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This broad and all-encompassing study focuses on Europe's new policy agendas. There are two key themes of particular salience for policy makers; the enlargement of the EU; and the place of Europe in international politics. An expansive list of important policy areas within these themes is explored.

4-Thio-5-bromo-2'-deoxyuridine (3a) is prepared from 5-bromo-2'-deoxyuridine (BrdU) and its key properties are explored. The thionucleoside (3a) can react readily with monobromobimane and produces high fluorescence. 3a has UV maximum absorption at 340 nm and can be incorporated into cellular DNA. The cells containing 3a become sensitive to UVA light, offering therapeutic potential for UVA-induced cell killing.

Modernizing civil services - an era of reform localism and exceptualism - comparing public sector reforms in European and Westminister systems protecting liberty and benefiting society - can market-based administrative reforms and market-based political institutions effectively co-exist in the USA? modernization as Europeanization - the impact of the European Union on public administration executive agencies and "modernizing government" devolution, integration and modernization in the United Kingdom civil service modernization and civil service accountability - the case of Scottish devolution implementation of the Human Rights Act 1998 in the Lord Chancellor's Department modernizing policy-making for the 21st century - the professional model civil society, virtue, trust - implications for the public service ethos in the age of modernity.

The contribution of defective DNA mismatch repair (MMR) to acquired resistance to cis-diamminedichloroplatinum(II) (cisplatin) has been investigated in two model systems: E coli dam mutants and the A2780 ovarian carcinoma cell line. Inactivation of MMR-as indicated by the acquisition of an elevated spontaneous mutator phenotype-was observed frequently among survivors of cisplatin-treated dam mutants. These survivors exhibited a stable resistance to further cisplatin treatment. In contrast, none of twelve independent clones of A2780 that had survived cisplatin exposure and acquired stable drug resistance were repair defective. None exhibited the hallmark methylation tolerant phenotype associated with a MMR defect, mRNAs encoding five MMR proteins were easily detectable in all twelve variants, and the levels of four key MMR proteins were similar to those in the repair proficient parental cells. Further analysis indicated two different mechanisms of acquired resistance in A2780. The first was a protective effect that reduced the level of DNA platination. The second was observed as a reduced sensitivity to cell cycle arrest after cisplatin treatment and a consequent reduced apoptosis. The data suggest that although loss of MMR is a significant mechanism of acquired drug resistance in dam bacteria, alterations related to DNA protection or cell cycle progression after drug damage appear to be more probable than abrogation of MMR as resistance modulators in human cells.

The thiopurines, 6-thioguanine and 6-mercaptopurine, are antileukemic agents that are incorporated into DNA following retrieval by the purine salvage pathway (see [1] for a review). Their toxicity requires active DNA mismatch repair (MMR), and thiopurine resistance is an acknowledged phenotype of MMR-defective cells [2, 3]. In addition to these direct cytotoxic effects, DNA thiobases have distinctive photochemical properties [4], the therapeutic potential of which has not been extensively evaluated. We report here that the thiopyrimidine nucleoside 4-thiothymidine is incorporated into DNA. It does not induce MMR-related toxicity, but it interacts synergistically with UVA light and dramatically sensitizes cultured human cells to very low, nonlethal UVA doses. 4-thiothymidine induced UVA dose enhancements of around 100-fold in DNA repair-proficient cells. Nucleotide excision repair-defective xeroderma pigmentosum cells were sensitized up to 1000-fold, implicating bulky DNA photoproducts in the lethal effect. The synergistic action of thiothymidine plus UVA required thymidine kinase, indicating a selective toxicity toward rapidly proliferating cells. Cooperative UVA cytotoxicity is a general property of DNA thiobases, and 6-thioguanine and 4-thiodeoxyuridine were also UVA sensitizers. Thiobase/UVA treatment may offer a novel therapeutic approach for the clinical management of nonmalignant conditions like psoriasis or for superficial tumors that are accessible to phototherapy.

Source Citation Jackson JL, Kuriyama A, Hayashino Y. Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA. 2012;307:1736-45. 22535858

The serine-threonine kinase Chk1 plays a critical role in cell cycle checkpoints induced in response to genotoxic stress and protecting tumour cells with a defective G1 checkpoint from DNA damage induced by cytotoxic chemotherapeutic drugs. Chk1 inhibitors are currently being pursued in the clinic as a therapeutic strategy to potentiate the anti-tumour efficacy of cytotoxic chemotherapeutic drugs without increasing their systemic toxicity. Several genetic studies have suggested that Chk1 may be critical to ensure accurate DNA replication and division during an unperturbed cell cycle and therefore Chk1 inhibitors, administered as single agents, may be beneficial anti-cancer treatments. Triple-negative breast cancer is characterised by the lack of expression of estrogen and progesterone receptors as well as Her2, along with a gene expression profile and phenotypic characteristics consistent with basal-like breast cancer. Such cancers initially respond well to cytotoxic chemotherapy and PARP inhibitors though the overall prognosis for patients with these tumour types is poor. We therefore hypothesised that triple-negative breast cancer may exhibit sensitivity to single-agent Chk1 inhibition. V158411 is a potent, selective inhibitor of the Chk1 and Chk2 kinases and potently inhibited the proliferation of triple-negative breast (average GI50 0.17µM) compared to ER-positive breast (2.3µM), lung (6.3µM) and colon (2.5µM) cancer cells. In addition, two out of three ovarian cell lines exhibited high sensitivity to growth inhibition by V158411 (SKOV-3 0.06µM and A2780 0.39µM). This sensitivity was independent of p53 mutational status, did not correlate with sensitivity to DNA damaging agents and could not be reversed in ER-positive breast cancer cells with 4-hydroxytamoxifen. Chk1 inhibition reduced triple-negative breast and ovarian cancer cell viability, activated H2AX phosphorylation and induced caspase-3/7 dependent apoptosis at doses that correlated with the anti-proliferative effects. V158411 did not induce a consistent cell cycle arrest or cells to undergo a premature mitosis. V158411 still potentiated the cytotoxicity of cisplatin and gemcitabine in p53 deficient cell lines. In an attempt to understand the sensitivity of certain cancer cell types and identify biomarkers to select sensitive patient populations, tumour cell lysates were profiled for proteins involved in the cell cycle, DNA damage response and apoptosis. Sensitivity to V158411 correlated with increased expression of pChk1(S296) and reduced expression of Mcl-1. This study suggests that triple-negative breast and ovarian cancers rely on Chk1 to complete an unperturbed cell cycle and that inhibiting Chk1 results in increased DNA damage and cell death in these tumour types. V158411, administered as a single agent or in combination with chemotherapy could be a novel, effective strategy in treating these cancer types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4458. doi:10.1158/1538-7445.AM2011-4458

