Quotas, Citizens, and Norms of Representation

The author gratefully acknowledges the financial support of the Leverhulme Trust, who funded this research via a Research Fellowship grant

Quotas for Men: Reframing Gender Quotas as a Means of Improving Representation for All

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Impact of Grassland Reseeding, Herbicide Spraying and Ploughing on Diversity and Abundance of Soil Arthropods

In order to determine the interactive effect of reseeding, herbicide spraying and ploughing on soil fauna communities, we conducted a grassland reseeding experiment combined with pre-reseed management to examine how with the whole reseeding process affects soil faunal composition. Sampling occasions and exact treatments were as follows: (1) before chemical herbicide spray; (2) after spray but before ploughing; (3) after ploughing but before reseeding; and (4) after 1 year of recovery. Our results demonstrate that, Acari and Collembola were the two soil fauna taxa with the highest abundance and accounted for around 96% of the relative total abundance among the various managements. Herbicide application tended to increase soil invertebrate abundance. Conversely, subsequent ploughing significantly reduced soil invertebrate abundance and had an obvious negative effect on soil primary and secondary decomposers, which were mainly due to the variations of Acari (especially Oribatida) and Coleoptera group abundance. Moreover, reseeding also reduced the individual number of the groups mentioned above, and favored those predators with a larger body size and individual weight. After 1 year recovery, Collembola abundance recovered to the pre-treatment levels, while with Arthropod and Acari groups were still fluctuating

Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma

Neuroblastoma is a childhood tumor in which MYC oncogenes are commonly activated to drive tumor progression. Survival for children with high-risk neuroblastoma remains poor despite treatment that incorporates high-dose chemotherapy, stem cell support, surgery, radiation therapy and immunotherapy. More effective and less toxic treatments are sought and one approach under clinical development involves re-purposing the anti-protozoan drug difluoromethylornithine (DFMO; Eflornithine) as a neuroblastoma therapeutic. DFMO is an irreversible inhibitor of ornithine decarboxylase (Odc), a MYC target gene, bona fide oncogene, and the rate-limiting enzyme in polyamine synthesis. DFMO is approved for the treatment of Trypanosoma brucei gambiense encephalitis (“African sleeping sickness”) since polyamines are essential for the proliferation of these protozoa. However, polyamines are also critical for mammalian cell proliferation and the finding that MYC coordinately regulates all aspects of polyamine metabolism suggests polyamines may be required to support cancer promotion by MYC. Pre-emptive blockade of polyamine synthesis is sufficient to block tumor initiation in an otherwise fully penetrant transgenic mouse model of neuroblastoma driven by MYCN, underscoring the necessity of polyamines in this process. Moreover, polyamine depletion regimens exert potent anti-tumor activity in pre-clinical models of established neuroblastoma as well, in combination with numerous chemotherapeutic agents and even in tumors with unfavorable genetic features such as MYCN, ALK or TP53 mutation. This has led to the testing of DFMO in clinical trials for children with neuroblastoma. Current trial designs include testing lower dose DFMO alone (2,000 mg/m2/day) starting at the completion of standard therapy, or higher doses combined with chemotherapy (up to 9,000 mg/m2/day) for patients with relapsed disease that has progressed. In this review we will discuss important considerations for the future design of DFMO-based clinical trials for neuroblastoma, focusing on the need to better define the principal mechanisms of anti-tumor activity for polyamine depletion regimens. Putative DFMO activities that are both cancer cell intrinsic (targeting the principal oncogenic driver, MYC) and cancer cell extrinsic (altering the tumor microenvironment to support anti-tumor immunity) will be discussed. Understanding the mechanisms of DFMO activity are critical in determining how it might be best leveraged in upcoming clinical trials. This mechanistic approach also provides a platform by which iterative pre-clinical testing using translational tumor models may complement our clinical approaches

Deletion of Rb Accelerates Pancreatic Carcinogenesis by Oncogenic Kras and Impairs Senescence in Pre-Malignant Lesions

