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SU-E-T-45: Antibody Mean Residence Time in Blood and Its Correlation with Protein Molecular Weight
Purpose: Animal biodistribution data are required prior to introducing a new radiopharmaceutical into clinical trials. Protein engineering, using recombinant DNA techniques can produce a large number of related (cognate) antibodies to a given molecular target. Thus, it is important that these constructs be numerically related to one another via a single criterion. In the following, we use the mean residence time (MRT) in murine blood as this criterion. Methods: Five cognate anti-CEA (Carcinoembryonic Antigen) antibodies were compared with regard to their MRT in whole blood of CEA-positive tumor-bearing (LS174T) mice. MRT was defined by blood AUC (area under the curve) divided by the initial blood uptake value; all in units of percent injected dose per gram (%ID/g). Cognates included single chain scFv (25 kDa), diabody (50 kDa), minibody (80 kDa), F(ab')2 (120 kDa), and intact (155 kDa) forms of the murine cT84.66 antibody against CEA. All were labeled with radioactive iodine. Results: The agents, in the sequence listed, exhibited MRT values of 1.16 +/- 0.01 h, 0.99 h, 5.06 +/- 0.70 h, 6.61 +/- 0.36 h, and 59.3 +/- 2.4 h respectively. Because of the monotonic nature of the sequence, a linear correlation analysis was performed between molecular weight (MW) and MRT or ln(MRT) of the 5 proteins. Probability of random correlation was 0.10 for MRT and 0.01 for ln(MRT). Conclusion: MRT values of cognate anti-CEA antibodies were found to be a monotonically increasing sequence with respect to MW. Cognate MW values correlated best to ln(MRT) of the protein species. Thus MRT was proportional to an exponential function of molecular weight. The extended intact antibody circulation time presumably reflected its relatively maximal MW. Presence of an intact FC segment on this native antibody may also have influenced these results.
Prototypes of self-powered radiation detectors employing intrinsic high-energy current
Purpose: The authors experimentally investigate the effect of direct energy conversion of x-rays via selfpowered Auger- and photocurrent, potentially suitable to practical radiation detection and dosimetry in medical applications. Experimental results are compared to computational predictions. The detector the authors consider is a thin-film multilayer device, composed of alternating disparate electrically conductive and insulating layers. This paper focuses on the experiments while a companion paper introduces the fundamental concepts of high-energy current (HEC) detectors. Methods: The energy of ionizing radiation is directly converted to detector signal via electric current induced by high-energy secondary electrons generated in the detector material by the incident primary radiation. The HEC electrons also ionize the dielectric and the resultant charge carriers are selfcollected due to the contact potential of the disparate electrodes. Thus, an electric current is induced in the conductors in two different ways without the need for externally applied bias voltage or amplification. Thus, generated signal in turn is digitized by a data acquisition system. To determine the fundamental properties of the HEC detector and to demonstrate its feasibility for medical applications, the authors used a planar geometry composed of multilayer microstructures. Various detectors with up to seven conducting layers with different combinations of materials (250 μm Al, 35 μm Cu, 100 μm Pb) and air gaps (100 μm) were exposed to nearly plane-parallel 60–120 kVp x-ray beams. For the experimental design and verification, the authors performed coupled electron–photon radiation transport computations. The detector signal was measured using a commercial data acquisition system with 24 bits dynamic range, 0.4 fC sensitivity, and 0.9 ms sampling time. Results: Measured signals for the prototype detector varied depending on the number of layers, material type, and incident photon energy, and it was in the range of 30–150 nA/cm{sup 2} for unit air kerma (1 Gy), which is viable for practical applications. The experiments had an excellent agreement with the computations. Within the examined range of 60–120 kVp, the energy dependence of the HEC (normalized to the x-ray tube output) was relatively small. Conclusions: Based on the experimental results for 100 ms sampling time, it would be possible to measure the time dependence of x-ray beams for x-ray tube current of 0.1 mA or higher. Significant advantages of the HEC device are that generation of its signal does not require external power supply, it can be made in any size and shape, including flexible curvilinear forms, and it is inexpensive. It remains to be determined, which of the potential applications in medical dosimetry (both in vivo and external), or radiation protection would benefit from such selfpowered detectors.
