HIF-1 and NF-kappaB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells

Hypoxic cancer cells are resistant to treatment, leading to the selection of cells with a more malignant phenotype. The expression of interleukin-8 (IL-8) plays an important role in the tumorigenesis and metastasis of solid tumors including prostate cancer. Recently, we detected elevated expression of IL-8 and IL-8 receptors in human prostate cancer tissue. The objective of the current study was to determine whether hypoxia increases IL-8 and IL-8 receptor expression in prostate cancer cells and whether this contributes to a survival advantage in hypoxic cells. IL-8, CXCR1 and CXCR2 messenger RNA (mRNA) expression in PC3 cells was upregulated in response to hypoxia in a time-dependent manner. Elevated IL-8 secretion following hypoxia was detected by enzyme-linked immunosorbent assay, while immunoblotting confirmed elevated receptor expression. Attenuation of hypoxia-inducible factor (HIF-1) and nuclear factor-kappaB (NF-kappaB) transcriptional activity using small interfering RNA (siRNA), a HIF-1 dominant-negative and pharmacological inhibitors, abrogated hypoxia-induced transcription of CXCR1 and CXCR2 in PC3 cells. Furthermore, chromatin-IP analysis demonstrated binding of HIF-1 and NF-kappaB to CXCR1. Finally, inhibition of IL-8 signaling potentiated etoposide-induced cell death in hypoxic PC3 cells. These results suggest that IL-8 signaling confers a survival advantage to hypoxic prostate cancer cells, and therefore, strategies to inhibit IL-8 signaling may sensitize hypoxic tumor cells to conventional treatments.

Competence in research planning in the fourth level of Spanish Secondary Education: a case study

In the last years, “Inquiry-Based Science Education” methodologies (IBSE) are being recommended by European institutions in order to improve the competence levels and the attitudes towards science of primary and secondary school students. Therefore, the aim of this study is to test the effectiveness of an IBSE methodology, the Methodology of Problem Solving as an Investigation (MPSI), for the teaching-learning process of planning of experiments in the fourth level of Spanish Secondary Education. By means of the students’ solutions for a series of open problems, the progress in the learning of the competences related to the planning of experiments has been analyzed, along with the influence of the methodology on the development of these competencies. The results show a students’ command from higher to lower levels on: emission of hypothesis, design of the experiment, qualitative analysis, identification of variables and reformulation of the open problem. Furthermore, the Methodology has contributed to an improvement of the scientific competence in the area of planning experiments.

Alien gosd in the new epics: Noah remythologised through the ancient astronaut hypothesis in Abel's Montagut's "La gesta d'Utnoa"

Modern scientific world-view has undermined traditional myths, the functional survival of which seems to depend today in the West on a positivist justification. This would place them in the field of real History, through their study and revitalization by pseudoscientific disciplines such as the Atlantis and the ancient astronaut hypotheses. These have inspired new epic poems in (regular) verse that combine classic and/or biblical myths with a (pseudo)scientific modern world-view. For example, the critical rewriting of Noah’s myth by using the ancient astronaut hypothesis as a fictional device to produce a contemporary kind of plausibility allowed Abel Montagut to renew epic poetry, updating it also by adopting science fiction chronotopes in order to structure his fictional construction and to generate a high ethical sense for our time. Thus, his Poemo de Utnoa (1993) / La gesta d���Utnoa (1996), which has become a major classic of the literature in Esperanto thanks to its original version in this language, is a landmark of both science fiction and neo-biblical epics. This poem is written from a secular and purely literary perspective.

WASP-3b: a strongly irradiated transiting gas-giant planet

We report the discovery of WASP-3b, the third transiting exoplanet to be discovered by the WASP and SOPHIE collaboration. WASP-3b transits its host star USNO-B1.01256-0285133 every 1.846834 +/- 0.000002 d. Our high-precision radial velocity measurements present a variation with amplitude characteristic of a planetary-mass companion and in phase with the light curve. Adaptive optics imaging shows no evidence for nearby stellar companions, and line-bisector analysis excludes faint, unresolved binarity and stellar activity as the cause of the radial velocity variations. We make a preliminary spectroscopic analysis of the host star and find it to have Teff = 6400 +/- 100K and log g = 4.25 +/- 0.05 which suggests it is most likely an unevolved main-sequence star of spectral type F7-8V. Our simultaneous modelling of the transit photometry and reflex motion of the host leads us to derive a mass of 1.76+0.08-0.14 MJ and radius 1.31+0.07-0.14 RJ for WASP-3b. The proximity and relative temperature of the host star suggests that WASP-3b is one of the hottest exoplanets known, and thus has the potential to place stringent constraints on exoplanet atmospheric models.

Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation

The aim of our study was to assess the importance of the CXC chemokine and interleukin (IL)-8 in promoting the transition of prostate cancer (CaP) to the androgen-independent state. Stimulation of the androgen-dependent cell lines, LNCaP and 22Rv1, with exogenous recombinant human interleukin-8 (rh-IL-8) increased androgen receptor (AR) gene expression at the messenger RNA (mRNA) and protein level, assessed by quantitative polymerase chain reaction and immunoblotting, respectively. Using an androgen response element-luciferase construct, we demonstrated that rh-IL-8 treatment also resulted in increased AR transcriptional activity in both these cell lines, and a subsequent upregulation of prostate-specific antigen and cyclin-dependent kinase 2 mRNA transcript levels in LNCaP cells. Blockade of CXC chemokine receptor-2 signaling using a small molecule antagonist (AZ10397767) attenuated the IL-8-induced increases in AR expression and transcriptional activity. Furthermore, in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, coadministration of AZ10397767 reduced the viability of LNCaP and 22Rv1 cells exposed to bicalutamide. Our data show that IL-8 signaling increases AR expression and promotes ligand-independent activation of this receptor in two androgen-dependent cell lines, describing two mechanisms by which this chemokine may assist in promoting the transition of CaP to the androgen-independent state. In addition, our data show that IL-8-promoted regulation of the AR attenuates the effectiveness of the AR antagonist bicalutamide in reducing CaP cell viability.

James Anderson's Political Economy--His Influence on Smith and Malthus

James Anderson's powerful critique of Adam Smith's position on the corn export bounty was published in 1777. It focuse d on Smith's proposition that the bounty could not lead to increased corn production because it could not increase corn's real price. Smit h's response to the critique is traced in later editions of Wealth of Nations. While Anderson's critique of Smith influenced Thomas Malthu s's writings from 1803 onwards, his theory of differential rent did n ot influence Malthus at this stage. An examination of the evolution o f Malthus's ideas on rent between 1803 and 1815, however, indicates t hat Malthus knew and used Anderson's work on rent.

"Irish Perspectives on EC Law by Mary Catherine Lucey and Cathrina Keville (eds.), Dublin, Thomson Round Hall, 2003 (ISBN 1-85800-280-X)"

Book Review

A commentary on climate change, stone decay dynamics and the ‘greening’ of natural stone buildings: new perspectives on ‘deep wetting’

Environmental controls on stone decay processes are rapidly changing as a result of changing climate. UKCP09 projections for the 2020s (2010–2039) indicate that over much of the UK seasonality of precipitation will increase. Summer dryness and winter wetness are both set to increase, the latter linked to projected precipitation increases in autumn and spring months. If so, this could increase the time that stone structures remain wet and possibly the depth of moisture penetration, and it appears that building stone in Northern Ireland has already responded through an increased incidence of algal ‘greening’.This paper highlights the need for understanding the effects of climate change through a series of studies of largely sandstone structures. Current and projected climatic trends are therefore considered to have aesthetic, physical and chemical implications that are not currently built into our models of sandstone decay, especially with respect to the role played by deep-seated wetness on sandstone deterioration and decay progression and the feedbacks associated with, for example surface algal growth. In particular,it is proposed that algal biofilms will aid moisture retention and further facilitate moisture and dissolved salt penetration to depth. Thus, whilst the outer surface of stone may continue to experience frequent wetting and drying associated with individual precipitation events, the latter is less likely to be complete, and the interiors of building blocks may only experience wetting/drying in response to seasonal cycling. A possible consequence of deeper salt penetration could be a delay in the onset of surface deterioration,but more rapid and effective retreat once it commences as decay mechanisms ‘tap into a reservoir of deep salt’.

The last meal of the Late Ordovician mollusc ‘Helminthochiton’ thraivensis Reed, 1911, from the Lady Burn Starfish Beds, southwest Scotland.

An exceptional specimen of the Late Ordovician mollusc ‘Helminthochiton’ thraivensis Reed, from the Katian of the Lady Burn Starfish Beds, southwest Scotland, preserves gut contents that include nine pelmatozoan ossicles. These are interpreted as including two nodal and five intermodal columnals, and two radice ossicles from the attachment structure. The stem was cyclocyclic and heteromorphic, possibly N212. Radice ossicles were wider than the height of nodals, so radice scars must have encroached onto the latera of adjacent pluricolumnals. These features were compared with the 26 known pelmatozoan taxa from the Lady Burn Starfish Beds. Paracrinoids (one species) and glyptocystitid rhombiferans (six species) were discounted as prey because of their cemented attachment, and incorrect columnal morphology and lack of attachment, respectively. Of 19 species of crinoids, eight are discounted in which the column is pentagonal, tetragonal or unknown. Of the remaining eleven species, only the monobathrid camerate Macrostylocrinus cirrifer Ramsbottom satisfies all criteria for identification of the prey, including heteromorphy and radice scars encroaching adjacent internodals.

The addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for advanced colorectal cancer: results of the MRC COIN trial.

Background: In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival.
Methods: In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448.
Findings: 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3—29·2] in the control group vs 17·0 months [9·4—30·1] in the cetuximab group; HR 1·04, 95% CI 0·87—1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0—12·5] in the control group vs 8·6 months [5·1—13·8] in the cetuximab group; HR 0·96, 0·82—1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5—27·4); KRAS mutant, 14·4 months (8·5—24·0); all wild-type, 20·1 months (11·5—31·7).
Interpretation: This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.