18 research outputs found
Double Arylation of the Indole Side Chain of Tri- and Tetrapodal Tryptophan Derivatives Renders Highly Potent HIVâ1 and EV-A71 Entry Inhibitors
This work is dedicated to Prof. Jan Balzarini (KU Leuven,
Belgium), on the occasion of his retirement, in recognition of
his constant encouragement and exemplary dedication to
virology.We have recently described a new generation of potent
human immunodeficiency virus (HIV) and EV-A71 entry inhibitors. The
prototypes contain three or four tryptophan (Trp) residues bearing an
isophthalic acid moiety at the C2 position of each side-chain indole ring.
This work is now extended by both shifting the position of the isophthalic
acid to C7 and synthesizing doubly arylated C2/C7 derivatives. The most
potent derivative (50% effective concentration (EC50) HIV-1, 6 nM; EC50
EV-A71, 40 nM), 33 (AL-518), is a C2/C7 doubly arylated tetrapodal
compound. Its superior anti-HIV potency with respect to the previous C2-
arylated prototype is in consonance with its higher affinity for the viral
gp120. 33 (AL-518) showed comparable antiviral activities against X4
and R5 HIV-1 strains and seems to interact with the tip and base of the
gp120 V3 loop. Taken together, these findings support the interest in 33
(AL-518) as a useful new prototype for anti-HIV/EV71 drug development.This work was supported by the Spanish MICINN (Projects
PID2019-104070RB-C21 and PID2019-104070RB-C22), the
Spanish Agencia Estatal Consejo Superior de Investigaciones
CientĂficas (CSIC, Projects CSIC-PIE-201980E100 and CSICPIE-
201980E028), âThe Centers of Excellenceâ of the KU
Leuven (EF-05/15 and PF-10/18), EU FP7 (FP7/2007-2013)
Project EUVIRNA (Grant 408 Agreement 264286), EU FP7
SILVER (Contract HEALTH-F3-2010-260644), a grant from
the Belgian Interuniversity Attraction Poles (IAP) Phase VIIâ
P7/45 (BELVIR), and the EU FP7 Industry-Academia
Partnerships and Pathways Project AIROPICO. Spanish
MEC/MINECO is also acknowledged for grants to B.M.-G.
and O.M.-M. and the China Scholarship Council (CSC)
(Grant 201403250056) for a grant to L.S. The authors also
thank Charlotte Vanderheydt, Evelyne Van Kerckhove,
Caroline Collard, Kim Donchers, and Sandra Claes for help
with the processing of the antiviral data. This work has been
awarded the Janssen (XVIII call) and Esteve (XIX call) prizes
within the âPrizes for Young Researchers of the Spanish
Society of Medicinal Chemistry (SEQT).âPeer reviewe
Development of a Novel SPR Assay to Study CXCR4-Ligand Interactions
G protein-coupled receptors (GPCRs) are involved in a plethora of different diseases. Consequently, these proteins are considered as an important class of drug targets. Measuring detailed kinetic information on these types of proteins has been challenging. Surface plasmon resonance (SPR) can provide this information, however, the use of SPR on GPCRs remains a complex issue. Here, we report an SPR assay to investigate the interactions between the full-length chemokine receptor CXCR4 and nanobody-Fc (Nb-Fc) ligands. Nb-Fcs consist of two monovalent VHH domains fused with an Fc domain of a human IgG molecule. The CXCR4 protein used in this assay was produced with a C-terminal 10x-histidine tag and was immobilized on a nitrilotriacetic acid chip. In order to verify the sensitivity and effectiveness of this assay, the results were compared to data obtained from cellular assays as well as from another SPR assay using CXCR4 virus-like particles (VLPs). CXCR4 remained intact and stable for at least 12 h, and the kinetic results correlated well with both the cellular assays and the VLP SPR assay results. Apart from determining the binding kinetics of Nb-Fc with CXCR4, our results contributed to understanding CXCR4 interaction dynamics. In conclusion, this assay provides a viable experimental platform that has high potential to be expanded for studying other molecules as well as other histidine-tagged GPCRs.status: publishe
Epigenetic and genetic disturbance of the imprinted 11p15 region in Beckwith-Wiedemann and Silver-Russell syndromes
Does Balloon Kyphoplasty Deliver More Cement Safely into Osteoporotic Vertebrae with Compression Fractures Compared with Vertebroplasty? A Study in Vertebral Analogues
A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus
The expression of imprinted genes is mediated by allele-specific epigenetic modification of genomic DNA and chromatin, including parent of origin-specific DNA methylation. Dysregulation of these genes causes a range of disorders affecting pre- and post-natal growth and neurological function. We investigated a cohort of 12 patients with transient neonatal diabetes whose disease was caused by loss of maternal methylation at the TNDM locus. We found that six of these patients showed a spectrum of methylation loss, mosaic with respect to the extent of the methylation loss, the tissues affected and the genetic loci involved. Five maternally methylated loci were affected, while one maternally methylated and two paternally methylated loci were spared. These patients had higher birth weight and were more phenotypically diverse than other TNDM patients with different aetiologies, presumably reflecting the influence of dysregulation of multiple imprinted genes. We propose the existence of a maternal hypomethylation syndrome, and therefore suggest that any patient with methylation loss at one maternally-methylated locus may also manifest methylation loss at other loci, potentially complicating or even confounding the clinical presentation.<br/
Effectiveness of Exercise Programs in Ankylosing Spondylitis: A Meta-Analysis of Randomized Controlled Trials
Bone health in chronic kidney disease-mineral and bone disorder: a clinical case seminar and update
Core outcome measurement set for shared decision making in rheumatic and musculoskeletal conditions: A scoping review to identify candidate instruments
OBJECTIVES
Shared decision making (SDM) is a central tenet in rheumatic and musculoskeletal care. The lack of standardization regarding SDM instruments and outcomes in clinical trials threatens the comparative effectiveness of interventions. The Outcome Measures in Rheumatology (OMERACT) SDM Working Group is developing a Core Outcome Set for trials of SDM interventions in rheumatology and musculoskeletal health. The working group reached consensus on a Core Outcome Domain Set in 2020. The next step is to develop a Core Outcome Measurement Set through the OMERACT Filter 2.2.
