Essential role for cholesterol in the delivery of exogenous antigens to the MHC class I-presentation pathway

Cross-presentation, which is crucial for the generation of immunity against virus-infected and tumor cells, requires exogenous antigens to be internalized into antigen-presenting cells (APCs) followed by translocation to the cytosol by unknown mechanisms. One important entry route for such antigens is macropinocytosis. We here describe that cholesterol is essential for cross-presentation of antigens loaded via macropinocytosis into APCs. Modification of antigens by palmitoylation to target antigens to cholesterol-enriched plasma membrane domains resulted in a dramatically increased T cell activation. These results define cholesterol as an essential factor for cross-presentation and suggest that specific modification of antigens to increase their affinity for cholesterol may be utilized to enhance immunit

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

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

Electroweak production of two jets in association with a Z boson in proton-proton collisions root s =13 TeV

A measurement of the electroweak (EW) production of two jets in association with a Z boson in proton-proton collisions at root s = 13 TeV is presented, based on data recorded in 2016 by the CMS experiment at the LHC corresponding to an integrated luminosity of 35.9 fb(-1). The measurement is performed in the lljj final state with l including electrons and muons, and the jets j corresponding to the quarks produced in the hard interaction. The measured cross section in a kinematic region defined by invariant masses m(ll) > 50 GeV, m(jj) > 120 GeV, and transverse momenta P-Tj > 25 GeV is sigma(EW) (lljj) = 534 +/- 20 (stat) fb (syst) fb, in agreement with leading-order standard model predictions. The final state is also used to perform a search for anomalous trilinear gauge couplings. No evidence is found and limits on anomalous trilinear gauge couplings associated with dimension-six operators are given in the framework of an effective field theory. The corresponding 95% confidence level intervals are -2.6 <cwww/Lambda(2) <2.6 TeV-2 and -8.4 <cw/Lambda(2) <10.1 TeV-2. The additional jet activity of events in a signal-enriched region is also studied, and the measurements are in agreement with predictions.Peer reviewe

Galaxy-2 trial: A randomized phase 3 study of ganetespid in combination with docetaxel versus docetaxel alone in patients with advanced non-small cell lung adenocarcinoma

Background: Hsp90 is a molecular chaperone recognized as a key facilitator of cancer cell growth and survival. Ganetespib is a resorcinolic Hsp90 inhibitor that has shown single-agent activity in patients with lung, breast, and other cancers after progression on standard treatments. Ganetespib in combination with docetaxel induces synergistic efficacy in human non-small-cell lung carcinoma (NSCLC) tumor xenografts. Ganetespib is well tolerated and has not shown severe liver or common ocular toxicities reported for other Hsp90 inhibitors. Transient diarrhea is the most common adverse event, and is manageable with appropriate supportive care. A large randomized Phase 2 study of ganetespib in combination with docetaxel in advanced NSCLC patients (GALAXY-1 Trial) indicated good tolerability of the combination, and improvement in efficacy, including OS. Methods: GALAXY-2 is a randomized (1:1), international, open-label Phase 3 study enrolling patients who received and progressed on 1 prior systemic platinum-based combination therapy for advanced NSCLC of adenocarcinoma histology, were diagnosed ≥6 months before study entry, and whose tumors are negative for both EGFR mutations and ALK translocation (Target Patient Population [TPP]). Patients (N=700 TPP) are prospectively stratified for ECOG PS, total screening LDH, and geographic region (North America and Western Europe vs Rest of World). The primary endpoint is OS in the TPP. Key secondary endpoints include PFS, ORR, DCR, and DOR in the TPP. OS will also be analyzed in 3 subpopulations of the TPP: mKRAS, elevated LDH, and elevated LDH5. Patients in the control arm are treated with docetaxel 75 mg/m2 on Day 1 of a 3-week cycle. In the combination arm, ganetespib 150 mg/m2 is given on Day 1 with 75 mg/m2 docetaxel, and ganetespib 150 mg/m2 alone is given on Day 15 of each 3-week cycle. Two interim analyses for OS will be performed. Tumor tissue and blood samples will be collected for planned translational studies. Clinical trial information: NCT01798485

GALAXY-1: Randomized phase II study of docetaxel with or without ganetespib in advanced lung adenocarcinoma: Results in biomarker sub-groups and all adenocarcinoma patients.

Background: Ganetespib (G) is a highly potent 2nd-generation Hsp90 inhibitor showing synergistic activity with docetaxel (D) in NSCLC xenografts. G has a favorable clinical safety profile and has shown single-agent clinical activity in NSCLC patients with tumors harboring EML4-ALK translocations and KRAS mutations (mKRAS). Methods: We conducted a randomized, international open-label Phase 2 study of D with or without G in patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1. D was given at 75 mg/m2 on Day 1 of a three-week cycle in both arms. In the combination arm, G was given at 150 mg/m2 on Days 1 and 15. The co-primary endpoints were PFS in patients with elevated LDH (eLDH) levels, or tumors harboring KRAS mutation. Key secondary endpoints were OS and PFS in all adenocarcinoma patients. Target enrollment was 240 adenocarcinoma patients, including 120 eLDH and 80 mKRAS patients. The study was initiated in all NSCLC patients and amended to include only those with adenocarcinoma histology. Results: Enrollment of 252 adenocarcinoma patients completed in November 2012; enrollment of eLDH (total N=112) and mKRAS (total N= 86) patients completed in May 2013. In all adenocarcinoma patients (N=252), baseline characteristics were balanced between the two arms (median age 60 years, males 56%, PS 0 41% and never-smokers 25%). Median numbers of cycles delivered were 6 and 4 for D+G and D, respectively. Grade 3/4 adverse events for the D+G and D alone arms were: neutropenia 37% vs. 38%; fatigue 6% vs. 3%; anemia 8% vs. 2%; diarrhea 3% vs. 0; fever with neutropenia 11% vs. 2%. A pre-specified analysis was conducted in May 2013. PFS HR for eLDH population (N=76) was 0.88 (90% CI: 0.57, 1.36, p=0.310); OS HR was 0.63 (90% CI: 0.40, 0.99, p=0.046). PFS HR for mKRAS population (N=63) was 0.83 (90% CI: 0.51, 1.37, p=0.271); and OS HR was 0.85 (90% CI: 0.48, 1.50, p=0.313). OS HR in the all adenocarcinoma population was 0.82 (90% CI: 0.62, 1.09, p=0.082), and the PFS HR was 0.84 (90% CI: 0.65, 1.07, p=0.038). For patients that were enrolled >6 months after diagnosis of advanced NSCLC (N=176), a pre-specified stratification factor, the OS HR was 0.61 (90% CI: 0.43, 0.87, p=0.0093), and the PFS HR was 0.61 (90% CI: 0.45, 0.83, p=0.0041). Final data analysis is expected by end of September 2013. Updated PFS and OS results for all populations will be presented at the meeting. Conclusion: Survival improvement was noted in all adenocarcinoma patients with the addition of ganetespib to docetaxel. The maximal benefit was achieved in patients with eLDH and those diagnosed with advanced NSCLC >6 months prior to study entry