tbuckley/cabot-search huggingface dataset:
THU0404 INFLUENCE OF URATE TRANSPORTOSOME FOR HYPERURICEMIA AND GOUT
Authors: B. Stiburkova, K. Pavelcova, J. Bohata, M. Pavlikova, T. Takada, Y. Toyoda, L. Hasikova, J. Zavada, K. Pavelka
Journal: Annals of the Rheumatic Diseases (2020)

Background: Gouty arthritis, caused by a persistent increase in serum uric acid level, can be caused by underexcretion of uric acid by uric transporters; however, the effects of allelic variants of urate transportosome are yet to be fully determined. Objectives: In this study we investigated the effects of 10 genes of urate transportosome in a cohort of patients with primary hyperuricemia and gout. Methods: The cohort consisted of 114 hyperuricemic individuals; 207 gout patients; and 274 normouricemic controls. Results: We identified 39 non-synonymous allelic variants in the 10 genes of urate transportosome in hyperuricemia/gout cohort. For 22 variants, a European MAF &lt;0.0001 is documented. From the total of 39 identified variants we selected 23 variants for functional characterization based on a) finding of a newly identified variant, b) MAF variant was significantly different in the group of patients with hyperuricemia/gout, c) with high probability, in silico predictions showed devastating influence of variant on protein function. Conclusion: Although further analyzes are needed to elucidate the contribution of urate transportosome to urate homeostasis, our results clearly show that ABCG2 transporter analysis has significant clinical potential. Of the identified non-synonymous allelic variants of the urate transportosome, rs2231142 (p.Q141K) in the ABCG2 gene, proved to be the most clinically significant on the age onset (P &lt; 0.0002, Kruskal-Wallis test). References: [1]Toyoda Y, et al. Cells. 2019 Apr 18;8(4). 2. Stiburkova B, et al. Rheumatology (Oxford). 2016 Jan;55(1):191-4. 3. Toyoda Y, et al. Arthritis Res Ther. 2019 Oct 28;21(1):219. Acknowledgments: This study was supported by the grant from the Czech Republic Ministry of Health AZV 15-26693A and RVO 00023728. Disclosure of Interests: : Blanka Stiburkova: None declared, Katerina Pavelcova: None declared, Jana Bohata: None declared, Marketa Pavlikova: None declared, Tappei Takada: None declared, Yu Toyoda: None declared, Lenka Hasikova: None declared, Jakub Zavada Speakers bureau: Abbvie, UCB, Sanofi, Elli-Lilly, Novartis, Zentiva, Accord, Karel Pavelka Consultant of: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen, Speakers bureau: Abbvie, MSD, BMS, Egis, Roche, UCB, Medac, Pfizer, Biogen
Splanchnic Nerve Block for Chronic Heart Failure
Authors: Marat Fudim, Richard L. Boortz-Marx, Arun Ganesh, Adam D. DeVore, Chetan B. Patel, Joseph G. Rogers, Aubrie Coburn, Inneke Johnson, Amanda Paul, Brian J. Coyne, Sunil V. Rao, J. Antonio Gutierrez, Todd L. Kiefer, David F. Kong, Cynthia L. Green, W. Schuyler Jones, G. Michael Felker, Adrian F. Hernandez, Manesh R. Patel
Journal: JACC Heart Failure (2020)
Passive antibody therapy in COVID-19
Authors: Jonathan Abraham
Journal: Nature reviews. Immunology (2020)

For over a century, transfusion of convalescent plasma from recovered individuals has been tried as a therapeutic approach when a novel pathogen emerges. As the world awaits SARS-CoV-2 vaccines to be tested and safely deployed, the rapidity with which antiviral monoclonal antibodies can be isolated and engineered offers an attractive alternative option for passive immunization. In this Comment, Jonathan Abraham highlights the potential of passive immunization strategies for COVID-19.
Discovery of novel diarylamides as orally active diuretics targeting urea transporters
Authors: Shun Zhang, Yan Zhao, Shuyuan Wang, Min Li, Yue Xu, Jianhua Ran, Xiaoqiang Geng, Jinzhao He, Jia Meng, Guangying Shao, Hong Zhou, Zemei Ge, Guangping Chen, Runtao Li, Baoxue Yang
Journal: Acta Pharmaceutica Sinica B (2020)

Urea transporters (UT) play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics. Thus, UT inhibitors are promising for development as novel diuretics. In the present study, a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening. Optimization of the inhibitor led to the identification of a promising preclinical candidate, N-[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide (1H), with excellent in vitro UT inhibitory activity at the submicromolar level. The half maximal inhibitory concentrations of 1H against UT-B in mouse, rat, and human erythrocyte were 1.60, 0.64, and 0.13 μmol/L, respectively. Further investigation suggested that 8 μmol/L 1H more powerfully inhibited UT-A1 at a rate of 86.8% than UT-B at a rate of 73.9% in MDCK cell models. Most interestingly, we found for the first time that oral administration of 1H at a dose of 100 mg/kg showed superior diuretic effect in vivo without causing electrolyte imbalance in rats. Additionally, 1H did not exhibit apparent toxicity in vivo and in vitro, and possessed favorable pharmacokinetic characteristics. 1H shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects.
Saving the Diabetic Foot During the COVID-19 Pandemic: A Tale of Two Cities
Authors: Laura Shin, Frank L. Bowling, David G. Armstrong, Andrew J.M. Boulton
Journal: Diabetes Care (2020)

Of all the late complications of diabetes, those involving the foot have traditionally required more face-to-face patient visits to clinics to treat wounds by debridement, offloading, and many other treatment modalities. The advent of the coronavirus disease 2019 (COVID-19) pandemic has resulted not only in the closing of most outpatient clinics for face-to-face consultations but also in the inability to perform most laboratory and imaging investigations. This has resulted in a paradigm shift in the delivery of care for those with diabetic foot ulcers. The approaches to this challenge in two centers with an interest in diabetic foot disease, including virtual consultations using physician-to-patient and physician–to–home nurse telemedicine as well as home podiatry visits, are described in this review and are illustrated by several case vignettes. The outcomes from these two centers suggest that we may be witnessing new possibilities in models of care for the diabetic foot.
Venoarterial Extracorporeal Membrane Oxygenation Support Rescue of Obstructive Shock Caused by Bulky Compressive Mediastinal Cancer
Authors: Simon Bourcier, Patricia Villie, Stéphanie Nguyen, Guillaume Hékimian, Pierre Demondion, Nicolas Bréchot, Charles-Edouard Luyt, Guillaume Lebreton, Alain Combes, Matthieu Schmidt
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Hookworm Treatment for Relapsing Multiple Sclerosis
Authors: Radu Tanasescu, Christopher R. Tench, Cris S. Constantinescu, Gary Telford, Sonika Singh, Nanci Frakich, David Onion, Dorothee P. Auer, Bruno Gran, Nikos Evangelou, Yasser Falah, Colin Ranshaw, Cinzia Cantacessi, Timothy P. Jenkins, David I. Pritchard
Journal: JAMA Neurology (2020)

Studies suggest gut worms induce immune responses that can protect against multiple sclerosis (MS). To our knowledge, there are no controlled treatment trials with helminth in MS.To determine whether hookworm treatment has effects on magnetic resonance imaging (MRI) activity and T regulatory cells in relapsing MS.This 9-month double-blind, randomized, placebo-controlled trial was conducted between September 2012 and March 2016 in a modified intention-to-treat population (the data were analyzed June 2018) at the University of Nottingham, Queen's Medical Centre, a single tertiary referral center. Patients aged 18 to 61 years with relapsing MS without disease-modifying treatment were recruited from the MS clinic. Seventy-three patients were screened; of these, 71 were recruited (2 ineligible/declined).Patients were randomized (1:1) to receive either 25 Necator americanus larvae transcutaneously or placebo. The MRI scans were performed monthly during months 3 to 9 and 3 months posttreatment.The primary end point was the cumulative number of new/enlarging T2/new enhancing T1 lesions at month 9. The secondary end point was the percentage of cluster of differentiation (CD) 4+CD25highCD127negT regulatory cells in peripheral blood.Patients (mean [SD] age, 45 [9.5] years; 50 women [71%]) were randomized to receive hookworm (35 [49.3%]) or placebo (36 [50.7%]). Sixty-six patients (93.0%) completed the trial. The median cumulative numbers of new/enlarging/enhancing lesions were not significantly different between the groups by preplanned Mann-Whitney U tests, which lose power with tied data (high number of zeroactivity MRIs in the hookworm group, 18/35 [51.4%] vs 10/36 [27.8%] in the placebo group). The percentage of CD4+CD25highCD127negT cells increased at month 9 in the hookworm group (hookworm, 32 [4.4%]; placebo, 34 [3.9%]; P = .01). No patients withdrew because of adverse effects. There were no differences in adverse events between groups except more application-site skin discomfort in the hookworm group (82% vs 28%). There were 5 relapses (14.3%) in the hookworm group vs 11 (30.6%) receiving placebo.Treatment with hookworm was safe and well tolerated. The primary outcome did not reach significance, likely because of a low level of disease activity. Hookworm infection increased T regulatory cells, suggesting an immunobiological effect of hookworm. It appears that a living organism can precipitate immunoregulatory changes that may affect MS disease activity.ClinicalTrials.gov Identifier: NCT01470521.
Re: Hung-Ming Lam, Holly M. Nguyen, Mark P. Labrecque, et al. Durable Response of Enzalutamide-resistant Prostate Cancer to Supraphysiological Testosterone Is Associated with a Multifaceted Growth Suppression and Impaired DNA Damage Response Transcriptomic Program in Patient-derived Xenografts. Eur Urol 2020;77:144–55
Authors: Giovanni Lavorgna, Francesco Montorsi, Andrea Salonia
Journal: European Urology (2020)
AB0605 CLINICAL PROFILE AND CHEST HIGH-RESOLUTION COMPUTED TOMOGRAPHY (HRCT) FINDINGS IN PATIENTS WITH CONNECTIVE TISSUE DISEASES AND INTERSTITIAL LUNG DISEASE: EXPERIENCE OF A SINGLE REFERENCE RHEUMATOLOGY CENTER
Authors: I. Rusu, L. Muntean, M. M. Tamas, I. Felea, L. Damian, I. Filipescu, S. P. Simon, C. Pamfil, C. M. Marinescu, M. A. Man, C. Csutak, S. Rednic
Journal: Annals of the Rheumatic Diseases (2020)

Background: Interstitial lung disease (ILD) is a common manifestation of connective tissue diseases (CTDs), and is associated with significant morbidity and mortality. Chest high-resolution computed tomography (HRCT) play an important role in the diagnosis of ILD and may provide prognostic information. Objectives: We aimed to characterize the clinical profile and chest HRCT abnormalities and patterns of patients diagnosed with CTDs and ILD. Methods: In this retrospective, observational study we included 80 consecutive patients with CTDs and ILD referred to a tertiary rheumatology center between 2015 and 2019. From hospital charts we collected clinical data, immunologic profile, chest HRCT findings. HRCT patterns were defined according to new international recommendations. Results: Out of 80 patients, 64 (80%) were women, with a mean age of 55 years old. The most common CTD associated with ILD was systemic sclerosis (38.8%), followed by polymyositis (22.5%) and rheumatoid arthritis (18.8%). The majority of patients had dyspnea on exertion (71.3%), bibasilar inspiratory crackles were present in 56.3% patients and 10% had clubbing fingers. Antinuclear antibodies (ANA) were present in 78.8% patients, and the most frequently detected autoantibodies against extractable nuclear antigen were anti-Scl 70 (28.8%), followed by anti-SSA (anti-Ro, 17.5%), anti-Ro52 (11.3%) and anti-Jo (7.5%). Intravenous cyclophosphamide therapy for 6-12 months was used in 35% of patients, while 5% of patients were treated with mycophenolate mofetil. The most frequent HRCT abnormalities were reticular abnormalities and ground glass opacity. Non-specific interstitial pneumonia (NSIP) was identified in 46.3% CTDs patients. A pattern suggestive of usual interstitial pneumonia (UIP) was present in 32.5% patients, mainly in patients with systemic sclerosis. In 21.3% patients the HRCT showed reticulo-nodular pattern, micronodules and other abnormalities, not diagnostic for UIP or NSIP pattern. Conclusion: Nonspecific interstitial pneumonia (NSIP) is the most common HRCT pattern associated with CTDs. Further prospective longitudinal studies are needed in order to determine the clinical and prognostic significance of various HRCT patterns encountered in CTD-associated ILD and for better patient management. References: [1]Ohno Y, Koyama H, Yoshikaua T, Seki S. State-of-the-Art Imaging of the Lung for Connective Tissue Disease (CTD). Curr Rheumatol Rep. 2015;17(12):69. [2]Walsh SLF, Devaraj A, Enghelmeyer JI, Kishi K, Silva RS, Patel N, et al. Role of imaging in progressive-fibrosing interstitial lung diseases. Eur Respir Rev. 2018;27(150) Disclosure of Interests: None declared
Imaging of Injectable Hydrogels Delivered into Myocardium with SPECT/CT
Authors: Selen Uman, Leo L. Wang, Stephanie L. Thorn, Zhao Liu, James S Duncan, Albert J. Sinusas, Jason A. Burdick
Journal: Advanced Healthcare Materials (2020)

Injectable hydrogels are being widely explored for treatment after myocardial infarction (MI) through mechanical bulking or the delivery of therapeutics. Despite this interest, there have been few approaches to image hydrogels upon injection to identify their location, volume, and pattern of delivery, features that are important to understand toward clinical translation. Using a hyaluronic acid (HA) hydrogel as an example, the aim of this study is to introduce radiopacity to hydrogels by encapsulating a clinically used contrast agent (Omnipaque Iohexol, GE Healthcare) for imaging upon placement in the myocardium. Specifically, iohexol is encapsulated into shear-thinning and self-healing hydrogels formed through the mixing of HA-hydrazide and HA-aldehyde. Upon examination of a range of iohexol concentrations, a concentration of 100 mg mL-1 iohexol is deemed optimal based on the greatest contrast, while maintaining hydrogel mechanical properties and acceptable injection forces. In an acute porcine model of MI, hybrid single-photon emission computed tomography/computed tomography (SPECT/CT) perfusion imaging is performed immediately and 3-4 days after hydrogel delivery to assess radiopacity and verify the hydrogel location within the perfusion defect. Hybrid SPECT/CT imaging demonstrates excellent radiopacity of the hydrogel within the perfusion defect immediately after intramyocardial hydrogel injection, demonstrating the feasibility of this method for short-term noninvasive hydrogel monitoring.
Chemokine (C-X-C Motif) Ligand 4 Is a Restrictor of Respiratory Syncytial Virus Infection and an Indicator of Clinical Severity
Authors: Zibo Han, Jian Rao, Zhengde Xie, Conghui Wang, Baoping Xu, Suyun Qian, Yingying Wang, Junlin Zhu, Bin Yang, Fengwen Xu, Xiaobo Lei, Fei Guo, Zhendong Zhao, Lili Ren, Jianwei Wang
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Respiratory syncytial virus (RSV) is the leading cause of childhood respiratory infections worldwide; however, no vaccine is available, and treatment options are limited. Identification of host factors pivotal to viral replication may inform the development of novel therapies, prophylaxes, or diagnoses.Objectives: To identify host factors involved in RSV replication and to evaluate their potential for disease management.Methods: A gain-of-function screening was performed on the basis of a genome-wide human complementary DNA library screen for host factors involved in RSV replication. The antiviral mechanism of CXCL4 (chemokine [C-X-C motif] ligand 4) was analyzed. Its clinical role was evaluated via nasopharyngeal aspirates and plasma samples from patients with RSV infection and different disease severities.Measurements and Main Results: Forty-nine host factors restricting RSV replication were identified by gain-of-function screening, with CXCL4 showing the strongest antiviral effect, which was secretion dependent. CXCL4 blocked viral attachment through binding to the RSV main receptor heparan sulfate, instead of through interacting with RSV surface proteins. Intranasal pretreatment with CXCL4 alleviated inflammation in RSV-infected mice, as shown by decreased concentrations of tumor necrosis factor and viral load in BAL fluid samples as well as by viral nucleocapsid protein histological staining in lungs. Compared with non-RSV infections, RSV infections induced elevated CXCL4 concentrations both in plasma and airway samples from mice and pediatric patients. The airway CXCL4 concentration was correlated with viral load and disease severity in patients (P < 0.001).Conclusions: Our results suggest that CXCL4 is an RSV restriction factor that can block viral entry and serve as an indicator of clinical severity in RSV infections.
Abstract 22: Toward automated design of mutant-selective tyrosine kinase inhibitors using dynamic pharmacophore mapping and machine learning
Authors: Benjamin P. Brown, Jeffrey Mendenhall, Christine Lovly, Jens Meiler
Journal: Clinical Cancer Research (2020)

Abstract Receptor tyrosine kinases (RTKs) constitute one of the most significant classes of oncologic therapeutic targets. For over a decade, all-atom molecular simulations have been employed to probe the determinants of tyrosine kinase inhibitor (TKI) selectivity. Today, we recognize that sequence and dynamical differences in key regions of kinases, such as the glycine-rich loop, DFG-motif, hinge-binding domain, and gatekeeper region, all contribute to the variability in TKI potency and selectivity across the kinome. This knowledge led to the structure-based rational design of the TKI osimertinib, which preferentially binds to the EGFR-T790M resistance mutant over wild-type EGFR. More recently, we demonstrated that a newly-identified EGFR osimertinib resistance mutation, G724S, develops in specific sequence variants of Ex19Del, but not in L858R, and we were able to attribute these differences to detailed changes in EGFR dynamics. Here, we present a strategy that leverages differences in protein dynamics between mutants to guide the design of mutant-selective inhibitors. Our algorithm employs machine learning-guided Monte Carlo-Metropolis (MCM) sampling of medicinal chemistry modifications to small-molecule scaffolds. The molecules are iteratively filtered through a pharmacophore map of the protein-ligand complex, where the softness of the edges scales with a molecular dynamics-derived measure of each residue’s flexibility with respect to the ligand. Citation Format: Benjamin P. Brown, Jeffrey Mendenhall, Christine Lovly, Jens Meiler. Toward automated design of mutant-selective tyrosine kinase inhibitors using dynamic pharmacophore mapping and machine learning [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 22.
Socio-demographic and epidemiological consideration of Africa’s COVID-19 response: what is the possible pandemic course?
Authors: Bamba Gaye, Stéphanie Khoury, Crystal W. Cene, Samuel Kingue, Roland N’Guetta, Camille Lassale, Dadhi Baldé, Ibrahima Bara Diop, Jennifer Beam Dowd, Melinda C. Mills, Xavier Jouven
Journal: Nature Medicine (2020)
Raster-scanning optoacoustic mesoscopy imaging as an objective disease severity tool in atopic dermatitis patients
Authors: Yik Weng Yew, Dinish Unnimadhava Kurup Soudamini Amma, Amanda Hui Yu Kuan, Xiuting Li, Kapil Dev, Amalina Binte Ebrahim Attia, Renzhe Bi, Mohesh Moothanchery, Ghayathri Balasundaram, Juan Aguirre, Vasilis Ntziachristos, Malini Olivo, Steven Tien Guan Thng
Journal: Journal of the American Academy of Dermatology (2020)
In HF with LVEF ≤ 42.5%, sacubitril–valsartan vs RAS inhibitors reduced a composite of CV death or HF hospitalization
Authors: Sounok Sen, L. Kristin Newby
Journal: Annals of Internal Medicine (2020)

ACP Journal Club16 June 2020In HF with LVEF ≤ 42.5%, sacubitril–valsartan vs RAS inhibitors reduced a composite of CV death or HF hospitalizationSounok Sen, MD, L. Kristin Newby, MD, MHSSounok Sen, MDDuke University School of Medicine, Durham, North Carolina, USA (S.S., L.K.N.)Search for more papers by this author, L. Kristin Newby, MD, MHSDuke University School of Medicine, Durham, North Carolina, USA (S.S., L.K.N.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ202006160-065 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationSolomon SD, Vaduganathan M, Claggett BL, et al. Sacubitril/valsartan across the spectrum of ejection fraction in heart failure. Circulation. 2020;141:352-61. https://pubmed.ncbi.nlm.nih.gov/31736342Clinical Impact RatingsGIM/FP/GP: Cardiology: Author, Article, and Disclosure InformationAffiliations: Duke University School of Medicine, Durham, North Carolina, USA (S.S., L.K.N.)Disclosures: The commentators have disclosed no conflicts of interest. The forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-3043.This article was published at Annals.org on -13 June 2020. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 16 June 2020Volume 172, Issue 12Page: JC65KeywordsClinical trialsDiureticsEjection fractionHeart failureHospitalizationsLeft ventricular ejection fractionMortalityN terminal pro brain natriuretic peptidesNatriuretic peptidesPhenotypes ePublished: 1 June 2020 Issue Published: 16 June 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...