332 research outputs found
Immunogenicity in Clinical Practice and Drug Development: When is it Significant?
Managing immunogenicity in clinical practice and during drug development was a recent topic at the ASCPT 2019 annual meeting. This commentary expands on the discussion to facilitate a broader engagement across the community. The intent is to provide a rationale for ongoing research into the current gaps in assessing and interpreting immunogenicity in drug development and managing clinical immunogenicity for an approved drug. The following are highlighted: (i) Immunogenicity Considerations in Clinical Practice, (ii) Immunogenicity Testing and Current Limitations, (iii) Immunogenicity Risk Assessment and Mitigation, and (iv) Quantitative Systems Pharmacology (QSP) models of Immunogenicity
A Flagellar A-Kinase Anchoring Protein with Two Amphipathic Helices Forms a Structural Scaffold in the Radial Spoke Complex
A-kinase anchoring proteins (AKAPs) contain an amphipathic helix (AH) that binds the dimerization and docking (D/D) domain, RIIa, in cAMP-dependent protein kinase A (PKA). Many AKAPs were discovered solely based on the AH–RIIa interaction in vitro. An RIIa or a similar Dpy-30 domain is also present in numerous diverged molecules that are implicated in critical processes as diverse as flagellar beating, membrane trafficking, histone methylation, and stem cell differentiation, yet these molecules remain poorly characterized. Here we demonstrate that an AKAP, RSP3, forms a dimeric structural scaffold in the flagellar radial spoke complex, anchoring through two distinct AHs, the RIIa and Dpy-30 domains, in four non-PKA spoke proteins involved in the assembly and modulation of the complex. Interestingly, one AH can bind both RIIa and Dpy-30 domains in vitro. Thus, AHs and D/D domains constitute a versatile yet potentially promiscuous system for localizing various effector mechanisms. These results greatly expand the current concept about anchoring mechanisms and AKAPs
Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution
The peroxisome proliferator-activated receptors (PPARs) regulate genes involved in lipid and carbohydrate metabolism, and are targets of drugs approved for human use. Whereas the crystallographic structure of the complex of full length PPARγ and RXRα is known, structural alterations induced by heterodimer formation and DNA contacts are not well understood. Herein, we report a small-angle X-ray scattering analysis of the oligomeric state of hPPARγ alone and in the presence of retinoid X receptor (RXR). The results reveal that, in contrast with other studied nuclear receptors, which predominantly form dimers in solution, hPPARγ remains in the monomeric form by itself but forms heterodimers with hRXRα. The low-resolution models of hPPARγ/RXRα complexes predict significant changes in opening angle between heterodimerization partners (LBD) and extended and asymmetric shape of the dimer (LBD-DBD) as compared with X-ray structure of the full-length receptor bound to DNA. These differences between our SAXS models and the high-resolution crystallographic structure might suggest that there are different conformations of functional heterodimer complex in solution. Accordingly, hydrogen/deuterium exchange experiments reveal that the heterodimer binding to DNA promotes more compact and less solvent-accessible conformation of the receptor complex
Discovering temporal regularities in retail customers’ shopping behavior
In this paper we investigate the regularities characterizing the temporal purchasing behavior of the customers of a retail market chain. Most of the literature studying purchasing behavior focuses on what customers buy while giving few importance to the temporal dimension. As a consequence, the state of the art does not allow capturing which are the temporal purchasing patterns of each customers. These patterns should describe the customerâ\u80\u99s temporal habits highlighting when she typically makes a purchase in correlation with information about the amount of expenditure, number of purchased items and other similar aggregates. This knowledge could be exploited for different scopes: set temporal discounts for making the purchases of customers more regular with respect the time, set personalized discounts in the day and time window preferred by the customer, provide recommendations for shopping time schedule, etc. To this aim, we introduce a framework for extracting from personal retail data a temporal purchasing profile able to summarize whether and when a customer makes her distinctive purchases. The individual profile describes a set of regular and characterizing shopping behavioral patterns, and the sequences in which these patterns take place. We show how to compare different customers by providing a collective perspective to their individual profiles, and how to group the customers with respect to these comparable profiles. By analyzing real datasets containing millions of shopping sessions we found that there is a limited number of patterns summarizing the temporal purchasing behavior of all the customers, and that they are sequentially followed in a finite number of ways. Moreover, we recognized regular customers characterized by a small number of temporal purchasing behaviors, and changing customers characterized by various types of temporal purchasing behaviors. Finally, we discuss on how the profiles can be exploited both by customers to enable personalized services, and by the retail market chain for providing tailored discounts based on temporal purchasing regularity
