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D. S. Akerib - One of the best experts on this subject based on the ideXlab platform.

  • the Lux zeplin lz experiment
    Nuclear Instruments & Methods in Physics Research Section A-accelerators Spectrometers Detectors and Associated Equipment, 2020
    Co-Authors: D. S. Akerib, S Alsum, C Akerlof, Yu D Akimov, A Alquahtani, T J Anderson, N Angelides, H M Araujo
    Abstract:

    Abstract We describe the design and assembly of the Lux-ZEPLIN experiment, a direct detection search for cosmic WIMP dark matter particles. The centerpiece of the experiment is a large liquid xenon time projection chamber sensitive to low energy nuclear recoils. Rejection of backgrounds is enhanced by a Xe skin veto detector and by a liquid scintillator Outer Detector loaded with gadolinium for efficient neutron capture and tagging. LZ is located in the Davis Cavern at the 4850’ level of the Sanford Underground Research Facility in Lead, South Dakota, USA. We describe the major subsystems of the experiment and its key design features and requirements.

  • Lux trigger efficiency
    Nuclear Instruments & Methods in Physics Research Section A-accelerators Spectrometers Detectors and Associated Equipment, 2018
    Co-Authors: D. S. Akerib, X. Bai, J. Balajthy, E. P. Bernard, S Alsum, H M Araujo, P Beltrame, A Bernstein
    Abstract:

    Author(s): Akerib, DS; Alsum, S; Araujo, HM; Bai, X; Balajthy, J; Beltrame, P; Bernard, EP; Bernstein, A; Biesiadzinski, TP; Boulton, EM; B. Boxer; Bras, P; S. Burdin; Byram, D; Carmona-Benitez, MC; Chan, C; Cutter, JE; Davison, TJR; Druszkiewicz, E; Fallon, SR; Fan, A; Fiorucci, S; Gaitskell, RJ; Genovesi, J; Ghag, C; Gilchriese, MGD; E. Grace; C. Gwilliam; Hall, CR; Haselschwardt, SJ; Hertel, SA; Hogan, DP; Horn, M; Huang, DQ; Ignarra, CM; Jacobsen, RG; Ji, W; Kamdin, K; Kazkaz, K; Khaitan, D; Knoche, R; E.V. Korolkova; S. Kravitz; V.A. Kudryavtsev; Lenardo, BG; Lesko, KT; Liao, J; J. Lin; Lindote, A; Lopes, MI; Manalaysay, A; Mannino, RL; Marangou, N; Marzioni, MF; McKinsey, DN; Mei, DM; Moongweluwan, M; Morad, JA; Murphy, ASJ; Nehrkorn, C; Nelson, HN; Neves, F; Oliver-Mallory, KC; Palladino, KJ; Pease, EK; G. Rischbieter; Rhyne, C; P. Rossiter; Shaw, S; Shutt, TA; Silva, C; Solmaz, M; Solovov, VN; Sorensen, P; Sumner, TJ; Szydagis, M; Taylor, DJ; Taylor, WC; Tennyson, BP; Terman, PA; Tiedt, DR; To, WH; Tripathi, M; Tvrznikova, L; Utku, U | Abstract: © 2018 Elsevier B.V. The Large Underground Xenon experiment (Lux) searches for dark matter using a dual-phase xenon detector. Lux uses a custom-developed trigger system for event selection. In this paper, the trigger efficiency, which is defined as the probability that an event of interest is selected for offline analysis, is studied using raw data obtained from both electron recoil (ER) and nuclear recoil (NR) calibrations. The measured efficiency exceeds 98% at a pulse area of 90 detected photons, which is well below the WIMP analysis threshold on the S2 pulse area. The efficiency also exceeds 98% at recoil energies of 0.2 keV and above for ER, and 1.3 keV and above for NR. The measured trigger efficiency varies between 99% and 100% over the fiducial volume of the detector.

