A comet assay of DNA damage and repair in K562 cells after photodynamic therapy using haematoporphyrin derivative, methylene blue and meso-tetrahydroxyphenylchlorin.

Single-cell electrophoresis (comet assay) has been used to evaluate DNA damage and repair in the human myeloid leukaemia cell line K562 after low-dose (predominantly sub-lethal) treatments of hyperthermia and photodynamic therapy (PDT). Three different photosensitizers were examined: haematoporphyrin derivative (HpD), methylene blue (MB) and meso-tetrahydroxyphenylchlorin (mTHPC). None of the drugs in the absence of light, nor in light alone, resulted in detectable DNA damage. However, a significant amount of DNA damage was detected immediately after treatment with haematoporphyrin derivative or methylene blue PDT compared with drug-only or light-only treatments; no residual level of DNA damage was evident for either drug following a 4-h post-treatment incubation at 37 degrees C. No significant DNA damage was detected after meso-tetrahydroxyphenylchlorin PDT or hyperthermia either immediately or 4 h after treatment. We conclude that the alkaline comet assay can be applied as an effective screening assay for DNA damage induced by a range of laser therapies

Sebomic identification of sex- and ethnicity-specific variations in residual skin surface components (RSSC) for bio-monitoring or forensic applications

Background: “Residual skin surface components” (RSSC) is the collective term used for the superficial layer of sebum, residue of sweat, small quantities of intercellular lipids and components of natural moisturising factor present on the skin surface. Potential applications of RSSC include use as a sampling matrix for identifying biomarkers of disease, environmental exposure monitoring, and forensics (retrospective identification of exposure to toxic chemicals). However, it is essential to first define the composition of “normal” RSSC. Therefore, the aim of the current study was to characterise RSSC to determine commonalities and differences in RSSC composition in relation to sex and ethnicity. Methods: Samples of RSSC were acquired from volunteers using a previously validated method and analysed by high-pressure liquid chromatography–atmospheric pressure chemical ionisation–mass spectrometry (HPLC-APCI-MS). The resulting data underwent sebomic analysis. Results: The composition and abundance of RSSC components varied according to sex and ethnicity. The normalised abundance of free fatty acids, wax esters, diglycerides and triglycerides was significantly higher in males than females. Ethnicity-specific differences were observed in free fatty acids and a diglyceride. Conclusions: The HPLC-APCI-MS method developed in this study was successfully used to analyse the normal composition of RSSC. Compositional differences in the RSSC can be attributed to sex and ethnicity and may reflect underlying factors such as diet, hormonal levels and enzyme expression.Peer reviewedFinal Published versio

Cellular Radiosensitivity: How much better do we understand it?

Purpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies. Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation

The clinical and economic benefits of capecitabine and tegafur with uracil in metastatic colorectal cancer

Two oral fluoropyrimidine therapies have been introduced for metastatic colorectal cancer. One is a 5-fluorouracil pro-drug, capecitabine; the other is a combination of tegafur and uracil administered together with leucovorin. The purpose of this study was to compare the clinical effectiveness and cost-effectiveness of these oral therapies against standard intravenous 5-fluorouracil regimens. A systematic literature review was conducted to assess the clinical effectiveness of the therapies and costs were calculated from the UK National Health Service perspective for drug acquisition, drug administration, and the treatment of adverse events. A cost-minimisation analysis was used; this assumes that the treatments are of equal efficacy, although direct randomised controlled trial (RCT) comparisons of the oral therapies with infusional 5-fluorouracil schedules were not available. The cost-minimisation analysis showed that treatment costs for a 12-week course of capecitabine (£2132) and tegafur with uracil (£3385) were lower than costs for the intravenous Mayo regimen (£3593) and infusional regimens on the de Gramont (£6255) and Modified de Gramont (£3485) schedules over the same treatment period. Oral therapies result in lower costs to the health service than intravenous therapies. Further research is needed to determine the relative clinical effectiveness of oral therapies vs infusional regimens

The ASAS-SN bright supernova catalogue - III. 2016

This catalogue summarizes information for all supernovae discovered by the All-Sky Automated Survey for SuperNovae (ASAS-SN) and all other bright (mpeak ≤ 17), spectroscopically confirmed supernovae discovered in 2016. We then gather the near-infrared through ultraviolet magnitudes of all host galaxies and the offsets of the supernovae from the centres of their hosts from public data bases. We illustrate the results using a sample that now totals 668 supernovae discovered since 2014 May 1, including the supernovae from our previous catalogues, with type distributions closely matching those of the ideal magnitude limited sample from Li et al. This is the third of a series of yearly papers on bright supernovae and their hosts from the ASAS-SN team

The ASAS-SN Bright Supernova Catalog - II. 2015

This manuscript presents information for all supernovae discovered by the All-Sky Automated Survey for SuperNovae (ASAS-SN) during 2015, its second full year of operations. The same information is presented for bright ($m_V\leq17$), spectroscopically confirmed supernovae discovered by other sources in 2015. As with the first ASAS-SN bright supernova catalog, we also present redshifts and near-UV through IR magnitudes for all supernova host galaxies in both samples. Combined with our previous catalog, this work comprises a complete catalog of 455 supernovae from multiple professional and amateur sources, allowing for population studies that were previously impossible. This is the second of a series of yearly papers on bright supernovae and their hosts from the ASAS-SN team

