The relationship between tissue levels of flavone acetic acid (NSC 347512) and site dependent anti-tumour activity in murine colon tumours.

Flavone acetic acid (FAA) is extremely active against subcutaneous transplantable tumours in mice, but disappointingly there has been no demonstrable clinical activity. Previous studies have shown that lung tumour deposits are less responsive than the same cells implanted subcutaneously. The aim of this study is to examine the tissue disposition of FAA in an attempt to explain this site-dependent activity. The data show clearly that FAA clearance curves are influenced by the presence of MAC 15A tumours growing either subcutaneously or systemically. The decreased clearance of FAA from MAC 15A tumour bearing animals does not however explain the resistance of lung deposits. Neither can this be explained by differences in metabolism in these different sites. Cytotoxic metabolites have not been detected either in vitro or in vivo and their role in the mechanism of action of FAA is questionable

Humour as social dreaming:Stand-up comedy as therapeutic performance

Stand-up comedy binds dramatic cultural spectacle to ritualised, intimate exposure. Examining ‘case’ examples from live comic performance, this paper describes stand-up as a kind of social dreaming. The article proposes a theoretical frame drawing on Thomas Ogden’s notion of ‘talking as dreaming’ and psychoanalytic accounts connecting humour and melancholia. Locating the stand-up comedian’s propensity for humour in a specialist capacity to hone, display and process traumata, the paper characterises stand-up as a performative oscillation evoking paranoid-schizoid and depressive anxieties. A psychosocial gloss places stand-up as a cultural resource in the service of the popular-as-therapeutic. The paper articulates complementarities between Henri Bergson’s formulations on the function of laughter and an emergent object relations account in order to help to recognise ‘containing’ and ‘cultural-restorative’ aspects of much stand-up, understood as contemporary psychosocial ritual

Skeletal responses to an all-female unassisted Antarctic traverse

Purpose: To investigate the skeletal effects of the first all-female trans-Antarctic traverse. Methods: Six women (mean ± SD, age 32 ±3 years, height 1.72 ± 0.07m, body mass 72.8 ± 4.0kg) hauled 80kg sledges over 1700km in 61days from coast-to-coast across the Antarctic. Whole-body areal bone mineral density (aBMD) (dual-energy X-ray absorptiometry) and tibial volumetric BMD (vBMD), geometry, microarchitecture and estimated mechanical properties (high-resolution peripheral quantitative computed tomography) were assessed 39 days before (pre-expedition) and 15 days after the expedition (post-expedition). Serum and plasma markers of bone turnover were assessed pre-expedition, and 4 and 15 days after the expedition. Results: There were reductions in trunk (−2.6%), ribs (−5.0%) and spine (−3.4%) a BMD from pre-to post-expedition (all P≤0.046); arms, legs, pelvis and total body a BMD were not different (all P≥0.075). Tibial v BMD, geometry, microarchitecture and estimated mechanical properties at the metaphysis (4% site) and diaphysis (30% site) were not different between pre-and post-expedition (all P≥0.082). Bone-specific alkaline phosphatase was higher 15days post-than 4 days post-expedition (1.7 μg∙l⁠−1, P=0.028). Total 25(OH) D decreased from pre-to 4 dayspost expedition (−36nmol∙l⁠−1,P=0.008).Sclerostin,procollagen1N-terminal propeptide, C-telopeptide cross-links of type 1 collagen and adjusted calcium were unchanged (allP≥0.154). Conclusion: Adecline in a BMD of the axial skeleton maybe due to indirect and direct effects of prolonged energy deficit. We propose that weight-bearing exercise was protective against the effects of energy deficit on tibial v BMD, geometry, microarchitecture and strength

Factors involved in the anti-cancer activity of the investigational agents LM985 (flavone acetic acid ester) and LM975 (flavone acetic acid).

