57 research outputs found
High-dose paclitaxel in combination with doxorubicin, cyclophosphamide and peripheral blood progenitor cell rescue in patients with high-risk primary and responding metastatic breast carcinoma: toxicity profile, relationship to paclitaxel pharmacokinetics and short-term outcome
We assessed the feasibility and pharmacokinetics of high-dose infusional paclitaxel in combination with doxorubicin, cyclophosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patients with high-risk primary [stage II with ≥ 10 axillary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53)] or with stage IV responsive breast cancer (n = 10) received paclitaxel 150–775 mg/m2infused over 24 hours, doxorubicin 165 mg/m2as a continuous infusion over 96 hours, and cyclophosphamide 100 mg kg–1. There were no treatment-related deaths. Dose-limiting toxicity was reversible, predominantly sensory neuropathy following administration of paclitaxel at the 775 mg/m2dose level. Paclitaxel pharmacokinetics were non-linear at higher dose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation between stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacokinetics was found. Kaplan–Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51–83%) and 77% (95% CI; 64–93%). Paclitaxel up to 725 mg/m2infused over 24 hours in combination with with doxorubicin 165 mg/m2and cyclophosphamide 100 mg kg–1is tolerable. A randomized study testing this regimen against high-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing. © 2001 Cancer Research Campaign http://www.bjcancer.co
Genome wide analysis of gene expression changes in skin from patients with type 2 diabetes
Non-healing chronic ulcers are a serious complication of diabetes and are a major healthcare problem. While a host of treatments have been explored to heal or prevent these ulcers from forming, these treatments have not been found to be consistently effective in clinical trials. An understanding of the changes in gene expression in the skin of diabetic patients may provide insight into the processes and mechanisms that precede the formation of non-healing ulcers. In this study, we investigated genome wide changes in gene expression in skin between patients with type 2 diabetes and non-diabetic patients using next generation sequencing. We compared the gene expression in skin samples taken from 27 patients (13 with type 2 diabetes and 14 non-diabetic). This information may be useful in identifying the causal factors and potential therapeutic targets for the prevention and treatment of diabetic related diseases
A unified framework for multi-locus association analysis of both common and rare variants
<p>Abstract</p> <p>Background</p> <p>Common, complex diseases are hypothesized to result from a combination of common and rare genetic variants. We developed a unified framework for the joint association testing of both types of variants. Within the framework, we developed a union-intersection test suitable for genome-wide analysis of single nucleotide polymorphisms (SNPs), candidate gene data, as well as medical sequencing data. The union-intersection test is a composite test of association of genotype frequencies and differential correlation among markers.</p> <p>Results</p> <p>We demonstrated by computer simulation that the false positive error rate was controlled at the expected level. We also demonstrated scenarios in which the multi-locus test was more powerful than traditional single marker analysis. To illustrate use of the union-intersection test with real data, we analyzed a publically available data set of 319,813 autosomal SNPs genotyped for 938 cases of Parkinson disease and 863 neurologically normal controls for which no genome-wide significant results were found by traditional single marker analysis. We also analyzed an independent follow-up sample of 183 cases and 248 controls for replication.</p> <p>Conclusions</p> <p>We identified a single risk haplotype with a directionally consistent effect in both samples in the gene <it>GAK</it>, which is involved in clathrin-mediated membrane trafficking. We also found suggestive evidence that directionally inconsistent marginal effects from single marker analysis appeared to result from risk being driven by different haplotypes in the two samples for the genes <it>SYN3 </it>and <it>NGLY1</it>, which are involved in neurotransmitter release and proteasomal degradation, respectively. These results illustrate the utility of our unified framework for genome-wide association analysis of common, complex diseases.</p
How did we do that? Histories and political economies of rapid and just transitions
It is becoming increasingly clear that deep and rapid transitions in technologies, infrastructures and ways of organising the economy are imperative if we are to live safely within planetary boundaries. But what historical precedents are there for such profound shifts within short spaces of time, and what were the enabling conditions? When have transitions in sectors such as energy, food, finance and transport come about before, and how would they be brought about again? Do these episodes shed any analogous light on our current collective predicament? This paper develops an account of the politics and prospects of deeper transitions towards sustainability based on a critical empirical, but theoretically informed, reading of previous socio-technical transitions. The scale and urgency of our current ecological predicament is daunting and can be disempowering in the absence of strategic thinking about when analogous challenges have been encountered before and how societies have sought to overcome them. Providing a combination of concrete empirical examples drawn both from academic literature and a series of public workshops reflecting on these themes, this paper seeks to provide a basis for understanding as well as engaging with the scope for accelerated transitions within and beyond capitalism
Observing America: what mass-observation reveals about British views of the USA
Since its foundation in 1937, the social research organisation Mass-Observation has systematically documented the opinions of a British public experiencing profound societal change. This includes the most extensive data available on grassroots attitudes towards the USA, from the outbreak of the Second World War to the final phase of the Cold War. Most of the scholarship on Anglo-American relations focuses on the political and diplomatic elites of Britain and the USA. The extent to which their interaction reflected and reinforced public opinion is seldom considered. This article uses the Mass-Observation archive to situate elite interaction within the broader context of public opinion. In so doing, it assesses the extent to which British political leaders have in their dealings with the USA represented the views of the electorate they serve
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Affective technologies of welfare deterrence in Australia and the United Kingdom
Across the political spectrum of different historical periods, welfare deterrence has shaped social security and immigration policy in both Australia and the United Kingdom. Deterrence discourages access to state welfare through the production and mobilization of negative affect to deter specific groups from claiming state support, and by crafting public affect (of fear and disgust) about these target populations in order to garner consent for punitive policies. In this paper, we argue that deterrence works as a human technology where the crafting of negative affect operates as a technology of statecraft. Through critical juxtaposition and multiple genealogies of deterrence, this paper meshes time and space, and colony/colonizer and metropole, to show the historical and contemporary connectivity of the affective nature of deterrence. We identify five main operations that produce the ‘feel’ of deterrence: stigmatization by design, destitution by design, deterrent architecture, the control of movement, and the centrality of labour; as well as tracing the political economy of deterrence
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A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: a California Cancer Consortium study.
Prostate cancer cells undergo neuroendocrine differentiation during androgen deprivation and secrete neuropeptides, hence activating androgen receptor-regulated genes. Src-family protein kinases are involved in neuropeptide-induced prostate cancer growth and migration. A phase II trial of AZD0530, an oral Src-family kinase inhibitor, in patients with advanced castration resistant prostate cancer was conducted. The primary endpoint was prostate cancer-specific antigen (PSA) response rate, defined as a 30% or greater decrease. A two-stage Simon design was used. Eligibility criteria included documentation of castration resistance (including antiandrogen withdrawal), adequate end-organ function, and performance status, and not more than one prior taxane-based chemotherapy regimen. AZD0530 was given at 175 mg orally once daily continuously. Rapid accrual led to 28 patients registering in the first stage. Median age was 67 years. Sixteen patients had performance status (PS) 0, eight patients had PS 1, and four patients had PS 2. Nine patients (32%) had prior docetaxel-based chemotherapy. Five patients had transient PSA reductions not meeting PSA response criteria. Median progression-free survival time was 8 weeks. Treatment was generally well tolerated. AZD0530, a potent oral Src kinase inhibitor, is feasible and tolerable in this pretreated patient population but possessed little clinical efficacy as monotherapy. Strong preclinical evidence warrants further investigation of AZD0530 in earlier-stage prostate cancer or as combination therapy
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