Cet article examine comment le Royaume-Uni procede a l’examen regulier de ses politiques publiques. Il montre que ces revisions se font en particulier sous l’angle de l’examen de leur performance et que la performance est entendue dans un sens large qui inclut meme l’utilite de la politique en question. Il montre egalement que les mesures de performance sont un souci ancien et bien ancre dans la culture administrative au Royaume-Uni qui y voit un retour necessaire en terme de responsabilite. Les instruments mis en œuvre pour obtenir les revisions des politiques publiques et les mesures de performance qui y sont liees n’offrent pas tous la meme efficacite ou la meme utilite.

The role of the 70 kDa heat shock protein isoforms (Hsc70 and Hsp70) in cancer development and progression through their ability to inhibit apoptosis and via their role as Hsp90 co-chaperones has been well documented. Dual targeting of Hsc70 and Hsp70 with siRNA has previously been demonstrated to induce proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition. The design and synthesis of novel adenosine-derived inhibitors of Hsp70, guided by modelling and X-ray crystallographic structures of these compounds in complex with Hsc70/BAG-1, has been described.1 These were the first inhibitors described to target the ATPase binding domain of this family of chaperones. Many of these compounds exhibited submicromolar affinity for Hsp70, were highly selective over Hsp90, and displayed in vitro activity against a variety of human tumor cell lines. We further describe the in vitro mode of action of one of the most potent analogues, VER-155008 in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell cycle, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors. VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI50s in the range 5.3 to 14.4 M, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 and HT29 cells. VER-155008 potentiated the apoptotic potential of the small molecule Hsp90 inhibitors VER-821602 and 17-AAG in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level. These data suggest that as a single agent, small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/Hsp70 inhibition remain to be determined. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A212.

Conventional chemotherapeutic agents such as gemcitabine, cisplatin or irinotecan induce DNA damage and activate cell cycle checkpoints. P53 defective tumors lack a functional G1 checkpoint and rely heavily on the S and G2 checkpoints, and the effector kinase Chk1, for protection against this DNA damage. Inhibiting Chk1 potentiates the anti-tumor effects of these cytotoxic chemotherapeutic agents. Targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor efficacy of DNA damaging cytotoxic chemotherapeutic drugs without increasing their toxicity to normal cells. Elaboration of a designed kinase directed fragment core utilizing X-ray structure guided design lead to the identification of a potent pyridone series of Chk1 inhibitors. Further profiling identified V158411 as the lead candidate. X-ray crystallography identified V158411 as being bound to the ATPase site in the kinase domain of Chk1. V158411 potently inhibited Chk1 and Chk2 with IC50s of 4.4 and 4.5nM respectively. The addition of V158411 to gemcitabine or camptothecin treated cells abrogated the cell cycle checkpoints induced by these agents resulting in the expected modulation of cell cycle proteins and increased apoptosis. V158411 potentiated the cytotoxicity of gemcitabine, cisplatin, SN38 and camptothecin in a variety of p53 deficient but not proficient human tumor cell lines in vitro. V158411 could be formulated in a simple aqueous form suitable for i.v. dosing. In nude mice, V158411 was well tolerated as a single agent (MTD >100mg/kg) and in combination with irinotecan. Intravenous administration to rats and mice resulted in low plasma clearances (20mL/min/kg) and long half-lives (2.9–3.7h). In tumor bearing animals, V158411 was detected at high concentrations in the tumor (tumor:plasma AUC ratio of 4.7) with a long tumor elimination half life of 22 hours. No pharmacologically relevant in vivo drug-drug interaction with irinotecan was identified. V158411 potentiated the anti-tumor activity of gemcitabine and irinotecan in a variety of human tumor xenograft models without additional systemic toxicity. These results demonstrate the potential of combining V158411 with standard of care chemotherapeutic agents to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Based on this data, the clinical development of V158411 is currently being actively pursued. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C207.

We recorded brainstem auditory evoked potentials (BAEPs) in two patients with Guillain-Barre syndrome (GBS). One patient was acutely deaf with total absence of BAEP waveforms indicative of acoustic nerve conduction block. Hearing improved during early convalescence, and there were prolonged wave I latencies. Normal BAEPs were recorded on recovery. A second patient had bilaterally prolonged wave I latencies. These BAEP findings suggest that acoustic nerve conduction abnormalities from demyelination may occur in GBS.