Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance

The apparent eta Carinae's long-term evolution and the critical role played by the strengthening of P Cygni absorption lines

Over the entire 20th century, Eta Carinae (\ec) has displayed a unique spectrum, which recently has been evolving towards that of a typical LBV. The two competing scenarios to explain such evolution are: (1) a dissipating occulter in front of a stable star or (2) a decreasing mass loss rate of the star. The first mechanism simultaneously explains why the central star appears to be secularly increasing its apparent brightness while its luminosity does not change; why the Homunculus' apparent brightness remains almost constant; and why the spectrum seen in direct light is becoming more similar to that reflected from the Homunculus (and which resembles a typical LBV). The second scenario does not account for these facts and predicts an increase in the terminal speed of the wind, contrary to observations. In this work, we present new data showing that the P Cygni absorption lines are secularly strengthening, which is not the expected behaviour for a decreasing wind-density scenario. CMFGEN modelling of the primary's wind with a small occulter in front agrees with observations. One could argue that invoking a dissipating coronagraphic occulter makes this object even more peculiar than it already appears to be. However, on the contrary, it solves the apparent contradictions between many observations. Moreover, by assigning the long-term behaviour to circumstellar causes and the periodic variations due to binarity, a star more stable after the 1900s than previously thought is revealed, contrary to the earlier paradigm of an unpredictable object.Comment: 17 pages, 12 figures, submitted to MNRA

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Selenium Toxicity to Honey Bee (Apis mellifera L.) Pollinators: Effects on Behaviors and Survival

We know very little about how soil-borne pollutants such as selenium (Se) can impact pollinators, even though Se has contaminated soils and plants in areas where insect pollination can be critical to the functioning of both agricultural and natural ecosystems. Se can be biotransferred throughout the food web, but few studies have examined its effects on the insects that feed on Se-accumulating plants, particularly pollinators. In laboratory bioassays, we used proboscis extension reflex (PER) and taste perception to determine if the presence of Se affected the gustatory response of honey bee (Apis mellifera L., Hymenoptera: Apidae) foragers. Antennae and proboscises were stimulated with both organic (selenomethionine) and inorganic (selenate) forms of Se that commonly occur in Se-accumulating plants. Methionine was also tested. Each compound was dissolved in 1 M sucrose at 5 concentrations, with sucrose alone as a control. Antennal stimulation with selenomethionine and methionine reduced PER at higher concentrations. Selenate did not reduce gustatory behaviors. Two hours after being fed the treatments, bees were tested for sucrose response threshold. Bees fed selenate responded less to sucrose stimulation. Mortality was higher in bees chronically dosed with selenate compared with a single dose. Selenomethionine did not increase mortality except at the highest concentration. Methionine did not significantly impact survival. Our study has shown that bees fed selenate were less responsive to sucrose, which may lead to a reduction in incoming floral resources needed to support coworkers and larvae in the field. If honey bees forage on nectar containing Se (particularly selenate), reductions in population numbers may occur due to direct toxicity. Given that honey bees are willing to consume food resources containing Se and may not avoid Se compounds in the plant tissues on which they are foraging, they may suffer similar adverse effects as seen in other insect guilds

A systematic review of clinical trials of pharmacological interventions for acute ischaemic stroke (1955-2008) that were completed, but not published in full

<p>Abstract</p> <p>Background</p> <p>We assessed the prevalence, and potential impact of, trials of pharmacological agents for acute stroke that were completed but not published in full. Failure to publish trial data is to be deprecated as it sets aside the altruism of participants' consent to be exposed to the risks of experimental interventions, potentially biases the assessment of the effects of therapies, and may lead to premature discontinuation of research into promising treatments.</p> <p>Methods</p> <p>We searched the Cochrane Stroke Group's Specialised Register of Trials in June 2008 for completed trials of pharmacological interventions for acute ischaemic stroke, and searched MEDLINE and EMBASE (January 2007 - March 2009) for references to recent full publications. We assessed trial completion status from trial reports, online trials registers and correspondence with experts.</p> <p>Results</p> <p>We identified 940 trials. Of these, 125 (19.6%, 95% confidence interval 16.5-22.6) were completed but not published in full by the point prevalence date. They included 16,058 participants (16 trials had over 300 participants each) and tested 89 different interventions. Twenty-two trials with a total of 4,251 participants reported the number of deaths. In these trials, 636/4251 (15.0%) died.</p> <p>Conclusions</p> <p>Our data suggest that, at the point prevalence date, a substantial body of evidence that was of relevance both to clinical practice in acute stroke and future research in the field was not published in full. Over 16,000 patients had given informed consent and were exposed to the risks of therapy. Responsibility for non-publication lies with investigators, but pharmaceutical companies, research ethics committees, journals and governments can all encourage the timely publication of trial data.</p

High-dose pantoprazole continuous infusion is superior to somatostatin after endoscopic hemostasis in patients with peptic ulcer bleeding

BACKGROUND: The best antisecretory treatment after endoscopic hemostasis in patients with ulcer bleeding is still in quest. OBJECTIVES: To compare pantoprazole and somatostatin continuous infusion after endoscopic hemostasis in patients with bleeding peptic ulcers. PATIENTS AND METHODS: A total of 164 consecutive patients with a bleeding peptic ulcer, after successful endoscopic hemostasis, were randomly assigned to receive, double blindly, continuous IV infusion of pantoprazole 8 mg/h for 48 h after a bolus of 40 mg (group P) or somatostatin 250 μg/h for 48 h after a bolus of 250 μg (group-S). Twenty-four-hour pH-metry was performed in the last 30 patients in each group. Endoscopy was performed, in case of bleeding nonrecurrence, every 48 h until disappearance of stigmata. RESULTS: Bleeding recurrence: group S 14 patients (17%) versus group P 4 (5%) (P = 0.046). In multivariate analysis, bleeding recurrence was 4.57 (CI 1.31-15.91) times more frequent in group S (P = 0.02). There was no difference in the need for surgery and mortality. Acid suppression over pH 6: group S 82.9% of the time versus group P 81.5% (P = 0.97). Acid suppression over pH 6 for >85% of the time: group S 14 (47%) patients versus group P 17 (57%) (P = 0.44). Disappearance of endoscopic stigmata after 48 h: group S 25/68 patients (37%) versus group P 72/78 (92%) (P < 0.0001). No major side effects identified in either study group. CONCLUSIONS: In patients with a bleeding ulcer, after successful endoscopic hemostasis, despite equipotent acid suppression, pantoprazole continuous infusion was superior to somatostatin to prevent bleeding recurrence and quick disappearance of the endoscopic stigmata. Nevertheless, no differences were seen in the need for surgery and mortality. © 2007 by Am. Coll. of Gastroenterology