METHODS
We conducted a scoping review (PRISMA-ScR) to identify candidate instruments for Powered by Editorial ManagerÂź and ProduXion ManagerÂź from Aries Systems Corporation the OMERACT Filter 2.2 We systematically reviewed five databases (Ovid MEDLINEÂź, Embase, Cochrane Library, CINAHL and Web of Science). An information specialist designed search strategies to identify all measurement instruments used in SDM studies in adults or children living with rheumatic or musculoskeletal diseases or their important others. Paired reviewers independently screened titles, abstracts, and full text articles. We extracted characteristics of all candidate instruments (e.g., measured construct, measurement properties). We classified candidate instruments and summarized evidence gaps with an adapted version of the Summary of Measurement Properties (SOMP) table.
RESULTS
We found 14,464 citations, read 239 full text articles, and included 99 eligible studies. We identified 220 potential candidate instruments. The five most used measurement instruments were the Decisional Conflict Scale (traditional and low literacy versions) (n=38), the Hip/Knee-Decision Quality Instrument (n=20), the Decision Regret Scale (n=9), the Preparation for Decision Making Scale (n=8), and the CollaboRATE (n=8). Only 44 candidate instruments (20%) had any measurement properties reported by the included studies. Of these instruments, only 57% matched with at least one of the 7-criteria adapted SOMP table.
CONCLUSION
We identified 220 candidate instruments used in the SDM literature among people with rheumatic and musculoskeletal diseases. Our classification of instruments showed evidence gaps and inconsistent reporting of measurement properties. The next steps for the OMERACT SDM Working Group are to match candidate instruments with Core Domains, assess feasibility and review validation studies of measurement instruments in rheumatic diseases or other conditions. Development and validation of new instruments may be required for some Core Domains
Endorsement of the OMERACT core domain set for shared decision making interventions in rheumatology trials: Results from a multi-stepped consensus-building approach
Objective: To gain consensus on the Outcome Measures in Rheumatology (OMERACT) core domain set for rheumatology trials of shared decision making (SDM) interventions.Methods: The process followed the OMERACT Filter 2.1 methodology, and used consensus-building methods, with patients involved since the inception. After developing the draft core domain set in previous research, we conducted five steps: (i) improving the draft core domain set; (ii) developing and disseminating whiteboard videos to promote its understanding; (iii) conducting an electronic survey to gather feedback on the draft core domain set; (iv) finalizing the core domain set and developing summaries, a plenary session video and discussion boards to promote its understanding; and (v) conducting virtual workshops with voting to endorse the core domain set.Results: A total of 167 participants from 28 countries answered the survey (62% were patients/caregivers). Most participants rated domains as relevant (81%-95%) and clear (82%-93%). A total of 149 participants (n = 48 patients/caregivers, 101 clinicians/researchers) participated in virtual workshops and voted on the proposed core domain set which received endorsement by 95%. Endorsed domains are: 1-Knowledge of options, their potential benefits and harms; 2-Chosen option aligned with each patient's values and preferences; 3-Confidence in the chosen option; 4-Satisfaction with the decision-making process; 5-Adherence to the chosen option and 6-Potential negative consequences of the SDM intervention.Conclusion: We achieved consensus among an international group of stakeholders on the OMERACT core domain set for rheumatology trials of SDM interventions. Future research will develop the Core Outcome Measurement Set.Clinical significance: Prior to this study, there had been no consensus on the OMERACT core domain set for SDM interventions. The current study shows that the OMERACT core domain set achieved a high level of endorsement by key stakeholders, including patients/caregivers, clinicians and researchers.(c) 2021 Elsevier Inc. All rights reserved.Pathophysiology and treatment of rheumatic disease