Substitution of Heavy Complementarity Determining Region 3 (CDR-H3) Residues Can Synergistically Enhance Functional Activity of Antibody and Its Binding Affinity to HER2 Antigen

To generate a biobetter that has improved therapeutic activity, we constructed scFv libraries via random mutagenesis of several residues of CDR-H3 and -L3 of hu4D5. The scFv clones were isolated from the phage display libraries by stringent panning, and their anti-proliferative activity against HER2-positive cancer cells was evaluated as a primary selection criterion. Consequently, we selected AH06 as a biobetter antibody that had a 7.2-fold increase in anti-proliferative activity (IC50: 0.81 nM) against the gastric cancer cell line NCI-N87 and a 7.4-fold increase in binding affinity (K-D : 60 pM) to HER2 compared to hu4D5. The binding energy calculation and molecular modeling suggest that the substitution of residues of CDR-H3 to W98, F100c, A101 and L102 could stabilize binding of the antibody to HER2 and there could be direct hydrophobic interactions between the aromatic ring of W98 and the aliphatic group of I613 within HER2 domain IV as well as the heavy and light chain hydrophobic interactions by residues F100c, A101 and L102 of CDR-H3. Therefore, we speculate that two such interactions were exerted by the residues W98 and F100c. A101 and L102 may have a synergistic effect on the increase in the binding affinity to HER2. AH06 specifically binds to domain IV of HER2, and it decreased the phosphorylation level of HER2 and AKT. Above all, it highly increased the overall level of p27 compared to hu4D5 in the gastric cancer cell line NCI-N82, suggesting that AH06 could potentially be a more efficient therapeutic agent than hu4D5.OAIID:RECH_ACHV_DSTSH_NO:T201620640RECH_ACHV_FG:RR00200001ADJUST_YN:EMP_ID:A002901CITE_RATE:2.67DEPT_NM:화학생물공학부EMAIL:[email protected]_YN:YCONFIRM:

Variability of Voriconazole Trough Levels in Haematological Patients: Influence of Comedications with cytochrome P450(CYP) Inhibitors and/or with CYP Inhibitors plus CYP Inducers

Voriconazole plasma exposure greatly varies among haematological patients. The purpose of this study was to identify the magnitude of influence of comedications with CYP inhibitors and/or with CYP inhibitors plus CYP inducers on voriconazole trough level (Cmin). Voriconazole Cmin was retrospectively assessed among haematological patients who underwent therapeutic drug monitoring (TDM). Univariate and multivariate linear mixed-effect regression analyses were performed to identify the independent predictors of normalized Cmin. Of the 83 included patients, 35 had comedications with CYP inhibitors (omeprazole or pantoprazole) and 21 with CYP inhibitors (omeprazole or pantoprazole) plus CYP inducers (methylprednisolone, dexamethasone, phenobarbital, rifampin or carbamazepine). Median Cmin value (n = 199) was 2.4 mg/L with a wide range of distribution (<0.2-13.5 mg/L). Median (IQR) normalized voriconazole Cmin value was significantly higher in the presence of CYP inhibitors (4.20 mg/L, 3.23-5.51 mg/L) than either in the absence of interacting cotreatments (2.55 mg/L, 1.54-3.47 mg/L) or in the presence of CYP inhibitors plus CYP inducers (2.16 mg/L, 1.19-3.09 mg/L). The presence of CYP inhibitors was highly significantly associated with Cmin >5.5 mg/L (OR: 23.22, 95% CI: 3.01-179.09, p = 0.003). No significant association emerged when CYP inhibitors were coadministered with CYP inducers (OR: 3.53, 95% CI: 0.36-34.95, p = 0.280). The amount of expected Cmin increase was significantly influenced by both the type and the dose of the administered proton pump inhibitor. The study highlights that the benefit from TDM of voriconazole may be maximal in those patients who are cotreated with CYP inhibitors and/or with CYP inhibitors plus CYP inducers, especially when receiving proton pump inhibitors (PPIs) at very high dosages intravenously

Medication Complications in Extracorporeal Membrane Oxygenation.

