bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutron Diffraction - A Probe for Grain Size and Preferred Orientation in Zircaloy-Clad Uranium
Authors: Richardson James W. , Mueller Melvin H. , Schultz Arthur J. , Ross Frederick K. , Reichel Daniel G.
Published: March 2019

A recent goal of the ANL Intense Pulsed Neutron Source (IPNS) has been the fabrication of a new enriched uranium target with increased neutron flux (by a factor of 3) which is dimensionally stable under irradiation. Neutron diffraction, using several instruments both at IPNS and MURR, has been used as a probe to characterize the target material vith respect to grain size and preferred orientation. The samples studied were portions of the uranium discs (4" diameter X 1/2" thick) which, when stacked, form the target assembly at IPNS. The old target discs were fabricated as slices from a fast cooled casting (arc-melted, water cooled in a cylindrical mold) and possess small grain size and negligible orientation. The new enriched target discs, on the other hand, are being fabricated from a slow cooled material (graphite book-mold, natural cooling) and, prior to additional treatment, have a large grain size and a high degree of preferred orientation which could produce dimensional changes during fission as the target is used. Our conclusion from this investigation is that a β-phase heat treatment (quench from 730°C) is necessary to produce a finer grain and more nearly random texture in thg new enriched material. Based on our detailed texture measurements the anticipated target lifetime of several years appears feasible.
PC Based Topography Technique
Authors: Leepa Douglas C. , Ananthanarayanan T. S. , Coyne Paul J.
Published: March 2019

This paper discusses the use of a personal computer in the x-ray diffraction laboratory. DARC (Digital Automated Hocking Curve) Topography is a system in which a PC is used extensively. Using this system as an example, the tsany uses and benefits of the PC as a tool will be explained.
Near-Surface Analysis of Semicondutor Using Grazing Incidence X-Ray Fluorescence
Authors: Iida Atsuo , Sakurai Kenji , Gohshi Yohichi
Published: March 2019

The X-ray external total reflection was used for the x-ray fluorescence analysis of the near surface layer of a GaAs wafer and a GaAlAs epilayer. Synchrotron radiation was used as an excitation source. The intensity ratio between the Ga K and As K fluorescence signals was measured as a function of the glancing angle. The reduction of As atoms near the surface of less than a hundred Å was observed for the high temperature annealed GaAlAs epilayer.
Application of Graded Multilayer Optics in X-Ray Diffraction
Authors: Schuster M. , Göbel H.
Published: March 2019

Periodic multilayers are ideally suited as high-reflectivity and wide-bandwidth Bragg reflectors. Their period can be matched laterally to the incidence angle so that for all points on the reflector, Bragg reflection is obtained for the same wavelength. Three major types of laterally graded multilayer optics were appJied to X-ray diffraction: (i) Parabolically curved multilayer mirrors were used to convert divergent radiation emerging from an X-ray source into a parallel beam. The parallel beam was applied in powder diffraction, grazing incidence diffraction, reflectometry, high-resolution diffraction, and protein crystallography, (ii) Elliptically curved multilayer mirrors focused the divergent radiation from the source into a line on the sample or detector. The high brilliance and small dimension of the focused beam make this mirror type suited for transmission diffractometry of capillary and fiber specimens, (iii) Planar multilayer mirrors were employed in divergent-beam optics. In Bragg-Brentano diffractometers, this mirror type can serve as a compact incident-beam monochromator for removing Kβ lines and Bremsstrahlung.
Development of μ-Fluorescent and Diffracted X-Ray Spectrometer with a Fine Focused X-Ray Beam and its Application for Ulsi Microanalysis
Authors: Yamamoto Naoki
Published: March 2019

A fluorescent and diffracted X-ray spectrometer with an X-ray sub-micron beam was developed for the analysis of stress, crystal structure, and contamination in micro-regions of ULSIs. A fine glass capillary with a parabolic cross-sectional inner wall surface was made to form a micro X-ray beam. A micro-focus X-ray generator with a membrane-type target was also developed for use with the capillary. The equipment was used to analyze the crystal phases of Ti silicide fine lines and the strains in Al interconnections.

The resistance of Ti-silicide lines increases the line width narrows under about 0.5 μrn. This is because of the growth of crystal phases of TiSi2(C49) and TiSi(B27) with high resistivity ﹛60 to 100 μΩ-cm).

Hillocks of Al grow at line edges when Al layers are compressed by Si substrates and surrounding insulating layers. On the other hand, when the Al is extended by these layers, voids form in the AI lines.
X-Ray Determination of Stresses Distribution in a Coarse Grained Silicon Billet
Authors: Gergaud P. , Dour G. , Inal K. , Lebrun J. L.
Published: March 2019

The present study concerns residual stresses analysis in porycrystalhtie solar silicon material, which is continuously cast in a cold crucible. The observation of cracks and a modeling of thermal stresses suggest us that stresses in the center region are tensile and the ones in the peripheral region are compressive. X-ray measurement of stresses would be an experimental proof of the observations and an evaluation of the stresses levels. Unfortunately, the obtained material exhibits coarse grains with the size of up to one millimeter. In this case, where only a few crystals are irradiated by the incident X-ray beam, the classical sin2Ψ method is no longer valid. A specific analysis must be carried out. The results are of good accuracy comparing the low stress levels observed. The measured stress distribution on a radius of the billet is not always in good agreement with the analytical calculus.
Residual Stress in Si3N4-Passivated GaAs Wafers
Authors: Ward Allan , Hendricks R. W.
Published: March 2019

