For a flat universe with a constant equation of state for dark energy w = $p_x$(pressure)/$\rho_x$(energy density), we find that $w < -0.55^{+0.18}_{-0.11}$ (68%) for the unconstrained case or $w < -0.41^{+0.28}_{-0.16}$ (68%) for the constrained case. For the equal frequencies of oblates and prolates, we find that $\sigma_{*}^{(e)} = 198^{+22}_{-18}$ km s$^{-1}$ (68%) for a `steep' $\alpha^{(e)}=-1$ or $\sigma_{*}^{(e)} = 181^{+18}_{-15}$ km s$^{-1}$ (68%) for a `shallow' $\alpha^{(e)}=-0.54$. Finally, from the relative frequencies of doubly-imaged sources and quadruply-imaged sources, we find that a mean projected mass ellipticity of early-type galaxies $\bar{\epsilon}_{\rm mass} = 0.42$ with a 68% lower limit of 0.28. (Abridged)Comment: 31 pages, 12figures, 6 tables, to appear in MNRAS (referee comments incorporated, a section on future prospects added

On the General Kerr/CFT Correspondence in Arbitrary Dimensions

We study conformal symmetries on the horizon of a general stationary and axisymmetric black hole. We find that there exist physically reasonable boundary conditions that uniquely determine a set of symmetry generators, which form one copy of the Virasoro algebra. For extremal black holes, Cardy's formula reproduces exactly the Bekenstein-Hawking entropy.Comment: 17 page