SU-F-T-258: Efficacy of Exit Fluence-Based Dose Calculation for Prostate Radiation Therapy
Purpose: To investigate the efficacy of exit-fluence-based dose computation for prostate radiotherapy by determining if it estimates true dose more accurately than the original planning dose. Methods: Virtual exit-fluencebased dose computation was performed for 19 patients, each with 9–12 repeat CT images. For each patient, a 78 Gy treatment plan was created utilizing 5 mm CTV-to-PTV and OAR-to-PRV margins. A Monte Carlo framework was used to compute dose and exit-fluence images for the planning image and for each repeat CT image based on boney-anatomyaligned and prostate-centroid-aligned CTs. Identical source particles were used for the MC dose-computations on the planning and repeat CTs to maximize correlation. The exit-fluence-based dose and image were computed by multiplying source particle weights by FC(x,y)=FP(x,y)/FT(x,y), where (x,y) are the source particle coordinates projected to the exit-fluence plane and we denote the dose/fluence from the plan by (DP,FP), from the repeat-CT as (DT,FT), and the exit-fluence computation by (DFC,FFC). DFC mimics exit-fluence backprojection through the planning image as FT=FFC. Dose estimates were intercompared to judge the efficacy of exit-fluence-based dose computation. Results: Boney- and prostate-centroid aligned results are combined as there is no statistical difference between them, yielding 420 dose comparisons per dose-volume metric. DFC is more accurate than DP for 46%, 33%, and 44% of cases in estimating CTV D98, D50, and D2 respectively. DFC improved rectum D50 and D2 estimates 54% and 49% respectively and bladder D50 and D2 47 and 49% respectively. While averaged over all patients and images DFC and DP were within 3.1% of DT, they differed from DT by as much as 22% for GTV D98, 71% for the Bladder D50, 17% for Bladder D2, 19% for Rectum D2. Conclusion: Exit-fluence based dose computations infrequently improve CTV or OAR dose estimates and should be used with caution. Research supported in part by Varian Medical Systems.
TH-CD-BRA-05: First Water Calorimetric Dw Measurement and Direct Measurement of Magnetic Field Correction Factors, KQ,B, in a 1.5 T B-Field of An MRI Linac
Purpose: Reference dosimetry in MR-guided radiotherapy is performed in the presence of a B-field. As a consequence the response of ionization chambers changes considerably and depends on parameters not considered in traditional reference dosimetry. Therefore future Codes of Practices need ionization chamber correction factors to correct for both the change in beam quality and the presence of a B-field. The objective was to study the feasibility of water calorimetric absorbed-dose measurements in a 1.5 T B-field of an MRLinac and the direct measurement of kQ,B calibration of ionization chambers. Methods: Calorimetric absorbed dose to water Dw was measured with a new water calorimeter in the bore of an MRLinac (TPR20,10 of 0.702). Two waterproof ionization chambers (PTW 30013, IBA FC-65G) were calibrated inside the calorimeter phantom (ND,w,Q,B). Both measurements were normalized to a monitor ionization chamber. Ionization chamber measurements were corrected for conventional influence parameter. Based on the chambers’ Co-60 calibrations (ND,w,Q0), measured directly against the calorimeter. In this study the correction factors kQ,B was determined as the ratio of the calibration coefficients in the MRLinac and in Co-60. Additionally, kB was determined based on kQ values obtained with the IAEA TRS-398 Code of Practice. Results: The kQ,B factors of the ionization chambers mentioned above were respectively 0.9488(8) and 0.9445(8) with resulting kB factors of 0.961(13) and 0.952(13) with standard uncertainties on the least significant digit(s) between brackets. Conclusion: Calorimetric Dw measurements and calibration of waterproof ionization chambers were successfully carried out in the 1.5 T B-field of an MRLinac with a standard uncertainty of 0.7%. Preliminary kQ,B and kB factors were determined with standard uncertainties of respectively 0.8% and 1.3%. The kQ,B agrees with an alternative method within 0.4%. The feasibility of water calorimetry in the presence of B-fields was demonstrated by the direct determination of Dw and kQ,B. This work was supported by EMRP grant HLT06. The EMRP is jointly funded by the EMRP participating countries within EURAMET and the European Union.
