Alternative implication of CXCR4 in JAK2/STAT3 activation in small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive, rapidly metastasising tumour. Previously, we demonstrated the influence of CXCL12–CXCR4 interaction on processes involved in metastasis and chemoresistance in SCLC. We show here that STAT3 is expressed in both primary SCLC tumour tissues and SCLC cell lines. We investigated the function of STAT3 upon CXCL12 stimulation in SCLC cell lines. Small cell lung cancer cell lines present constitutive phosphorylation of STAT3, and in the reference cell lines NCI-H69 and NCI-H82 constitutive phosphorylation was further increased by CXCL12 stimulation. Further investigating this signalling cascade, we showed that it involves interactions between CXCR4 and JAK2 in both cell lines. However CXCL12-induced adhesion to VCAM-1 could be completely inhibited by the JAK2 inhibitor AG490 only in NCI-H82. Furthermore, CXCR4 antagonist but not AG490 inhibited cell adhesion whereas both antagonisms were shown to inhibit growth of the cells in soft agar, indicating the central involvement of this signalling in anchorage-independent growth of SCLC cells. Most interestingly, while using primary tumour material, we observed that in contrast to non-small-cell lung cancer samples from primary tumour tissues, all analysed samples from SCLC were strongly positive for tyrosine-phosphorylated STAT3. Taken together, these data indicate that STAT3 is constitutively phosphorylated in SCLC and is important in SCLC growth and spreading thus presenting an interesting target for therapy

Background matching in the brown shrimp Crangon crangon : adaptive camouflage and behavioural-plasticity

A combination of burrowing behaviour and very efficient background matching makes the brown shrimp Crangon crangon almost invisible to potential predators and preys. This raises questions on how shrimp succeed in concealing themselves in the heterogeneous and dynamic estuarine habitats they inhabit and what type of environmental variables and behavioural factors affect their colour change abilities. Using a series of behavioural experiments, we show that the brown shrimp is capable of repeated fast colour adaptations (20% change in dark pigment cover within one hour) and that its background matching ability is mainly influenced by illumination and sediment colour. Novel insights are provided on the occurrence of non-adaptive (possibly stress) responses to background changes after long-time exposure to a constant background colour or during unfavourable conditions for burying. Shrimp showed high levels of intra- and inter-individual variation, demonstrating a complex balance between behavioural-plasticity and environmental adaptation. As such, the study of crustacean colour changes represents a valuable opportunity to investigate colour adaptations in dynamic habitats and can help us to identify the mayor environmental and behavioural factors influencing the evolution of animal background matching

Strengths and limitations of period estimation methods for circadian data

A key step in the analysis of circadian data is to make an accurate estimate of the underlying period. There are many different techniques and algorithms for determining period, all with different assumptions and with differing levels of complexity. Choosing which algorithm, which implementation and which measures of accuracy to use can offer many pitfalls, especially for the non-expert. We have developed the BioDare system, an online service allowing data-sharing (including public dissemination), data-processing and analysis. Circadian experiments are the main focus of BioDare hence performing period analysis is a major feature of the system. Six methods have been incorporated into BioDare: Enright and Lomb-Scargle periodograms, FFT-NLLS, mFourfit, MESA and Spectrum Resampling. Here we review those six techniques, explain the principles behind each algorithm and evaluate their performance. In order to quantify the methods' accuracy, we examine the algorithms against artificial mathematical test signals and model-generated mRNA data. Our re-implementation of each method in Java allows meaningful comparisons of the computational complexity and computing time associated with each algorithm. Finally, we provide guidelines on which algorithms are most appropriate for which data types, and recommendations on experimental design to extract optimal data for analysis

Reduced exposure to vasopressors through permissive hypotension to reduce mortality in critically ill peoble aged 65 and over; the 65 RCT

Background: Vasopressors are administered to critical care patients to avoid hypotension, which is associated with myocardial injury, kidney injury and death. However, they work by causing vasoconstriction, which may reduce blood flow and cause other adverse effects. A mean arterial pressure target typically guides administration. An individual patient data meta-analysis (Lamontagne F, Day AG, Meade MO, Cook DJ, Guyatt GH, Hylands M, et al. Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy septic and vasodilatory shock. Intensive Care Med 2018;44:12–21) suggested that greater exposure, through higher mean arterial pressure targets, may increase risk of death in older patients. Objective: To estimate the clinical effectiveness and cost-effectiveness of reduced vasopressor exposure through permissive hypotension (i.e. a lower mean arterial pressure target of 60–65 mmHg) in older critically ill patients. Design A pragmatic, randomised clinical trial with integrated economic evaluation. Setting Sixty-five NHS adult general critical care units. Participants Critically ill patients aged ≥ 65 years receiving vasopressors for vasodilatory hypotension. Interventions Intervention – permissive hypotension (i.e. a mean arterial pressure target of 60–65 mmHg). Control (usual care) – a mean arterial pressure target at the treating clinician’s discretion. Main outcome measures: The primary clinical outcome was 90-day all-cause mortality. The primary cost-effectiveness outcome was 90-day incremental net monetary benefit. Secondary outcomes included receipt and duration of advanced respiratory and renal support, mortality at critical care and acute hospital discharge, and questionnaire assessment of cognitive decline and health-related quality of life at 90 days and 1 year. Results: Of 2600 patients randomised, 2463 (permissive hypotension, n = 1221; usual care, n = 1242) were analysed for the primary clinical outcome. Permissive hypotension resulted in lower exposure to vasopressors than usual care [mean duration 46.0 vs. 55.9 hours, difference –9.9 hours (95% confidence interval –14.3 to –5.5 hours); total noradrenaline-equivalent dose 31.5 mg vs. 44.3 mg, difference –12.8 mg (95% CI –18.0 mg to –17.6 mg)]. By 90 days, 500 (41.0%) patients in the permissive hypotension group and 544 (43.8%) patients in the usual-care group had died (absolute risk difference –2.85%, 95% confidence interval –6.75% to 1.05%; p = 0.154). Adjustment for prespecified baseline variables resulted in an odds ratio for 90-day mortality of 0.82 (95% confidence interval 0.68 to 0.98) favouring permissive hypotension. There were no significant differences in prespecified secondary outcomes or subgroups; however, patients with chronic hypertension showed a mortality difference favourable to permissive hypotension. At 90 days, permissive hypotension showed similar costs to usual care. However, with higher incremental life-years and quality-adjusted life-years in the permissive hypotension group, the incremental net monetary benefit was positive, but with high statistical uncertainty (£378, 95% confidence interval −£1347 to £2103). Limitations: The intervention was unblinded, with risk of bias minimised through central allocation concealment and a primary outcome not subject to observer bias. The control group event rate was higher than anticipated. Conclusions: In critically ill patients aged ≥ 65 years receiving vasopressors for vasodilatory hypotension, permissive hypotension did not significantly reduce 90-day mortality compared with usual care. The absolute treatment effect on 90-day mortality, based on 95% confidence intervals, was between a 6.8-percentage reduction and a 1.1-percentage increase in mortality. Future work: Future work should (1) update the individual patient data meta-analysis, (2) explore approaches for evaluating heterogeneity of treatment effect and (3) explore 65 trial conduct, including use of deferred consent, to inform future trials. Trial registration: Current Controlled Trials ISRCTN10580502