41 research outputs found

    AhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer

    Get PDF
    Cancer cells have higher reactive oxygen species (ROS) than normal cells, due to genetic and metabolic alterations. An emerging scenario is that cancer cells increase ROS to activate protumorigenic signaling while activating antioxidant pathways to maintain redox homeostasis. Here we show that, in basal-like and BRCA1-related breast cancer (BC), ROS levels correlate with the expression and activity of the transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, ROS triggers AhR nuclear accumulation and activation to promote the transcription of both antioxidant enzymes and the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). In a mouse model of BRCA1-related BC, cancer-associated AhR and AREG control tumor growth and production of chemokines to attract monocytes and activate proangiogenic function of macrophages in the tumor microenvironment. Interestingly, the expression of these chemokines as well as infiltration of monocyte-lineage cells (monocyte and macrophages) positively correlated with ROS levels in basal-like BC. These data support the existence of a coordinated link between cancer-intrinsic ROS regulation and the features of tumor microenvironment. Therapeutically, chemical inhibition of AhR activity sensitizes human BC models to Erlotinib, a selective EGFR tyrosine kinase inhibitor, suggesting a promising combinatorial anticancer effect of AhR and EGFR pathway inhibition. Thus, AhR represents an attractive target to inhibit redox homeostasis and modulate the tumor promoting microenvironment of basal-like and BRCA1-associated BC

    Difficult tracheal intubation in neonates and infants. NEonate and Children audiT of Anaesthesia pRactice IN Europe (NECTARINE): a prospective European multicentre observational study

    Get PDF
    BACKGROUND: Neonates and infants are susceptible to hypoxaemia in the perioperative period. The aim of this study was to analyse interventions related to anaesthesia tracheal intubations in this European cohort and identify their clinical consequences. METHODS: We performed a secondary analysis of tracheal intubations of the European multicentre observational trial (NEonate and Children audiT of Anaesthesia pRactice IN Europe [NECTARINE]) in neonates and small infants with difficult tracheal intubation. The primary endpoint was the incidence of difficult intubation and the related complications. The secondary endpoints were the risk factors for severe hypoxaemia attributed to difficult airway management, and 30 and 90 day outcomes. RESULTS: Tracheal intubation was planned in 4683 procedures. Difficult tracheal intubation, defined as two failed attempts of direct laryngoscopy, occurred in 266 children (271 procedures) with an incidence (95% confidence interval [CI]) of 5.8% (95% CI, 5.1–6.5). Bradycardia occurred in 8% of the cases with difficult intubation, whereas a significant decrease in oxygen saturation (SpO2<90% for 60 s) was reported in 40%. No associated risk factors could be identified among co-morbidities, surgical, or anaesthesia management. Using propensity scoring to adjust for confounders, difficult anaesthesia tracheal intubation did not lead to an increase in 30 and 90 day morbidity or mortality. CONCLUSIONS: The results of the present study demonstrate a high incidence of difficult tracheal intubation in children less than 60 weeks post-conceptual age commonly resulting in severe hypoxaemia. Reassuringly, the morbidity and mortality at 30 and 90 days was not increased by the occurrence of a difficult intubation event

    A target-protection mechanism of antibiotic resistance at atomic resolution: insights into FusB-type fusidic acid resistance

    Get PDF
    Antibiotic resistance in clinically important bacteria can be mediated by proteins that physically associate with the drug target and act to protect it from the inhibitory effects of an antibiotic. We present here the first detailed structural characterization of such a target protection mechanism mediated through a protein-protein interaction, revealing the architecture of the complex formed between the FusB fusidic acid resistance protein and the drug target (EF-G) it acts to protect. Binding of FusB to EF G induces conformational and dynamic changes in the latter, shedding light on the molecular mechanism of fusidic acid resistance

    Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

    Get PDF
    BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≄week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

    Temperature independent threshold voltage for an electrooptic effect

    No full text
    The threshold voltage of the cholesteric-nematic phase change effect in general decreases considerably with increasing temperature. The temperature dependence for the threshold voltage can be compensated by using an induced cholesteric phase with a helix pitch decreasing sufficiently with increasing temperature. The appropriate temperature dependence of the pitch can be obtained if the nematic phase is doped with two chiral compounds which induce opposite sign of the helix screw sense when used separately. The efficacy of this method was investigated for the two nematic mixtures E 8 and S 1132 to which the two chiral compounds CB 15 and S 811 had been added, the induced pitch values being 3-5 ÎŒm. The threshold voltage measured in samples of 23.5 ÎŒm and 13 ÎŒm thickness using homeotropic boundary conditions are found to be constant within ± 3 % over a temperature range of 50 K.Normalement la tension seuil de l'effet de transition cholestĂ©rique-nĂ©matique se rĂ©duit considĂ©rablement si la tempĂ©rature monte. Cette dĂ©pendance de la tempĂ©rature peut ĂȘtre compensĂ©e en utilisant des phases cholestĂ©riques induites dont le pas hĂ©licoĂŻdal diminue suffisamment si la tempĂ©rature monte. La dĂ©pendance souhaitĂ©e du pas de l'hĂ©lice en fonction de la tempĂ©rature est obtenue en mĂ©langeant Ă  la phase nĂ©matique deux composĂ©s chiraux de signe contraire. Nous prĂ©sentons ici des rĂ©sultats obtenus sur des mĂ©langes nĂ©matiques E 8 et S 1132 dopĂ©s avec les composĂ©s chiraux CB 15 et S 811, les valeurs de pas obtenues Ă©tant 3-5 ÎŒm. La tension seuil mesurĂ©e pour des Ă©paisseurs de couches de 23,5 ÎŒm et 13 ÎŒm respectivement et pour des alignements homĂ©otropes se rĂ©vĂšle ĂȘtre constante Ă  ± 3 % dans une gamme de tempĂ©rature de 50 K

    An Observer-Based Fusion Method using Multicore Optical Shape Sensors and Ultrasound Images for Magnetically-Actuated Catheters

    Get PDF
    Minimally invasive surgery involves using flexible medical instruments such as endoscopes and catheters. Magnetically actuated catheters can provide improved steering precision over conventional catheters. However, besides the actuation method, an accurate tip position is required for precise control of the medical instruments. In this study, the tip position obtained from transverse 2D ultrasound images and multicore optical shape sensors are combined using a robust sensor fusion algorithm. The tip position is tracked in the ultrasound images using a template-based tracker and a convolutional neural network based tracker, respectively. Experimental results for a rhombus path are presented, where data obtained from both tracking sources are fused using Luenberger and Kalman state estimators. The mean and standard deviation of the Euclidean error for the Luenberger observer is 0.2+-0.11 [mm] whereas for the Kalman filter it is 0.18+-0.13 [mm], respectively
    corecore