High-temperature low-humidity proton exchange membrane with “stream-reservoir” ionic channels for high-power-density fuel cells
The perfluorosulfonic acid (PFSA) proton exchange membrane (PEM) is the key component for hydrogen fuel cells (FCs). We used in situ synchrotron scattering to investigate the PEM morphology evolution and found a “stream-reservoir” morphology, which enables efficient proton transport. The short-side-chain (SSC) PFSA PEM is fabricated under the guidance of morphology optimization, which delivered a proton conductivity of 193 milliSiemens per centimeter [95% relativity humidity (RH)] and 40 milliSiemens per centimeter (40% RH) at 80°C. The improved glass transition temperature, water permeability, and mechanical strength enable high-temperature low-humidity FC applications. Performance improvement by 82.3% at 110°C and 25% RH is obtained for SSC-PFSA PEM FCs compared to Nafion polymer PEM devices. The insights in chain conformation, packing mechanism, crystallization, and phase separation of PFSAs build up the structure-property relationship. In addition, SSC-PFSA PEM is ideal for high-temperature low-humidity FCs that are needed urgently for high-power-density and heavy-duty applications.
Single-dose mucosal replicon-particle vaccine protects against lethal Nipah virus infection up to 3 days after vaccination
Nipah virus (NiV) causes a highly lethal disease in humans who present with acute respiratory or neurological signs. No vaccines against NiV have been approved to date. Here, we report on the clinical impact of a novel NiV-derived nonspreading replicon particle lacking the fusion (F) protein gene (NiVΔF) as a vaccine in three small animal models of disease. A broad antibody response was detected that included immunoglobulin G (IgG) and IgA subtypes with demonstrable Fc-mediated effector function targeting multiple viral antigens. Single-dose intranasal vaccination up to 3 days before challenge prevented clinical signs and reduced virus levels in hamsters and immunocompromised mice; decreases were seen in tissues and mucosal secretions, critically decreasing potential for virus transmission. This virus replicon particle system provides a vital tool to the field and demonstrates utility as a highly efficacious and safe vaccine candidate that can be administered parenterally or mucosally to protect against lethal Nipah disease.
Human V H 1-69 Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis
Staphylococcus aureus is an important human pathogen that infects nearly every human tissue. Like most organisms, the acquisition of nutrient iron is necessary for its survival. One route by which it obtains this metal is through the iron-regulated surface determinant (Isd) system that scavenges iron from the hemoglobin of the host. We show that the heavy chain variable region IGHV1-69 gene commonly encodes human monoclonal antibodies (mAbs) targeting IsdB-NEAT2. Remarkably, these antibodies bind to multiple antigenic sites. One class of IGHV1-69-encoded mAbs blocks S. aureus heme acquisition by binding to the heme-binding site of NEAT2, while two additional classes reduce the bacterial burden in vivo by an alternative Fc receptor-mediated mechanism. We further identified clonal lineages of IGHV1-69-encoded mAbs using donor samples, showing that each lineage diversifies during infection by somatic hypermutation. These studies reveal that IGHV1-69-encoded antibodies contribute to a protective immune response, furthering our understanding of the correlates of protection against S. aureus infection.
