Interleukin-8 signaling attenuates TRAIL- and chemotherapy-induced apoptosis through transcriptional regulation of c-FLIP in prostate cancer cells

Chemotherapy-induced interleukin-8 (IL-8) signaling reduces the sensitivity of prostate cancer cells to undergo apoptosis. In this study, we investigated how endogenous and drug-induced IL-8 signaling altered the extrinsic apoptosis pathway by determining the sensitivity of LNCaP and PC3 cells to administration of the death receptor agonist tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL induced concentration-dependent decreases in LNCaP and PC3 cell viability, coincident with increased levels of apoptosis and the potentiation of IL-8 secretion. Administration of recombinant human IL-8 was shown to increase the mRNA transcript levels and expression of c+FLIPL and c-FLIPS, two isoforms of the endogenous caspase-8 inhibitor. Pretreatment with the CXCR2 antagonist AZ10397767 significantly attenuated IL-8-induced c-FLIP mRNA up-regulation whereas inhibition of androgen receptor- and/or nuclear factor-kappa B-mediated transcription attenuated IL-8-induced c-FLIP expression in LNCaP and PC3 cells, respectively. Inhibition of c-FLIP expression was shown to induce spontaneous apoptosis in both cell lines and to sensitize these prostate cancer cells to treatment with TRAIL, oxaliplatin, and docetaxel. Coadministration of AZ10397767 also increased the sensitivity of PC3 cells to the apoptosis-inducing effects of recombinant TRAIL, most likely due to the ability of this antagonist to block TRAIL- and IL-8-induced up-regulation of c-FLIP in these cells. We conclude that endogenous and TRAIL-induced IL-8 signaling can modulate the extrinsic apoptosis pathway in prostate cancer cells through direct transcriptional regulation of c-FLIP. Therefore, targeted inhibition of IL-8 signaling or c-FLIP expression in prostate cancer may be an attractive therapeutic strategy to sensitize this stage of disease to chemotherapy.

Frequency of participation of 8-12 year old children with cerebral palsy: a multi-centre cross sectional European study

Participation in home, school and community is important for all children; and little is known about the frequency of participation of disabled children. Frequency of participation is a valuable outcome measure for evaluating habilitation programmes for disabled children and for planning social and health services.

We investigated how frequency of participation varied between children with cerebral palsy and the general population; and examined variation across countries to understand better how the environmental factors such as legislation, public attitudes and regulation in different countries might influence participation.

We undertook a multi-centre, population-based study in children with and without cerebral palsy. Working from the Life-H instrument, we developed a questionnaire to capture frequency of participation in 8–12-year-old children. In nine regions of seven European countries, parents of 813 children with cerebral palsy and 2939 children from the general populations completed the questionnaire.

Frequency of participation for each question was dichotomised about the median; multivariable logistic regressions were carried out.

In the general population, frequency of participation varied between countries. Children with cerebral palsy participated less frequently in many but not all areas of everyday life, compared with children from the general population. There was regional variation in the domains with reduced participation and in the magnitude of the differences. We discuss how this regional variation might be explained by the different environments in which children live. Attending a special school or class was not associated with further reduction in participation in most areas of everyday life.

Electron impact excitation of S-like iron

Energy levels and radiative rates for transitions among the lowest 48 fine-structure levels belonging to the (1s(2) 2s(2) 2p (6)) 3s (2)3p (4) , 3s3p(5), 3s (2)3p (3) 3d and 3p(6) configurations of Fe xi have been calculated using the fully relativistic grasp code. Additionally, collision strengths for transitions among these levels have also been computed using the Dirac Atomic R-matrix Code (darc) of Norrington & Grant. Radiative rates and oscillator strengths are tabulated for all allowed transitions among the 48 fine-structure levels, while collision strengths are reported at three energies above thresholds, i.e. 8, 16 and 24 Ryd for a few representative transitions. Furthermore, excitation rates have been calculated in a wide electron temperature range below 5 x 10(6) K, and the contribution of resonances has been included in the threshold regions. Comparisons are made with the earlier available theoretical and experimental rates, and it is concluded that the experimental rates are overestimated by up to a factor of 2.

