Ellesmere Port Sure Start parent satisfaction survey 2003

This report discusses awareness of Sure Start, use of Sure Start services, satisfaction with services, and access to childcare in Ellesmere Port. Recommendations are made.Commissioned and funded by Ellesmere Port Sure Start

Blacon Sure Start parent satisfaction survey

This report evaluates Sure Start in Blacon during 2003.Commissioned and funded by Blacon Sure Start

How did kinsmen influence the careers of clerics? Uncles and nephews among the clergy 800-1200

Julia Barrow ‘How did kinsmen influence the careers of clerics? Uncles and nephews among the clergy 800-1200’ Historians have often noticed individual pairs of clerical uncles and nephews in medieval sources, but the social and institutional implications of this pattern have not often been explored in depth. In a forthcoming book (The Clergy in the Medieval World: Secular Clerics, Their Families and Careers in North-Western Europe c.800-c.1200 (Cambridge: Cambridge University Press, 2015)) I have examined the relations between clerics and their kinsfolk, especially clerical kinsmen, as part of a study of how clergy built up their careers between the reign of Charlemagne and the pontificate of Innocent III. By 800 a tendency towards child entry into the clergy, which was already very marked in the seventh century, had become pretty well universal, and this strengthened the influence of parents. Where fathers of future clerics were laymen but had brothers or brothers in law who were clerics, they often made use of them to ensure their sons’ futures. In my lecture, I intend to give an overview of entry into the clergy and early education c.800-c.1100, before turning to look at the role of parents, the transmission of property within families and the extent to which clerics might benefit from this, and the roles of uncles towards nephews. Areas of Europe in which clerical marriage was more entrenched produce a somewhat different pattern of clerical upbringing and provide a useful contrast. Both patterns were challenged by new social forces from the end of the eleventh century onwards, above all changes in the running of schools. Most of the evidence I will be considering will be taken from charter and narrative sources for Northern France, England and also Germany, but I hope to include one or two twelfth-century Spanish examples.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Real Academia de Nobles Artes de Antequera

Einstein billiards and spatially homogeneous cosmological models

In this paper, we analyse the Einstein and Einstein-Maxwell billiards for all spatially homogeneous cosmological models corresponding to 3 and 4 dimensional real unimodular Lie algebras and provide the list of those models which are chaotic in the Belinskii, Khalatnikov and Lifschitz (BKL) limit. Through the billiard picture, we confirm that, in D=5 spacetime dimensions, chaos is present if off-diagonal metric elements are kept: the finite volume billiards can be identified with the fundamental Weyl chambers of hyperbolic Kac-Moody algebras. The most generic cases bring in the same algebras as in the inhomogeneous case, but other algebras appear through special initial conditions.Comment: 27 pages, 10 figures, additional possibility analysed in section 4.3, references added, typos correcte

Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro

Introduction: Upregulation of PI3K/Akt/mTOR signalling in endocrine-resistant breast cancer (BC) has identified mTOR as an attractive target alongside anti-hormones to control resistance. RAD001 (everolimus/Afinitor®), an allosteric mTOR inhibitor, is proving valuable in this setting; however, some patients are inherently refractory or relapse during treatment requiring alternative strategies. Here we evaluate the potential for novel dual mTORC1/2 mTOR kinase inhibitors, exemplified by AZD8055, by comparison with RAD001 in ER + endocrine resistant BC cells. Methods: In vitro models of tamoxifen (TamR) or oestrogen deprivation resistance (MCF7-X) were treated with RAD001 or AZD8055 alone or combined with anti-hormone fulvestrant. Endpoints included growth, cell proliferation (Ki67), viability and migration, with PI3K/AKT/mTOR signalling impact monitored by Western blotting. Potential ER cross-talk was investigated by immunocytochemistry and RT-PCR. Results: RAD001 was a poor growth inhibitor of MCF7-derived TamR and MCF7-X cells (IC50 ≥1 μM), rapidly inhibiting mTORC1 but not mTORC2/AKT signalling. In contrast AZD8055, which rapidly inhibited both mTORC1 and mTORC2/AKT activity, was a highly effective (P <0.001) growth inhibitor of TamR (IC50 18 nM) and MCF7-X (IC50 24 nM), and of a further T47D-derived tamoxifen resistant model T47D-tamR (IC50 19 nM). AZD8055 significantly (P <0.05) inhibited resistant cell proliferation, increased cell death and reduced migration. Furthermore, dual treatment of TamR or MCF7-X cells with AZD8055 plus fulvestrant provided superior control of resistant growth versus either agent alone (P <0.05). Co-treating with AZD8055 alongside tamoxifen (P <0.01) or oestrogen deprivation (P <0.05) also effectively inhibited endocrine responsive MCF-7 cells. Although AZD8055 inhibited oestrogen receptor (ER) ser167 phosphorylation in TamR and MCF7-X, it had no effect on ER ser118 activity or expression of several ER-regulated genes, suggesting the mTOR kinase inhibitor impact was largely ER-independent. The capacity of AZD8055 for ER-independent activity was further evidenced by growth inhibition (IC5018 and 20 nM) of two acquired fulvestrant resistant models lacking ER. Conclusions: This is the first report demonstrating dual mTORC1/2 mTOR kinase inhibitors have potential to control acquired endocrine resistant BC, even under conditions where everolimus fails. Such inhibitors may prove of particular benefit when used alongside anti-hormonal treatment as second-line therapy in endocrine resistant disease, and also potentially alongside anti-hormones during the earlier endocrine responsive phase to hinder development of resistance

4th generation nonsteroidal aromatase inhibitors: An iterative SAR-guided design, synthesis, and biological evaluation towards picomolar dual binding inhibitors

One in every eight women will be diagnosed with breast cancer during their lifetime and approximately 70% of all patients are oestrogen receptor (ER) positive depending upon oestrogen for their growth accounting for third generation aromatase (CYP19A1) inhibitors being the mainstay in the treatment of ER-positive breast cancer. Despite the success of current aromatase inhibitors, acquired resistance occurs after prolonged therapy. Although the precise mechanisms of resistance are not known, lack of cross resistance among aromatase inhibitors drives the need for a newer generation of inhibitors to overcome this resistance alongside minimising toxicity and adverse effects. Novel triazole-based inhibitors were designed based on previously published parent compound 5a, making use of the now available crystal structure of CYP19A1 (PDB 3S79), to make modifications at specific sites to explore the potential of dual binding at both the active site and the access channel. Modifications included adding long chain substituents e.g. but-2-ynyloxy and pent-2-ynyloxy at different positions including the most active compound 13h with IC50 value in the low picomolar range (0.09 nM). Aromatase inhibition results paired with molecular dynamics studies provided a clear structure activity relationship and favourable dual binding mode was verified. Toxicity assays and CYP selectivity profile studies for some example compounds were performed to assess the safety profile of the prepared inhibitors providing the basis for the 4th generation nonsteroidal aromatase inhibitors

Oscillatory regime in the Multidimensional Homogeneous Cosmological Models Induced by a Vector Field

We show that in multidimensional gravity vector fields completely determine the structure and properties of singularity. It turns out that in the presence of a vector field the oscillatory regime exists in all spatial dimensions and for all homogeneous models. By analyzing the Hamiltonian equations we derive the Poincar\'e return map associated to the Kasner indexes and fix the rules according to which the Kasner vectors rotate. In correspondence to a 4-dimensional space time, the oscillatory regime here constructed overlap the usual Belinski-Khalatnikov-Liftshitz one.Comment: 9 pages, published on Classical and Quantum Gravit

erbB3 recruitment of insulin receptor substrate 1 modulates insulin-like growth factor receptor signalling in oestrogen receptor-positive breast cancer cell lines