The nature of residual stress was determined in single crystal gallium arsenide (GaAs) bare wafers, silicon nitride-passivated GaAs wafers, and fully processed die. A methodology to determine strain in single crystals using X-ray diffraction was developed and applied to the specific case of gallium arsenide. The data show an increase in residual stress associated with the application of the Si3N4 passivation layer to approximately 60% of the fracture stress of the material. Further device processing only slightly increased residual stress values.
X-Ray Stress Measurement of Hexagonal Polycrystals with [001] Fiber Texture
Authors: Tanaka Keisuke , Ishihara Keisaku , Akiniwa Yoshiaki
Published: March 2019

A new method of X-ray measurements of triaxial residual stresses was proposed for hexagonal polycrystals with the [001] fiber texture. The relation between the strain and sin2ψ is linear for the cases of the fiber axis perpendicular or parallel to the specimen surface, provided that there is no shear stress acting on the specimen surface. The in-plane stresses, σ11, σ22, and σ12, and the normal stress perpendicular to the specimen surface, σ33, are determined from the slope and the intercept of the linear regression line for the relation between the X-ray strain and sin2ψ obtained for three different directions.
Measurement of the Refraction Correction for Asymmetric Grazing Incidence Xrd From Rough Surfaces and Powders
Authors: Ely T. , Predecki P. K. , Zhu X. , Eatough M. , Goehner R. , Lucernoni R.
Published: March 2019

The refraction effect at small incidence angles was investigated for solid Al2O3 disks of varying surface roughness, and Al2O3 and LaB6 powder layers of varying thickness and roughness using pseudo parallel beam optics. For the disks the peak shift Δ2θ correlated approximately inversely with ζmax, the maximum slope of a sinusoidal model of the surface roughness. For a disk polished with 3θm diamond, Δ2θ exceeded that predicted by the James equation. For the powder layers Δ2θ was very small for the thinnest layers. For thicker, rougher layers Δ2θ was larger and was probably due to displacement error from the 0.4° divergence of the Soller slit used and specular reflection of the diffracted beam from the Soller slit leaves.
Software for Comparative Analysis of Diffraction-Line Broadening
Authors: Balzar Davor , Ledbetter Hassel
Published: March 2019

Program “Breadth” was written for analyzing diffraction-line broadening. The physically broadened line profiles are required as input. The results are calculated according to three ”simplified” integral-breadth methods: Cauchy-Cauchy, Cauchy-Gauss, and Gauss-Gauss. The program output includes volume-weighted coherent domain size and a maximum strain. Furthermore, the root-mean-square strain and both surface-weighted and volume-weighted domain sizes are calculated according to the “double-Voigt” method. This method also allows the accurate determination of both surface-weighted and volume-weighted domain-size distribution functions for specimens showing a dominant size-broadening effect, which gives more detailed information than the mere average value of coherent-domain size. Some examples for ball-milled W (shows simultaneous size-strain broadening) and NiFe2O4 (shows pronounced pure-size broadening) are included.
X-Ray Quantitative Analysis of Transformed Martensite in Austentic Stainless Steel
Authors: Yajima Zenjiro , Kishi Yoichi , Hirose Yukio
Published: March 2019

Austenitic stainless steel has large toughness and high corrosion resistance compared to other alloy steels. The austenite near the fracture surface will be transformed to the martensite when it is fractured. In the present study, X-ray fractography is applied to a fatigue fracture surface of austenitic stainless steel. The fatigue tests were carried out on compact tension ( CT ) type specimens. The volume fraction of transformed martensite was quantitatively evaluated on fatigue fracture surfaces by the X-ray method. The plastic strain on the fracture surface was estimated by measuring the line broadening of X-ray diffraction profiles. The size of plastic zone left on the fatigue fracture surface was determined from the distribution of the line broadening
Pair-Density Function of Nano-Scale Morphology in Oriented Polymer Fibers: Application to Nomex Aramid
Authors: Rosenfield H. D. , Barton R.
Published: March 2019

We have developed a novel method of determining polymer fiber morphology. Analysis of pair-density functions obtained from synchrotron x-ray diffraction patterns with scattering vectors lying in the meridional direction and equatorial plane allows for the determination of crystallite dimensions, volume fractions of crystalline and amorphous phases, and the probability distribution of crystallite c axis orientation relative to the fiber axis. This method is independent of details regarding the structure of the amorphous phase, and may be successfully applied to both highly crystalline and poorly crystalline samples. Here we describe this new polymer fiber morphological analysis technique, and present examples of its application to three NOMEX aramid samples of widely differing morphologies.
Refined Determination of the Structure of Kerogen Etc. by Xrd and its Significance
Authors: Mingxin Wei , Delian Liu , Deyu Chen , Guanxin Wang
Published: March 2019

The aromaticity fa, crystallite parameters dm, dy, La, Lc, Mc, and RDF parameters r1 and Ka have been determined for sedimentary organic matter, such as kerogens, coals, and bitumens. Here, the rt value is the interatomic distance between the nearest neighbors of carbon atoms, and Ka is an empirical coefficient as an indicator of the degree of order-stacking for aromatic clusters. The refined methods of X-ray diffraction include the improved experimental conditions and new computer programs. The computer programs are composed of four software: AMORPHOUS software; NORMALIZATION software; RDF (Radial Distribution Function) software; and MPS (Multiple Peak Separation) software.
Characterisation and Modelling of Peak Shifts in Conventional Powder Diffractometry
Authors: Cheary Robert W. , Cline James P. , Anast Maree
Published: March 2019