Influence of a Strong Magnetic Field on Magnetic Order in Polycrystalline Layered Cobaltites EuBaCo{sub 2 –x}O{sub 5.5 – δ}
The magnetic properties of polycrystalline EuBaCo{sub 2 –x}O{sub 5.5 – δ} (x ≤ 0.1, δ ≤ 0.14) are studied in the temperature range 2 K < T < 300 K in magnetic fields H ≤ 90 kOe. A comparison is made of the dependencies of magnetization M on temperature T and magnetic field H for polycrystalline and single crystal EuBaCo{sub 1.90}O{sub 5.36}, in which only Cu(III) ions are present. It is shown that in the magnetically ordered temperature range of magnetic order, the samples are ferrimagnetic, in which antiferromagnetic interactions between the nearest Co{sup 3+} ions with the same spins compete with the ferromagnetic exchange. With a decrease in temperature, a strong magnetic field affects the magnetic order. At T = 2 K in fields H = 50–90 kOe, all samples exhibit the properties of mictomagnetism. There are a shift in the hysteresis loops M(H) and a large difference in the values of the magnetization of the sample cooled in a magnetic field M (FC) and without a field M (ZFC) due to unidirectional magnetic anisotropy. In this case, there is no saturation of magnetization. The field dependences of magnetization taken in the cooling and heating in unequal fields (CHUF) mode indicate a metastable magnetic state. Near T = 20–30 K, an orientational transition characteristic of micromagnets takes place and a complex ferrimagnetic structure is formed. The main reasons for the manifestation of mictomagnetism properties in layered cobaltites are the presence of magnetoactive Co{sup 3+} ions in the states with intermediate and high spins at low temperatures and structural defects that affect the exchange interaction between the nearest neighbors. Nonmagnetic Co{sup 3+} ions in the low-spin state can also act as defects.
Application of the theory of open quantum systems to nuclear physics problems
Quantum diffusion equations with transport coefficients explicitly depending on time are derived from the generalized non-Markovian Langevin equations. The asymptotic behavior of the friction and diffusion coefficients is investigated in the case of the FC and RWA couplings between the collective and internal subsystems. An asymptotic expression is obtained for the propagator of the density matrix of the open quantum system with the general quadratic Hamiltonian, linearly coupled (in coordinate and momentum) to internal degrees of freedom. The effect of different sets of transport coefficients on the decoherence and decay rate of the metastable state is investigated using the master equation for the reduced density matrix of open quantum systems. The developed approach is used to study the capture of the projectile nucleus by the target nucleus at energies near the Coulomb barrier. Capture cross sections in asymmetric reactions are well described with allowance for the calculated capture probabilities. Particular cases where dissipation favors penetration through the potential barrier are found. The generalized Kramers formula for the quasi-stationary decay rate of the quantum metastable systems is analytically derived.
Position-Sensitive Spectrometric Module for Detecting Ionizing Radiation by Semiconductor Strip Detectors
A position-sensitive module for detecting ionizing radiation based on semiconductor strip detectors and a multichannel spectrometric route has been developed and implemented. The dynamic range of the detected charge generated by an ionizing particle in the detector is 5–250 fC. The position-sensitive module is a structurally complete device with the functions of amplifying the spectrometric signal, digitizing, buffering, preprocessing, and transmitting data to a computer.
Electrochemistry of Redox Active Ferrocene Covalently Attached to Glassy Carbon Electrodes
Formation of well-ordered redox active monolayers is desirable for systematic study of electron transfer for sensor applications and generation of tailored hybrid materials. We have covalently attached 6-bromohexylferrocene (Fc(CH 2 ) 6 Br) to glassy carbon electrodes through a Grignard reaction and used cyclic voltammetry to characterize interfacial electron transfer and probe disorder in these modified electrodes. X-ray photoelectron spectroscopy (XPS) and cyclic voltammetry confirmed attachment of the expected Fe(II) species and reversible electron transfer is observed. However, the full width at half max of the cyclic voltammogram features deviates from the ideal value of 90.6 mV and varies with surface coverage, indicating a disordered surface. As a result, we determine this disorder arises from phase segregation where some domains have a high loading of the hexylferrocene chains while others have a lower loading of hexylferrocene resulting in different local environments that are distinguishable by cyclic voltammetry.