The need for extracorporeal membrane oxygenation (ECMO) therapy is a marker of disease severity for which multiple medications are required. The therapy causes physiologic changes that impact drug pharmacokinetics. These changes can lead to exposure-driven decreases in efficacy or increased incidence of side effects. The pharmacokinetic changes are drug specific and largely undefined for most drugs. We review available drug dosing data and provide guidance for use in the ECMO patient population

The opto-mechanical design of the GMT-Consortium Large Earth Finder (G-CLEF)

The GMT-Consortium Large Earth Finder (G-CLEF) will be part of the first generation instrumentation suite for the Giant Magellan Telescope (GMT). G-CLEF is a general purpose echelle spectrograph operating in the optical passband with precision radial velocity (PRV) capability. The measurement precision goal of G-CLEF is 10 cm/sec; necessary for the detection of Earth analogues. This goal imposes challenging stability requirements on the optical mounts and spectrograph support structures especially when considering the instrument's operational environment. G-CLEF's accuracy will be influenced by changes in temperature and ambient air pressure, vibration, and micro gravity-vector variations caused by normal telescope motions. For these reasons we have chosen to enclose G-CLEF's spectrograph in a wellinsulated, vibration-isolated vacuum chamber in a gravity invariant location on GMT's azimuth platform. Additional design constraints posed by the GMT telescope include; a limited space envelope, a thermal leakage ceiling, and a maximum weight allowance. Other factors, such as manufacturability, serviceability, available technology, and budget are also significant design drivers. G-CLEF will complete its Critical Design phase in mid-2018. In this paper, we discuss the design of GCLEF's optical mounts and support structures including the choice of a low-CTE carbon-fiber optical bench. We discuss the vacuum chamber and vacuum systems. We discuss the design of G-CLEF's insulated enclosure and thermal control systems which simultaneously maintain the spectrograph at milli-Kelvin level stability and limit thermal leakage into the telescope dome. Also discussed are micro gravity-vector variations caused by normal telescope slewing, their uncorrected influence on image motion, and how they are dealt with in the design. We discuss G-CLEF's front-end assembly and fiber-feed system as well as other interface, integration and servicing challenges presented by the telescope, enclosure, and neighboring instrumentation. This work has been supported by the GMTO Corporation, a non-profit organization operated on behalf of an international consortium of universities and institutions: Arizona State University, Astronomy Australia Ltd, the Australian National University, the Carnegie Institution for Science, Harvard University, the Korea Astronomy and Space Science Institute, the São Paulo Research Foundation, the Smithsonian Institution, the University of Texas at Austin, Texas AM University, the University of Arizona, and the University of Chicago

Simulating image coaddition with the Nancy Grace Roman Space Telescope: I. Simulation methodology and general results

The upcoming Nancy Grace Roman Space Telescope will carry out a wide-area survey in the near infrared. A key science objective is the measurement of cosmic structure via weak gravitational lensing. Roman data will be undersampled, which introduces new challenges in the measurement of source galaxy shapes; a potential solution is to use linear algebra-based coaddition techniques such as Imcom that combine multiple undersampled images to produce a single oversampled output mosaic with a desired "target" point spread function (PSF). We present here an initial application of Imcom to 0.64 square degrees of simulated Roman data, based on the Roman branch of the Legacy Survey of Space and Time (LSST) Dark Energy Science Collaboration (DESC) Data Challenge 2 (DC2) simulation. We show that Imcom runs successfully on simulated data that includes features such as plate scale distortions, chip gaps, detector defects, and cosmic ray masks. We simultaneously propagate grids of injected sources and simulated noise fields as well as the full simulation. We quantify the residual deviations of the PSF from the target (the "leakage"), as well as noise properties of the output images; we discuss how the overall tiling pattern as well as Moir\'e patterns appear in the final leakage and noise maps. We include appendices on interpolation algorithms and the interaction of undersampling with image processing operations that may be of broader applicability. The companion paper ("Paper II") explores the implications for weak lensing analyses.Comment: 28 pages, 19 figures, matches version accepted by MNRA

Simulating image coaddition with the Nancy Grace Roman Space Telescope: II. Analysis of the simulated images and implications for weak lensing