Increased renal sodium absorption by inhibition of prostaglandin synthesis during fasting in healthy man. A possible role of the epithelial sodium channels

<p>Abstract</p> <p>Background</p> <p>Treatment with prostaglandin inhibitors can reduce renal function and impair renal water and sodium excretion. We tested the hypotheses that a reduction in prostaglandin synthesis by ibuprofen treatment during fasting decreased renal water and sodium excretion by increased absorption of water and sodium via the aquaporin2 water channels and the epithelial sodium channels.</p> <p>Methods</p> <p>The effect of ibuprofen, 600 mg thrice daily, was measured during fasting in a randomized, placebo-controlled, double-blinded crossover study of 17 healthy humans. The subjects received a standardized diet on day 1, fasted at day 2, and received an IV infusion of 3% NaCl on day 3. The effect variables were urinary excretions of aquaporin2 (u-AQP2), the beta-fraction of the epithelial sodium channel (u-ENaCbeta), cyclic-AMP (u-cAMP), prostaglandin E2 (u-PGE2). Free water clearance (CH2O), fractional excretion of sodium (FENa), and plasma concentrations of vasopressin, angiotensin II, aldosterone, atrial-, and brain natriuretic peptide.</p> <p>Results</p> <p>Ibuprofen decreased u-AQP2, u-PGE2, and FENa at all parts of the study. During the same time, ibuprofen significantly increased u-ENaCbeta. Ibuprofen did not change the response in p-AVP, u-c-AMP, urinary output, and free water clearance during any of these periods. Atrial-and brain natriuretic peptide were higher.</p> <p>Conclusion</p> <p>During inhibition of prostaglandin synthesis, urinary sodium excretion decreased in parallel with an increase in sodium absorption and increase in u-ENaCbeta. U-AQP2 decreased indicating that water transport via AQP2 fell. The vasopressin-c-AMP-axis did not mediate this effect, but it may be a consequence of the changes in the natriuretic peptide system and/or the angiotensin-aldosterone system</p> <p>Trial Registration</p> <p>Clinical Trials Identifier: NCT00281762</p

In vitro studies on the modification of low-dose hyper-radiosensitivity in prostate cancer cells by incubation with genistein and estradiol

<p>Abstract</p> <p>Background</p> <p>As the majority of prostate cancers (PC) express estrogen receptors, we evaluated the combination of radiation and estrogenic stimulation (estrogen and genistein) on the radiosensitivity of PC cells in vitro.</p> <p>Methods</p> <p>PC cells LNCaP (androgen-sensitive) and PC-3 (androgen-independent) were evaluated. Estrogen receptor (ER) expression was analyzed by means of immunostaining. Cells were incubated in FCS-free media with genistein 10 μM and estradiol 10 μM 24 h before irradiation and up to 24 h after irradiation. Clonogenic survival, cell cycle changes, and expression of p21 were assessed.</p> <p>Results</p> <p>LNCaP expressed both ER-α and ER-β, PC-3 did not. Incubation of LNCaP and PC-3 with genistein resulted in a significant reduction of clonogenic survival. Incubation with estradiol exhibited in low concentrations (0.01 μM) stimulatory effects, while higher concentrations did not influence survival. Both genistein 10 μM and estradiol 10 μM increased low-dose hyper-radiosensitivity [HRS] in LNCaP, while hormonal incubation abolished HRS in PC-3. In LNCaP cells hormonal stimulation inhibited p21 induction after irradiation with 4 Gy. In PC-3 cells, the proportion of cells in G2/M was increased after irradiation with 4 Gy.</p> <p>Conclusion</p> <p>We found an increased HRS to low irradiation doses after incubation with estradiol or genistein in ER-α and ER-β positive LNCaP cells. This is of high clinical interest, as this tumor model reflects a locally advanced, androgen dependent PC. In contrast, in ER-α and ER-β negative PC-3 cells we observed an abolishing of the HRS to low irradiation doses by hormonal stimulation. The effects of both tested compounds on survival were ER and p53 independent. Since genistein and estradiol effects in both cell lines were comparable, neither ER- nor p53-expression seemed to play a role in the linked signalling. Nevertheless both compounds targeted the same molecular switch. To identify the underlying molecular mechanisms, further studies are needed.</p

The ASAS-SN bright supernova catalogue - III. 2016

This catalogue summarizes information for all supernovae discovered by the All-Sky Automated Survey for SuperNovae (ASAS-SN) and all other bright (mpeak ≤ 17), spectroscopically confirmed supernovae discovered in 2016. We then gather the near-infrared through ultraviolet magnitudes of all host galaxies and the offsets of the supernovae from the centres of their hosts from public data bases. We illustrate the results using a sample that now totals 668 supernovae discovered since 2014 May 1, including the supernovae from our previous catalogues, with type distributions closely matching those of the ideal magnitude limited sample from Li et al. This is the third of a series of yearly papers on bright supernovae and their hosts from the ASAS-SN team