Transient receptor potential melastatin 8 (TRPM8) channel involvement in the regulation of vascular tone

The transient receptor potential melastatin 8 (TRPM8) channel has been characterized as a cold and menthol receptor expressed in a subpopulation of sensory neurons but was recently identified in other tissues, including the respiratory tract, urinary system, and vasculature. Thus TRPM8 may play multiple functional roles, likely to be in a tissue- and activation state-dependent manner. We examined the TRPM8 channel presence in large arteries from rats and the functional consequences of their activation. We also aimed to examine whether these channels contribute to control of conscious human skin blood flow. TRPM8 mRNA and protein were detected in rat tail, femoral and mesenteric arteries, and thoracic aorta. This was confirmed in single isolated vascular myocytes by immunocytochemistry. Isometric contraction studies on endothelium-denuded relaxed rat vessels found small contractions on application of the TRPM8-specific agonist menthol (300 microM). However, both menthol and another agonist icilin (50 microM) caused relaxation of vessels precontracted with KCl (60 mM) or the alpha-adrenoceptor agonist phenylephrine (2 microM) and a reduction in sympathetic nerve-mediated contraction. These effects were antagonized by bromoenol lactone treatment, suggesting the involvement of Ca(2+)-independent phospholipase A(2) activation in TRPM8-mediated vasodilatation. In thoracic aorta with intact endothelium, menthol-induced inhibition of KCl-induced contraction was enhanced. This was unaltered by preincubation with either N(omega)-nitro-l-arginine methyl ester (l-NAME; 100 nM), a nitric oxide synthase inhibitor, or the ACh receptor antagonist atropine (1 microM). Application of menthol (3% solution, topical application) to skin caused increased blood flow in conscious humans, as measured by laser Doppler fluximetry. Vasodilatation was markedly reduced or abolished by prior application of l-NAME (passive application, 10 mM) or atropine (iontophoretic application, 100 nM, 30 s at 70 microA). We conclude that TRPM8 channels are present in rat artery vascular smooth muscle and on activation cause vasoconstriction or vasodilatation, dependent on previous vasomotor tone. TRPM8 channels may also contribute to human cutaneous vasculature control, likely with the involvement of additional neuronal mechanisms.

SDSS J150722.30+523039.8: a cataclysmic variable formed directly from a detached white dwarf/brown dwarf binary?

We present high-speed, three-colour photometry of the eclipsing cataclysmic variable SDSS J150722.30+523039.8 (hereafter SDSS J1507). This system has an orbital period of 66.61 min, placing it below the observed `period minimum' for cataclysmic variables. We determine the system parameters via a parametrized model of the eclipse fitted to the observed lightcurve by ?2 minimization. We obtain a mass ratio of q = 0.0623 +/- 0.0007 and an orbital inclination . The primary mass is Mw = 0.90 +/- 0.01Msolar. The secondary mass and radius are found to be Mr = 0.056 +/- 0.001Msolar and Rr = 0.096 +/- 0.001Rsolar, respectively. We find a distance to the system of 160 +/- 10pc. The secondary star in SDSS J1507 has a mass substantially below the hydrogen burning limit, making it the second confirmed substellar donor in a cataclysmic variable. The very short orbital period of SDSS J1507 is readily explained if the secondary star is nuclearly evolved, or if SDSS J1507 formed directly from a detached white dwarf/brown dwarf binary. Given the lack of any visible contribution from the secondary star, the very low secondary mass and the low HeI ?6678/Ha emission-line ratio, we argue that SDSS J1507 probably formed directly from a detached white dwarf/brown dwarf binary. If confirmed, SDSS J1507 will be the first such system identified. The implications for binary star evolution, the brown dwarf desert and the common envelope phase are discussed.

The Newsletter of the International Federation for Research in Women's History: Presentation to Its Conference in Sofia, 8 August 2007

Presented as part of the twentieth anniversary celebrations of the International Federation for Research in Women's History in Sofia in August 2007, this paper examines the association's newsletter to explore what it reveals about the expansion of the academic infrastructure for women's history from 1987 to 2007. It looks at the rapid advancement of the subject in the 1980s and early 1990s and its slower growth in the following decade. It also explores briefly the problems that the establishment of Women's Studies Centres presented for women's history.

“The new Cagliostro”: Onofroff, Rubén Darío and his story "La esfinge"

The article retraces the career of the famous hypnotist Onofroff and particularly his visit to Buenos Aires, where his activity, in 1895, provoked many discussions and some public embarrassment. In this context Darío, using a pseudonym, published his crónica “La esfinge”. We reproduce “La esfinge”, transcribing the original text of La Nación, with annotations identifying the literary and theosophical sources Darío used when he wrote it.