The peak angle 2θpis one of the most commonly measured parameters in powder diffractometry, but there is little understanding of the extent to which the instrument affects this measurement. The majority of theoretical and experimental studies of the effects of instrumental aberrations have been based on the peak centroid 29c. In this investigation we have examined the extent to which peak angles in a conventional powder diffractometer shift for different combinations of divergence slit, Soller slits and receiving slit. The line profile standard SRM 660 (LaB6) was used to generate instrument profiles and X-ray data were collected from a diffractometer fitted with a fine focus Cu X-ray tube and a graphite post-monochromator set for CuKa. The effect of the instrument is greatest at low angles, but shifts arising from axial divergence can also be detected above 2θ=120°. Below 2θ = 40° changing the divergence slits from 0.3° to 1.0°, or removing one of the Soller slits, can move 2θpby up to 0.025°.
Quantitative X-Ray Diffraction Analysis of Smectites: II -- Reference Intensity Ratio Calculations for Smectite Analysis
Authors: Chen Hong , Davis Briant L.
Published: March 2019

In quantitative x-ray diffraction (XRD) analysis, the reference intensity ratio (ki or RIR) is one of the most important parameters of the reference intensity method (RIM). The ki is a function of the intensity of x-ray reflection and the mass attenuation coefficient of the sample for the “Lki” method (Davis, 1992). The intensities for 00l reflections have been calculated, and also the reference intensity ratios corresponding to the 001 reflection have been estimated in this part of the work, which is very important for investigating the iron influence on the XRD analysis of smectites. The Reynolds’ proposed glycol-expanded montmorillonite structure was used as a basis for the calculations.
On the Sampling Depth of Total Electron Yield (Tey) Measurements
Authors: Ebel Horst , Svagera Robert , Ebel Maria F. , Zagler Norbert , Wemer Wolfgang S.M. , Stön Herbert , Gröschl Martin
Published: March 2019

Photoabsorption of x-rays in solids causes primary and secondary photo and Auger electrons. The latter are from self absorption of characteristic radiations which have been produced in the solid by radiative de-excitation of photoionized atoms. Whereas the energy of the electrons at the origin is described by discrete values of a few eV up to nearly the energy of the photoabsorbed photons, we observe after the escape of the electrons from the solid a continuous energy distribution with a superposition of the original line spectrum. This is explained by inelastic collisions of the electrons in the course of their migration through the solid and the subsequent loss of kinetic energy. Since the electron range decreases with decreasing kinetic energy, only a relatively small amount of electrons is able to reach the surface and to escape from there.
X-Ray Characterization of Phase Equilibria of the Raveau and 2212 Phases in the Bi-Sr-Ca-Cu-0 System
Authors: Wong-Ng Winnie , Cook Lawrence P. , Jiang F.
Published: March 2019

Phase equilibria of two superconductor phases, namely the 20K Raveau phase (Bi2.2-xSr1.8+xCuOz, currently referred to as the 11905 phase) and the 80K 2212 phase of the Bi-Sr-Ca-Cu-0 system were investigated. The amount of Ca-substitution of the Raveau solid solution was determined and the solid solution region can be approximately described as Bi2.2+xSr1.8-X-YCayCu1±x/2Ow(referred to as the Ca-Raveau phase or the 119x5, ‘ with 0<x<0.15, 0<y<0.5. To determine the melting equilibria of the 2212 phase, a procedure involving the use of a wicking technique to capture the melt was applied. X-ray powder diffraction (XPD) and quantitative energy dispersive x-ray spectroscopy (EDS) were used to analyse the phases present in the residual and melt, respectively. The approximate primary crystallization field of the incongruently melting 2212 phase was illustrated.
An Update on Standards Activity for Txrf and the Challenges Ahead
Authors: Hockett R. S.
Published: March 2019

Standards organizations active in surface analysis using TXRF and VPD/TXRF include: (a) American Society for Testing and Materials (ASTM), (b) Semiconductor Equipment and Materials International (SEMI), (c) Ultra Clean Society of Japan (UCS), and (d) International Standards Organization Technical Committee 201 (ISO TC/201). The standards activities are presently dynamic, and they are on an international scale, This paper provides an update on the status of these activities, and presents the challenges ahead yet to be resolved.
Recent Developments in Txrf of Light Elements
Authors: Streli Christina , Bauer V. , Wobrauschek P.
Published: March 2019

Total Reflection X-ray Fluorescence Analysis (TXRF) has been proved to be well suited for the energy dispersive analysis of light elements, as B, C, N, O, F, Na, Mg,.,. using a special spectrometer. It is equipped with a Ge(HP) detector offering a sufficient detection efficiency from 180 eV upwards. The obtainable detection limits especially of the light elements are mainly influenced by the excitation source, which should provide a large number of photons with an energy near the K-absorption edge of these elements (from 200 eV upwards). Commercially available X-ray tubes do not offer characteristic X-rays in that range. In former experiments a windowless X-ray tube was built to prevent the low energy X-rays from being attenuated in the Be window. Experiments have been performed using Cu as anode material.
Early Achilles Enthesis Involvement in a Murine Model of Spondyloarthropathy: Morphological Imaging with Ultrashort Echo-Time Sequences and Ultrasmall Superparamagnetic Iron Oxide (USPIO) Particle Evaluation in Macrophagic Detection
Authors: Dallaudiere Benjamin , Trotier Aurelien J. , Ribot Emeline J. , Loubrie Stéphane , Miraux Sylvain , Hauger Olivier
Published: March 2019