LM985 has been shown previously to hydrolyse to flavone acetic acid (LM975) in mouse plasma and to produce significant anti-tumour effects in transplantable mouse colon tumours (MAC). It has undergone Phase I clinical trials and dose limiting toxicity was acute reversible hypotension. Substantially higher doses of LM975 can be given clinically without dose limiting toxicity. We have investigated the activity of LM975 against a panel of MAC tumours and also the in vitro cytotoxicity of both LM985 and LM975 in two cell lines derived from MAC tumours. LM985 is considerably more cytotoxic than LM975 in vitro but increased length of exposure to LM975 results in improved activity. Single in vivo injection of LM975 showed no activity against the ascitic tumour MAC 15A, moderate activity against the s.c. poorly differentiated tumour MAC 13 and produced a significant growth delay in the well differentiated MAC 26. These latter responses were considerably enhanced by repeated injection 7 days later. Pharmacokinetic studies in mice following i.p. injection of LM985 demonstrated rapid degradation of LM985 to LM975 in the peritoneum. Length of exposure as well as drug concentration appear important factors in determining anti-tumour responses

In vitro activity of the novel indoloquinone EO-9 and the influence of pH on cytotoxicity.

The novel indoloquinone compound EO-9 is shortly to undergo phase I clinical evaluation as a potential bioreductive drug. Preclinical studies have shown that EO-9 has greater activity against cells derived from human solid tumours than leukaemias in vitro. The results of this study extend the preclinical data available on EO-9 by demonstrating that EO-9 induces a broad spectrum of activity (IC50 values range from 8 to 590 ng ml-1) against a panel of human and murine tumour cell lines. Some evidence exists of selectivity towards leukaemia and human colon cell lines as opposed to murine colon cells. The response of cells to Mitomycin C were not comparable to EO-9 suggesting that the mechanism of action of these compounds is different. The cytotoxic properties of EO-9 under aerobic conditions are significantly influenced by extracellular pH. Reduction of pH from 7.4 to 5.8 increases cell kill from 40% to 95% in DLD-1 cells. In addition, EO-9 is unstable at acidic pH (T1/2 = 37 min at pH 5.5) compared to neutral pH T1/2 = 6.3 h). The major breakdown product in vitro was identified as EO-5A which proved relatively inactive compared to EO-9 (IC50 = 50 and 0.6 ug ml-1 respectively). These studies suggest that if EO-9 can be delivered to regions of low pH within solid tumours, a therapeutic advantage may be obtained

The Effect of Input DNA Copy Number on Genotype Call and Characterising SNP Markers in the Humpback Whale Genome Using a Nanofluidic Array

Recent advances in nanofluidic technologies have enabled the use of Integrated Fluidic Circuits (IFCs) for high-throughput Single Nucleotide Polymorphism (SNP) genotyping (GT). In this study, we implemented and validated a relatively low cost nanofluidic system for SNP-GT with and without Specific Target Amplification (STA). As proof of principle, we first validated the effect of input DNA copy number on genotype call rate using well characterised, digital PCR (dPCR) quantified human genomic DNA samples and then implemented the validated method to genotype 45 SNPs in the humpback whale, Megaptera novaeangliae, nuclear genome. When STA was not incorporated, for a homozygous human DNA sample, reaction chambers containing, on average 9 to 97 copies, showed 100% call rate and accuracy. Below 9 copies, the call rate decreased, and at one copy it was 40%. For a heterozygous human DNA sample, the call rate decreased from 100% to 21% when predicted copies per reaction chamber decreased from 38 copies to one copy. The tightness of genotype clusters on a scatter plot also decreased. In contrast, when the same samples were subjected to STA prior to genotyping a call rate and a call accuracy of 100% were achieved. Our results demonstrate that low input DNA copy number affects the quality of data generated, in particular for a heterozygous sample. Similar to human genomic DNA, a call rate and a call accuracy of 100% was achieved with whale genomic DNA samples following multiplex STA using either 15 or 45 SNP-GT assays. These calls were 100% concordant with their true genotypes determined by an independent method, suggesting that the nanofluidic system is a reliable platform for executing call rates with high accuracy and concordance in genomic sequences derived from biological tissue

Effectiveness of mitigation measures to reduce interactions between commercial fishing gear and whales

Effectiveness of mitigation measures to reduce interactions between commercial fishing gear and whales. Objectives: 1. Start to collect additional information required to determine the spatial and temporal extent of migrating whales and how this overlaps with commercial fishing gear. 2. Examine the effectiveness of potential gear modifications to the float rigs of fishing pots/traps to reduce their likelihood of entangling whales