  • position reconstruction in Lux
    Journal of Instrumentation, 2018
    Co-Authors: D. S. Akerib, X. Bai, A. J. Bailey, J. Balajthy, S Alsum, H M Araujo, P Beltrame, E. P. Bernard
    Abstract:

    Author(s): Akerib, DS; Alsum, S; Arauandjo, HM; Bai, X; Bailey, AJ; Balajthy, J; Beltrame, P; Bernard, EP; Bernstein, A; Biesiadzinski, TP; Boulton, EM; Braands, P; Byram, D; Cahn, SB; Carmona-Benitez, MC; Chan, C; Currie, A; Cutter, JE; Davison, TJR; Dobi, A; Druszkiewicz, E; Edwards, BN; Fallon, SR; Fan, A; Fiorucci, S; Gaitskell, RJ; Genovesi, J; Ghag, C; Gilchriese, MGD; Hall, CR; Hanhardt, M; Haselschwardt, SJ; Hertel, SA; Hogan, DP; Horn, M; Huang, DQ; Ignarra, CM; Jacobsen, RG; Ji, W; Kamdin, K; Kazkaz, K; Khaitan, D; Knoche, R; Larsen, NA; Lenardo, BG; Lesko, KT; Lindote, A; Lopes, MI; Manalaysay, A; Mannino, RL; Marzioni, MF; McKinsey, DN; Mei, DM; Mock, J; Moongweluwan, M; Morad, JA; Murphy, ASJ; Nehrkorn, C; Nelson, HN; Neves, F; O'Sullivan, K; Oliver-Mallory, KC; Palladino, KJ; Pease, EK; Rhyne, C; Shaw, S; Shutt, TA; Silva, C; Solmaz, M; Solovov, VN; Sorensen, P; Sumner, TJ; Szydagis, M; Taylor, DJ; Taylor, WC; Tennyson, BP; Terman, PA; Tiedt, DR; To, WH; Tripathi, M; Tvrznikova, L; Uvarov, S; Velan, V; Verbus, JR; Webb, RC | Abstract: © 2018 IOP Publishing Ltd and Sissa Medialab. The (x, y) position reconstruction method used in the analysis of the complete exposure of the Large Underground Xenon (Lux) experiment is presented. The algorithm is based on a statistical test that makes use of an iterative method to recover the photomultiplier tube (PMT) light response directly from the calibration data. The light response functions make use of a two dimensional functional form to account for the photons reflected on the inner walls of the detector. To increase the resolution for small pulses, a photon counting technique was employed to describe the response of the PMTs. The reconstruction was assessed with calibration data including 83mKr (releasing a total energy of 41.5 keV) and 3H (andbeta;- with Q = 18.6 keV) decays, and a deuterium-deuterium (D-D) neutron beam (2.45 MeV) . Within the detector's fiducial volume, the reconstruction has achieved an (x, y) position uncertainty of andsigma; = 0.82 cm and andsigma; = 0.17 cm for events of only 200 and 4,000 detected electroluminescence photons respectively. Such signals are associated with electron recoils of energies andsim;0.25 keV and andsim;10 keV, respectively. The reconstructed position of the smallest events with a single electron emitted from the liquid surface (22 detected photons) has a horizontal (x, y) uncertainty of 2.13 cm.

  • The Lux Experiment
    Physics Procedia, 2015
    Co-Authors: D. S. Akerib, Henrique Araujo, X. Bai, A. J. Bailey, J. Balajthy, E. P. Bernard, Adam Bernstein, A. W. Bradley, D. Byram, Sidney Cahn
    Abstract:

    © 2015 The Authors. We present the status and prospects of the Lux experiment, which employs approximately 300 kg of two-phase xenon to search for WIMP dark matter interactions. The Lux detector was commissioned at the surface laboratory of the Sanford Underground Research Facility in Lead, SD, between December 2011 and February 2012 and the detector has been operating underground since January, 2013. These proceedings review the results of the commissioning run as well as the status of underground data-taking through the summer of 2013.

  • Data Acquisition and Readout System for the Lux Dark Matter Experiment
    Nuclear Instruments and Methods in Physics Research Section A: Accelerators Spectrometers Detectors and Associated Equipment, 2012
    Co-Authors: D. S. Akerib, X. Bai, E. P. Bernard, Adam Bernstein, A. W. Bradley, Sidney Cahn, S. Bedikian, M. C. Carmona-benitez, D. Carr, J.j. Chapman
    Abstract:

    Lux is a two-phase (liquid/gas) xenon time projection chamber designed to detect nuclear recoils from interactions with dark matter particles. Signals from the Lux detector are processed by custom-built analog electronics which provide properly shaped signals for the trigger and data acquisition (DAQ) systems. The DAQ is comprised of commercial digitizers with firmware customized for the Lux experiment. Data acquisition systems in rare-event searches must accommodate high rate and large dynamic range during precision calibrations involving radioactive sources, while also delivering low threshold for maximum sensitivity. The Lux DAQ meets these challenges using real-time baseline suppression that allows for a maximum event acquisition rate in excess of 1.5 kHz with virtually no deadtime. This paper describes the Lux DAQ and the novel acquisition techniques employed in the Lux experiment.

