Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells

The SRC-family kinase LYN is highly expressed in triple-negative/basal-like breast cancer (TNBC) and in the cell of origin of these tumors, c-KIT-positive luminal progenitors. Here, we demonstrate LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress. LYN activity is modulated by PIN1, a prolyl isomerase, and in BRCA1 mutant TNBC PIN1 upregulation activates LYN independently of c-KIT. Furthermore, the full-length LYN splice isoform (as opposed to the Δaa25-45 variant) drives migration and invasion of aggressive TNBC cells, while the ratio of splice variants is informative for breast cancer-specific survival across all breast cancers. Thus, dual mechanisms-uncoupling from upstream signals and splice isoform ratios-drive the activity of LYN in aggressive breast cancers

Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis

Background Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis. Methods Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored. Results Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9 ± 2.4 μM (normal range 50-70 μM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury. Conclusions Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury

'Crawling in the Flanders mud': Samuel Beckett, war writing and scatological pacifism

This article explores the depiction of wounded soldiers in Samuel Beckett’s novel Mercier and Camier (written in French in 1946, published in 1970, and translated and published in English in 1974). This aspect of the novel is discussed from two perspectives: the Irish military history which Beckett repeatedly invokes in the novel, notably the Boer War and World War I; and the relation between the novel and the ‘war books’ which followed World War I, many of which express pacifist ideals by laying bare the suffering which combatant bodies experience. Drawing attention to the hitherto neglected context of war writing for the image of the wounded soldier in Beckett’s work, this article uses Mercier and Camier to consider the political implications of the author’s allusions to military history following World War II

For a Migrant Art: Samuel Beckett and Cultural Nationalism

This essay charts Samuel Beckett’s linguistic migration from English to French at the end of the Second World War, locating this within the context of other twentieth-century literary migrations. It then proceeds to identify some of the principal ways in which Beckett seeks to resist forms of cultural nationalism (Irish, French and German). The distance that Beckett takes from these European forms of cultural nationalism is reflected not only in the migrant status of his characters, but also in the way in which he deploys national-cultural references. The essay argues that Beckett’s aim in this respect bears comparison with that of the ‘good European’ as defined by Nietzsche. An important difference, however, is that in Beckett’s case the emphasis falls not upon cosmopolitanism but rather upon a perpetual migrancy that is captured above all in his movement between languages

Beckett at eighty A celebration

Souvenir programme of events for the Reading Festival of Arts 9-17 May 1986SIGLEAvailable from British Library Document Supply Centre-DSC:97/20421 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Genetically Thermo-Stabilised, Immunogenic Poliovirus Empty Capsids; a Strategy for Non-replicating Vaccines.

While wild type polio has been nearly eradicated there will be a need to continue immunisation programmes for some time because of the possibility of re-emergence and the existence of long term excreters of poliovirus. All vaccines in current use depend on growth of virus and most of the non-replicating (inactivated) vaccines involve wild type viruses known to cause poliomyelitis. The attenuated vaccine strains involved in the eradication programme have been used to develop new inactivated vaccines as production is thought safer. However it is known that the Sabin vaccine strains are genetically unstable and can revert to a virulent transmissible form. A possible solution to the need for virus growth would be to generate empty viral capsids by recombinant technology, but hitherto such particles are so unstable as to be unusable. We report here the genetic manipulation of the virus to generate stable empty capsids for all three serotypes. The particles are shown to be extremely stable and to generate high levels of protective antibodies in animal models