Introduction Recently we reported that insulin receptor substrate 1 (IRS-1), classically an adaptor protein for the insulin-like growth factor type I receptor (IGF-IR), associates with the epidermal growth factor receptor in oestrogen receptor (ER)-positive (ER+) tamoxifen-resistant breast cancer cells. In this study, we examined whether IRS-1 also associates with another erbB receptor family member, erbB3, and what impact this might have on IGF-IR signalling in three ER+ breast cancer cell lines. Methods Immunoprecipitation and Western blot analysis were utilised to examine the potential association between erbB3 and IRS-1 in MCF-7, T47D and BT-474 cells in the absence and presence of the erbB3/4 ligand heregulin β1 (HRGβ1). Subsequently, the impact of a selective IGF-IR/IR inhibitor 4-anilino-5-bromo-2-[4-(2-hydroxy-3-(N, N-dimethylamino)propoxy)anilino]pyrimidine on this association and HRGβ1 signalling was assessed in these cell lines. Immunohistochemical analysis of a small cohort of ER+ breast cancer patient samples was also performed to determine the potential clinical relevance of this novel interaction. Results Immunoprecipitation and Western blot analysis revealed an interaction between erbB3 and IRS-1 in MCF-7, T47D and BT-474 cells, with HRGβ1 significantly enhancing this recruitment and promoting IRS-1 phosphorylation at Y612. IRS-1 participates in erbB3 signalling in MCF-7 and T47D cells as IRS-1 knockdown impaired HRGβ1 signalling. Importantly, recruitment of IRS-1 by erbB3 reduced IRS-1 association with IGF-IR in MCF-7 and T47D cells, whilst blockade of IGF-IR-enhanced erbB3-IRS-1 interaction and sensitised both cell lines to HRGβ1, allowing HRGβ1 to override IGF-IR blockade. Consequently, suppression of IRS-1 signalling enhanced the effects of IGF-IR inhibition in these cells. This novel interaction may have clinical relevance, as immunohistochemical analysis of a small ER+ breast tumour series revealed significant positive correlations between phosphorylated IRS-1 Y612 expression and total erbB3, phosphorylated Akt and Ki-67 expression. Conclusions IRS-1 can be recruited to IGF-IR and erbB3 in ER+ breast cancer cells, and this provides an adaptive resistance mechanism when these receptors are targeted individually. Consequently, cotargeting IGF-IR and either erbB3 or IRS-1 should prove to be a more effective strategy for the treatment of ER+ breast cancer

Correction to: Heregulin ?1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells

© 2018 The Author(s). After the publication of this work [1], an error was noticed in Fig. 2b and Fig. 4b as well as Fig. 4b. and Fig. 5d. Images of the ERK1/2 blots were accidentally duplicated. In Fig. 5a. and Fig. 5c., the last lane for p-ERK1/2 was mistakenly cropped out of the final image. The original blot for Fig. 4b., "total EGFR" (or lane 2) is shown below to avoid any misunderstanding of the data. We apologize for this error, which did not affect any of the interpretations or conclusions of the article

Superstring Cosmology

Aspects of superstring cosmology are reviewed with an emphasis on the cosmological implications of duality symmetries in the theory. The string effective actions are summarized and toroidal compactification to four dimensions reviewed. Global symmetries that arise in the compactification are discussed and the duality relationships between the string effective actions are then highlighted. Higher-dimensional Kasner cosmologies are presented and interpreted in both string and Einstein frames, and then given in dimensionally reduced forms. String cosmologies containing both non-trivial Neveu-Schwarz/Neveu-Schwarz and Ramond-Ramond fields are derived by employing the global symmetries of the effective actions. Anisotropic and inhomogeneous cosmologies in four-dimensions are also developed. The review concludes with a detailed analysis of the pre-big bang inflationary scenario. The generation of primordial spectra of cosmological perturbations in such a scenario is discussed. Possible future directions offered in the Horava-Witten theory are outlined.Comment: 161 pages, latex with epsf, 15 figures. Minor changes, additional references and figures. Version to appear in Physics Report