1,721,003 research outputs found
Quantification of therapeutic antibodies and endogenous proteins with LC-MS/MS
No full textTherapeutic monoclonal antibodies are widely used for the treatment of various diseases were
conventional small molecule based drugs are not effective. For patients with inflammatory
autoimmune disease for example, the overproduction of TNF-alpha protein causes painful
inflammatory symptoms. The level of TNF-alpha can be reduced through treatment with
therapeutic monoclonal antibodies such as infliximab or adalimumab. However, some
patients develop anti-drug antibodies that target these therapeutic ‘exogenous’ proteins thus
reducing the drug concentration in plasma. This in turn renders the treatment ineffective.
In this case quantitative proteomics is used for therapeutic drug monitoring (TDM) of drug
concentration in plasma. This can provide the clinician useful insight to what is happening in
the patient’s body and can be used to tailor the patient’s care.
Quantitative proteomics can also be used for endogenous proteins. Endogenous proteins are
synthesized by the DNA within the cell nucleus. Endogenous proteins are the building blocks
for all cells that make up the organism, they play a role in food digestion, they offer protection
from pathogens and they heal the cells when damaged. The ability to determine whether
these proteins are present in the required concentration in plasma can help the clinician
to diagnose a disease but also to personalize the treatment plan. Patients with hemophilia
A for example, have a mutation in the X chromosome in locus q28. This portion of the X
chromosome codes for the synthesis of the 2351 amino acid long FVIII protein. However,
if FVIII is not synthesized correctly, this happens when one amino acid is swapped for
another, misshaped or misfolded FVIII protein might be formed which could compromise
the binding efficiency to its stabilizer protein von Willebrand or to the other factors FIX and
FX involved in coagulation, resulting in prolonged bleeding times. Different dosing schemes
with recombinant FVIII are thus incorporated dependent on the level of FVIII deficiency.
This thesis provides a tutorial for quantitative proteomics with liquid chromatography−
tandem mass spectrometry (LC-MS/MS), furthermore various examples of bioanalytical
quantification of endogenous and therapeutic proteins in human plasma are presented. Novel
sample purification strategies are introduced and optimized though experimental design.
Some of these methods such as infliximab and adalimumab are already in use for routine
TDM. Others, such as coagulation FVIII, neutralizing anti-drug antibodies, dinutuximab and
active anti-thymocyte globulin (ATG) were developed for ongoing pharmacokinetics and
pharmacodynamics studies
Accelerated autoantibody clearance by intravenous immunoglobulin therapy: studies in experimental models to determine the magnitude and time course of the effect
Full text linkRecently, it has been postulated that the beneficial effect of intravenous immunoglobulins (IVIGs) in antibody-mediated autoimmune disorders is based on accelerated catabolism of autoantibodies. In the current study, in vivo experiments were performed with mice in which autoantibody production was mimicked by continuous infusion of monoclonal antibodies. In this model, a single dose of IVIG reduced the plasma concentrations of the infused immunoglobulin (Ig)G1 monoclonal antibody (mAb) by approximately 40% after 3 days, whereas the concentration of an IgA mAb was not affected. To extrapolate these findings to humans, a computational model for IgG clearance was established that accurately predicted the time course and magnitude of the decrease in IgG plasma levels observed in mice. Adapted for humans, this model predicted a gradually occurring decrease in autoantibody levels after IVIG administration (2 g/kg), with a maximum reduction of approximately 25% after 3 to 4 weeks and a continued decrease of several months. In conclusion, a single high dose of IVIG induces a relatively small but long-lasting reduction of autoantibody levels by accelerated IgG clearance. This mechanism has clinical relevance in the sense that it can fully explain, as the sole mechanism, the gradual decrease in autoantibody levels observed in several patient studies. However, in some clinical studies, larger or more rapid effects have been observed that cannot be explained by accelerated clearance. Hence, IVIG can also reduce autoantibody levels through mechanisms such as down-regulation of antibody production or neutralization by anti-idiotypic antibodies
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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