Sarayut Lucien Geater - One of the best experts on this subject based on the ideXlab platform.

  • afatinib versus cisplatin based chemotherapy for egfr mutation positive lung adenocarcinoma Lux lung 3 and Lux lung 6 analysis of overall survival data from two randomised phase 3 trials
    Lancet Oncology, 2015
    Co-Authors: James Chihhsin Yang, Martin Schuler, Caicun Zhou, Jifeng Feng, Martin Sebastian, Sanjay Popat, Nobuyuki Yamamoto, Kenneth J Obyrne, Yunchao Huang, Sarayut Lucien Geater
    Abstract:

    Summary Background We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials. Methods Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in Lux-Lung 3 (n=345) and Lux-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [Lux-Lung 3] or gemcitabine-cisplatin [Lux-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (Lux-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (Lux-Lung 3) and 237 (Lux-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393. Findings Median follow-up in Lux-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in Lux-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In Lux-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In Lux-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in Lux-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in Lux-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in Lux-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in Lux-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 [16%] of 229 patients in Lux-Lung 3 and 35 [15%] of 239 patients in Lux-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in Lux-Lung 3 only), and stomatitis or mucositis (13 [5%] in Lux-Lung 6 only). In Lux-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3–4 adverse events, while in Lux-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). Interpretation Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials. Funding Boehringer Ingelheim.

  • afatinib versus cisplatin based chemotherapy for egfr mutation positive lung adenocarcinoma Lux lung 3 and Lux lung 6 analysis of overall survival data from two randomised phase 3 trials
    Institute of Health and Biomedical Innovation, 2015
    Co-Authors: James Chihhsin Yang, Martin Schuler, Caicun Zhou, Jifeng Feng, Martin Sebastian, Sanjay Popat, Nobuyuki Yamamoto, Kenneth J Obyrne, Yunchao Huang, Sarayut Lucien Geater
    Abstract:

    Background We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials. Methods Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in Lux-Lung 3 (n=345) and Lux-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [Lux-Lung 3] or gemcitabine-cisplatin [Lux-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (Lux-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (Lux-Lung 3) and 237 (Lux-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393. Findings Median follow-up in Lux-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in Lux-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In Lux-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In Lux-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in Lux-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in Lux-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in Lux-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in Lux-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 [16%] of 229 patients in Lux-Lung 3 and 35 [15%] of 239 patients in Lux-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in Lux-Lung 3 only), and stomatitis or mucositis (13 [5%] in Lux-Lung 6 only). In Lux-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3–4 adverse events, while in Lux-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). Interpretation Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials.

Robert A Larossa - One of the best experts on this subject based on the ideXlab platform.

  • Microbial sensors of ultraviolet radiation based on recA’::Lux fusions
    Applied Biochemistry and Biotechnology, 2000
    Co-Authors: Rachel Rosen, Robert A Larossa, Yaakov Davidov, Shimshon Belkin
    Abstract:

    Escherichia coli strains containing plasmid-borne fusions of the recA promoter-operator region to the Vibrio fischeri Lux genes were previously shown to increase their luminescence in the presence of DNA damage hazards, and thus to be useful for genotoxicant detection. The present study expands previous work by demonstrating and investigating the luminescent response of these strains to ultraviolet radiation. Several genetic variants of the basic recA’::Lux design were examined, including a tolC modification of membrane effLux capacity, a chromosomal integration of the recA’::Lux fusion, a different Lux reporter (Photorhabdus luminescens instead of V. fischeri, allowing the assay to be run at 37°C), and a different host bacterium (Salmonella typhimurium instead of E. coli). Generally, two modifications provided the fastest responses: the use of the S. typhimurium host or the P. luminescens Lux reporter. Highest sensitivity, however, was demonstrated in an E. coli strain in which a single copy of the V. fischeri Lux fusion was integrated into the bacterial chromosome.