Paul Karl Feyerabend Las proyecciones de la proliferación teórica en la relación ciencia-metafísica

La doctrina de la Proliferación teórica de Paul Karl Feyerabend ha sido interpretada por sus especialistas como un intento de salvaguardar el ideal del progreso científico. Aunque tales estudios hacen justicia, en parte, a la intencionalidad de nuestro filósofo no explicitan la crítica fundamental que implica para Feyerabend el pluralismo teórico. La proliferación teórica constituye en sí misma una reductio ad absurdum de los distintos intentos del positivismo lógico y del racionalismo crítico por definir la ciencia a expensas de lo metafísico. Este artículo presenta la proliferación teórica como una reivindicación del papel positivo que ocupa la metafísica en el quehacer científico. Se consigna la defensa que hace Feyerabend de la metafísica en cuanto que ésta constituye la posibilidad de superar el conservadurismo conceptual, aumentar de contenido empírico de la ciencia y recuperar el valor descriptivo de las teorías científicas.

Radiocarbon wiggle-match dating of proglacial lake sediments - Implications for the 8.2 ka event

The problem of insufficient age-control limits the utilisation of the 8.2 ka BP event for modelling freshwater forcing in climate change studies. High-resolution radiocarbon dates, magnetic susceptibility and lithostratigraphic evidence from a lake sediment core from Nedre Hervavatnet located at Sygnefjell in western Norway provide a record of the early Holocene. We use the method of radiocarbon wiggle-match dating of the lake sediments using the non-linear relationship between the C-14 calibration curve and the consecutive accumulation order of the sample series in order to build a high-resolution age-model. The timing and duration of Holocene environmental changes is estimated using 38 AMS radiocarbon dates on terrestrial macrofossils, insects and chironomids covering the time period from 9750 to 1180 cal BP. Chironomids, Salix and Betula leaves produce the most consistent results. Sedimentological and physical properties of the core suggest that three meltwater events with high sedimentation rates are superimposed on a long-term trend with glacier retreat between 9750 and 8000 cal BP. The lake sediment sequence of Nedre Hervavatnet demonstrates the following: only a reliable high-resolution geochronology based on carefully selected terrestrial macrofossils allows the reconstruction of a more refined and complex environmental change history before and during the 8.2 ka event. (C) 2009 Elsevier Ltd. All rights reserved.

The persistence of the HgCl2 molecule in five new compounds in the system (NH4)(w)HgxCly(H2O)(z) with w : x : y : z=1 : 5 : 11 : 0, 2 : 3 : 8 : 1, 4 : 3 : 10 : 2, 2 : 1 : 4 : 1, and 10 : 3 : 16 : 0

Five new compounds in the system (NH4)Cl/HgCl2/H2O have been obtained as colourless single crystals, (NH4)Hg5Cl11, (NH4)(2)Hg3Cl8(H2O), (NH4)(4)Hg3Cl10(H2O)(2), (NH4)(2)HgCl4(H2O), and (NH4)(10)Hg3Cl16. In all of these, as in HgCl2 itself, (almost) linear HgCl2 molecules persist with Hg-Cl distances varying from 229 to 236 pm. In (NH4)(10)Hg3Cl16 there are also tetrahedra [HgCl4] with d(Hg-Cl) = 247 pm present. If larger Hg-Cl distances (of up to 340 pm) are considered as belonging to the coordination sphere of Hg-II, the structures may be described as consisting of isolated octahedra and tetrahedra as in (NH4)(10)Hg3Cl16, edge-connected chains as in (NH4)(2)HgCl4(H2O), edge-connected chains and layers of octahedra as in (NH4)(4)Hg3Cl10(H2O)(2), corrugated layers of edge-connected octahedra as in (NH4)(2)Hg3Cl8(H2O), and, finally, a three-dimensional network of connected six- and seven-coordinate Hg-Cl polyhedra as in (NH4)Hg5Cl11. The water molecules are never attached to Hg-II. The (NH4)(+) cations, and sometimes Cl- anions, play a role for electroneutrality only.

Palladium-mediated reductive coupling, a stereoselective approach to the 8-dehydropumiliotoxin skeleton

Reductive cyclisation of ail E-vinyl bromide with ail allylic acetate proceeds under palladium catalysis 10 give the 8-dehydropumiliotoxin skeleton, a potential advanced precursor to 8-deoxypumiliotoxin alkaloids. Control of the stereochemistry of the E-vinyl bromide precursor is achieved readily using the Kogen or Bruckner bromophosphonate reagents and the reductive cyclisation proceeds with retention of the vinyl bromide stereochemistry. The mechanism for the cyclisation involves an in situ conversion of the allylic acetate to ail allyl stannane followed by ail intramolecular Stille-type coupling.