Purpose. To confirm the interest of 3-dimensional ultrashort echo-time (3D-UTE) sequences to assess morphologic aspects in normal and pathological Achilles entheses in a rat model of spondyloarthropathy (SpA) with histological correlations, in comparison with conventional RARE T2 Fat-Sat sequences, and, furthermore, to evaluate the feasibility of a 3D multiecho UTE sequence performed before and after the intravenous injection of ultrasmall superparamagnetic iron oxide (USPIO) particles to assess macrophagic involvement in the Achilles enthesis in the same rat model of SpA. Materials and Methods. Fourteen rats underwent in vivo MRI of the ankle at 4.7 T, including a 3D RARE T2 Fat-Sat sequence and a 3D ultrashort echo-time (UTE) sequence for morphologic assessment at baseline and day 3 after induction of an SpA model, leading to Achilles enthesopathy in the left paw (right paw serving as a control). A 3D multiecho UTE sequence was also performed at day 3 before and then 24 (4 rats) and 48 (2 rats) hours after intravenous injection of USPIO. Visual analysis and signal intensity measurements of all images were performed at different locations of the Achilles enthesis and preinsertional area. Visual analysis and T2∗ measurements were performed before and after USPIO injection, on the 3D multiecho UTE sequence in the same locations. Normal and pathological values were compared by Wilcoxon signed-rank tests. MR findings were compared against histological data. Results. 3D-UTE sequences enabled morphologic identification of the anterior fibrocartilage and posterior collagenic areas of the Achilles enthesis. Visual analysis and signal intensity measurements distinguished SpA-affected entheses from healthy ones at day 3 (P=0.02). After administration of USPIO, no differences in signals were detected. Similarly, both visual analysis and signal T2∗ measurements in the enthesis were unable to distinguish the SpA-affected tendons from healthy ones (P=0.914). Neither the normal anatomy of the enthesis nor its pathological pattern could be distinguished using the standard RARE sequence. Histology confirmed the absence of USPIO in Achilles entheses, despite marked signs of inflammation. Conclusion. Unlike conventional RARE T2 Fat-Sat sequences, 3D-UTE sequences enable morphologic assessment of normal enthesis anatomy and early detection of abnormalities in pathological conditions. However, 3D multiecho UTE sequences combined with USPIO injections with T2∗ measurements were unable to detect macrophagic involvement in these pathological conditions.
The Association between Depression and Type 1 Diabetes Mellitus: Inflammatory Cytokines as Ferrymen in between?
Authors: Wang Kexin , Li Fangna , Cui Yixin , Cui Chunhui , Cao Zhenzhen , Xu Kai , Han Shuhong , Zhu Ping , Sun Yu
Published: March 2019

The depression incidence is much higher in patients with diabetes mellitus (DM), and the majority of these cases remain under-diagnosed. Type 1 diabetes mellitus (T1D) is now widely thought to be an organ-specific autoimmune disease. As a chronic autoimmune condition, T1D is characterized by T cell-mediated selective loss of insulin-producingβ-cells. The age of onset of T1D is earlier than T2D, and T1D patients have an increased vulnerability to depression due to its diagnosis and treatment burden occurring in a period when the individuals are young. The literature has suggested that inflammatory cytokines play a wide role in both diseases. In this review, the mechanisms behind the initiation and propagation of the autoimmune response in T1D and depression are analyzed, and the contribution of cytokines to both conditions is discussed. This review outlines the immunological mechanism of T1D and depression, with a particular emphasis on the role of tumor necrosis factor-α(TNF-α), IL-1β, and interferon-γ(IFN-γ) cytokines and their signaling pathways. The purpose of this review is to highlight the possible pathways of the cytokines shared by these two diseases via deciphering their cytokine cascades. They may provide a basic groundwork for future study of the possible mechanism that links these two diseases and to develop new compounds that target the same pathway but can conquer two diseases.
A Statistical Channel Model for Stochastic Antenna Inclination Angles
Authors: Liu Gang , Zhang Ming , Bo Yaming
Published: March 2019

The actions of a person holding a mobile device are not a static state but can be considered as a stochastic process since users can change the way they hold the device very frequently in a short time. The change in antenna inclination angles with the random actions will result in varied received signal intensity. However, very few studies and conventional channel models have been performed to capture the features. In this paper, the relationships between the statistical characteristics of the electric field and the antenna inclination angles are investigated and modeled based on a three-dimensional (3D) fast ray-tracing method considering both the diffraction and reflections, and the radiation patterns of an antenna with arbitrary inclination angles are deducted and included in the method. Two different conditions of the line-of-sight (LOS) and non-line-of-sight (NLOS) in the indoor environment are discussed. Furthermore, based on the statistical analysis, a semiempirical probability density function of antenna inclination angles is presented. Finally, a novel statistical channel model for stochastic antenna inclination angles is proposed, and the ergodic channel capacity is analyzed.
Uncertainty Quantification for the Transient Response of Human Equivalent Antenna Using the Stochastic Collocation Approach
Authors: Šušnjara Anna , Poljak Dragan
Published: March 2019

The paper deals with the uncertainty quantification of the transient axial current induced along the human body exposed to electromagnetic pulse radiation. The body is modeled as a straight wire antenna whose length and radius exhibit random nature. The uncertainty is propagated to the output transient current by means of the stochastic collocation method. The stochastic approach is entirely nonintrusive and serves as a wrapper around the deterministic code. The numerical deterministic model is based on the time domain Hallen integral equation solved by means of the Galerkin-Bubnov indirect boundary element method (GB-IBEM). The stochastic moments, i.e., the mean and the variance of the transient current, are calculated. Confidence margins are obtained for the whole duration of the transient response as well as for the maximal current value. The presented approach enables the estimation of the probability for the induced current to exceed the basic restrictions prescribed by regulatory bodies. The sensitivity analysis of the input parameters indicates to which extent the variation of the input parameter set influences the output values which is particularly interesting for the design of the human equivalent antenna.
Inhaled Nitric Oxide as an Adjunct to Thrombolytic Therapy in a Patient with Submassive Pulmonary Embolism and Severe Hypoxemia
Authors: Toolsie Omesh , Gomceli Umut , Diaz-Fuentes Gilda
Published: March 2019

Introduction. Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator with limited indications in adults. We present a patient with hypoxemia and right ventricular dysfunction due to submassive acute pulmonary emboli where iNO was used as a bridge to thrombolysis. Case. A 29-year-old male was admitted to the intensive care unit (ICU) for alcohol intoxication complicated with aspiration pneumonia and acute respiratory failure requiring mechanical ventilation. His medical history included morbid obesity (BMI 43) and alcohol dependence syndrome. Nine days after admission, he developed severe acute hypoxia and tachycardia with arterial oxygen tension (PaO2) of 52 mmHg requiring a positive end-expiratory pressure (PEEP) of 14 cmH2O and fraction of inspired oxygen (FiO2) of 1. Chest computed tomography (CT) revealed a large embolus in the right main pulmonary artery and transthoracic echocardiogram (TTE) reported new right ventricular dilatation with decreased right ventricular function. Due to the severe hypoxemia, he was started on iNO via the breathing circuit of the ventilator at a concentration of 20 parts per million (ppm) with steady improvement in oxygenation after 1 hour with a PaO2 of 81 mmHg on the same ventilator setting. The patient was given thrombolysis with alteplase and the iNO was slowly tapered off during the subsequent four days with concomitant successful tapering of PEEP to 8 cmH2O and FiO2 of 0.45. Conclusion. Inhaled NO has been used to improve ventilation-perfusion matching and also to reduce pulmonary vascular resistance (PVR). Its effects on PVR may be useful in the setting of acute pulmonary emboli where vascular obstruction and vasoconstriction contribute to increased pulmonary arterial pressure and PVR which can present as acute right heart failure. We suggest that iNO, if available, could be considered in those patients with acute pulmonary emboli associated with significant hypoxemia as an adjunctive therapy or bridge to thrombolysis or thrombectomy.
Primary Alveolar Rhabdomyosarcoma of the Breast in an Adult: An Extremely Rare Case
Authors: Trihia Helen J. , Novkovic Natasa , Provatas Ioannis , Mavrogiorgis Anastasios , Lianos Evangelos
Published: March 2019

Sarcomas of the breast constitute less than 1% of all malignant breast tumors and primary rhabdomyosarcoma (RMS) is a very rare entity with limited case reports in the literature. RMS is common in children and adolescents and rare in adults. Primary RMS arising from the breast is exceedingly rare in adults. We report a case of a primary RMS of the breast in a 60-year-old woman, who presented in an early stage, mimicking invasive ductal carcinoma clinically and is in complete remission after three years of diagnosis and one year of treatment.
Knowledge and Utilization of Iodized Salt and Its Associated Factors at Household Level in Mecha District, Northwest Ethiopia
Authors: Tariku Walleligne Beyene , Mazengia Amare Lisanu
Published: March 2019

Background. Iodine is one of the essential elements that enables the thyroid gland to produce thyroid hormones, which is vital for growth and development of the brain and central nervous system. More than two billion individuals worldwide live in iodine-deficient areas. Objectives. The aim of this study was to assess knowledge and utilization of iodized salt at the household level and associated factors in the Mecha district, Northwest Ethiopia. Methods. A community-based cross-sectional study was conducted from March 10 to April 10, 2018. Data were collected using a pretested and structured questionnaire by a face-to-face interview technique. The use of iodized salt at the household level was tested with the iodine rapid test kit. Data were checked, coded, and entered to EPi Info version 3.5.1 and were exported to SPSS (Statistical Package for Social Science) version 20 for analysis. Result. A total of 700 head of households were included in the study, of which 639 (91.3%) were females. The overall prevalence of knowledge was 201 (28.7%). Availability of adequately iodized salt was 443 (63.3%). The proportion of proper utilization of adequately iodized salt at the household level was 180 (25.7%). Occupational status, educational status, and residence were predictors of knowledge on the use of iodized salt. Educational status, packaging, and knowledge of respondents on iodized salt were significant to utilization. Conclusion and Recommendation. Knowledge, availability, and utilization of adequately iodized salt remain very low in the district. Concerned body should improve awareness and availability of adequately iodized salt and how to utilize it properly.
Anti-CD24 Antibody–Nitric Oxide Conjugate Selectively and Potently Suppresses Hepatic Carcinoma
Authors: Sun Fumou , Wang Yang , Luo Xiaojun , Ma Zhaoxiong , Xu Yao , Zhang Xinrong , Lv Tian , Zhang Yihua , Wang Min , Huang Zhangjian , Zhang Juan
Published: March 2019

