173. Does the correlation between chemotherapy-induced leukopenia with response in locally advanced breast cancer exist?

PurposeThe correlation between chemotherapy-induced toxicity and treatment outcome in cancer patients has not been thoroughly studied. Our aim was to evaluate whether leukopenia following primary chemotherapy may be predictive for response in patients with locally advanced breast cancer.Patients and MethodsThe records of 164 breast cancer patients administered primary chemotherapy between 1985 and 1995 were analysed. Most of the patients presented with locally advanced disease, however included were also patients with large operable tumours. Chemotherapy included one of the three combinations: CMF; modified Cooper regimen (CMFVP); 31 patients (19%), anthracycline-based regimens (FAC and FEC); 16 patients (10%) and 118 patients (71%).ResultsThe objective response rate in the entire group was 58%; 75% in patients who developed grade 2–3 leukopenia during induction chemotherapy, and 52% in those who had no or grade 1 leukopenia (p < 0.01, multivariate analysis). No other patient- or treatment-related factor including age, performance status, T stage, N stage, supraclavicular Iymph node involvement, inflammatory carcinoma or chemotherapy regimen correlated with response to chemotherapy. There was no correlation between treatment-induced leukopenia and overall survival.ConclusionsThese findings suggest a relationship between chemotherapy induced leukopenia and tumour response in patients with locally advanced breast cancer. The prognostic impact of leukopenia is negliglble

Human rights and ethical reasoning : capabilities, conventions and spheres of public action

This interdisciplinary article argues that human rights must be understood in terms of opportunities for social participation and that social and economic rights are integral to any discussion of the subject. We offer both a social constructionist and a normative framework for a sociology of human rights which reaches beyond liberal individualism, combining insights from the work of Amartya Sen and from French convention theory. Following Sen, we argue that human rights are founded on the promotion of human capabilities as ethical demands shaped by public reasoning. Using French convention theory, we show how the terms of such deliberation are shaped by different constructions of collectively held values and the compromises reached between them. We conclude by demonstrating how our approach offers a new perspective on spheres of public action and the role these should play in promoting social cohesion, individual capabilities and human rights

Neoliberalism, managerialism and the reconfiguring of social work in Sweden and the United Kingdom

This is the author's manuscript of an article published in Archaeological Dialogues. http://dx.doi.org/10.1177/1350508412448222This paper considers some of the ways in which neoliberalism, through the processes of managerialism, has impacted on the occupation of social work in Sweden and the UK. It is argued that there are similar implications in both countries, through the managerial drive for increased performance in economy, efficiency and effectiveness, but also in the development of evidence based practice. Whilst the key focus of the paper is on similarities between these two countries, differences are also noted. There is also recognition of the way in which resistance to the reconfiguration of social work is taking shape

DDX3 depletion represses translation of mRNAs with complex 5' UTRs

DDX3 is an RNA chaperone of the DEAD-box family that regulates translation. Ded1, the yeast ortholog of DDX3, is a global regulator of translation, whereas DDX3 is thought to preferentially affect a subset of mRNAs. However, the set of mRNAs that are regulated by DDX3 are unknown, along with the relationship between DDX3 binding and activity. Here, we use ribosome profiling, RNA-seq, and PAR-CLIP to define the set of mRNAs that are regulated by DDX3 in human cells. We find that while DDX3 binds highly expressed mRNAs, depletion of DDX3 particularly affects the translation of a small subset of the transcriptome. We further find that DDX3 binds a site on helix 16 of the human ribosomal rRNA, placing it immediately adjacent to the mRNA entry channel. Translation changes caused by depleting DDX3 levels or expressing an inactive point mutation are different, consistent with different association of these genetic variant types with disease. Taken together, this work defines the subset of the transcriptome that is responsive to DDX3 inhibition, with relevance for basic biology and disease states where DDX3 is altered

CSAP localizes to polyglutamylated microtubules and promotes proper cilia function and zebrafish development

The diverse populations of microtubule polymers in cells are functionally distinguished by different posttranslational modifications, including polyglutamylation. Polyglutamylation is enriched on subsets of microtubules including those found in the centrioles, mitotic spindle, and cilia. However, whether this modification alters intrinsic microtubule dynamics or affects extrinsic associations with specific interacting partners remains to be determined. Here we identify the microtubule-binding protein centriole and spindle–associated protein (CSAP), which colocalizes with polyglutamylated tubulin to centrioles, spindle microtubules, and cilia in human tissue culture cells. Reducing tubulin polyglutamylation prevents CSAP localization to both spindle and cilia microtubules. In zebrafish, CSAP is required for normal brain development and proper left–right asymmetry, defects that are qualitatively similar to those reported previously for depletion of polyglutamylation-conjugating enzymes. We also find that CSAP is required for proper cilia beating. Our work supports a model in which polyglutamylation can target selected microtubule-associated proteins, such as CSAP, to microtubule subpopulations, providing specific functional capabilities to these populations.National Institutes of Health (U.S.) (Grant no. GM074746)American Cancer Society. Research Scholar Grant (121776)National Institute of General Medical Sciences (U.S.) (GM088313

Population screening for hereditary haemochromatosis in Australia: Construction and validation of a state-transition cost-effectiveness model

INTRODUCTION: HFE-associated haemochromatosis, the most common monogenic disorder amongst populations of northern European ancestry, is characterised by iron overload. Excess iron is stored in parenchymal tissues, leading to morbidity and mortality. Population screening programmes are likely to improve early diagnosis, thereby decreasing associated disease. Our aim was to develop and validate a health economics model of screening using utilities and costs from a haemochromatosis cohort. METHODS: A state-transition model was developed with Markov states based on disease severity. Australian males (aged 30 years) and females (aged 45 years) of northern European ancestry were the target populations. The screening strategy was the status quo approach in Australia; the model was run over a lifetime horizon. Costs were estimated from the government perspective and reported in 2015 Australian dollars ($A); costs and quality-adjusted life-years (QALYs) were discounted at 5$A22,737 (3670-85,793) for males and $A13,840 (1335-67,377) for females. Sensitivity analyses revealed discount rates and prevalence had the greatest impacts on outcomes. CONCLUSION: We have developed a transparent, validated health economics model of C282Y homozygote haemochromatosis. The model will be useful to decision makers to identify cost-effective screening strategies