  • detection of dna damage by use of escherichia coli carrying reca Lux uvra Lux or alka Lux reporter plasmids
    Applied and Environmental Microbiology, 1997
    Co-Authors: Amy Cheng Vollmer, Shimshon Belkin, Dana R Smulski, T K Van Dyk, Robert A Larossa
    Abstract:

    Plasmids were constructed in which DNA damage-inducible promoters recA, uvrA, and alkA from Escherichia coli were fused to the Vibrio fischeri LuxCDABE operon. Introduction of these plasmids into E. coli allowed the detection of a dose-dependent response to DNA-damaging agents, such as mitomycin and UV irradiation. Bioluminescence was measured in real time over extended periods. The fusion of the recA promoter to LuxCDABE showed the most dramatic and sensitive responses. lexA dependence of the bioluminescent SOS response was demonstrated, confirming that this biosensor’s reports were transmitted by the expected regulatory circuitry. Comparisons were made between LuxCDABE and lacZ fusions to each promoter. It is suggested that the Lux biosensors may have use in monitoring chemical, physical, and genotoxic agents as well as in further characterizing the mechanisms of DNA repair. Bacterial repair of DNA damage is mediated by at least two inducible systems, the recA-independent, ada-controlled adaptive response and the recA-dependent, lexA-controlled SOS response. The former responds specifically to the presence of methylated phosphotriesters generated by DNA alkylation (39). This signal activates the ada gene product, which in turn

Martin Schuler - One of the best experts on this subject based on the ideXlab platform.

  • first line afatinib for advanced egfrm nsclc analysis of long term responders in the Lux lung 3 6 and 7 trials
    Lung Cancer, 2019
    Co-Authors: Martin Schuler, L Pazares, Lecia V Sequist, Vera Hirsh, Ki Hyeong Lee, Caicun Zhou, Jifeng Feng, Stuart H Ellis, Carl Samuelsen, W Tang
    Abstract:

    Objectives In patients with advanced epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC), first-line afatinib significantly improved progression-free survival (PFS) and objective response vs. platinum-doublet chemotherapy in the phase III Lux-Lung 3 and Lux-Lung 6 trials, and significantly improved PFS, time to treatment failure and objective response vs. gefitinib in the phase IIb Lux-Lung 7 trial. We report post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in these trials. Methods Treatment-naive patients with stage IIIB/IV EGFRm + NSCLC randomized to afatinib in Lux-Lung 3/Lux-Lung 6/Lux-Lung 7 were included in the analysis. Patients treated with afatinib for ≥ 3 years were defined as LTRs. Results In Lux-Lung 3, Lux-Lung 6, and Lux-Lung 7, 24/229 (10%), 23/239 (10%) and 19/160 (12%) afatinib-treated patients were LTRs. Baseline characteristics were similar to the study populations, except for the proportions of women (Lux-Lung 3/Lux-Lung 6 only; 92/78% vs. 64% overall) and Del19-positive patients (63-79% vs. 49-58% overall). Median treatment duration among LTRs was 50, 56 and 42 months, and median PFS was 49.5, 55.5, and 42.2 months in Lux-Lung 3/Lux-Lung 6/Lux-Lung 7, respectively. Median overall survival could not be estimated. Frequency of afatinib dose reduction was consistent with the Lux-Lung 3/Lux-Lung 6/Lux-Lung 7 overall populations. PROs were stable in LTRs, with slight improvements after 3 years of afatinib treatment vs. baseline scores. Conclusions In the Lux-Lung 3/Lux-Lung 6/Lux-Lung 7 trials, 10-12% of afatinib-treated patients were LTRs. Long-term afatinib treatment was independent of tolerability-guided dose adjustment and had no detrimental impact on safety or PROs.

  • afatinib versus cisplatin based chemotherapy for egfr mutation positive lung adenocarcinoma Lux lung 3 and Lux lung 6 analysis of overall survival data from two randomised phase 3 trials
    Lancet Oncology, 2015
    Co-Authors: James Chihhsin Yang, Martin Schuler, Caicun Zhou, Jifeng Feng, Martin Sebastian, Sanjay Popat, Nobuyuki Yamamoto, Kenneth J Obyrne, Yunchao Huang, Sarayut Lucien Geater
    Abstract:

    Summary Background We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials. Methods Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in Lux-Lung 3 (n=345) and Lux-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [Lux-Lung 3] or gemcitabine-cisplatin [Lux-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (Lux-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (Lux-Lung 3) and 237 (Lux-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393. Findings Median follow-up in Lux-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in Lux-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In Lux-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In Lux-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in Lux-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in Lux-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in Lux-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in Lux-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 [16%] of 229 patients in Lux-Lung 3 and 35 [15%] of 239 patients in Lux-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in Lux-Lung 3 only), and stomatitis or mucositis (13 [5%] in Lux-Lung 6 only). In Lux-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3–4 adverse events, while in Lux-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). Interpretation Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials. Funding Boehringer Ingelheim.