Nitric oxide (NO) has a wide range of potential applications in tumor therapy. However, a targeted delivery system for NO donors has remained elusive, creating a bottleneck that limits its druggability. The antibody–drug conjugate (ADC) is a targeted drug delivery system composed of an antibody linked to an active cytotoxic drug. This design may compensate for the weak targeting ability and various biological functions of the NO donor. In this study, we designed the NO donor HL-2, which had a targeted, cleaved disulfide bond and an attachable maleimide terminal. We conjugated HL-2 with an antibody that targeted CD24 through a thioether bond to generate an ADC-like immunoconjugate, antibody-nitric oxide conjugate (ANC), which we named HN-01. HN-01 showed efficient internalization and significantly increased the release of NO in hepatic carcinoma cells in vitro. HN-01 induced apoptosis of tumor cells and suppressed tumor growth in hepatic carcinoma-bearing nude mice through antibody-dependent co-toxicity; HN-01 also increased NO levels in tumor cells. Collectively, this study expands the concept of ADC and provides an innovative NO donor and ANC to address current challenges in targeted delivery of NO. This new inspiration for an ANC design can also be used in future studies for other molecules with intracellular targets.

Significance:

This study is the first to expand the concept of ADC with an antibody-nitric oxide conjugate that suppresses hepatic carcinoma in vitro and in vivo.
Immunotherapy of Melanoma: Facts and Hopes
Authors: Weiss Sarah A. , Wolchok Jedd D. , Sznol Mario
Published: March 2019

Melanoma is among the most sensitive of malignancies to immune modulation. Although multiple trials conducted over decades with vaccines, cytokines, and cell therapies demonstrated meaningful responses in a small subset of patients with metastatic disease, a true increase in overall survival (OS) within a randomized phase III trial was not observed until the development of anti–CTLA-4 (ipilimumab). Further improvements in OS for metastatic disease were observed with the anti–PD-1–based therapies (nivolumab, pembrolizumab) as single agents or combined with ipilimumab. A lower bound for expected 5-year survival for metastatic melanoma is currently approximately 35% and could be as high as 50% for the nivolumab/ipilimumab combination among patients who would meet criteria for clinical trials. Moreover, a substantial fraction of long-term survivors will likely remain progression-free without continued treatment. The hope and major challenge for the future is to understand the immunobiology of tumors with primary or acquired resistance to anti–PD-1 or anti–PD-1/anti–CTLA-4 and to develop effective immune therapies tailored to individual patient subsets not achieving long-term clinical benefit. Additional goals include optimal integration of immune therapy with nonimmune therapies, the development and validation of predictive biomarkers in the metastatic setting, improved prognostic and predictive biomarkers for the adjuvant setting, understanding mechanisms of and decreasing toxicity, and optimizing the duration of therapy.
Targeting Multiple Myeloma with AMG 424, a Novel Anti-CD38/CD3 Bispecific T-cell–recruiting Antibody Optimized for Cytotoxicity and Cytokine Release
Authors: Zuch de Zafra Christina L. , Fajardo Flordeliza , Zhong Wendy , Bernett Matthew J. , Muchhal Umesh S. , Moore Gregory L. , Stevens Jennitte , Case Ryan , Pearson Joshua T. , Liu Siyuan , McElroy Patricia L. , Canon Jude , Desjarlais John R. , Coxon Angela , Balazs Mercedesz , Nolan-Stevaux Olivier
Published: March 2019

Purpose:

Despite advances in the treatment of multiple myeloma, new therapies are needed to induce more profound clinical responses. T-cell–redirected lysis triggered by bispecific antibodies recruiting T cells to cancer cells is a clinically validated mechanism of action against hematologic malignancies and CD38 is a tumor-associated antigen with near-universal expression in multiple myeloma. Thus, an anti-CD38/CD3 bispecific T-cell–recruiting antibody has the potential to be an effective new therapeutic for multiple myeloma.

Experimental Design:

Anti-CD38/CD3 XmAb T-cell–recruiting antibodies with different affinities for CD38 and CD3 were assessed in vitro and in vivo for their redirected T-cell lysis activity against cancer cell lines, their lower levels of cytokine release, and their potency in the presence of high levels of soluble CD38. Select candidates were further tested in cynomolgus monkeys for B-cell depletion and cytokine release properties.

Results:

AMG 424 was selected on the basis of its ability to kill cancer cells expressing high and low levels of CD38 in vitro and trigger T-cell proliferation, but with attenuated cytokine release. In vivo, AMG 424 induces tumor growth inhibition in bone marrow–invasive mouse cancer models and the depletion of peripheral B cells in cynomolgus monkeys, without triggering excessive cytokine release. The activity of AMG 424 against normal immune cells expressing CD38 is also presented.