Sensitivity Analysis and Effective Parametrization of PEM Fuel Cell Models
The cost of proton-exchange-membrane fuel cells (PEMFCs) remains a major hurdle in large-scale commercialization of this technology. To improve their performance and reduce cost, novel materials and electrode designs are continuously envisioned, e.g., non-PGM catalyst layers, ultra-thin Pt/Pt-Ni based catalyst layers, structured ionomer arrays or NSTF catalyst layers.1 Understanding the impact of these improvement strategies can be extremely time and cost intensive due to complex physical phenomena and large design space. We have previously developed a PEMFC modeling framework2 which has been a time and cost effective tool for understanding and optimizing the complex multi-physics phenomena within PEMFCs; however, several of the cell parameters used in the modeling have large spread in measured data.3 Furthermore, several transport parameters such as water adsorption kinetics have not been accurately measured and the approximations are spread over several orders of magnitude. These uncertainties cause problems in ascertaining accuracy of the modeling approach and they reduce the predictive power of the numerical models. The aim of this work is to identify the sensitivity of PEFC numerical model outputs to various input parameters. The previously in-house developed MEA modeling framework2 is used for PEMFC modeling. The sensitivity of the model outputs with respect to inputs parameters is obtained by analyzing the condition numbers for different output-input pairs at varying operating conditions. An example of the sensitivity analysis is shown in Figure 1. The condition numbers are obtained for the entire possible range of input parameters at varying operating conditions to identify the most crucial parameters of the PEMFC model. Based on our preliminary analysis, parameters related to kinetics (exchange current density and ECSA) and heat/water management in electrodes and ionomer (ionomer fraction, thermal conductivity) are most crucial. One of the major goals of this work is to identify the most crucial set of parameters towards which the model shows maximum sensitivity. This will guide future experimentalists to measure these properties with higher accuracy. Furthermore, the sensitivity analysis will also enable us to optimize the PEMFC performance by selectively targeting the most sensitive parameters and thereby making the largest impact. Acknowledgements The work is funded under the Fuel Cell Performance and Durability Consortium (FC-PAD), by the Fuel Cell Technologies Office (FCTO), Office of Energy Efficiency and Renewable Energy (EERE), of the U.S. Department of Energy under contract number DE-AC02-05CH11231. The authors would like to thank Nathan Craig at Robert Bosch LLC for his valuable input in designing the sensitivity analysis. The authors would also like to thank Giovanna Bucci and Matthias Hanauer at Robert Bosch for their valuable inputs and discussion. References P. K. Sinha, W. Gu, A. Kongkanand and E. Thompson, J. Electrochem. Soc., 158, B831 (2011). L. M. Pant, M. R. Gerhardt, N. Macauley, R. Mukundan, R. L. Borup and A. Z. Weber, Electrochim. Acta, 326, 134963 (2019). R. Vetter and J. O. Schumacher, ArXiv181110091 Phys. (2018). Figure 1
Myocardial Oxidative Metabolism and Protein Synthesis during Mechanical Circulatory Support by Extracorporeal Membrane Oxygenation
Extracorporeal membrane oxygenation (ECMO) provides mechanical circulatory support essential for survival in infants and children with acute cardiac decompensation. However, ECMO also causes metabolic disturbances, which contribute to total body wasting and protein loss. Cardiac stunning can also occur which prevents ECMO weaning, and contributes to high mortality. The heart may specifically undergo metabolic impairments, which influence functional recovery. We tested the hypothesis that ECMO alters oxidative. We focused on the amino acid leucine, and integration with myocardial protein synthesis. We used a translational immature swine model in which we assessed in heart (i) the fractional contribution of leucine (FcLeucine) and pyruvate (FCpyruvate) to mitochondrial acetyl-CoA formation by nuclear magnetic resonance and (ii) global protein fractional synthesis (FSR) by gas chromatography-mass spectrometry. Immature mixed breed Yorkshire male piglets (n = 22) were divided into four groups based on loading status (8 hours of normal circulation or ECMO) and intracoronary infusion [13C6,15N]-L-leucine (3.7 mM) alone or with [2-13C]-pyruvate (7.4 mM). ECMO decreased pulse pressure and correspondingly lowered myocardial oxygen consumption (~ 40%, n = 5), indicating decreased overall mitochondrial oxidative metabolism. However, FcLeucine was maintained and myocardial protein FSR was marginally increased. Pyruvate addition decreased tissue leucine enrichment, FcLeucine, and Fc for endogenous substrates as well as protein FSR. Conclusion: The heart under ECMO shows reduced oxidative metabolism of substrates, including amino acids, while maintaining (i) metabolic flexibility indicated by ability to respond to pyruvate, and (ii) a normal or increased capacity for global protein synthesis, suggesting an improved protein balance.
Pan-H7 influenza human antibody virus neutralization depends on avidity and steric hindrance
H7N9 avian influenza virus is a zoonotic influenza virus of public health concern, with a 39% mortality rate in humans. H7N9-specific prevention or treatments for humans have not been approved. We previously isolated a human monoclonal antibody (mAb) designated H7-235 that broadly reacts to diverse H7 viruses and neutralizes H7N9 viruses in vitro. Here, we report the crystal structure of H7 HA1 bound to the fragment antigen-binding region (Fab) of recombinant H7-235 (rH7-235). The crystal structure revealed that rH7-235 recognizes residues near but outside of the receptor binding site (RBS). Nevertheless, the rH7-235 IgG potently inhibits hemagglutination mediated by H7N9 viruses due to avidity effect and Fc steric hindrance. This mAb prophylactically protects mice against weight loss and death caused by challenge with lethal H7N9 viruses in vivo. rH7-235 mAb neutralizing activity alone is sufficient for protection when used at a high dose in a prophylactic setting. This study provides insights into mechanisms of viral neutralization by protective, broadly reactive anti-H7 antibodies, informing the rational design of therapeutics and vaccines against H7N9 influenza virus.
Plasma proteomic biomarkers of physical frailty in heart failure: a propensity score matched discovery-based pilot study
Background: Physical frailty is highly prevalent in heart failure (HF), but we lack an understanding of the underlying pathophysiology. Proteomics evaluation of plasma samples may elucidate potential mechanisms and biomarkers of physical frailty in HF. We aimed to identify plasma proteomic biomarkers that are differentially expressed between physically frail and non physically frail adults with HF. Methods: This was a secondary analysis of a subset of data and plasma samples from a study of frailty among patients with New York Heart Association (NYHA) Functional Classification I-IV HF. Physical frailty was measured using the Frailty Phenotype Criteria. Propensity score matching was used to match pairs of physically frail (n = 20) vs. non-physically frail (n = 20) patients on clinical characteristics. Plasma samples were processed using a sensitive liquid chromatography mass spectrometry platform, utilizing a multiplexed tandem mass tag-labeled quantitative proteomics approach. Differentially expressed proteins were quantified individually using paired t tests with associated log fold change of 0.3 and Fisher’s combined p values. Results: The sample (n = 40) was 62.8±16.9 years old, 58% female, and 55% NYHA Class III/IV. Proteomics analysis revealed 7 proteins differentially expressed using full differential criteria: matrix metalloproteinase-14 was downregulated in frailty, and copine-1, low affinity immunoglobulin gamma Fc region receptor III-A and III-B, probable non-functional immunoglobulin kappa variable 2D-24, glutathione S-transferase Mu 1, and argininosuccinate lyase were upregulated in frailty. Conclusions: Proteomic biomarkers related to the immune system, stress response, and detoxification were differentially expressed between physically frail and non-physically frail adults with HF.
Fluorescent Labeling of Antibody Fragments Using Split GFP
Antibody fragments are easily isolated from in vitro selection systems, such as phage and yeast display. Lacking the Fc portion of the antibody, they are usually labeled using small peptide tags recognized by antibodies. In this paper we present an efficient method to fluorescently label single chain Fvs (scFvs) using the split green fluorescent protein (GFP) system. A 13 amino acid tag, derived from the last beta strand of GFP (termed GFP11), is fused to the C terminus of the scFv. This tag has been engineered to be non-perturbing, and we were able to show that it exerted no effect on scFv expression or functionality when compared to a scFv without the GFP11 tag. Effective functional fluorescent labeling is demonstrated in a number of different assays, including fluorescence linked immunosorbant assays, flow cytometry and yeast display. Furthermore, we were able to show that this split GFP system can be used to determine the concentration of scFv in crude samples, as well an estimate of antibody affinity, without the need for antibody purification. We anticipate this system will be of widespread interest in antibody engineering and in vitro display systems.