One challenge for applying current weak lensing analysis tools to the Nancy Grace Roman Space Telescope is that individual images will be undersampled. Our companion paper presented an initial application of Imcom - an algorithm that builds an optimal mapping from input to output pixels to reconstruct a fully sampled combined image - on the Roman image simulations. In this paper, we measure the output noise power spectra, identify the sources of the major features in the power spectra, and show that simple analytic models that ignore sampling effects underestimate the power spectra of the coadded noise images. We compute the moments of both idealized injected stars and fully simulated stars in the coadded images, and their 1- and 2-point statistics. We show that the idealized injected stars have root-mean-square ellipticity errors (1 - 6) x 10-4 per component depending on the band; the correlation functions are >= 2 orders of magnitude below requirements, indicating that the image combination step itself is using a small fraction of the overall Roman 2nd moment error budget, although the 4th moments are larger and warrant further investigation. The stars in the simulated sky images, which include blending and chromaticity effects, have correlation functions near the requirement level (and below the requirement level in a wide-band image constructed by stacking all 4 filters). We evaluate the noise-induced biases in the ellipticities of injected stars, and explain the resulting trends with an analytical model. We conclude by enumerating the next steps in developing an image coaddition pipeline for Roman.Comment: 25 pages, 20 figures. Submitted to MNRA

The spanish Blue Division in Y. Revista para la mujer (1941-1943)

Los cerca de 45.000 hombres que formaron parte de la División Azul estuvieron acompañados por un grupo de enfermeras españolas en el frente del Este. Los soldados, además, recibían desde España las cartas de las madrinas de guerra y la ayuda de la Sección Femenina. Estas acciones fueron altamente publicitadas por la propaganda del Régimen a través de las revistas para mujeres. El objetivo de este artículo es analizar cómo les fue contada a las mujeres la experiencia de la División Azul en Y. Revista para la mujer. Para ello, estudiamos los artículos sobre el tema en tres secciones específicas: las mujeres que viajaron a la Unión Soviética, las que colaboraron desde casa y la imagen del voluntario como héroe masculino.The about 45.000 men that were part of the Spanish Blue Division were accompanied by a group of Spanish nurses in the Eastern Front. The soldiers, moreover, received from Spain the letters of the godmothers of war and the aid of Falange Women’s Section. These actions were highly publicized by the regime’s propaganda through the women’s magazines. The aim of this paper is to analyze how the experience of the Spanish Blue Division was told to women in Y. Revista para la mujer. For it, we study the articles about the theme in three specific sections: the women who travelled to the Soviet Union, those who collaborated from Spain and the image of the volunteer as a male hero

Three year naturalistic outcome study of panic disorder patients treated with paroxetine

BACKGROUND: This naturalistic open label follow-up study had three objectives: 1) To observe the course of illness in Panic Disorder patients receiving long-term versus intermediate-term paroxetine treatment 2) To compare the relapse rates and side-effect profile after long-term paroxetine treatment between patients with Panic Disorder and Panic Disorder with Agoraphobia. 3) To observe paroxetine's tolerability over a 24 month period. METHODS: 143 patients with panic disorder (PD), with or without agoraphobia, successfully finished a short-term (ie 12 week) trial of paroxetine treatment. All patients then continued to receive paroxetine maintenance therapy for a total of 12 months. At the end of this period, 72 of the patients chose to discontinue paroxetine pharmacotherapy and agreed to be monitored throughout a one year discontinuation follow-up phase. The remaining 71 patients continued on paroxetine for an additional 12 months and then were monitored, as in the first group, for another year while medication-free. The primary limitation of our study is that the subgroups of patients receiving 12 versus 24 months of maintenance paroxetine therapy were selected according to individual patient preference and therefore were not assigned in a randomized manner. RESULTS: Only 21 of 143 patients (14%) relapsed during the one year medication discontinuation follow-up phase. There were no significant differences in relapse rates between the patients who received intermediate-term (up to 12 months) paroxetine and those who chose the long-term course (24 month paroxetine treatment). 43 patients (30.1%) reported sexual dysfunction. The patients exhibited an average weight gain of 5.06 kg. All patients who eventually relapsed demonstrated significantly greater weight increase (7.3 kg) during the treatment phase. CONCLUSIONS: The extension of paroxetine maintenance treatment from 12 to 24 months did not seem to further decrease the risk of relapse after medication discontinuation. Twenty-four month paroxetine treatment is accompanied by sexual side effects and weight gain similar to those observed in twelve month treatment

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration