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1,646 results on '"E, Adam"'

56. Abstract 1111: Identification of selective IKZF2 degraders that reprogram suppressive regulatory T cells in solid tumors

Author

Thompson, Peggy A., primary, Yang, Pengyu, additional, Li, Xiaoming, additional, Chien, Stephen, additional, Spalding, Mary E., additional, Dearie, Alejandro, additional, Daniele, Elizabeth, additional, Yang, Linette, additional, Kallel, E Adam, additional, Jamborcic, Aleksandar, additional, Toth, Julia, additional, Parker, Gregory, additional, and Bailey, Simon, additional

Published
2022
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57. Abstract 421: PLX-3618, a potent, selective monovalent BRD4 degrader demonstrates activity in models of prostate cancer

Author

Steadman, Kenneth, primary, Parker, Gregory S., additional, Leriche, Geoffray, additional, Fish, Sarah, additional, Toth, Julia, additional, Spalding, Mary E., additional, Daniele, Elizabeth, additional, Jamborcic, Aleksandar, additional, Li, Xiaoming, additional, Kallel, E Adam, additional, Barmare, Farhana, additional, Chng, Kenneth, additional, Green, Erika, additional, Hocker, Michael, additional, Imler, Elliot, additional, Zhang, Yi, additional, Thompson, Peggy A., additional, and Bailey, Simon, additional

Published
2022
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58. Development and validation of colorimetric method for the determination of pregabalin in bulk and pharmaceutical formulations

Author

Tilal Elsaman, Mohammed A. E. Adam, Shaza W. Shantier, Areej Abdelmonim Mohamed, and Elrasheed A Gadkariem

Subjects
Absorption (pharmacology), Solvent, Detection limit, Chromatography, Chemistry, Reagent, Extraction (chemistry), Relative standard deviation, General Pharmacology, Toxicology and Pharmaceutics, Ascorbic acid, Routine analysis
Abstract

A simple, accurate and precise colorimetric method was developed for the quantification of pregabalin (PGN) in bulk and pharmaceutical formulations. The method was based on the production of a colored complex by reacting PGN with ascorbic acid in DMSO solvent. The resultant complex exhibits absorption maxima at 390 and 532 nm. The factors that affect the complex development and stability were studied and optimized. The reaction stoichiometry of drug: reagent was found to be 1:2. The method was then validated according to ICH guidelines. Regression analysis of Beer's plot showed good correlation (r2 value more than 0.998) within a concentration range of 5-30μg/ml. Linearity was confirmed by standardized residuals versus fitted value plots using Minitab14 software. The limits of detection and quantification at 390 and 532nm were 1.34μg/ml, 1.09μg/ml and 4.05μg/ml, 3.294μg/ml, respectively. Added recovery measurements were found to be 100.04±2.07% and 99.58 ±1.98% at 390nm and 532nm, respectively, which reflect the accuracy of the method and freedom from interference (relative standard deviation values were less than or equal 0.2%). The average assay for the commercial capsule preparation (PGN 150mg/capsule) was found to be 101.373±0.49 and 101.812±0.73 at 390 and 532nm, respectively. The developed method is an inexpensive, extraction free and can be applied for routine analysis of PGN in most of analytical laboratories.

Published
2020
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59. Synthesis, Structural and Magnetic properties of Mg 0.25 Co 0.75 Fe2OSynthesis, Structural and Magnetic properties of Mg 0.25 Co 0.75 Fe2O4 Nanoparticles Ferrites using Wet chemical routestes

Author

Mohamed I. M. Omer, Yousef A. Alsabah, Adam. A. E. Adam, and A.A. Elbadawi

Abstract

Ferrite nanoparticles are interesting materials due to their rich and unique physical and chemical properties. They find applications in catalysis, bio-processing, medicine, magnetic recording, adsorption, devices, etc. Nanoparticles of Mg0.25Co0.75Fe2O4 were synthesized by co-precipitation method. Using stable ferric, magnesium and cobalt salts with oleic acid as the surfactant Structural studies are carried out using X-ray diffraction (XRD). The XRD pattern of the sample provides information about single – phase formation of spinel structure with cubic symmetry and space group (SG Fd3m) and 0.834 nm lattice constant, which is confirmed by micro Raman measurements at room temperature. From the analysis of powder X-ray diffraction patterns, the nanocrystallite size was calculated from the most intense peak (3 1 1) using Scherrer formula. Thus, the size of the particles is found to be ~ 16 ± 5 nm. The lattice constant is obtained using XRD data. The structural morphology of the nanoparticles is studied using Scanning Electron Microscopy (SEM). Formation of spinel structure is confirmed using Fourier transform infrared spectroscopy (FTIR). Vibration frequency and force constant are discussed with the help of FTIR data. The M–H loop of Mg0.25Co0.75Fe2O4 has been traced using the Vibrating Sample Magnetometer (VSM) and magnetic parameters such as saturation magnetization (MS), coercivity (HC) and retentivity (MR) are obtained from VSM data. Mössbauer spectroscopy measurements revealed that the sample was ferromagnetic material. جزيئات الحديد النانوية تعد مواد جاذبة من خلال صفاتها الفيزيائية والكيميائية الفريدة. حيث يوجد استخدامها في المحفزات والعمليات الحيوية والطب والتسجسل المغناطيسي والادمصاص والأجهزة وغيرها. حُضِر مركب Mg 0.25 Co 0.75 Fe2O4 النانوي بطريقة البادرات المترافقة. باستخدام حديد واملاح المغنيسيوم والكوبالت المستقرة مع حمض الأوليك كمحفز. دُرِست الخصائص التركيبية عن طريق جهاز حيود الأشعة السينية (XRD) والتي اظهرت المعلومات المأخوذة من الطيف أن الطور أحادي ويأخذ التركيب البلوري المكعبي بشبيكة فراغية SG) (Fd3m وثابت شبيكة 0.834 nm، ودُعِم ذلك من خلال قياسات رامان في درجة حرارة الغرفة. من خلال تحليل طيف حيود الأشعة السينية حُسِب حجم الشبيكة النانوية عبر أعلى قمة (3 1 1) من خلال صيغة شيرار حيث وُجِد أن حجم الجسيمات حوالي .16 ± 5 nm إذ وُجِد ثابت الشبيكة من خلال بيانات جهاز حيود الأشعة السينية (XRD) والتركيب التضاريسي دُرِس عبر مطياف الماسح الألكتروني (SEM). الصيغة التركيبية للأسبنل أُكِدت باستخدم مطياف فورير للأشعة تحت الحمراء. والذي بمساعدة بياناته نوقِش التردد الأهتزازي وثابت القوه. منحنى M–H أُخِذ بمِغناط اهتزاز العينة (VSM) وكذلك المعاملات المغناطيسية مثل التشبع المغناطيسي (MS) و القسرية (HC) و التخلفية (MR). قياسات مطياف المسباور أظهرت أن العينة من المغناطيسيات الحديدية

Published
2020
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60. Embeddedness of Timelike Maximal Surfaces in $$(1+2)$$-Minkowski Space

Author

E. Adam Paxton

Subjects
Mathematics - Differential Geometry, Nuclear and High Energy Physics, Pure mathematics, FOS: Physical sciences, Unit tangent vector, General Relativity and Quantum Cosmology (gr-qc), 01 natural sciences, General Relativity and Quantum Cosmology, Mathematics - Analysis of PDEs, Planar, 0103 physical sciences, Minkowski space, FOS: Mathematics, Immersion (mathematics), 0101 mathematics, Mathematical Physics, Physics, Mean curvature, 010308 nuclear & particles physics, 010102 general mathematics, Tangent, Cauchy distribution, Statistical and Nonlinear Physics, Differential Geometry (math.DG), Embedding, Mathematics::Differential Geometry, Analysis of PDEs (math.AP)
Abstract

We prove that if$$\phi :\mathbb {R}^2 \rightarrow \mathbb {R}^{1+2}$$ϕ:R2→R1+2is a smooth, proper, timelike immersion with vanishing mean curvature, then necessarily$$\phi $$ϕis an embedding, and every compact subset of$$\phi (\mathbb {R}^2)$$ϕ(R2)is a smooth graph. It follows that if one evolves any smooth, self-intersecting spacelike curve (or any planar spacelike curve whose unit tangent vector spans a closed semi-circle) so as to trace a timelike surface of vanishing mean curvature in$$\mathbb {R}^{1+2}$$R1+2, then the evolving surface will either fail to remain timelike, or it will fail to remain smooth. We show that, even allowing for null points, such a Cauchy evolution will be$$C^2$$C2inextendible beyond some singular time. In addition we study the continuity of the unit tangent for the evolution of a self-intersecting curve in isothermal gauge, which defines a well-known evolution beyond singular time.

Published
2020
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62. Development and Validation of Uv-Spectrophotometric Method for the Determination of Atorvastatin Calcium Using Sodium Citrate as Hydrotropic Agent

Author

Enas Ibrahim, Tilal Elsaman, and Mohamed E. Adam

Subjects
Pharmacology, Detection limit, Chromatography, 010405 organic chemistry, Chemistry, Atorvastatin, Uv absorbance, 01 natural sciences, Dosage form, 0104 chemical sciences, Drug content, 010404 medicinal & biomolecular chemistry, chemistry.chemical_compound, Atorvastatin calcium, Standard addition, Drug Discovery, Sodium citrate, medicine, medicine.drug
Abstract

Simple, rapid, precise, accurate and specific UV-spectrophotometric method has been developed for atorvastatin calcium determination in bulk and in tablets dosage form. The method was based on using sodium citrate 0.01M as hydrotropic agent. Measurements of the UV absorbance were performed at 241 nm, and the developed method was validated as per ICH guidelines. The method obeyed Beer’s law (R2 = 0.999) in a concentration range of 2 – 20 μg/mL. The limits of detection (LOD) and quantification (LOQ) were 0.64 and 1.9 μg/mL, respectively. At all levels of precision, RSD% values were below 2%. Accuracy of the proposed method was ascertained by standard addition method and the percentage recovery (n = 3) was within 100 – 100.43%. The method was applied to analysis of three atorvastatin tablet brands each claimed to contain 20 mg atorvastatin, and the percentage drug content was found to be 101.42 ± 1.56%, 99.04 ± 0.33%, and 97.71 ± 0.98%.

Published
2020
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63. Climate Modelling in Low-Precision: Effects of both Deterministic & Stochastic Rounding

Author

E. Adam Paxton, Tim Palmer, Milan Klöwer, Matthew Chantry, and Leo Saffin

Subjects
Atmospheric Science, Computer science, Rounding, Weather forecasting, FOS: Physical sciences, Double-precision floating-point format, Atmospheric model, computer.software_genre, Physics - Atmospheric and Oceanic Physics, Wasserstein metric, Climatology, Atmospheric and Oceanic Physics (physics.ao-ph), Range (statistics), Climate model, Round-off error, computer, Algorithm
Abstract

Motivated by recent advances in operational weather forecasting, we study the efficacy of low-precision arithmetic for climate simulations. We develop a framework to measure rounding error in a climate model, which provides a stress test for a low-precision version of the model, and we apply our method to a variety of models including the Lorenz system, a shallow water approximation for flow over a ridge, and a coarse-resolution spectral global atmospheric model with simplified parameterizations (SPEEDY). Although double precision [52 significant bits (sbits)] is standard across operational climate models, in our experiments we find that single precision (23 sbits) is more than enough and that as low as half precision (10 sbits) is often sufficient. For example, SPEEDY can be run with 12 sbits across the code with negligible rounding error, and with 10 sbits if minor errors are accepted, amounting to less than 0.1 mm (6 h)−1 for average gridpoint precipitation, for example. Our test is based on the Wasserstein metric and this provides stringent nonparametric bounds on rounding error accounting for annual means as well as extreme weather events. In addition, by testing models using both round-to-nearest (RN) and stochastic rounding (SR) we find that SR can mitigate rounding error across a range of applications, and thus our results also provide some evidence that SR could be relevant to next-generation climate models. Further research is needed to test if our results can be generalized to higher resolutions and alternative numerical schemes. However, the results open a promising avenue toward the use of low-precision hardware for improved climate modeling. Significance Statement Weather and climate models provide vital information for decision-making, and will become ever more important in the future with a changed climate and more extreme weather. A central limitation to improved models are computational resources, which is why some weather forecasters have recently shifted from conventional 64-bit to more efficient 32-bit computations, which can provide equally accurate forecasts. Climate models, however, still compute in 64 bits, and adapting to lower precision requires a detailed analysis of rounding errors. We develop methods to quantify rounding error in a climate model, and find similar precision acceptable across weather and climate models, with even 16 bits often sufficient for an accurate climate. This opens a promising avenue for computational efficiency gains in climate modeling.

Published
2022
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68. Quantifying head impacts and neurocognitive performance in collegiate boxers

Author

Brandon K, Doan, Kristin J, Heaton, Brian P, Self, Michelle A, Butler Samuels, and Gina E, Adam

Subjects
Male, Cognition, Acceleration, Humans, Boxing, Neuropsychological Tests, Brain Concussion
Abstract

Head impacts and neurocognition were quantified in 27 intercollegiate male boxers engaged in two, two-minute sparring rounds. Head impacts were measured using Instrumented Boxing Headgear (IBH). Pre and post-sparring neurocognitive performance was compared using two computerized neuropsychological test batteries (CNTs): Immediate Post-concussion Assessment and Cognitive Testing (ImPACT™) and Automated Neuropsychological Assessment Metrics - Military Battery (ANAM4® MIL). An average of 27.63 ± 17.87 impacts above the 9.6 g IBH threshold were recorded per boxer, with average peak linear acceleration of 23.48 ± 15.20 g and average peak rotational acceleration of 1761.40 ± 1064.34 rad/s

Published
2021

69. Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery.

Author

Sean Ekins, Jair Lage de Siqueira-Neto, Laura-Isobel McCall, Malabika Sarker, Maneesh Yadav, Elizabeth L Ponder, E Adam Kallel, Danielle Kellar, Steven Chen, Michelle Arkin, Barry A Bunin, James H McKerrow, and Carolyn Talcott

Subjects
Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract

BACKGROUND:Chagas disease is a neglected tropical disease (NTD) caused by the eukaryotic parasite Trypanosoma cruzi. The current clinical and preclinical pipeline for T. cruzi is extremely sparse and lacks drug target diversity. METHODOLOGY/PRINCIPAL FINDINGS:In the present study we developed a computational approach that utilized data from several public whole-cell, phenotypic high throughput screens that have been completed for T. cruzi by the Broad Institute, including a single screen of over 300,000 molecules in the search for chemical probes as part of the NIH Molecular Libraries program. We have also compiled and curated relevant biological and chemical compound screening data including (i) compounds and biological activity data from the literature, (ii) high throughput screening datasets, and (iii) predicted metabolites of T. cruzi metabolic pathways. This information was used to help us identify compounds and their potential targets. We have constructed a Pathway Genome Data Base for T. cruzi. In addition, we have developed Bayesian machine learning models that were used to virtually screen libraries of compounds. Ninety-seven compounds were selected for in vitro testing, and 11 of these were found to have EC50 < 10 μM. We progressed five compounds to an in vivo mouse efficacy model of Chagas disease and validated that the machine learning model could identify in vitro active compounds not in the training set, as well as known positive controls. The antimalarial pyronaridine possessed 85.2% efficacy in the acute Chagas mouse model. We have also proposed potential targets (for future verification) for this compound based on structural similarity to known compounds with targets in T. cruzi. CONCLUSIONS/ SIGNIFICANCE:We have demonstrated how combining chemoinformatics and bioinformatics for T. cruzi drug discovery can bring interesting in vivo active molecules to light that may have been overlooked. The approach we have taken is broadly applicable to other NTDs.

Published
2015
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72. A cross-sectional survey to establish Theileria parva prevalence and vector control at the wildlife-livestock interface, Northern Tanzania

Author

Emmanuel Sindoya, Rachel S. Lea, Jennifer S. Lord, Harriet Auty, Edith Paxton, Furaha Mramba, Geofrey Mbata, Mechtilda Byamungu, Katherine E. Adam, Ian Handel, Liam J. Morrison, W. Ivan Morrison, Fiona K. Allan, and Stephen J. Torr

Subjects
Veterinary medicine, Livestock, Theileria parva, Animals, Wild, Tick, Tanzania, Article, Wildlife-livestock interface, Food Animals, parasitic diseases, Theileria, Prevalence, Rhipicephalus, Animals, East Coast fever, Acaricides, qx_4, Tick Control, biology, business.industry, Acaricide, biology.organism_classification, qx_45, Tick Infestations, Cross-Sectional Studies, qx_479, Herd, Cattle, Animal Science and Zoology, Vector, Rhipicephalus appendiculatus, business
Abstract

East Coast fever (ECF) in cattle is caused by the protozoan parasite Theileria parva, transmitted by Rhipicephalus appendiculatus ticks. In cattle ECF is often fatal, causing annual losses >$500 million across its range. The African buffalo (Syncerus caffer) is the natural host for T. parva but the transmission dynamics between wild hosts and livestock are poorly understood. This study aimed to determine the prevalence of T. parva in cattle, in a 30 km zone adjacent to the Serengeti National Park, Tanzania where livestock and buffalo co-exist, and to ascertain how livestock keepers controlled ECF and other vector-borne diseases of cattle.\ud \ud A randomised cross-sectional cattle survey and questionnaire of vector control practices were conducted. Blood samples were collected from 770 cattle from 48 herds and analysed by PCR to establish T. parva prevalence. Half body tick counts were recorded on every animal. Farmers were interviewed (n = 120; including the blood sampled herds) using a standardised questionnaire to obtain data on vector control practices. Local workshops were held to discuss findings and validate results.\ud \ud Overall prevalence of T. parva in cattle was 5.07% (CI: 3.70-7.00%), with significantly higher prevalence in older animals. Although all farmers reported seeing ticks on their cattle, tick counts were very low with 78% cattle having none. Questionnaire analysis indicated significant acaricide use with 79% and 41% of farmers reporting spraying or dipping with cypermethrin-based insecticides, respectively. Some farmers reported very frequent spraying, as often as every four days. However, doses per animal were often insufficient.\ud \ud These data indicate high levels of acaricide use, which may be responsible for the low observed tick burdens and low ECF prevalence. This vector control is farmer-led and aimed at both tick- and tsetse-borne diseases of livestock. The levels of acaricide use raise concerns regarding sustainability; resistance development is a risk, particularly in ticks. Integrating vaccination as part of this community-based disease control may alleviate acaricide dependence, but increased understanding of the Theileria strains circulating in wildlife-livestock interface areas is required to establish the potential benefits of vaccination.

Published
2021
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73. Some Neutrosophic Triplet Subgroup Properties and Homomorphism Theorems in Singular Weak Commutative Neutrosophic Extended Triplet Group

Author

T`Em´ıt´O.P´E. Gb´O. L´Ah`An Jaiy´Eo. L´A, K´E.H`ınd´E Adam Ol´Urˇod`E, and Benard Osoba

Subjects
Mathematics::General Mathematics, Group, Neutrosophic Extended Triplet Group, Weakly Commutative Neutrosophic Extended Triplet Group, Isomorphism Theorems
Abstract

In 2018, the study of neutrosophic triplet cosets and neutrosophic triplet quotient group of a neutrosophic extended triplet group was initiated with a follow up of the establishment of fundamental homomorphism theorems for neutrosophic extended triplet group. But some lapses in these earlier results were identified and revised through the introducing of special kind of weak commutative neutrosophic extended triplet group (WCNETG) called perfect neutrosophic extended triplet group. Furthermore, neutro-homomorphism basic theorem has been established for commutative neutrosophic extended triplet group. In this current work, the generalization and extention of the above results was done by investigating neutro-homomorphism in singular WCNETG. This was achieved with the introduction and study of some new types of NT-subgroups that are right (left) cancellative, semi-strong, and maximally normal in a singular WCNETG. For any given non-empty subset S and NT-subgroup H of a singular WCNETG X, some of these new NT-subgroups were shown to exist as non-empty neutrosophic triplet normalizer, generated subset and centralizer of S, closure of H, derived subset of X and center of X. With these, the first, second and third neutro-isomorphism and neutro-correspondence theorems were established. This finally led to the proof of the neutro-Zassenhaus Lemma (Neutro-Butterfly Theorem).

Published
2021
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74. Design and Validation of UV Spectrophotometric Method for Estimation and the Routine Quality Control Analysis of Sildenafil Citrate in Bulk and in Tablet Formulations

Author

Abdrhman Mahmoud Gamil, Fatehalrahman F. Magbool, Mohamd E. Adam, and Mahmoud A. Ibrahim

Subjects
chemistry.chemical_compound, Chromatography, chemistry, Sildenafil, Sildenafil citrate, UV Spectrophotometric method, Validation, Correlation coefficient, Quality control, media_common.quotation_subject, Quality (business), Mathematics, media_common
Abstract

A Simple, sensitive, specific, UV Spectrophotometric method has been designed and developed for the determination of sildenafil citrate in bulk power and in pharmaceutical dosage form as well as its application for the routine quality control analysis of Sildenafil in bulk as well as in tablet formulations. The optimum condition for the analysis of the drug was established. Sildenafil citrate exhibiting absorption at 295 nm. The proposed method exhibited good levels of detection and quantitation. The specificity of the method was determined by checking the interference of placebo with analyte. There was no interference is observed. The regression equation for the Beer-Lambert’s plot of pure Sildenafil citrate was found to be; Y = 0.190 x and the correlation coefficient (R2) of 0.9990. The Beer’s plot was obeyed in concentration range between 0.001-0.005 mg/mL. There is good correlation between absorbance and concentration. Which is the basis of this method of analysis. The repeatability and intermediate precision were also assessed. The developed method was found to be precise as the % RSD values. The application of the validated method to the three brands showed that all brands had values within the range specified in the IP (90-110%). The results and the statistical parameters demonstrate that the proposed UV spectrophotometric method is simple, rapid, specific, accurate and precise. Since the method can be used for estimation and routine quality control of Sildenafil in bulk as well as in tablet formulations.

Published
2021

78. Mass-Spectrometry Analysis of Mixed-Breath, Isolated-Bronchial-Breath, and Gastric-Endoluminal-Air Volatile Fatty Acids in Esophagogastric Cancer

Author

Mina E. Adam, Piers R. Boshier, Matyas Fehervari, Sung-Tong Chin, Andrea Romano, George B. Hanna, Geng-Ping Lin, and Sacheen Kumar

Subjects
medicine.medical_specialty, Esophageal Neoplasms, 010402 general chemistry, Mass spectrometry, 01 natural sciences, Gastroenterology, Gas Chromatography-Mass Spectrometry, Mass Spectrometry, Analytical Chemistry, Butyric acid, chemistry.chemical_compound, Volatile fatty acids, Stomach Neoplasms, In vivo, Esophagogastric cancer, Internal medicine, medicine, Humans, Upper gastrointestinal, Breath test, medicine.diagnostic_test, 010401 analytical chemistry, Fatty Acids, Volatile, 0104 chemical sciences, Breath Tests, ROC Curve, chemistry, Case-Control Studies, Ex vivo
Abstract

A noninvasive breath test has the potential to improve survival from esophagogastric cancer by facilitating earlier detection. This study aimed to investigate the production of target volatile fatty acids (VFAs) in esophagogastric cancer through analysis of the ex vivo headspace above underivatized tissues and in vivo analysis within defined anatomical compartments, including analysis of mixed breath, isolated bronchial breath, and gastric-endoluminal air. VFAs were measured by PTR-ToF-MS and GC-MS. Levels of VFAs (acetic, butyric, pentanoic, and hexanoic acids) and acetone were elevated in ex vivo experiments in the headspace above esophagogastric cancer compared with the levels in samples from control subjects with morphologically normal and benign conditions of the upper gastrointestinal tract. In 25 patients with esophagogastric cancer and 20 control subjects, receiver-operating-characteristic analysis for the cancer-specific VFAs butyric acid ( P0.001) and pentatonic acid ( P = 0.005) within in vivo gastric-endoluminal air gave an area under the curve of 0.80 (95% confidence interval of 0.65 to 0.93, P = 0.01). Compared with mixed- and bronchial-breath samples, all examined VFAs were found in highest concentrations within esophagogastric-endoluminal air. In addition, VFAs were higher in all samples derived from cancer patients compared with in the controls. Equivalence of VFA levels within the mixed and bronchial breath of cancer patients suggests that their origin within breath is principally derived from the lungs and, by inference, from the systemic circulation as opposed to direct passage from the upper gastrointestinal tract. These findings highlight the potential to utilize VFAs for endoluminal-gas biopsies and noninvasive mixed-exhaled-breath testing for esophagogastric-cancer detection.