Laughter and humor as complementary and alternative medicines for dementia patients
<p>Abstract</p> <p>Background</p> <p>The number of dementia patients has increased worldwide, with an estimated 13.7 million dementia patients in the Asia Pacific region alone. This number is expected to increase to 64.6 million by the year 2050.</p> <p>Discussion</p> <p>As a result of advances in research, there several pharmacological therapies available for the treatment of dementia patients. However, current treatments do not suppress the disease process and cannot prevent dementia, and it will be some time before these goals are realized. In the meantime, complementary and alternative medicine (CAM) is an important aspect in the treatment of dementia patients to improve their quality of life throughout the long course of the disease. Considering the individuality of dementia patients, applicability of laughter and humor therapy is discussed. Even though there are many things that need to be elucidated regarding the mechanisms underlying the beneficial effects of laughter and humor, both may be good CAM for dementia patients if they are applied carefully and properly.</p> <p>Summary</p> <p>In this debate article, the physiological basis and actual application of laughter and humor in the treatment of dementia patients are presented for discussion on the applicability to dementia patients.</p
Axial stent strut angle influences wall shear stress after stent implantation: analysis using 3D computational fluid dynamics models of stent foreshortening
INTRODUCTION: The success of vascular stents in the restoration of blood flow is limited by restenosis. Recent data generated from computational fluid dynamics (CFD) models suggest that the vascular geometry created by an implanted stent causes local alterations in wall shear stress (WSS) that are associated with neointimal hyperplasia (NH). Foreshortening is a potential limitation of stent design that may affect stent performance and the rate of restenosis. The angle created between axially aligned stent struts and the principal direction of blood flow varies with the degree to which the stent foreshortens after implantation. METHODS: In the current investigation, we tested the hypothesis that stent foreshortening adversely influences the distribution of WSS and WSS gradients using time-dependent 3D CFD simulations of normal arteries based on canine coronary artery measurements of diameter and blood flow. WSS and WSS gradients were calculated using conventional techniques in ideal (16 mm) and progressively foreshortened (14 and 12 mm) stented computational vessels. RESULTS: Stent foreshortening increased the intrastrut area of the luminal surface exposed to low WSS and elevated spatial WSS gradients. Progressive degrees of stent foreshortening were also associated with strut misalignment relative to the direction of blood flow as indicated by analysis of near-wall velocity vectors. CONCLUSION: The current results suggest that foreshortening may predispose the stented vessel to a higher risk of neointimal hyperplasia
Hypothermia following antipsychotic drug use
Objective: Hypothermia is an adverse drug reaction (ADR) of
antipsychotic drug (APD) use. Risk factors for hypothermia in
ADP users are unknown. We studied which risk factors for
hypothermia can be identified based on case reports.
Method: Case reports of hypothermia in APD-users found in
PUBMED or EMBASE were searched for risk factors. The
WHO international database for Adverse Drug Reactions was
searched for reports of hypothermia and APD use.
Results: The literature search resulted in 32 articles containing
43 case reports. In the WHO database, 480 reports were
registered of patients developing hypothermia during the
use of APDs which almost equals the number of reports for
hyperthermia associated with APD use (n=524). Hypothermia
risk seems to be increased in the first days following start
or dose increase of APs. APs with strong 5-HT2 antagonism
seem to be more involved in hypothermia; 55% of hypothermia
reports are for atypical antipsychotics. Schizophrenia was
the most prevalent diagnosis in the case reports.
Conclusion: Especially in admitted patients who are not able
to control their own environment or physical status, frequent
measurements of body temperature (with a thermometer that
can measure low body temperatures) must be performed in
order to detect developing hypothermia
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