Pharmacokinetics and ex vivo whole blood clot formation of a new recombinant FVIII (N8) in haemophilia A dogs

N8, a new recombinant factor VIII (rFVIII) compound developed for the treatment of haemophilia A, is produced in Chinese hamster ovary (CHO) cells and formulated without human- or animal-derived materials. The aim of the present study was to compare the pharmacokinetics (PK) and the procoagulant effect, measured by ex vivo whole blood clot formation, of N8 and a commercial rFVIII in a cross-over study in haemophilia A dogs. N8 and Advate® (100 IU kg−1) were administered intravenously to three haemophilia A dogs. Blood was sampled between 0 and 120 h postdose and FVIII:C analysed. PK parameters maximum plasma concentration, area under the curve, half-life (t½), clearance, mean residence time (MRT) and volume of distribution and incremental recovery were calculated. Whole blood clotting time (WBCT) and thromboelastography (TEG®) were used to determine the haemostatic potential. No adverse reactions were observed with N8 or Advate®. N8 and Advate® exhibited similar PK parameters, with t½ 7.7–11 h and MRT 11–14 h. Both rFVIII compounds corrected the prolonged WBCT (>48 min) to the range of normal dogs (8–12 min), i.e. N8 to 7.5–10.5 min and Advate® to 7.5–11.5 min. N8 and Advate® also normalized the whole blood clot formation according to TEG®. The native whole blood clotting assays (WBCT, TEG®) appeared to be more sensitive to low concentrations of FVIII than assays in citrated plasma samples. In conclusion, comparison of N8 and Advate® in haemophilia A dogs revealed similar safety, similar PK and similar effects in whole blood clot formation assays

The democratic interface: technology, political organization, and diverging patterns of electoral representation

Democracies are experiencing historic disruptions affecting how people engage with core institutions such as the press, civil society organizations, parties, and elections. These processes of citizen interaction with institutions operate as a democratic interface shaping self-government and the quality of public life. The electoral dimension of the interface is important, as its operation can affect all others. This analysis explores a growing left-right imbalance in the electoral connection between citizens, parties, elections, and government. This imbalance is due, in part, to divergent left-right preferences for political engagement, organization, and communication. Support on the right for clearer social rules and simpler moral, racial and nationalist agendas are compatible with hierarchical, leader-centered party organizations that compete more effectively in elections. Parties on the left currently face greater challenges engaging citizens due to the popular meta-ideology of diversity and inclusiveness and demands for direct or deliberative democracy. What we term connective parties are developing technologies to perform core organizational functions, and some have achieved electoral success. However, when connective parties on the left try to develop shared authority processes, online and offline, they face significant challenges competing with more conventionally organized parties on the right

Nanoethics, science communication, and a fourth model for public engagement

This paper develops a fourth model of public engagement with science, grounded in the principle of nurturing scientific agency through online participatory bioethics. It argues that social media is an effective device through which to enable such engagement, as it has the capacity to empower users and transforms audiences into co-producers of knowledge, rather than consumers of content, the value of which is recognised within the citizen science movement. Social media also fosters greater engagement with the political and legal implications of science, thus promoting the value of scientific citizenship through the acquisition of science capital. This argument is explored by considering the case of nanoscience and nanotechnology, as an exemplar for how emerging technologies may be handled by the scientific community and science policy makers, and as a technology that has defined a second era of science communication

DNA methylation and nucleosome occupancy regulate the cancer germline antigen gene MAGEA11

MAGEA11 is a cancer germline (CG) antigen and androgen receptor co-activator. Its expression in cancers other than prostate, and its mechanism of activation, has not been reported. In silico analyses reveal that MAGEA11 is frequently expressed in human cancers, is increased during tumor progression, and correlates with poor prognosis and survival. In prostate and epithelial ovarian cancers (EOC), MAGEA11 expression was associated with promoter and global DNA hypomethylation, and with activation of other CG genes. Pharmacological or genetic inhibition of DNA methyltransferases (DNMTs) and/or histone deacetylases (HDACs) activated MAGEA11 in a cell line specific manner. MAGEA11 promoter activity was directly repressed by DNA methylation, and partially depended on Sp1, as pharmacological or genetic targeting of Sp1 reduced MAGEA11 promoter activity and endogenous gene expression. Importantly, DNA methylation regulated nucleosome occupancy specifically at the -1 positioned nucleosome of MAGEA11. Methylation of a single Ets site near the transcriptional start site (TSS) correlated with -1 nucleosome occupancy and, by itself, strongly repressed MAGEA11 promoter activity. Thus, DNA methylation regulates nucleosome occupancy at MAGEA11, and this appears to function cooperatively with sequence-specific transcription factors to regulate gene expression. MAGEA11 regulation is highly instructive for understanding mechanisms regulating CG antigen genes in human cancer

Social Media, Professional Media, and Mobilization in Contemporary Britain:Explaining the Strengths and Weaknesses of the Citizens’ Movement 38 Degrees

This article was published in the journal Political Studies [SAGE © The Author(s)] and the definitive version is available at: https://doi.org/10.1177/0032321716631350Digital media continue to reshape political activism in unexpected ways. Within a period of a few years, the internet-enabled UK citizens’ movement 38 Degrees has amassed a membership of 3 million and now sits alongside similar entities such as America’s MoveOn, Australia’s GetUp! and the transnational movement Avaaz. In this article, we contribute to current thinking about digital media and mobilisation by addressing some of the limitations of existing research on these movements and on digital activism more generally. We show how 38 Degrees’ digital network repertoires coexist interdependently with its strategy of gaining professional news media coverage. We explain how the oscillations between choreographic leadership and member influence and between digital media horizontalism and elite media-centric work constitute the space of interdependencies in which 38 Degrees acts. These delicately balanced relations can quickly dissolve and be replaced by simpler relations of dependence on professional media. Yet despite its fragility, we theorise about how 38 Degrees may boost individuals’ political efficacy, irrespective of the outcome of individual campaigns. Our conceptual framework can be used to guide research on similar movements

HDAC Inhibitors Act with 5-aza-2′-Deoxycytidine to Inhibit Cell Proliferation by Suppressing Removal of Incorporated Abases in Lung Cancer Cells

5-aza-2′-deoxycytidine (5-aza-CdR) is used extensively as a demethylating agent and acts in concert with histone deacetylase inhibitors (HDACI) to induce apoptosis or inhibition of cell proliferation in human cancer cells. Whether the action of 5-aza-CdR in this synergistic effect results from demethylation by this agent is not yet clear. In this study we found that inhibition of cell proliferation was not observed when cells with knockdown of DNA methyltransferase 1 (DNMT1), or double knock down of DNMT1-DNMT3A or DNMT1-DNMT3B were treated with HDACI, implying that the demethylating function of 5-aza-CdR may be not involved in this synergistic effect. Further study showed that there was a causal relationship between 5-aza-CdR induced DNA damage and the amount of [3H]-5-aza-CdR incorporated in DNA. However, incorporated [3H]-5-aza-CdR gradually decreased when cells were incubated in [3H]-5-aza-CdR free medium, indicating that 5-aza-CdR, which is an abnormal base, may be excluded by the cell repair system. It was of interest that HDACI significantly postponed the removal of the incorporated [3H]-5-aza-CdR from DNA. Moreover, HDAC inhibitor showed selective synergy with nucleoside analog-induced DNA damage to inhibit cell proliferation, but showed no such effect with other DNA damage stresses such as γ-ray and UV, etoposide or cisplatin. This study demonstrates that HDACI synergistically inhibits cell proliferation with nucleoside analogs by suppressing removal of incorporated harmful nucleotide analogs from DNA