Conclusions:

These findings support the clinical development of AMG 424, an affinity-optimized T-cell–recruiting antibody with the potential to elicit significant clinical activity in patients with multiple myeloma.
Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer
Authors: Kregel Steven , Malik Rohit , Asangani Irfan A. , Wilder-Romans Kari , Rajendiran Thekkelnaycke , Xiao Lanbo , Vo Josh N. , Soni Tanu , Cieslik Marcin , Fernadez-Salas Ester , Zhou Bing , Cao Xuhong , Speers Corey , Wang Shaomeng , Chinnaiyan Arul M.
Published: March 2019

Purpose:

The bromodomain and extraterminal (BET)-containing proteins (BRD2/3/4) are essential epigenetic coregulators for prostate cancer growth. BRD inhibitors have shown promise for treatment of metastatic castration-resistant prostate cancer (mCRPC), and have been shown to function even in the context of resistance to next-generation AR-targeted therapies such as enzalutamide and abiraterone. Their clinical translation, however, has been limited by off-target effects, toxicity, and rapid resistance.

Experimental Design:

We have developed a series of molecules that target BET bromodomain proteins through their proteasomal degradation, improving efficacy and specificity of standard inhibitors. We tested their efficacy by utilizing prostate cancer cell lines and patient-derived xenografts, as well as several techniques including RNA-sequencing, mass spectroscopic proteomics, and lipidomics.

Results:

BET degraders function in vitro and in vivo to suppress prostate cancer growth. These drugs preferentially affect AR-positive prostate cancer cells (22Rv1, LNCaP, VCaP) over AR-negative cells (PC3 and DU145), and proteomic and genomic mechanistic studies confirm disruption of oncogenic AR and MYC signaling at lower concentrations than BET inhibitors. We also identified increases in polyunsaturated fatty acids (PUFA) and thioredoxin-interacting protein (TXNIP) as potential pharmacodynamics biomarkers for targeting BET proteins.

Conclusions:

Compounds inducing the pharmacologic degradation of BET proteins effectively target the major oncogenic drivers of prostate cancer, and ultimately present a potential advance in the treatment of mCRPC. In particular, our compound dBET-3, is most suited for further clinical development.
Whole-Genome and Transcriptional Analysis of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer Demonstrates Intraclass Heterogeneity
Authors: Aggarwal Rahul R. , Quigley David A. , Huang Jiaoti , Zhang Li , Beer Tomasz M. , Rettig Matthew B. , Reiter Rob E. , Gleave Martin E. , Thomas George V. , Foye Adam , Playdle Denise , Lloyd Paul , Chi Kim N. , Evans Christopher P. , Lara Primo N. , Feng Felix Y. , Alumkal Joshi J. , Small Eric J.
Published: March 2019

Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) can be accompanied by treatment-emergent small-cell neuroendocrine carcinoma (t-SCNC), a morphologically distinct subtype. We performed integrative whole-genome and -transcriptome analysis of mCRPC tumor biopsies including paired biopsies after progression, and multiple samples from the same individual. t-SCNC was significantly less likely to have amplification of AR or an intergenic AR-enhancer locus, and demonstrated lower expression of AR and its downstream transcriptional targets. Genomic and transcriptional hallmarks of t-SCNC included biallelic loss of RB1, elevated expression levels of CDKN2A and E2F1, and loss of expression of the AR and AR-responsive genes including TMPRSS2 and NKX3-1. We identified three tumors that converted from adenocarcinoma to t-SCNC and demonstrate spatial and temporal intrapatient heterogeneity of metastatic tumors harboring adenocarcinoma, t-SCNC, or mixed expression phenotypes, with implications for treatment strategies in which dual targeting of adenocarcinoma and t-SCNC phenotypes may be necessary.

Implications:

The t-SCNC phenotype is characterized by lack of AR enhancer gain and loss of RB1 function, and demonstrates both interindividual and intraindividual heterogeneity.

Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/6/1235/F1.large.jpg.
Comparison Study of ASCO and TOAST Classification System in Chinese Minor Stroke Patients
Authors: Xin Xiao-Yu , Cheng Lin , Yang Zhao , Zhang Yu , Zeng Li-Li , Liu Jian-Rong
Published: March 2019

Background: Precise subtype classification based on underlying pathophysiology is important to prevent recurrent attack in minor stroke patients. A newly developed Atherosclerosis, Small vessel disease, Cardiac source, Others (ASCO) phenotypic classification system aims to characterize patients using different grades of evidence for stroke subtypes. However, this system has not been specifically applied to minor stroke population. In our study, the impact of using the newer ASCO criteria on minor stroke etiologies was investigated, and compared with that of Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. Methods: Consecutive patients with minor ischemic stroke (NIHSS ≤3) were assessed and subtyped by the ASCO and TOAST systems. Stroke etiologies were presented and compared. The McNemar test and k statistic were used to analyze the difference and concordance between the 2 algorithms, respectively. Results: A total of 604 first-ever minor stroke patients were analyzed in the present study. Using TOAST classification, large artery atherosclerosis was the most frequent subtype (281, 46.5%), followed by small artery occlusion category (165, 27.3%). When ASCO was applied, 37 different profiles of stroke etiologies were identified. Using grade 1 of evidence, atherosclerosis (A1) was the most frequent subtype (308, 51.0%), followed by small vessel disease (S1, 178, 29.5%). Under consideration of grades 1 and 2, 239 (39.6%) patients were classified into more than 1 category. The ASCO system revealed determined etiologies in 104 of the 137 patients classified to cause undetermined subtype by TOAST classification. Good to very good accordance was observed between ASCO grade 1 and TOAST schemes across etiologic subtypes (κ = 0.719–0.832) except cause undetermined category (κ = 0.470). Conclusion: Application of ASCO decreased the proportion of patients assigned to cause undermined category compared to TOAST system. Comprehensive characteristics of ASCO system might be helpful in the personalized therapy or secondary prevention for individual patients in the future.
Atrial Fibrillation Catheter Ablation Increases the Left Atrial Pressure
Authors: Park Je-Wook , Yu Hee Tae , Kim Tae-Hoon , Uhm Jae-Sun , Joung Boyoung , Lee Moon-Hyoung , Hwang Chun , Pak Hui-Nam
Published: March 2019