Published
2019
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80. Endogenous aldehyde accumulation generates genotoxicity and exhaled biomarkers in esophageal adenocarcinoma

Author

Christopher J. Peters, Haonan Lu, Mina E. Adam, Piers R. Boshier, Hani Gabra, George B. Hanna, Tom Wiggins, Zoltan Takats, Zsolt Bodai, Francesca Rosini, Nagy A. Habib, Robert D. Goldin, Yan Mei Goh, Sheraz R. Markar, Hiromi Kudo, Catherine M. Green, Daniela Moralli, Rebecca C. Fitzgerald, Stefan Antonowicz, Imperial College London, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, University of Cambridge [UK] (CAM), Antonowicz, Stefan [0000-0002-9182-7753], Goh, Yan Mei [0000-0001-6964-0979], Goldin, Robert [0000-0001-5184-4519], Moralli, Daniela [0000-0001-7977-8496], Gabra, Hani [0000-0002-3322-4399], Fitzgerald, Rebecca C [0000-0002-3434-3568], Hanna, George B [0000-0003-2897-0140], Apollo - University of Cambridge Repository, INSERM, Université de Lille, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192, University of Cambridge [UK] [CAM], Fitzgerald, Rebecca C. [0000-0002-3434-3568], and Hanna, George B. [0000-0003-2897-0140]

Subjects
0301 basic medicine, Esophageal Neoplasms, [SDV]Life Sciences [q-bio], General Physics and Astronomy, 692/4028/67/1504/1477, Endogeny, medicine.disease_cause, Aldehyde, chemistry.chemical_compound, DNA Adducts, 0302 clinical medicine, chemistry.chemical_classification, Multidisciplinary, Chemistry, Oesophageal cancer, food and beverages, 140/58, Aldehyde Oxidoreductases, Metformin, Multidisciplinary Sciences, 030220 oncology & carcinogenesis, Toxicity, 38/77, Science & Technology - Other Topics, medicine.drug, Science, 631/337/1427/1979, Adenocarcinoma, Article, General Biochemistry, Genetics and Molecular Biology, 82/80, 03 medical and health sciences, Esophagus, Detoxification, medicine, Biomarkers, Tumor, Metabolomics, Humans, DNA adducts, Aldehydes, Science & Technology, 631/45/320, General Chemistry, Decanal, Aldehyde Dehydrogenase, Genes, p53, In vitro, 030104 developmental biology, Cancer research, sense organs, Genotoxicity, DNA Damage
Abstract

Volatile aldehydes are enriched in esophageal adenocarcinoma (EAC) patients’ breath and could improve early diagnosis, however the mechanisms of their production are unknown. Here, we show that weak aldehyde detoxification characterizes EAC, which is sufficient to cause endogenous aldehyde accumulation in vitro. Two aldehyde groups are significantly enriched in EAC biopsies and adjacent tissue: (i) short-chain alkanals, and (ii) medium-chain alkanals, including decanal. The short-chain alkanals form DNA-adducts, which demonstrates genotoxicity and confirms inadequate detoxification. Metformin, a putative aldehyde scavenger, reduces this toxicity. Tissue and breath concentrations of the medium-chain alkanal decanal are correlated, and increased decanal is linked to reduced ALDH3A2 expression, TP53 deletion, and adverse clinical features. Thus, we present a model for increased exhaled aldehydes based on endogenous accumulation from reduced detoxification, which also causes therapeutically actionable genotoxicity. These results support EAC early diagnosis trials using exhaled aldehyde analysis., Volatile aldehydes can be enriched in esophageal adenocarcinoma patients’ breath. Here, the authors reveal corresponding metabolic changes in EAC tumours, which may be caused by impaired detoxification of endogenous metabolites.

Published
2021
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82. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), Willer, C. J. (Cristen J.), Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), and Willer, C. J. (Cristen J.)

Abstract

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4‐23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.

Published
2021

83. Abstract 421: PLX-3618, a potent, selective monovalent BRD4 degrader demonstrates activity in models of prostate cancer

Author

Kenneth Steadman, Gregory S. Parker, Geoffray Leriche, Sarah Fish, Julia Toth, Mary E. Spalding, Elizabeth Daniele, Aleksandar Jamborcic, Xiaoming Li, E Adam Kallel, Farhana Barmare, Kenneth Chng, Erika Green, Michael Hocker, Elliot Imler, Yi Zhang, Peggy A. Thompson, and Simon Bailey

Subjects
Cancer Research, Oncology
Abstract

Prostate cancer is the second most common cause of cancer related deaths in men in the United States. Pathogenesis is driven by the androgen receptor (AR), which has led to front-line treatment modalities that are based on androgen deprivation therapy (ADT). About 10-20% of all prostate cancers evolve to resist ADT and are classified as castration-resistant prostate cancer (CRPC) indicating the continued need for new treatment options. Bromodomain-containing protein 4 (BRD4) is an acetylated-chromatin associating protein that is involved in transcriptional elongation, mRNA splicing, epigenetic bookmarking, and super-enhancer activity. The BRD4 protein has been shown to both bind and colocalize with AR at androgen response elements (AREs) on chromatin. Furthermore, elevated BRD4 expression is prognostic of increased prostate specific antigen (PSA) levels following radical prostatectomy and is correlated with higher Gleason scores and poor overall survival. The intertwined activity of BRD4 with multiple essential driver mechanisms of prostate cancer suggests it may be a key target for developing novel therapeutics. Using our ultra-high throughput cell-based screening platform, which directly measures degradation of pathogenic proteins upon exposure to diverse chemical libraries, we identified a series of novel monovalent BRD4 degraders that was optimized to produce our lead compound PLX-3618. A cancer cell panel screen for antiproliferative effects of PLX-3618 indicated enhanced sensitivity in subsets of prostate cancer lines. PLX-3618 elicited selective, rapid, and deep degradation of BRD4 protein in prostate cancer cell models, without degrading the closely related BRD2 and BRD3 proteins. Addition of either proteosome or neddylation inhibitors blocked BRD4 degradation indicating a ubiquitin-proteosome system mediated clearance mechanism. Degradation of BRD4 led to sustained multimodal inhibition of the AR pathway and disruption of key oncogene enhancer networks. When compared to pan-BET inhibitors, treatment of select prostate cancer cell lines with PLX-3618 resulted in increased levels of the tumor suppressors p53 and p21, an aberrant DNA damage response, and substantially amplified apoptosis. Finally, in in vivo preclinical models of prostate cancer, PLX-3618 showed far superior efficacy over a pan-BET inhibitor. Taken together, the selective degradation of BRD4 via the potent monovalent degrader PLX-3618 represents a novel strategy in treating prostate cancer. Citation Format: Kenneth Steadman, Gregory S. Parker, Geoffray Leriche, Sarah Fish, Julia Toth, Mary E. Spalding, Elizabeth Daniele, Aleksandar Jamborcic, Xiaoming Li, E Adam Kallel, Farhana Barmare, Kenneth Chng, Erika Green, Michael Hocker, Elliot Imler, Yi Zhang, Peggy A. Thompson, Simon Bailey. PLX-3618, a potent, selective monovalent BRD4 degrader demonstrates activity in models of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 421.

Published
2022
Full Text
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84. Abstract 1111: Identification of selective IKZF2 degraders that reprogram suppressive regulatory T cells in solid tumors

Author

Peggy A. Thompson, Pengyu Yang, Xiaoming Li, Stephen Chien, Mary E. Spalding, Alejandro Dearie, Elizabeth Daniele, Linette Yang, E Adam Kallel, Aleksandar Jamborcic, Julia Toth, Gregory Parker, and Simon Bailey

Subjects
Cancer Research, Oncology
Abstract

Targeted protein degradation (TPD) using the endogenous Ubiquitin Proteasome System (UPS) is a rapidly growing drug discovery strategy to eliminate pathogenic proteins. Molecular glues are small molecules that promote a novel interaction between a protein of interest with an E3 ubiquitin ligase leading to proximity induced protein degradation. This has enabled targeting undruggable proteins, such as the zinc-finger transcription factor Helios (IKZF2), that have no known small molecule binding pocket. Despite recent clinical breakthroughs in checkpoint blockade in treating solid tumors, suppression of the antitumor immune response in the tumor microenvironment (TME) is a major obstacle to tumor regression. Regulatory T cells (Tregs) in the TME are potent immunosuppressive cells that promote progression of cancer. IKZF2 has been shown to be a marker of highly suppressive Treg cells and is critical for maintaining the anergic and suppressive phenotype in the highly inflammatory tumor microenvironment. Genetic depletion of IKZF2 in Treg cells results in both loss of suppressive activity and conversion of Tregs into T effector cells, leading to enhanced anti-tumor immunity. Collectively, these findings support that an IKZF2-specific degrader could be beneficial in enhancing the efficacy of current immunotherapies. Here we report our efforts leading to the development of a series of potent and selective IKZF2 degraders for the treatment of cancer. Our lead compound, PLX-4107, is a novel molecular glue that was optimized to be a highly selective, deep, and rapid IKZF2 degrader via the redirection of the E3 substrate receptor, cereblon. Proteome-wide analysis demonstrated that PLX-4107 depletes IKZF2 protein levels without degrading other known cereblon neo-substrates. PLX-4107 mediated degradation of IKZF2 resulted in conversion of highly suppressive Tregs into T effector cells, coupled with an increased expression of the effector cytokines IL2 and IFNγ. Oral administration of PLX-4107 to cynomolgus monkeys caused rapid, complete, and prolonged degradation of IKZF2 in Tregs, indicative of the catalytic nature of degraders where sustained pharmacodynamic response is observed well beyond plasma drug exposure levels. These preliminary data provide a strong rationale for developing small molecule therapeutics that target the undruggable IKZF2 transcription factor with the potential to enhance the efficacy of immune checkpoint therapy. Citation Format: Peggy A. Thompson, Pengyu Yang, Xiaoming Li, Stephen Chien, Mary E. Spalding, Alejandro Dearie, Elizabeth Daniele, Linette Yang, E Adam Kallel, Aleksandar Jamborcic, Julia Toth, Gregory Parker, Simon Bailey. Identification of selective IKZF2 degraders that reprogram suppressive regulatory T cells in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1111.

Published
2022
Full Text
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86. The Disciplines Speak I : Rewarding the Scholarly, Professional, and Creative Work of Faculty

Author

Robert M Diamond, Bronwyn E Adam, Robert M Diamond, and Bronwyn E Adam

Subjects
LB2333
Abstract

This set of two volumes offers statements from disciplinary/professional societies on what faculty work deserves recognition and reward in their unique culture/community. Volume I covers religion, history, geography, math, chemistry, the arts, business, journalism, and family/consumer science, plus the National Education Association.

Published
2023

88. [Pregastroplasty psychological assessment at the CHU of Liege using the BIPASS]

Author

I, Mayers, V, Charland-Verville, A, De Roover, A, Haumann, L, Kohnen, J, De Flines, and E, Adam

Subjects
Treatment Outcome, Bariatric Surgery, Humans, Comorbidity, Obesity, Obesity, Morbid
Abstract

Obesity is a chronic disease that has become a major public health problem with a prevalence that has doubled in the past two decades in most industrialized and developing countries. Currently, bariatric surgery represents the most effective treatment for extreme or severe overweight (BMI ? 40 kg/m² or ? 35 kg/m2 with weight-related comorbidities). Pre-operative bariatric surgery psychiatric and psychological assessment is essential for various reasons. In addition to the selection of candidates for the operation, its objectives are to prepare patients for future postoperative changes as well as to optimize their psychological and psychiatric care. This article describes a standardized tool, the BIPASS (Bariatric Interprofessional Psychosocial Assessment Suitability Scale), which allows a quality assessment in the field.L’obésité est une maladie chronique devenue un problème de santé publique majeur, avec une prévalence qui a doublé au cours des deux dernières décennies dans la majaorité des pays industrialisés et en voie de développement. Actuellement, la chirurgie bariatrique représente le traitement le plus efficace afin de remédier à cette problématique de surcharge pondérale sévère (IMC ? 40 ou ? 35 kg/m² avec complications). L’évaluation psychiatrique et psychologique préopératoire dans le cadre d’une chirurgie bariatrique s’impose pour divers enjeux. Outre la sélection des candidats à l’opération, ses objectifs sont, notamment, de préparer au mieux les patients aux changements futurs postopératoires ainsi que d’optimiser leur prise en charge psychologique et, éventuellement, psychiatrique. Cet article décrit un outil standardisé, le BIPASS (Bariatric Interprofessional Psychosocial Assessment Suitability Scale), qui permet une évaluation de qualité dans le domaine.

Published
2020

89. Unraveling novel survivin mRNA transcripts in cancer cells using an in-house developed targeted high-throughput sequencing approach

Author

Panagiotis G. Adamopoulos, Eleni E. Adam, Andreas Scorilas, and Panagiotis Tsiakanikas

Subjects
0106 biological sciences, Cellular differentiation, Survivin, Computational biology, Biology, Inhibitor of apoptosis, 01 natural sciences, DNA sequencing, 03 medical and health sciences, Exon, Jurkat Cells, Genetics, Humans, RNA, Messenger, Gene, 030304 developmental biology, 0303 health sciences, Alternative splicing, High-Throughput Nucleotide Sequencing, Hep G2 Cells, HCT116 Cells, Alternative Splicing, HEK293 Cells, A549 Cells, Cancer cell, MCF-7 Cells, Caco-2 Cells, HT29 Cells, 010606 plant biology & botany, HeLa Cells
Abstract

The human baculoviral IAP repeat containing 5 (BIRC5), also known as survivin, is a conserved member of the inhibitor of apoptosis protein (IAPs) family, which is normally expressed during embryonic and fetal development. Although the expression levels of survivin are low in terminally differentiated cells and/or tissues, they can be found notably increased in certain pathological conditions including malignant tumors. Conventional cloning and sequencing techniques have already confirmed that alternative splicing events of the survivin pre-mRNA result in five distinct alternative transcript variants. In the present study, however, we implemented an innovative, in-house developed, targeted DNA-seq assay to identify novel survivin alternative transcript variants with increased depth and coverage that high-throughput sequencing approaches offer. Bioinformatics analysis of the derived NGS datasets unveiled several novel splice junctions between annotated exons of survivin gene as well as the existence of a novel exon of 117 nt, spanning between the annotated exons 3 and 3B. Validation of the NGS findings with PCR-based assays, using variant-specific primers, led to the identification of fourteen novel survivin alternative splice variants (BIRC5 v.4 - v.17), which demonstrate wide expression profiles in a broad established panel of human cell lines. Although the presented novel findings provide a crystal-clear overview of the survivin mRNAs that are actually generated from the pre-mRNA, future studies should focus on the impending necessity of characterizing the biological function of all novel alternative transcript variants as well as the putative protein isoforms. Such studies will further contribute to our understanding of how the balance between survivin isoforms regulate malignant cell proliferation and apoptosis, providing novel diagnostic, prognostic and predictive biomarkers as well as therapeutic targets.

Published
2020

90. Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors

Author

Eric Brown, E. Adam Kallel, Donald D. Lorimer, Arshil Master, Ken McCormack, Alexandra Fetsko, David M. Dranow, Nadezda V. Sokolova, Rana Sidhu, Alexander N. Freiberg, Vidyasagar Reddy Gantla, Plewe Michael Bruno, Jameson Bullen, Greg Henkel, Junru Wang, Shibani Naik, Birte Kalveram, Hayden Smutney, and Lihong Zhang

Subjects
Cell entry, chemistry.chemical_classification, Ebola virus, 010405 organic chemistry, medicine.drug_class, viruses, Adamantane, Organic Chemistry, Carboxamide, medicine.disease_cause, 01 natural sciences, Biochemistry, Virology, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, chemistry.chemical_compound, chemistry, Drug Discovery, medicine, Glycoprotein
Abstract

[Image: see text] We identified and explored the structure–activity-relationship (SAR) of an adamantane carboxamide chemical series of Ebola virus (EBOV) inhibitors. Selected analogs exhibited half-maximal inhibitory concentrations (EC(50) values) of ∼10–15 nM in vesicular stomatitis virus (VSV) pseudotyped EBOV (pEBOV) infectivity assays, low hundred nanomolar EC(50) activity against wild type EBOV, aqueous solubility >20 mg/mL, and attractive metabolic stability in human and nonhuman liver microsomes. X-ray cocrystallographic characterizations of a lead compound with the EBOV glycoprotein (GP) established the EBOV GP as a target for direct compound inhibitory activity and further provided relevant structural models that may assist in identifying optimized therapeutic candidates.

Published
2020

94. Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950–2019:a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Author

Wang, H. (Haidong), Abbas, K. M. (Kaja M.), Abbasifard, M. (Mitra), Abbasi-Kangevari, M. (Mohsen), Abbastabar, H. (Hedayat), Abd-Allah, F. (Foad), Abdelalim, A. (Ahmed), Abolhassani, H. (Hassan), Abreu, L. G. (Lucas Guimaraes), Abrigo, M. R. (Michael R. M.), Abushouk, A. I. (Abdelrahman I.), Adabi, M. (Maryam), Adair, T. (Tim), Adebayo, O. M. (Oladimeji M.), Adedeji, I. A. (Isaac Akinkunmi), Adekanmbi, V. (Victor), Adeoye, A. M. (Abiodun Moshood), Adetokunboh, O. O. (Olatunji O.), Advani, S. M. (Shailesh M.), Afshin, A. (Ashkan), Aghaali, M. (Mohammad), Agrawal, A. (Anurag), Ahmadi, K. (Keivan), Ahmadieh, H. (Hamid), Ahmed, M. B. (Muktar Beshir), Al-Aly, Z. (Ziyad), Alam, K. (Khurshid), Alam, T. (Tahiya), Alanezi, F. M. (Fahad Mashhour), Alanzi, T. M. (Turki M.), Alcalde-Rabanal, J. E. (Jacqueline Elizabeth), Ali, M. (Muhammad), Alicandro, G. (Gianfranco), Alijanzadeh, M. (Mehran), Alinia, C. (Cyrus), Alipour, V. (Vahid), Alizade, H. (Hesam), Aljunid, S. M. (Syed Mohamed), Allebeck, P. (Peter), Almadi, M. A. (Majid Abdulrahman Hamad), Almasi-Hashiani, A. (Amir), Al-Mekhlafi, H. M. (Hesham M.), Altirkawi, K. A. (Khalid A.), Alumran, A. K. (Arwa Khalid), Alvis-Guzman, N. (Nelson), Amini-Rarani, M. (Mostafa), Aminorroaya, A. (Arya), Amit, A. M. (Arianna Maever L.), Ancuceanu, R. (Robert), Andrei, C. L. (Catalina Liliana), Androudi, S. (Sofia), Angus, C. (Colin), Anjomshoa, M. (Mina), Ansari, F. (Fereshteh), Ansari, I. (Iman), Ansari-Moghaddam, A. (Alireza), Antonio, C. A. (Carl Abelardo T.), Antony, C. M. (Catherine M.), Anvari, D. (Davood), Appiah, S. C. (Seth Christopher Yaw), Arabloo, J. (Jalal), Arab-Zozani, M. (Morteza), Aravkin, A. Y. (Aleksandr Y.), Aremu, O. (Olatunde), Arnlov, J. (Johan), Aryal, K. K. (Krishna K.), Asadi-Pooya, A. A. (Ali A.), Asgari, S. (Samaneh), Jafarabadi, M. A. (Mohammad Asghari), Atteraya, M. S. (Madhu Sudhan), Ausloos, M. (Marcel), Avila-Burgos, L. (Leticia), Avokpaho, E. F. (Euripide Frinel Gbenato Arthur), Quintanilla, B. P. (Beatriz Paulina Ayala), Ayano, G. (Getinet), Ayanore, M. A. (Martin Amogre), Azarian, G. (Ghasem), Babaee, E. (Ebrahim), Badiye, A. D. (Ashish D.), Bagli, E. (Eleni), Bahrami, M. A. (Mohammad Amin), Bakhtiari, A. (Ahad), Balassyano, S. (Shelly), Banach, M. (Maciej), Banik, P. C. (Palash Chandra), Barker-Collo, S. L. (Suzanne Lyn), Barnighausen, T. W. (Till Winfried), Barzegar, A. (Akbar), Basu, S. (Sanjay), Baune, B. T. (Bernhard T.), Bayati, M. (Mohsen), Bazmandegan, G. (Gholamreza), Bedi, N. (Neeraj), Bell, M. L. (Michellr L.), Bennett, D. A. (Derrick A.), Bensenor, I. M. (Isabela M.), Berhe, K. (Kidanemaryam), Berman, A. E. (Adam E.), Bertolacci, G. J. (Gregory J.), Bhageerathy, R. (Reshmi), Bhala, N. (Neeraj), Bhattacharyya, K. (Krittika), Bhutta, Z. A. (Zulfiqar A.), Bijani, A. (Ali), Biondi, A. (Antonio), Bisanzio, D. (Donal), Bisignano, C. (Catherine), Biswas, R. K. (Raaj Kishore), Bjrge, T. (Tone), Bohlouli, S. (Somayeh), Bohluli, M. (Mehdi), Bolla, S. R. (Srinivasa Rao Rao), Borzi, A. M. (Antonio Maria), Borzouei, S. (Shiva), Brady, O. J. (Oliver J.), Braithwaite, D. (Dejana), Brauer, M. (Michael), Briko, A. N. (Andrey Nikolaevich), Briko, N. I. (Nikolay Ivanovich), Bumgarner, B. R. (Blair R.), Nagaraja, S. B. (Sharath Burugina), Butt, Z. A. (Zahid A.), dos Santos, F. L. (Florentino Luciano Caetano), Cai, T. (Tianji), Callender, C. S. (Charlton S. K. H.), Camera, L. L. (Luis L. A. Alberto), Campos-Nonato, I. R. (Ismael R.), Cardenas, R. (Rosario), Carreras, G. (Giulia), Carrero, J. J. (Juan J.), Carvalho, F. (Felix), Castaldelli-Maia, J. M. (Joao Mauricio), Castelpietra, G. (Giulio), Castro, F. (Franz), Catala-Lopez, F. (Ferran), Cederroth, C. R. (Christopher R.), Cerin, E. (Ester), Chattu, V. K. (Vijay Kumar), Chin, K. L. (Ken Lee), Chu, D.-T. (Dinh-Toi), Ciobanu, L. G. (Liliana G.), Cirillo, M. (Massimo), Comfort, H. (Haley), Costa, V. M. (Vera Marisa), Cowden, R. G. (Richard G.), Cromwell, E. A. (Elizabeth A.), Croneberger, A. J. (Andrew J.), Cunningham, M. (Matthew), Dahlawi, S. M. (Saad M. A.), Damiani, G. (Giovanni), D'Amico, E. (Emanuele), Dandona, L. (Lalit), Dandona, R. (Rakhi), Dargan, P. I. (Paul I.), Darwesh, A. M. (Aso Mohammad), Daryani, A. (Ahmad), Das Gupta, R. (Rajat), das Neves, J. (Jose), Davletov, K. (Kairat), De Leo, D. (Diego), Denova-Gutierrez, E. (Edgar), Deribe, K. (Kebede), Dervenis, N. (Nikolaos), Desai, R. (Rupak), Dhungana, G. P. (Govinda Prasad), da Silva, D. D. (Diana Dias), Diaz, D. (Daniel), Dippenaar, I. N. (Ilse N.), Djalalinia, S. (Shirin), Do, H. T. (Hoa Thi), Dokova, K. (Klara), Doku, D. T. (David Teye), Dorostkar, F. (Fariba), Doshi, C. P. (Chirag P.), Doshmangir, L. (Leila), Doyle, K. E. (Kerrie E.), Dubljanin, E. (Eleonora), Duraes, A. R. (Andre Rodrigues), Edvardsson, D. (David), Effiong, A. (Andem), El Sayed, I. (Iman), El Tantawi, M. (Maha), Elbarazi, I. (Iffat), El-Jaafary, S. I. (Shaimaa I.), Emamian, M. H. (Mohammad Hassan), Eskandarieh, S. (Sharareh), Esmaeilzadeh, F. (Firooz), Estep, K. (Kara), Farahmand, M. (Mohammad), Faraj, A. (Anwar), Fareed, M. (Mohammad), Faridnia, R. (Roghiyeh), Faro, A. (Andre), Farzadfar, F. (Farshad), Fattahi, N. (Nazir), Fazaeli, A. A. (Ali Akbar), Fazlzadeh, M. (Mehdi), Feigin, V. L. (Valery L.), Fereshtehnejad, S.-M. (Seyed-Mohammad), Fernandes, E. (Eduarda), Ferreira, M. L. (Manuela L.), Filip, I. (Irina), Fischer, F. (Florian), Flohr, C. (Carsten), Foigt, N. A. (Nataliya A.), Folayan, M. O. (Morenike Oluwatoyin), Fomenkov, A. A. (Artem Alekseevich), Freitas, M. (Marisa), Fukumoto, T. (Takeshi), Fuller, J. E. (John E.), Furtado, J. M. (Joao M.), Gad, M. M. (Mohamed M.), Gakidou, E. (Emmanuela), Gallus, S. (Silvano), Gebrehiwot, A. M. (Abiyu Mekonnen), Gebremedhin, K. B. (Ketema Bizuwork), Gething, P. W. (Peter W.), Ghamari, F. (Farhad), Ghashghaee, A. (Ahmad), Gholamian, A. (Asadollah), Gilani, S. A. (Syed Amir), Gitimoghaddam, M. (Mojgan), Glushkova, E. V. (Ekaterina Vladimirovna), Gnedovskaya, E. V. (Elena V.), Gopalani, S. V. (Sameer Vali), Goulart, A. C. (Alessandra C.), Gugnani, H. C. (Harish Chander), Guo, Y. (Yuming), Gupta, R. (Rajeev), Gupta, S. S. (Subodh Sharan), Haagsma, J. A. (Juanita A.), Haj-Mirzaian, A. (Arvin), Haj-Mirzaian, A. (Arya), Halvaei, I. (Iman), Hamadeh, R. R. (Randah R.), Abdullah, K. H. (Kanaan Hamagharib), Han, C. (Chieh), Handiso, D. W. (Demelash Woldeyohannes), Hankey, G. J. (Graeme J.), Haririan, H. (Hamidreza), Haro, J. M. (Josep Maria), Hasaballah, A. I. (Ahmed I.), Hassanipour, S. (Soheil), Hassankhani, H. (Hadi), Hay, S. I. (Simon I.), Heibati, B. (Behzad), Heidari-Soureshjani, R. (Reza), Henny, K. (Kiana), Henry, N. J. (Nathaniel J.), Herteliu, C. (Claudiu), Heydarpour, F. (Fatemeh), Hole, M. K. (Michael K.), Hoogar, P. (Praveen), Hosgood, H. D. (H. Dean), Hossain, N. (Naznin), Hosseinzadeh, M. (Mehdi), Hostiuc, M. (Mihaela), Hostiuc, S. (Sorin), Househ, M. (Mowafa), Hoy, D. G. (Damian G.), Hu, G. (Guoqing), Huda, T. M. (Tanvir M.), Ibitoye, S. E. (Segun Emmanuel), Ikuta, K. S. (Kevin S.), Ilesanmi, O. S. (Olayinka Stephen), Ilic, I. M. (Irena M.), Ilic, M. D. (Milena D.), Imani-Nasab, M. H. (Mohammad Hasan), Islam, M. (MdMohaimenul), Iso, H. (Hiroyasu), Iwu, C. J. (Chinwe Juliana), Jaafari, J. (Jalil), Jacobsen, K. H. (Kathryn H.), Jahagirdar, D. (Deepa), Jahanmehr, N. (Nader), Jalali, A. (Amir), Jalilian, F. (Farzad), James, S. L. (Spencer L.), Janjani, H. (Hosna), Jenabi, E. (Ensiyeh), Jha, R. P. (Ravi Prakash), Jha, V. (Vivekanand), Ji, J. S. (John S.), Jonas, J. B. (Jost B.), Joukar, F. (Farahnaz), Jozwiak, J. J. (Jacek Jerzy), Jurisson, M. (Mikk), Kabir, Z. (Zubair), Kalani, H. (Hamed), Kalankesh, L. R. (Leila R.), Kamiab, Z. (Zahra), Kanchan, T. (Tanuj), Kapoor, N. (Neeti), Karch, A. (Andre), Karimi, S. E. (Salah Eddin), Karimi, S. A. (Seyed Asaad), Kassebaum, N. J. (Nicholas J.), Katikireddi, S. V. (Srinivasa Vittal), Kawakami, N. (Norito), Kayode, G. A. (Gbenga A.), Keiyoro, P. N. (Peter Njenga), Keller, C. (Cathleen), Khader, Y. S. (Yousef Saleh), Khalid, N. (Nauman), Khan, E. A. (Ejaz Ahmad), Khan, M. (Maseer), Khang, Y.-H. (Young-Ho), Khater, A. M. (Amir M.), Khater, M. M. (Mona M.), Khazaei, S. (Salman), Khazaie, H. (Habibolah), Khodayari, M. T. (Mohammad Taghi), Khubchandani, J. (Jagdish), Kianipour, N. (Neda), Kim, C.-i. (Cho-il), Kim, Y.-E. (Young-Eun), Kim, Y. J. (Yun Jin), Kinfu, Y. (Yohannes), Kisa, A. (Adnan), Kisa, S. (Sezer), Kissimova-Skarbek, K. (Katarzyna), Kivimaki, M. (Mika), Komaki, H. (Hamidreza), Kopec, J. A. (Jacek A.), Kosen, S. (Soewarta), Koul, P. A. (Parvaiz A.), Koyanagi, A. (Ai), Kravchenko, M. A. (Michael A.), Krishan, K. (Kewal), Krohn, K. J. (Kris J.), Defo, B. K. (Barthelemy Kuate), Kumar, G. A. (G. Anil), Kumar, M. (Manasi), Kumar, P. (Pushpendra), Kumar, V. (Vivek), Kusuma, D. (Dian), Kyu, H. H. (Hmwe Hmwe), La Vecchia, C. (Carlo), Lacey, B. (Ben), Lal, D. K. (Dharmesh Kumar), Lalloo, R. (Ratilal), Lami, F. H. (Faris Hasan), Lansky, S. (Sonia), Larson, S. L. (Samantha Leigh), Larsson, A. O. (Anders O.), Lasrado, S. (Savita), Lassi, Z. S. (Zohra S.), Lazarus, J. V. (Jeffrey V.), Lee, P. H. (Paul H.), Lee, S. W. (Shaun Wen Huey), Leever, A. T. (Andrew T.), LeGrand, K. E. (Kate E.), Leonardi, M. (Matilde), Li, S. (Shanshan), Lim, L.-L. (Lee-Ling), Lim, S. S. (Stephen S.), Linn, S. (Shai), Lodha, R. (Rakesh), Logroscino, G. (Giancarlo), Lopez, A. D. (Alan D.), Lopukhov, P. D. (Platon D.), Lotufo, P. A. (Paulo A.), Lozano, R. (Rafael), Lu, A. (Alton), Lunevicius, R. (Raimundas), Madadin, M. (Mohammed), Maddison, E. R. (Emilie R.), Abd El Razek, H. M. (Hassan Magdy), Abd El Razek, M. M. (Muhammed Magdy), Mahasha, P. W. (Phetole Walter), Mahdavi, M. M. (Mokhtar Mahdavi), Malekzadeh, R. (Reza), Mamun, A. A. (Abdullah A.), Manafi, N. (Navid), Mansour-Ghanaei, F. (Fariborz), Mansouri, B. (Borhan), Mansournia, M. A. (Mohammad Ali), Mapoma, C. C. (Chabila Christopher), Martini, S. (Santi), Martins-Melo, F. R. (Francisco Rogerlandio), Masaka, A. (Anthony), Mastrogiacomo, C. I. (Claudia I.), Mathur, M. R. (Manu Raj), May, E. A. (Erin A.), McAlinden, C. (Colm), McGrath, J. J. (John J.), McKee, M. (Martin), Mehndiratta, M. M. (Man Mohan), Mehri, F. (Fereshteh), Mehta, K. M. (Kala M.), Meitei, W. B. (Wahengbam Bigyananda), Memiah, P. T. (Peter T. N.), Mendoza, W. (Walter), Menezes, R. G. (Ritesh G.), Mengesha, E. W. (Endalkachew Worku), Mensah, G. A. (George A.), Meretoja, A. (Atte), Meretoja, T. J. (Tuomo J.), Mestrovic, T. (Tomislav), Michalek, I. M. (Irmina Maria), Mihretie, K. M. (Kebadnew Mulatu), Miller, T. R. (Ted R.), Mills, E. J. (Edward J.), Milne, G. J. (George J.), Mirrakhimov, E. M. (Erkin M.), Mirzaei, H. (Hamed), Mirzaei, M. (Maryam), Mirzaei-Alavijeh, M. (Mehdi), Misganaw, A. T. (Awoke Temesgen), Moazen, B. (Babak), Moghadaszadeh, M. (Masoud), Mohamadi, E. (Efat), Mohammad, D. K. (Dara K.), Mohammad, Y. (Yousef), Mezerji, N. M. (Naser Mohammad Gholi), Mohammadbeigi, A. (Abolfazl), Mohammadian-Hafshejani, A. (Abdollah), Mohammadpourhodki, R. (Reza), Mohammed, H. (Hussen), Mohammed, S. (Shafiu), Mohebi, F. (Farnam), Bandpei, M. A. (Mohammad A. Mohseni), Mokari, A. (Amin), Mokdad, A. H. (Ali H.), Momen, N. C. (Natalie C.), Monasta, L. (Lorenzo), Mooney, M. D. (Meghan D.), Moradi, G. (Ghobad), Moradi, M. (Masoud), Moradi-Joo, M. (Mohammad), Moradi-Lakeh, M. (Maziar), Moradzadeh, R. (Rahmatollah), Moraga, P. (Paula), Velasquez, I. M. (Ilais Moreno), Morgado-da-Costa, J. (Joana), Morrison, S. D. (Shane Douglas), Mosser, J. F. (Jonathan F.), Mouodi, S. (Simin), Mousavi, S. M. (Seyyed Meysam), Khaneghah, A. M. (Amin Mousavi), Mueller, U. O. (Ulrich Otto), Musa, K. I. (Kamarul Imran), Muthupandian, S. (Saravanan), Nabavizadeh, B. (Behnam), Naderi, M. (Mehdi), Nagarajan, A. J. (Ahamarshan Jayaraman), Naghavi, M. (Mohsen), Naghshtabrizi, B. (Behshad), Naik, G. (Gurudatta), Najafi, F. (Farid), Nangia, V. (Vinay), Nansseu, J. R. (Jobert Richie), Ndwandwe, D. E. (Duduzile Edith), Negoi, I. (Ionut), Negoi, R. I. (Ruxandra Irina), Ngunjiri, J. W. (Josephine W.), Nguyen, H. L. (Huong Lan Thi), Nguyen, T. H. (Trang Huyen), Nigatu, Y. T. (Yeshambel T.), Nikbakhsh, R. (Rajan), Nikpoor, A. R. (Amin Reza), Nixon, M. R. (Molly R.), Nnaji, C. A. (Chukwudi A.), Nomura, S. (Shuhei), Noubiap, J. J. (Jean Jacques), Motlagh, S. N. (Soraya Nouraei), Nowak, C. (Christoph), Otoiu, A. (Adrian), Odell, C. M. (Christopher M.), Oh, I.-H. (In-Hwan), Oladnabi, M. (Morteza), Olagunju, A. T. (Andrew T.), Olusanya, B. O. (Bolajoko Olubukunola), Olusanya, J. O. (Jacob Olusegun), Bali, A. O. (Ahmed Omar), Ong, K. L. (Kanyin L.), Onwujekwe, O. E. (Obinna E.), Ortiz, A. (Alberto), Otstavnov, N. (Nikita), Otstavnov, S. S. (Stanislav S.), Overland, S. (Simon), Owolabi, M. O. (Mayowa O.), Mahesh, P. A. (P. A.), Padubidri, J. R. (Jagadish Rao), Pakshir, K. (Keyvan), Palladino, R. (Raffaele), Pana, A. (Adrian), Panda-Jonas, S. (Songhomitra), Park, J. (James), Pasupula, D. K. (Deepak Kumar), Patel, J. R. (Jenil R.), Patel, S. K. (Sangram Kishor), Patton, G. C. (George C.), Paulson, K. R. (Katherine R.), Toroudi, H. P. (Hamidreza Pazoki), Pease, S. A. (Spencer A.), Peden, A. E. (Amy E.), Pepito, V. C. (Veincent Christian Filipino), Peprah, E. K. (Emmanuel K.), Pereira, A. (Alexandre), Pereira, D. M. (David M.), Perico, N. (Norberto), Pigott, D. M. (David M.), Pilgrim, T. (Thomas), Pilz, T. M. (Tessa M.), Piradov, M. A. (Michael A.), Pirsaheb, M. (Meghdad), Pokhrel, K. N. (Khem Narayan), Postma, M. J. (Maarten J.), Pourjafar, H. (Hadi), Pourmalek, F. (Farshad), Pourshams, A. (Akram), Poznanska, A. (Anna), Prada, S. I. (Sergio I.), Prakash, S. (Sanjay), Preotescu, L. (Liliana), Syed, Z. Q. (Zahiruddin Quazi), Rabiee, M. (Mohammad), Rabiee, N. (Navid), Radfar, A. (Amir), Rafiei, A. (Alireza), Raggi, A. (Alberto), Rahman, M. A. (Muhammad Aziz), Rajabpour-Sanati, A. (Ali), Ram, P. (Pradhum), Ranabhat, C. L. (Chhabi Lal), Rao, S. J. (Sowmya J.), Rasella, D. (Davide), Rashedi, V. (Vahid), Rastogi, P. (Prateek), Rathi, P. (Priya), Rawal, L. (Lal), Remuzzi, G. (Giuseppe), Renjith, V. (Vishnu), Renzaho, A. M. (Andre M. N.), Resnikoff, S. (Serge), Rezaei, N. (Nima), Rezai, M. s. (Mohammad sadegh), Rezapour, A. (Aziz), Rickard, J. (Jennifer), Roever, L. (Leonardo), Ronfani, L. (Luca), Roshandel, G. (Gholamreza), Rostamian, M. (Morteza), Rubagotti, E. (Enrico), Rwegerera, G. M. (Godfrey M.), Sabour, S. (Siamak), Saddik, B. (Basema), Sadeghi, E. (Ehsan), Sadeghi, M. (Masoumeh), Moghaddam, S. S. (Sahar Saeedi), Safari, Y. (Yahya), Safi, S. (Sare), Safiri, S. (Saeid), Sagar, R. (Rajesh), Sahebkar, A. (Amirhossein), Sahraian, M. A. (Mohammad Ali), Sajadi, S. M. (S. Mohammad), Salahshoor, M. R. (Mohammad Reza), Salama, J. S. (Joseph S.), Salamati, P. (Payman), Salem, M. R. (Marwa R. Rashad), Salimi, Y. (Yahya), Salomon, J. A. (Joshua A.), Salz, I. (Inbal), Samad, Z. (Zainab), Samy, A. M. (Abdallah M.), Sanabria, J. (Juan), Santric-Milicevic, M. M. (Milena M.), Saraswathy, S. Y. (Sivan Yegnanarayana Iyer), Sartorius, B. (Benn), Sarveazad, A. (Arash), Sathian, B. (Brijesh), Sathish, T. (Thirunavukkarasu), Sattin, D. (Davide), Saylan, M. (Mete), Schaeffer, L. E. (Lauren E.), Schiavolin, S. (Silvia), Schwebel, D. C. (David C.), Schwendicke, F. (Falk), Sekerija, M. (Mario), Senbeta, A. M. (Anbissa Muleta), Senthilkumaran, S. (Subramanian), Sepanlou, S. G. (Sadaf G.), Servan-Mori, E. (Edson), Shabani, M. (Mahsima), Shahabi, S. (Saeed), Shahbaz, M. (Mohammad), Shaheen, A. A. (Amira A.), Shaikh, M. A. (Masood Ali), Shalash, A. S. (Ali S.), Shams-Beyranvand, M. (Mehran), Shamsi, M. (MohammadBagher), Shamsizadeh, M. (Morteza), Shannawaz, M. (Mohammed), Sharafi, K. (Kiomars), Sharafi, Z. (Zeinab), Sharara, F. (Fablina), Sharma, R. (Rajesh), Shaw, D. H. (David H.), Sheikh, A. (Aziz), Il Shin, J. (Jae), Shiri, R. (Rahman), Shrime, M. G. (Mark G.), Shuval, K. (Kerem), Siabani, S. (Soraya), Sigfusdottir, I. D. (Inga Dora), Sigurvinsdottir, R. (Rannveig), Silva, D. A. (Diego Augusto Santos), Simonetti, B. (Biagio), Simpson, K. E. (Kyle E.), Singh, J. A. (Jasvinder A.), Skiadaresi, E. (Eirini), Skryabin, V. Y. (Valentin Yurievich), Soheili, A. (Amin), Sokhan, A. (Anton), Sorensen, R. J. (Reed J. D.), Soriano, J. B. (Joan B.), Sorrie, M. B. (Muluken Bekele), Soyiri, I. N. (Ireneous N.), Spurlock, E. E. (Emma Elizabeth), Sreeramareddy, C. T. (Chandrashekhar T.), Stockfelt, L. (Leo), Stokes, M. A. (Mark A.), Stubbs, J. L. (Jacob L.), Sudaryanto, A. (Agus), Sufiyan, M. B. (Mu'awiyyah Babale), Abdulkader, R. S. (Rizwan Suliankatchi), Sykes, B. L. (Bryan L.), Tabares-Seisdedos, R. (Rafael), Tabb, K. M. (Karen M.), Tadakamadla, S. K. (Santosh Kumar), Taherkhani, A. (Amir), Tang, M. (Muming), Taveira, N. (Nuno), Taylor, H. J. (Heather Jean), Teagle, W. L. (Whitney L.), Tehrani-Banihashemi, A. (Arash), Teklehaimanot, B. F. (Berhane Fseha), Tessema, Z. T. (Zemenu Tadesse), Thankappan, K. R. (Kavumpurathu Raman), Thomas, N. (Nihal), Thrift, A. G. (Amanda G.), Titova, M. V. (Mariya Vladimirovna), Tohidinik, H. R. (Hamid Reza), Tonelli, M. (Marcello), Topor-Madry, R. (Roman), Topouzis, F. (Fotis), Tovani-Palone, M. R. (Marcos Roberto Roberto), Traini, E. (Eugenio), Tran, B. X. (Bach Xuan), Travillian, R. (Ravensara), Trias-Llimos, S. (Sergi), Truelsen, T. C. (Thomas Clement), Car, L. T. (Lorainne Tudor), Unnikrishnan, B. (Bhaskaran), Upadhyay, E. (Era), Vacante, M. (Marco), Vakilian, A. (Alireza), Valdez, P. R. (Pascual R.), Valli, A. (Alessandro), Vardavas, C. (Constantine), Vasankari, T. J. (Tommi Juhani), Vasconcelos, A. M. (Ana Maria Nogales), Vasseghian, Y. (Yasser), Veisani, Y. (Yousef), Venketasubramanian, N. (Narayanaswamy), Vidale, S. (Simone), Violante, F. S. (Francesco S.), Vlassov, V. (Vasily), Vollset, S. E. (Stein Emil), Vos, T. (Theo), Vujcic, I. S. (Isidora S.), Vukovic, A. (Ana), Vukovic, R. (Rade), Waheed, Y. (Yasir), Wallin, M. T. (Mitchell Taylor), Walters, M. K. (Magdalene K.), Wang, H. (Hongbo), Wang, Y.-P. (Yuan-Pang), Watson, S. (Stefanie), Wei, J. (Jingkai), Weiss, J. (Jordan), Weldesamuel, G. T. (Girmay Teklay), Werdecker, A. (Andrea), Westerman, R. (Ronny), Whiteford, H. A. (Harvey A.), Wiangkham, T. (Taweewat), Wiens, K. E. (Kirsten E.), Wijeratne, T. (Tissa), Wiysonge, C. S. (Charles Shey), Wojtyniak, B. (Bogdan), Wolfe, C. D. (Charles D. A.), Wondmieneh, A. B. (Adam Belay), Wool, E. E. (Eve E.), Wu, A.-M. (Ai-Min), Wu, J. (Junjie), Xu, G. (Gelin), Yamada, T. (Tomohide), Yamagishi, K. (Kazumasa), Yano, Y. (Yuichiro), Yaya, S. (Sanni), Yazdi-Feyzabadi, V. (Vahid), Yearwood, J. A. (Jamal A.), Yeheyis, T. Y. (Tomas Y.), Yilgwan, C. S. (Christopher Sabo), Yip, P. (Paul), Yonemoto, N. (Naohiro), Yoon, S.-J. (Seok-Jun), Lebni, J. Y. (Javad Yoosefi), York, H. W. (Hunter W.), Younis, M. Z. (Mustafa Z.), Younker, T. P. (Theodore Patrick), Yousefi, Z. (Zabihollah), Yousefinezhadi, T. (Taraneh), Yousuf, A. Y. (Abdilahi Yousuf), Yusefzadeh, H. (Hasan), Moghadam, T. Z. (Telma Zahirian), Zakzuk, J. (Josefina), Bin Zaman, S. (Sojib), Zamani, M. (Mohammad), Zamanian, M. (Maryam), Zandian, H. (Hamed), Zhang, Z.-J. (Zhi-Jiang), Zheng, P. (Peng), Zhou, M. (Maigeng), Ziapour, A. (Arash), Murray, C. J. (Christopher J. L.), Wang, H. (Haidong), Abbas, K. M. (Kaja M.), Abbasifard, M. (Mitra), Abbasi-Kangevari, M. (Mohsen), Abbastabar, H. (Hedayat), Abd-Allah, F. (Foad), Abdelalim, A. (Ahmed), Abolhassani, H. (Hassan), Abreu, L. G. (Lucas Guimaraes), Abrigo, M. R. (Michael R. M.), Abushouk, A. I. (Abdelrahman I.), Adabi, M. (Maryam), Adair, T. (Tim), Adebayo, O. M. (Oladimeji M.), Adedeji, I. A. (Isaac Akinkunmi), Adekanmbi, V. (Victor), Adeoye, A. M. (Abiodun Moshood), Adetokunboh, O. O. (Olatunji O.), Advani, S. M. (Shailesh M.), Afshin, A. (Ashkan), Aghaali, M. (Mohammad), Agrawal, A. (Anurag), Ahmadi, K. (Keivan), Ahmadieh, H. (Hamid), Ahmed, M. B. (Muktar Beshir), Al-Aly, Z. (Ziyad), Alam, K. (Khurshid), Alam, T. (Tahiya), Alanezi, F. M. (Fahad Mashhour), Alanzi, T. M. (Turki M.), Alcalde-Rabanal, J. E. (Jacqueline Elizabeth), Ali, M. (Muhammad), Alicandro, G. (Gianfranco), Alijanzadeh, M. (Mehran), Alinia, C. (Cyrus), Alipour, V. (Vahid), Alizade, H. (Hesam), Aljunid, S. M. (Syed Mohamed), Allebeck, P. (Peter), Almadi, M. A. (Majid Abdulrahman Hamad), Almasi-Hashiani, A. (Amir), Al-Mekhlafi, H. M. (Hesham M.), Altirkawi, K. A. (Khalid A.), Alumran, A. K. (Arwa Khalid), Alvis-Guzman, N. (Nelson), Amini-Rarani, M. (Mostafa), Aminorroaya, A. (Arya), Amit, A. M. (Arianna Maever L.), Ancuceanu, R. (Robert), Andrei, C. L. (Catalina Liliana), Androudi, S. (Sofia), Angus, C. (Colin), Anjomshoa, M. (Mina), Ansari, F. (Fereshteh), Ansari, I. (Iman), Ansari-Moghaddam, A. (Alireza), Antonio, C. A. (Carl Abelardo T.), Antony, C. M. (Catherine M.), Anvari, D. (Davood), Appiah, S. C. (Seth Christopher Yaw), Arabloo, J. (Jalal), Arab-Zozani, M. (Morteza), Aravkin, A. Y. (Aleksandr Y.), Aremu, O. (Olatunde), Arnlov, J. (Johan), Aryal, K. K. (Krishna K.), Asadi-Pooya, A. A. (Ali A.), Asgari, S. (Samaneh), Jafarabadi, M. A. (Mohammad Asghari), Atteraya, M. S. (Madhu Sudhan), Ausloos, M. (Marcel), Avila-Burgos, L. (Leticia), Avokpaho, E. F. (Euripide Frinel Gbenato Arthur), Quintanilla, B. P. (Beatriz Paulina Ayala), Ayano, G. (Getinet), Ayanore, M. A. (Martin Amogre), Azarian, G. (Ghasem), Babaee, E. (Ebrahim), Badiye, A. D. (Ashish D.), Bagli, E. (Eleni), Bahrami, M. A. (Mohammad Amin), Bakhtiari, A. (Ahad), Balassyano, S. (Shelly), Banach, M. (Maciej), Banik, P. C. (Palash Chandra), Barker-Collo, S. L. (Suzanne Lyn), Barnighausen, T. W. (Till Winfried), Barzegar, A. (Akbar), Basu, S. (Sanjay), Baune, B. T. (Bernhard T.), Bayati, M. (Mohsen), Bazmandegan, G. (Gholamreza), Bedi, N. (Neeraj), Bell, M. L. (Michellr L.), Bennett, D. A. (Derrick A.), Bensenor, I. M. (Isabela M.), Berhe, K. (Kidanemaryam), Berman, A. E. (Adam E.), Bertolacci, G. J. (Gregory J.), Bhageerathy, R. (Reshmi), Bhala, N. (Neeraj), Bhattacharyya, K. (Krittika), Bhutta, Z. A. (Zulfiqar A.), Bijani, A. (Ali), Biondi, A. (Antonio), Bisanzio, D. (Donal), Bisignano, C. (Catherine), Biswas, R. K. (Raaj Kishore), Bjrge, T. (Tone), Bohlouli, S. (Somayeh), Bohluli, M. (Mehdi), Bolla, S. R. (Srinivasa Rao Rao), Borzi, A. M. (Antonio Maria), Borzouei, S. (Shiva), Brady, O. J. (Oliver J.), Braithwaite, D. (Dejana), Brauer, M. (Michael), Briko, A. N. (Andrey Nikolaevich), Briko, N. I. (Nikolay Ivanovich), Bumgarner, B. R. (Blair R.), Nagaraja, S. B. (Sharath Burugina), Butt, Z. A. (Zahid A.), dos Santos, F. L. (Florentino Luciano Caetano), Cai, T. (Tianji), Callender, C. S. (Charlton S. K. H.), Camera, L. L. (Luis L. A. Alberto), Campos-Nonato, I. R. (Ismael R.), Cardenas, R. (Rosario), Carreras, G. (Giulia), Carrero, J. J. (Juan J.), Carvalho, F. (Felix), Castaldelli-Maia, J. M. (Joao Mauricio), Castelpietra, G. (Giulio), Castro, F. (Franz), Catala-Lopez, F. (Ferran), Cederroth, C. R. (Christopher R.), Cerin, E. (Ester), Chattu, V. K. (Vijay Kumar), Chin, K. L. (Ken Lee), Chu, D.-T. (Dinh-Toi), Ciobanu, L. G. (Liliana G.), Cirillo, M. (Massimo), Comfort, H. (Haley), Costa, V. M. (Vera Marisa), Cowden, R. G. (Richard G.), Cromwell, E. A. (Elizabeth A.), Croneberger, A. J. (Andrew J.), Cunningham, M. (Matthew), Dahlawi, S. M. (Saad M. A.), Damiani, G. (Giovanni), D'Amico, E. (Emanuele), Dandona, L. (Lalit), Dandona, R. (Rakhi), Dargan, P. I. (Paul I.), Darwesh, A. M. (Aso Mohammad), Daryani, A. (Ahmad), Das Gupta, R. (Rajat), das Neves, J. (Jose), Davletov, K. (Kairat), De Leo, D. (Diego), Denova-Gutierrez, E. (Edgar), Deribe, K. (Kebede), Dervenis, N. (Nikolaos), Desai, R. (Rupak), Dhungana, G. P. (Govinda Prasad), da Silva, D. D. (Diana Dias), Diaz, D. (Daniel), Dippenaar, I. N. (Ilse N.), Djalalinia, S. (Shirin), Do, H. T. (Hoa Thi), Dokova, K. (Klara), Doku, D. T. (David Teye), Dorostkar, F. (Fariba), Doshi, C. P. (Chirag P.), Doshmangir, L. (Leila), Doyle, K. E. (Kerrie E.), Dubljanin, E. (Eleonora), Duraes, A. R. (Andre Rodrigues), Edvardsson, D. (David), Effiong, A. (Andem), El Sayed, I. (Iman), El Tantawi, M. (Maha), Elbarazi, I. (Iffat), El-Jaafary, S. I. (Shaimaa I.), Emamian, M. H. (Mohammad Hassan), Eskandarieh, S. (Sharareh), Esmaeilzadeh, F. (Firooz), Estep, K. (Kara), Farahmand, M. (Mohammad), Faraj, A. (Anwar), Fareed, M. (Mohammad), Faridnia, R. (Roghiyeh), Faro, A. (Andre), Farzadfar, F. (Farshad), Fattahi, N. (Nazir), Fazaeli, A. A. (Ali Akbar), Fazlzadeh, M. (Mehdi), Feigin, V. L. (Valery L.), Fereshtehnejad, S.-M. (Seyed-Mohammad), Fernandes, E. (Eduarda), Ferreira, M. L. (Manuela L.), Filip, I. (Irina), Fischer, F. (Florian), Flohr, C. (Carsten), Foigt, N. A. (Nataliya A.), Folayan, M. O. (Morenike Oluwatoyin), Fomenkov, A. A. (Artem Alekseevich), Freitas, M. (Marisa), Fukumoto, T. (Takeshi), Fuller, J. E. (John E.), Furtado, J. M. (Joao M.), Gad, M. M. (Mohamed M.), Gakidou, E. (Emmanuela), Gallus, S. (Silvano), Gebrehiwot, A. M. (Abiyu Mekonnen), Gebremedhin, K. B. (Ketema Bizuwork), Gething, P. W. (Peter W.), Ghamari, F. (Farhad), Ghashghaee, A. (Ahmad), Gholamian, A. (Asadollah), Gilani, S. A. (Syed Amir), Gitimoghaddam, M. (Mojgan), Glushkova, E. V. (Ekaterina Vladimirovna), Gnedovskaya, E. V. (Elena V.), Gopalani, S. V. (Sameer Vali), Goulart, A. C. (Alessandra C.), Gugnani, H. C. (Harish Chander), Guo, Y. (Yuming), Gupta, R. (Rajeev), Gupta, S. S. (Subodh Sharan), Haagsma, J. A. (Juanita A.), Haj-Mirzaian, A. (Arvin), Haj-Mirzaian, A. (Arya), Halvaei, I. (Iman), Hamadeh, R. R. (Randah R.), Abdullah, K. H. (Kanaan Hamagharib), Han, C. (Chieh), Handiso, D. W. (Demelash Woldeyohannes), Hankey, G. J. (Graeme J.), Haririan, H. (Hamidreza), Haro, J. M. (Josep Maria), Hasaballah, A. I. (Ahmed I.), Hassanipour, S. (Soheil), Hassankhani, H. (Hadi), Hay, S. I. (Simon I.), Heibati, B. (Behzad), Heidari-Soureshjani, R. (Reza), Henny, K. (Kiana), Henry, N. J. (Nathaniel J.), Herteliu, C. (Claudiu), Heydarpour, F. (Fatemeh), Hole, M. K. (Michael K.), Hoogar, P. (Praveen), Hosgood, H. D. (H. Dean), Hossain, N. (Naznin), Hosseinzadeh, M. (Mehdi), Hostiuc, M. (Mihaela), Hostiuc, S. (Sorin), Househ, M. (Mowafa), Hoy, D. G. (Damian G.), Hu, G. (Guoqing), Huda, T. M. (Tanvir M.), Ibitoye, S. E. (Segun Emmanuel), Ikuta, K. S. (Kevin S.), Ilesanmi, O. S. (Olayinka Stephen), Ilic, I. M. (Irena M.), Ilic, M. D. (Milena D.), Imani-Nasab, M. H. (Mohammad Hasan), Islam, M. (MdMohaimenul), Iso, H. (Hiroyasu), Iwu, C. J. (Chinwe Juliana), Jaafari, J. (Jalil), Jacobsen, K. H. (Kathryn H.), Jahagirdar, D. (Deepa), Jahanmehr, N. (Nader), Jalali, A. (Amir), Jalilian, F. (Farzad), James, S. L. (Spencer L.), Janjani, H. (Hosna), Jenabi, E. (Ensiyeh), Jha, R. P. (Ravi Prakash), Jha, V. (Vivekanand), Ji, J. S. (John S.), Jonas, J. B. (Jost B.), Joukar, F. (Farahnaz), Jozwiak, J. J. (Jacek Jerzy), Jurisson, M. (Mikk), Kabir, Z. (Zubair), Kalani, H. (Hamed), Kalankesh, L. R. (Leila R.), Kamiab, Z. (Zahra), Kanchan, T. (Tanuj), Kapoor, N. (Neeti), Karch, A. (Andre), Karimi, S. E. (Salah Eddin), Karimi, S. A. (Seyed Asaad), Kassebaum, N. J. (Nicholas J.), Katikireddi, S. V. (Srinivasa Vittal), Kawakami, N. (Norito), Kayode, G. A. (Gbenga A.), Keiyoro, P. N. (Peter Njenga), Keller, C. (Cathleen), Khader, Y. S. (Yousef Saleh), Khalid, N. (Nauman), Khan, E. A. (Ejaz Ahmad), Khan, M. (Maseer), Khang, Y.-H. (Young-Ho), Khater, A. M. (Amir M.), Khater, M. M. (Mona M.), Khazaei, S. (Salman), Khazaie, H. (Habibolah), Khodayari, M. T. (Mohammad Taghi), Khubchandani, J. (Jagdish), Kianipour, N. (Neda), Kim, C.-i. (Cho-il), Kim, Y.-E. (Young-Eun), Kim, Y. J. (Yun Jin), Kinfu, Y. (Yohannes), Kisa, A. (Adnan), Kisa, S. (Sezer), Kissimova-Skarbek, K. (Katarzyna), Kivimaki, M. (Mika), Komaki, H. (Hamidreza), Kopec, J. A. (Jacek A.), Kosen, S. (Soewarta), Koul, P. A. (Parvaiz A.), Koyanagi, A. (Ai), Kravchenko, M. A. (Michael A.), Krishan, K. (Kewal), Krohn, K. J. (Kris J.), Defo, B. K. (Barthelemy Kuate), Kumar, G. A. (G. Anil), Kumar, M. (Manasi), Kumar, P. (Pushpendra), Kumar, V. (Vivek), Kusuma, D. (Dian), Kyu, H. H. (Hmwe Hmwe), La Vecchia, C. (Carlo), Lacey, B. (Ben), Lal, D. K. (Dharmesh Kumar), Lalloo, R. (Ratilal), Lami, F. H. (Faris Hasan), Lansky, S. (Sonia), Larson, S. L. (Samantha Leigh), Larsson, A. O. (Anders O.), Lasrado, S. (Savita), Lassi, Z. S. (Zohra S.), Lazarus, J. V. (Jeffrey V.), Lee, P. H. (Paul H.), Lee, S. W. (Shaun Wen Huey), Leever, A. T. (Andrew T.), LeGrand, K. E. (Kate E.), Leonardi, M. (Matilde), Li, S. (Shanshan), Lim, L.-L. (Lee-Ling), Lim, S. S. (Stephen S.), Linn, S. (Shai), Lodha, R. (Rakesh), Logroscino, G. (Giancarlo), Lopez, A. D. (Alan D.), Lopukhov, P. D. (Platon D.), Lotufo, P. A. (Paulo A.), Lozano, R. (Rafael), Lu, A. (Alton), Lunevicius, R. (Raimundas), Madadin, M. (Mohammed), Maddison, E. R. (Emilie R.), Abd El Razek, H. M. (Hassan Magdy), Abd El Razek, M. M. (Muhammed Magdy), Mahasha, P. W. (Phetole Walter), Mahdavi, M. M. (Mokhtar Mahdavi), Malekzadeh, R. (Reza), Mamun, A. A. (Abdullah A.), Manafi, N. (Navid), Mansour-Ghanaei, F. (Fariborz), Mansouri, B. (Borhan), Mansournia, M. A. (Mohammad Ali), Mapoma, C. C. (Chabila Christopher), Martini, S. (Santi), Martins-Melo, F. R. (Francisco Rogerlandio), Masaka, A. (Anthony), Mastrogiacomo, C. I. (Claudia I.), Mathur, M. R. (Manu Raj), May, E. A. (Erin A.), McAlinden, C. (Colm), McGrath, J. J. (John J.), McKee, M. (Martin), Mehndiratta, M. M. (Man Mohan), Mehri, F. (Fereshteh), Mehta, K. M. (Kala M.), Meitei, W. B. (Wahengbam Bigyananda), Memiah, P. T. (Peter T. N.), Mendoza, W. (Walter), Menezes, R. G. (Ritesh G.), Mengesha, E. W. (Endalkachew Worku), Mensah, G. A. (George A.), Meretoja, A. (Atte), Meretoja, T. J. (Tuomo J.), Mestrovic, T. (Tomislav), Michalek, I. M. (Irmina Maria), Mihretie, K. M. (Kebadnew Mulatu), Miller, T. R. (Ted R.), Mills, E. J. (Edward J.), Milne, G. J. (George J.), Mirrakhimov, E. M. (Erkin M.), Mirzaei, H. (Hamed), Mirzaei, M. (Maryam), Mirzaei-Alavijeh, M. (Mehdi), Misganaw, A. T. (Awoke Temesgen), Moazen, B. (Babak), Moghadaszadeh, M. (Masoud), Mohamadi, E. (Efat), Mohammad, D. K. (Dara K.), Mohammad, Y. (Yousef), Mezerji, N. M. (Naser Mohammad Gholi), Mohammadbeigi, A. (Abolfazl), Mohammadian-Hafshejani, A. (Abdollah), Mohammadpourhodki, R. (Reza), Mohammed, H. (Hussen), Mohammed, S. (Shafiu), Mohebi, F. (Farnam), Bandpei, M. A. (Mohammad A. Mohseni), Mokari, A. (Amin), Mokdad, A. H. (Ali H.), Momen, N. C. (Natalie C.), Monasta, L. (Lorenzo), Mooney, M. D. (Meghan D.), Moradi, G. (Ghobad), Moradi, M. (Masoud), Moradi-Joo, M. (Mohammad), Moradi-Lakeh, M. (Maziar), Moradzadeh, R. (Rahmatollah), Moraga, P. (Paula), Velasquez, I. M. (Ilais Moreno), Morgado-da-Costa, J. (Joana), Morrison, S. D. (Shane Douglas), Mosser, J. F. (Jonathan F.), Mouodi, S. (Simin), Mousavi, S. M. (Seyyed Meysam), Khaneghah, A. M. (Amin Mousavi), Mueller, U. O. (Ulrich Otto), Musa, K. I. (Kamarul Imran), Muthupandian, S. (Saravanan), Nabavizadeh, B. (Behnam), Naderi, M. (Mehdi), Nagarajan, A. J. (Ahamarshan Jayaraman), Naghavi, M. (Mohsen), Naghshtabrizi, B. (Behshad), Naik, G. (Gurudatta), Najafi, F. (Farid), Nangia, V. (Vinay), Nansseu, J. R. (Jobert Richie), Ndwandwe, D. E. (Duduzile Edith), Negoi, I. (Ionut), Negoi, R. I. (Ruxandra Irina), Ngunjiri, J. W. (Josephine W.), Nguyen, H. L. (Huong Lan Thi), Nguyen, T. H. (Trang Huyen), Nigatu, Y. T. (Yeshambel T.), Nikbakhsh, R. (Rajan), Nikpoor, A. R. (Amin Reza), Nixon, M. R. (Molly R.), Nnaji, C. A. (Chukwudi A.), Nomura, S. (Shuhei), Noubiap, J. J. (Jean Jacques), Motlagh, S. N. (Soraya Nouraei), Nowak, C. (Christoph), Otoiu, A. (Adrian), Odell, C. M. (Christopher M.), Oh, I.-H. (In-Hwan), Oladnabi, M. (Morteza), Olagunju, A. T. (Andrew T.), Olusanya, B. O. (Bolajoko Olubukunola), Olusanya, J. O. (Jacob Olusegun), Bali, A. O. (Ahmed Omar), Ong, K. L. (Kanyin L.), Onwujekwe, O. E. (Obinna E.), Ortiz, A. (Alberto), Otstavnov, N. (Nikita), Otstavnov, S. S. (Stanislav S.), Overland, S. (Simon), Owolabi, M. O. (Mayowa O.), Mahesh, P. A. (P. A.), Padubidri, J. R. (Jagadish Rao), Pakshir, K. (Keyvan), Palladino, R. (Raffaele), Pana, A. (Adrian), Panda-Jonas, S. (Songhomitra), Park, J. (James), Pasupula, D. K. (Deepak Kumar), Patel, J. R. (Jenil R.), Patel, S. K. (Sangram Kishor), Patton, G. C. (George C.), Paulson, K. R. (Katherine R.), Toroudi, H. P. (Hamidreza Pazoki), Pease, S. A. (Spencer A.), Peden, A. E. (Amy E.), Pepito, V. C. (Veincent Christian Filipino), Peprah, E. K. (Emmanuel K.), Pereira, A. (Alexandre), Pereira, D. M. (David M.), Perico, N. (Norberto), Pigott, D. M. (David M.), Pilgrim, T. (Thomas), Pilz, T. M. (Tessa M.), Piradov, M. A. (Michael A.), Pirsaheb, M. (Meghdad), Pokhrel, K. N. (Khem Narayan), Postma, M. J. (Maarten J.), Pourjafar, H. (Hadi), Pourmalek, F. (Farshad), Pourshams, A. (Akram), Poznanska, A. (Anna), Prada, S. I. (Sergio I.), Prakash, S. (Sanjay), Preotescu, L. (Liliana), Syed, Z. Q. (Zahiruddin Quazi), Rabiee, M. (Mohammad), Rabiee, N. (Navid), Radfar, A. (Amir), Rafiei, A. (Alireza), Raggi, A. (Alberto), Rahman, M. A. (Muhammad Aziz), Rajabpour-Sanati, A. (Ali), Ram, P. (Pradhum), Ranabhat, C. L. (Chhabi Lal), Rao, S. J. (Sowmya J.), Rasella, D. (Davide), Rashedi, V. (Vahid), Rastogi, P. (Prateek), Rathi, P. (Priya), Rawal, L. (Lal), Remuzzi, G. (Giuseppe), Renjith, V. (Vishnu), Renzaho, A. M. (Andre M. N.), Resnikoff, S. (Serge), Rezaei, N. (Nima), Rezai, M. s. (Mohammad sadegh), Rezapour, A. (Aziz), Rickard, J. (Jennifer), Roever, L. (Leonardo), Ronfani, L. (Luca), Roshandel, G. (Gholamreza), Rostamian, M. (Morteza), Rubagotti, E. (Enrico), Rwegerera, G. M. (Godfrey M.), Sabour, S. (Siamak), Saddik, B. (Basema), Sadeghi, E. (Ehsan), Sadeghi, M. (Masoumeh), Moghaddam, S. S. (Sahar Saeedi), Safari, Y. (Yahya), Safi, S. (Sare), Safiri, S. (Saeid), Sagar, R. (Rajesh), Sahebkar, A. (Amirhossein), Sahraian, M. A. (Mohammad Ali), Sajadi, S. M. (S. Mohammad), Salahshoor, M. R. (Mohammad Reza), Salama, J. S. (Joseph S.), Salamati, P. (Payman), Salem, M. R. (Marwa R. Rashad), Salimi, Y. (Yahya), Salomon, J. A. (Joshua A.), Salz, I. (Inbal), Samad, Z. (Zainab), Samy, A. M. (Abdallah M.), Sanabria, J. (Juan), Santric-Milicevic, M. M. (Milena M.), Saraswathy, S. Y. (Sivan Yegnanarayana Iyer), Sartorius, B. (Benn), Sarveazad, A. (Arash), Sathian, B. (Brijesh), Sathish, T. (Thirunavukkarasu), Sattin, D. (Davide), Saylan, M. (Mete), Schaeffer, L. E. (Lauren E.), Schiavolin, S. (Silvia), Schwebel, D. C. (David C.), Schwendicke, F. (Falk), Sekerija, M. (Mario), Senbeta, A. M. (Anbissa Muleta), Senthilkumaran, S. (Subramanian), Sepanlou, S. G. (Sadaf G.), Servan-Mori, E. (Edson), Shabani, M. (Mahsima), Shahabi, S. (Saeed), Shahbaz, M. (Mohammad), Shaheen, A. A. (Amira A.), Shaikh, M. A. (Masood Ali), Shalash, A. S. (Ali S.), Shams-Beyranvand, M. (Mehran), Shamsi, M. (MohammadBagher), Shamsizadeh, M. (Morteza), Shannawaz, M. (Mohammed), Sharafi, K. (Kiomars), Sharafi, Z. (Zeinab), Sharara, F. (Fablina), Sharma, R. (Rajesh), Shaw, D. H. (David H.), Sheikh, A. (Aziz), Il Shin, J. (Jae), Shiri, R. (Rahman), Shrime, M. G. (Mark G.), Shuval, K. (Kerem), Siabani, S. (Soraya), Sigfusdottir, I. D. (Inga Dora), Sigurvinsdottir, R. (Rannveig), Silva, D. A. (Diego Augusto Santos), Simonetti, B. (Biagio), Simpson, K. E. (Kyle E.), Singh, J. A. (Jasvinder A.), Skiadaresi, E. (Eirini), Skryabin, V. Y. (Valentin Yurievich), Soheili, A. (Amin), Sokhan, A. (Anton), Sorensen, R. J. (Reed J. D.), Soriano, J. B. (Joan B.), Sorrie, M. B. (Muluken Bekele), Soyiri, I. N. (Ireneous N.), Spurlock, E. E. (Emma Elizabeth), Sreeramareddy, C. T. (Chandrashekhar T.), Stockfelt, L. (Leo), Stokes, M. A. (Mark A.), Stubbs, J. L. (Jacob L.), Sudaryanto, A. (Agus), Sufiyan, M. B. (Mu'awiyyah Babale), Abdulkader, R. S. (Rizwan Suliankatchi), Sykes, B. L. (Bryan L.), Tabares-Seisdedos, R. (Rafael), Tabb, K. M. (Karen M.), Tadakamadla, S. K. (Santosh Kumar), Taherkhani, A. (Amir), Tang, M. (Muming), Taveira, N. (Nuno), Taylor, H. J. (Heather Jean), Teagle, W. L. (Whitney L.), Tehrani-Banihashemi, A. (Arash), Teklehaimanot, B. F. (Berhane Fseha), Tessema, Z. T. (Zemenu Tadesse), Thankappan, K. R. (Kavumpurathu Raman), Thomas, N. (Nihal), Thrift, A. G. (Amanda G.), Titova, M. V. (Mariya Vladimirovna), Tohidinik, H. R. (Hamid Reza), Tonelli, M. (Marcello), Topor-Madry, R. (Roman), Topouzis, F. (Fotis), Tovani-Palone, M. R. (Marcos Roberto Roberto), Traini, E. (Eugenio), Tran, B. X. (Bach Xuan), Travillian, R. (Ravensara), Trias-Llimos, S. (Sergi), Truelsen, T. C. (Thomas Clement), Car, L. T. (Lorainne Tudor), Unnikrishnan, B. (Bhaskaran), Upadhyay, E. (Era), Vacante, M. (Marco), Vakilian, A. (Alireza), Valdez, P. R. (Pascual R.), Valli, A. (Alessandro), Vardavas, C. (Constantine), Vasankari, T. J. (Tommi Juhani), Vasconcelos, A. M. (Ana Maria Nogales), Vasseghian, Y. (Yasser), Veisani, Y. (Yousef), Venketasubramanian, N. (Narayanaswamy), Vidale, S. (Simone), Violante, F. S. (Francesco S.), Vlassov, V. (Vasily), Vollset, S. E. (Stein Emil), Vos, T. (Theo), Vujcic, I. S. (Isidora S.), Vukovic, A. (Ana), Vukovic, R. (Rade), Waheed, Y. (Yasir), Wallin, M. T. (Mitchell Taylor), Walters, M. K. (Magdalene K.), Wang, H. (Hongbo), Wang, Y.-P. (Yuan-Pang), Watson, S. (Stefanie), Wei, J. (Jingkai), Weiss, J. (Jordan), Weldesamuel, G. T. (Girmay Teklay), Werdecker, A. (Andrea), Westerman, R. (Ronny), Whiteford, H. A. (Harvey A.), Wiangkham, T. (Taweewat), Wiens, K. E. (Kirsten E.), Wijeratne, T. (Tissa), Wiysonge, C. S. (Charles Shey), Wojtyniak, B. (Bogdan), Wolfe, C. D. (Charles D. A.), Wondmieneh, A. B. (Adam Belay), Wool, E. E. (Eve E.), Wu, A.-M. (Ai-Min), Wu, J. (Junjie), Xu, G. (Gelin), Yamada, T. (Tomohide), Yamagishi, K. (Kazumasa), Yano, Y. (Yuichiro), Yaya, S. (Sanni), Yazdi-Feyzabadi, V. (Vahid), Yearwood, J. A. (Jamal A.), Yeheyis, T. Y. (Tomas Y.), Yilgwan, C. S. (Christopher Sabo), Yip, P. (Paul), Yonemoto, N. (Naohiro), Yoon, S.-J. (Seok-Jun), Lebni, J. Y. (Javad Yoosefi), York, H. W. (Hunter W.), Younis, M. Z. (Mustafa Z.), Younker, T. P. (Theodore Patrick), Yousefi, Z. (Zabihollah), Yousefinezhadi, T. (Taraneh), Yousuf, A. Y. (Abdilahi Yousuf), Yusefzadeh, H. (Hasan), Moghadam, T. Z. (Telma Zahirian), Zakzuk, J. (Josefina), Bin Zaman, S. (Sojib), Zamani, M. (Mohammad), Zamanian, M. (Maryam), Zandian, H. (Hamed), Zhang, Z.-J. (Zhi-Jiang), Zheng, P. (Peng), Zhou, M. (Maigeng), Ziapour, A. (Arash), and Murray, C. J. (Christopher J. L.)

Abstract

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated us

Published
2020

95. Balancing conflicting demands: factors influencing vets’ choice of antimicrobial agent

Author

Katherine E. Adam

Subjects
Swine, 040301 veterinary sciences, Denmark, media_common.quotation_subject, Veterinarians, 0403 veterinary science, Antibiotic resistance, Anti-Infective Agents, Animals, Humans, Antimicrobial stewardship, Production (economics), Marketing, Productivity, media_common, General Veterinary, 0402 animal and dairy science, Stakeholder, 04 agricultural and veterinary sciences, General Medicine, Antimicrobial, 040201 dairy & animal science, Intestinal Diseases, Order (business), Business, Welfare
Abstract

Antimicrobial resistance (AMR) is a major threat to both human and animal health.1,2 Antimicrobial stewardship – also referred to as prudent or responsible antimicrobial use – by veterinary surgeons is a central strategy to prevent the development of AMR.3 In order to define responsible use, it is useful to identify the different stakeholder groups involved and their primary responsibilities in relation to antimicrobial use. The phrase ‘as little as possible, as much as necessary’ is frequently used to summarise the conflict between public and private interests that lies at the heart of efforts to combat AMR, and can refer to the choice of antimicrobial agent as well as the quantity used. The primary responsibility at a population level is to protect human and animal health by restricting the use of antimicrobial agents, and selecting lower priority drugs where possible, in order to minimise the development of resistance (ie, as little as possible).4 Conversely, the primary responsibility of the vet is to safeguard the health, welfare and productivity of their clients’ animals (ie, as much as necessary).5 Prudent AMU in animals and people, therefore, involves a trade-off between these competing demands in order to select an antimicrobial that will be clinically effective while also minimising the risk of AMR.6,7 The factors influencing vets’ decisions regarding prescribing antimicrobial agents in pig production have been explored using both qualitative8–10 and quantitative11–13 approaches. In a paper summarised on p 798 of this issue of Vet Record , Eriksen and colleagues have built upon this existing knowledge by quantifying and comparing the influence of the factors identified …

Published
2019
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98. Altering the allowed/forbidden gap in cyclobutene electrocyclic reactions: experimental and theoretical evaluations of the effect of planarity constraints

Author

Lee, Patrick S., Sakai, Shogo, Horstermann, Peter, Roth, Wolfgang R., Kallel, E. Adam, and Houk, K.N.

Subjects
Pericyclic reactions -- Usage, Butylene -- Structure, Butylene -- Research, Butylene -- Electric properties, Chemistry
Abstract

The allowed-forbidden gap of cyclobutene ring-opening is dependent on the planarity of the ring-opening transition structure. Skeletal structures that prevent the transition state from achieving the cyclic delocalization that is intrinsic to pericyclic transition states would reduce, or even eliminate, the energy of concert of a pericyclic reaction.

Published
2003

99. Torqueselectivity induced by lone-pair conjugation in the electrocyclic reactions of 1-azopolyenes

Author

Walker, Matthew J., Hietbrink, Bruce N., Thomas, Bert E., IV, Nakamura, Kensuke, Kallel, E. Adam, and Houk, K. N.

Subjects
Chemistry, Organic -- Research, Isomerization -- Physiological aspects, Heterocyclic compounds -- Physiological aspects, Biological sciences, Chemistry
Abstract

Research has been conducted on the torqueselectivity. The electrocyclic interconversion torqueselectivity of 1-azopolyenes and their heterocyclic isomers has been theoretically investigated and the results of this study are discussed.

Published
2001

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