  • afatinib versus cisplatin based chemotherapy for egfr mutation positive lung adenocarcinoma Lux lung 3 and Lux lung 6 analysis of overall survival data from two randomised phase 3 trials
    Institute of Health and Biomedical Innovation, 2015
    Co-Authors: James Chihhsin Yang, Martin Schuler, Caicun Zhou, Jifeng Feng, Martin Sebastian, Sanjay Popat, Nobuyuki Yamamoto, Kenneth J Obyrne, Yunchao Huang, Sarayut Lucien Geater
    Abstract:

    Background We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials. Methods Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in Lux-Lung 3 (n=345) and Lux-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [Lux-Lung 3] or gemcitabine-cisplatin [Lux-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (Lux-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (Lux-Lung 3) and 237 (Lux-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393. Findings Median follow-up in Lux-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in Lux-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In Lux-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In Lux-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in Lux-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in Lux-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in Lux-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in Lux-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 [16%] of 229 patients in Lux-Lung 3 and 35 [15%] of 239 patients in Lux-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in Lux-Lung 3 only), and stomatitis or mucositis (13 [5%] in Lux-Lung 6 only). In Lux-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3–4 adverse events, while in Lux-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). Interpretation Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials.

Gennadii B. Zavilgelsky - One of the best experts on this subject based on the ideXlab platform.

  • Ammonium perchlorate detection in natural environments using specific Lux biosensors
    Russian Journal of Physical Chemistry B, 2017
    Co-Authors: Vladimir P Balabanov, V. Yu. Kotova, S. A. Khrulnova, Gennadii B. Zavilgelsky
    Abstract:

    A procedure involving specific Lux biosensors has been applied to rapid detection of environmental ammonium perchlorate (AP) under both laboratory and field conditions. The procedure is based on evaluating the influence of AP on the level of bioluminescence of Lux biosensors. Two Lux biosensors—Escherichia coli MG1655 katG::kan (pKatG-Lux) and E. coli MG1655 (pSoxS-Lux)—have been employed in testing the ability of AP to cause an oxidative stress associated with the appearance of hydrogen peroxide and superoxide anion radicals in the cell. The Lux biosensors designed contain hybrid plasmids with appropriate regulatory DNA regions transcriptionally fused with the bacterial luciferase Lux genes as reporter genes. AP at concentrations of 5–50 mmol/L exerts an effect on the induction of luminescence of the Lux biosensors with the PkatG and PsoxS promoters. The intensity of the bioluminescence of the cells that contain the pKatG-Lux and pSoxS-Lux plasmids and have been treated with AP is 5–10 higher than the intensity of the bioluminescence of the untreated cells. Therefore, AP induces an oxidative stress in the bacterial cells through the formation of reactive oxygen species, namely, hydrogen peroxide and the superoxide anion radical. The high sensitivity and specificity of the Lux biosensors makes them usable in AP detection in the environment.

  • Inducible specific Lux-biosensors for the detection of antibiotics: construction and main parameters
    Prikladnaia biokhimiia i mikrobiologiia, 2014
    Co-Authors: V. Yu. Kotova, K. V. Ryzhenkova, Ilya V. Manukhov, Gennadii B. Zavilgelsky
    Abstract:

    Based on Escherichia coli, highly sensitive specific Lux-biosensors for the detection of tetracycline and β-lactam antibiotics, quinolones, and aminoglycosides have been obtained. To make biosensors, bacteria were used that contained hybrid plasmids pTetA’::Lux, pAmpC’::Lux, pColD’::Lux, and pIbpA’::Lux, in which transcription of the reporter Photorhabdus luminescens LuxCDABE genes occurred from the inducible promoters of the tetA, ampC, cda, and ibpA genes, respectively. The main parameters (threshold sensitivity and response time) of Lux-biosensors were measured. The high specificity of biosensors responding only to antibiotics of a certain type was demonstrated.

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