Background:

We previously reported that a high left atrial (LA) pressure is associated with LA stiffness and poor rhythm outcomes after de novo catheter ablation of atrial fibrillation. Herein, we investigated whether radiofrequency catheter ablation generally changes the LA pressure among patients undergoing repeat procedures.

Methods:

Among 1848 patients who underwent atrial fibrillation catheter ablation, we measured the LA pressure during sinus rhythm in 1687 patients before the de novo ablation (59±11 years, 72.4% men, 72.8% paroxysmal atrial fibrillation) and in 142 with second procedures. We measured the LA pressure immediately after the transseptal puncture at the beginning of the procedure.

Results:

In the same 142 patients, the degree of LA stiffness, reflected by the LA pulse pressure (LA
pp
), was significantly higher in the second procedure than in the de novo procedure (
P
<0.001). The degree of the LA
pp
increase (ΔLA
pp
) was significantly higher in patients who underwent additional extrapulmonary vein LA ablation than in those who underwent circumferential pulmonary vein isolation alone (
P
=0.010). Extrapulmonary vein LA ablation was independently associated with the ΔLA
pp
(β=5.70 [0.12–11.27];
P
=0.045). An increased LA
pp
during repeat procedures was independently associated with a reduced diastolic function (β=2.01 [0.08–3.93];
P
=0.041) without a worsening symptoms (EuroQol-five dimensions) score, 22.2±17.9 months after the de novo ablation.

Conclusions:

Atrial fibrillation catheter ablation, especially extrapulmonary vein LA ablation, increased the LA stiffness and was associated with a worsening postablation diastolic function. However, the symptom score did not significantly change.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02138695.
High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways
Authors: Åkerborg Örjan , Spalinskas Rapolas , Pradhananga Sailendra , Anil Anandashankar , Höjer Pontus , Poujade Flore-Anne , Folkersen Lasse , Eriksson Per , Sahlén Pelin
Published: March 2019

Background:

Genetic variant landscape of coronary artery disease is dominated by noncoding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct genes both to gain insights into perturbed functions and better assess the risk of disease.

Methods:

In this study, we generated high-resolution genomic interaction maps (≈750 bases) in aortic endothelial, smooth muscle cells and THP-1 (human leukemia monocytic cell line) macrophages stimulated with lipopolysaccharide using Hi-C coupled with sequence capture targeting 25 429 features, including variants associated with coronary artery disease. We also sequenced their transcriptomes and mapped putative enhancers using chromatin immunoprecipitation with an antibody against H3K27Ac.

Results:

The regions interacting with promoters showed strong enrichment for enhancer elements and validated several previously known interactions and enhancers. We detected interactions for 727 risk variants obtained by genome-wide association studies and identified novel, as well as established genes and functions associated with cardiovascular diseases. We were able to assign potential target genes for additional 398 genome-wide association studies variants using haplotype information, thereby identifying additional relevant genes and functions. Importantly, we discovered that a subset of risk variants interact with multiple promoters and their expression levels were strongly correlated.

Conclusions:

In summary, we present a catalog of candidate genes regulated by coronary artery disease–related variants and think that it will be an invaluable resource to further the investigation of cardiovascular pathologies and disease.
Device-Based Neuromodulation for Resistant Hypertension Therapy
Authors: Lohmeier Thomas E. , Hall John E.
Published: March 2019

Despite availability of effective drugs for hypertension therapy, significant numbers of hypertensive patients fail to achieve recommended blood pressure levels on ≥3 antihypertensive drugs of different classes. These individuals have a high prevalence of adverse cardiovascular events and are defined as having resistant hypertension (RHT) although nonadherence to prescribed antihypertensive medications is common in patients with apparent RHT. Furthermore, apparent and true RHT often display increased sympathetic activity. Based on these findings, technology was developed to treat RHT by suppressing sympathetic activity with electrical stimulation of the carotid baroreflex and catheter-based renal denervation (RDN). Over the last 15 years, experimental and clinical studies have provided better understanding of the physiological mechanisms that account for blood pressure lowering with baroreflex activation and RDN and, in so doing, have provided insight into which patients in this heterogeneous hypertensive population are most likely to respond favorably to these device-based therapies. Experimental studies have also played a role in modifying device technology after early clinical trials failed to meet key endpoints for safety and efficacy. At the same time, these studies have exposed potential differences between baroreflex activation and RDN and common challenges that will likely impact antihypertensive treatment and clinical outcomes in patients with RHT. In this review, we emphasize physiological studies that provide mechanistic insights into blood pressure lowering with baroreflex activation and RDN in the context of progression of clinical studies, which are now at a critical point in determining their fate in RHT management.