Rb1 encodes a cell-cycle regulator that is functionally disrupted in most human cancers. Pancreatic ductal adenocarcinomas (PDACs) have a high frequency of mutations in KRAS and INK4A/CDKN2A that might allow cells to bypass the regulatory actions of retinoblastoma (RB). To determine the role of loss of RB function in PDAC progression, we investigated the effects of Rb disruption during pancreatic malignant transformation initiated by oncogenic Kras.We generated mice with pancreas-specific disruption of Rb, in the absence or presence of oncogenic Kras, to examine the role of RB in pancreatic carcinogenesis

Kinematics of Stellar Populations with RAVE Data

We study the kinematics of the Galactic thin and thick disk populations using stars from the RAVE survey's second data release together with distance estimates from Breddels et al. (2009). The velocity distribution exhibits the expected moving groups present in the solar neighborhood. We separate thick and thin disk stars by applying the X (stellar-population) criterion of Schuster et al. (1993), which takes into account both kinematic and metallicity information. For 1906 thin disk and 110 thick disk stars classified in this way, we find a vertical velocity dispersion, mean rotational velocity and mean orbital eccentricity of (sigma_W, Vphi, e)_thin = (18\pm0.3 km/s, 223\pm0.4 km/s, 0.07\pm0.07) and (sigma_W, Vphi, e)_thick = (35\pm2 km/s, 163\pm2 km/s, 0.31\pm0.16), respectively. From the radial Jeans equation, we derive a thick disk scale length in the range 1.5-2.2 kpc, whose greatest uncertainty lies in the adopted form of the underlying potential. The shape of the orbital eccentricity distribution indicates that the thick disk stars in our sample most likely formed in situ with minor gas-rich mergers and/or radial migration being the most likely cause for their orbits. We further obtain mean metal abundances of _thin = +0.03 \pm 0.17, and _thick = -0.51\pm0.23, in good agreement with previous estimates. We estimate a radial metallicity gradient in the thin disk of -0.07 dex/kpc, which is larger than predicted by chemical evolution models where the disk grows insideout from infalling gas. It is, however, consistent with models where significant migration of stars shapes the chemical signature of the disk, implying that radial migration might play at least part of a role in the thick disk's formation.Comment: 27 pages, 7 figures, accepted for publication in New Astronom

Enhancing the anti-angiogenic action of histone deacetylase inhibitors

<p>Abstract</p> <p>Background</p> <p>Histone deacetylase inhibitors (HDACIs) have many effects on cancer cells, such as growth inhibition, induction of cell death, differentiation, and anti-angiogenesis, all with a wide therapeutic index. However, clinical trials demonstrate that HDACIs are more likely to be effective when used in combination with other anticancer agents. Moreover, the molecular basis for the anti-cancer action of HDACIs is still unknown. In this study, we compared different combinations of HDACIs and anti-cancer agents with anti-angiogenic effects, and analysed their mechanism of action.</p> <p>Results</p> <p>Trichostatin A (TSA) and α-interferon (IFNα) were the most effective combination across a range of different cancer cell lines, while normal non-malignant cells did not respond in the same manner to the combination therapy. There was a close correlation between absence of basal p21^WAF1expression and response to TSA and IFNα treatment. Moreover, inhibition of p21^WAF1expression in a p21^WAF1-expressing breast cancer cell line by a specific siRNA increased the cytotoxic effects of TSA and IFNα. <it>In vitro </it>assays of endothelial cell function showed that TSA and IFNα decreased endothelial cell migration, invasion, and capillary tubule formation, without affecting endothelial cell viability. TSA and IFNα co-operatively inhibited gene expression of some pro-angiogenic factors: vascular endothelial growth factor, hypoxia-inducible factor 1α and matrix metalloproteinase 9, in neuroblastoma cells under hypoxic conditions. Combination TSA and IFNα therapy markedly reduced tumour angiogenesis in neuroblastoma-bearing transgenic mice.</p> <p>Conclusion</p> <p>Our results indicate that combination TSA and IFNα therapy has potent co-operative cytotoxic and anti-angiogenic activity. High basal p21^WAF1expression appears to be acting as a resistance factor to the combination therapy.</p