Sox2 promotes tamoxifen resistance in breast cancer cells

Development of resistance to therapy continues to be a serious clinical problem in breast cancer management. Cancer stem/progenitor cells have been shown to play roles in resistance to chemo- and radiotherapy. Here, we examined their role in the development of resistance to the oestrogen receptor antagonist tamoxifen. Tamoxifen-resistant cells were enriched for stem/progenitors and expressed high levels of the stem cell marker Sox2. Silencing of the SOX2 gene reduced the size of the stem/progenitor cell population and restored sensitivity to tamoxifen. Conversely, ectopic expression of Sox2 reduced tamoxifen sensitivity in vitro and in vivo. Gene expression profiling revealed activation of the Wnt signalling pathway in Sox2-expressing cells, and inhibition of Wnt signalling sensitized resistant cells to tamoxifen. Examination of patient tumours indicated that Sox2 levels are higher in patients after endocrine therapy failure, and also in the primary tumours of these patients, compared to those of responders. Together, these results suggest that development of tamoxifen resistance is driven by Sox2-dependent activation of Wnt signalling in cancer stem/progenitor cells

Population-based colorectal cancer screening programmes using a faecal immunochemical test:Should faecal haemoglobin cut-offs differ by age and sex?

Abstract Background The Basque Colorectal Cancer Screening Programme has both high participation rate and high compliance rate of colonoscopy after a positive faecal occult blood test (FIT). Although, colorectal cancer (CRC) screening with biannual (FIT) has shown to reduce CRC mortality, the ultimate effectiveness of the screening programmes depends on the accuracy of FIT and post-FIT colonoscopy, and thus, harms related to false results might not be underestimated. Current CRC screening programmes use a single faecal haemoglobin concentration (f-Hb) cut-off for colonoscopy referral for both sexes and all ages. We aimed to determine optimum f-Hb cut-offs by sex and age without compromising neoplasia detection and interval cancer proportion. Methods Prospective cohort study using a single-sample faecal immunochemical test (FIT) on 444,582 invited average-risk subjects aged 50–69 years. A result was considered positive at ≥20 μg Hb/g faeces. Outcome measures were analysed by sex and age for a wide range of f-Hb cut-offs. Results We analysed 17,387 positive participants in the programme who underwent colonoscopy. Participation rate was 66.5%. Men had a positivity rate for f-Hb of 8.3% and women 4.8% (p < 0.0001). The detection rate for advanced neoplasia (cancer plus advanced adenoma) was 44.0‰ for men and 15.9‰ for women (p < 0.0001). The number of colonoscopies required decreased in both sexes and all age groups through increasing the f-Hb cut-off. However, the loss in CRC detection increased by up to 28.1% in men and 22.9% in women. CRC missed were generally at early stages (Stage I-II: from 70.2% in men to 66.3% in women). Conclusions This study provides detailed outcomes in men and women of different ages at a range of f-Hb cut-offs. We found differences in positivity rates, neoplasia detection rate, number needed to screen, and interval cancers in men and women and in younger and older groups. However, there are factors other than sex and age to consider when consideration is given to setting the f-Hb cut-off

Euskara sustatzeko eleaniztasuna: ikastolen kasua

En este artículo presentaremos las bases y los resultados del "plurilingüismo articulado en torno al euskara", puesto en marcha por las ikastolas, y mencionaremos las conclusiones del camino realizado por las ikastolas en el desarrollo de ese modelo escolar plurilingüe y las líneas a seguir cara al futuro.Artikulu honetan Ikastolek abian duten "euskaran ardaztutako eleaniztasuna"ren oinarriak eta emaitzak aurkeztu eta eskola eredu eleanitz horren garapean Ikastolek egin duten bidearen ondorioak nahiz etorkizunerako ildoak aipatuko ditugu.Cet article présente les fondement s et les résultat s du "plurilinguisme articulé autour de l'euskara", mis en oeuvre par les ikastolas, ainsi que les conclusions du travail réalisé par les ikastolas pour le développement du modèle d'école plurilingue, ainsi que les lignes directrices à suivre face l'avenir.This paper presents the bases and result s of the scheme "Multilingualism around the hub of Basque" launched by the Basque-medium schools or Ikastolas, and deals not only with the consequences of the way paved by the Ikastolas in the development of this multilingual school model, but also with the lines for the future

Amplification and disruption of the phenylacetyl-CoA ligase gene of Penicillium chrysogenum encoding an aryl-capping enzyme that supplies phenylacetic acid to the isopenicillin N-acyltransferase

A gene, phl, encoding a phenylacetyl-CoA ligase was cloned from a phage library of Penicillium chrysogenum AS-P-78. The presence of five introns in the phl gene was confirmed by reverse transcriptase-PCR. The phl gene encoded an aryl-CoA ligase closely related to Arabidopsis thaliana 4-coumaroyl-CoA ligase. The Phl protein contained most of the amino acids defining the aryl-CoA (4-coumaroyl-CoA) ligase substrate-specificity code and differed from acetyl-CoA ligase and other acyl-CoA ligases. The phl gene was not linked to the penicillin gene cluster. Amplification of phl in an autonomous replicating plasmid led to an 8-fold increase in phenylacetyl-CoA ligase activity and a 35% increase in penicillin production. Transformants containing the amplified phl gene were resistant to high concentrations of phenylacetic acid (more than 2.5 g/l). Disruption of the phl gene resulted in a 40% decrease in penicillin production and a similar reduction of phenylacetyl-CoA ligase activity. The disrupted mutants were highly susceptible to phenylacetic acid. Complementation of the disrupted mutants with the phl gene restored normal levels of penicillin production and resistance to phenylacetic acid. The phenylacetyl-CoA ligase encoded by the phl gene is therefore involved in penicillin production, although a second aryl-CoA ligase appears to contribute partially to phenylacetic acid activation. The Phl protein lacks a peptide-carrier-protein domain and behaves as an aryl-capping enzyme that activates phenylacetic acid and transfers it to the isopenicillin N acyltransferase. The Phl protein contains the peroxisome-targeting sequence that is also present in the isopenicillin N acyltransferase. The peroxisomal co-localization of these two proteins indicates that the last two enzymes of the penicillin pathway form a peroxisomal functional complex