1,720,966 research outputs found
From Evasion to Elimination: Enhancing IgA therapy through myeloid checkpoint inhibition
No full textThis thesis explores the potential of IgA antibodies in cancer treatment, presenting a promising alternative to the currently used IgG antibodies in immunotherapy. Although IgG antibodies have been the main antibody isotype used in cancer therapy due to their stability and long half-life, they are not effective for all patients, with some developing resistance. This highlights the urgent need for new therapeutic strategies. IgA antibodies, particularly in their monomeric form, offer a unique opportunity. They activate different immune cells, including neutrophils, through the Fc-alpha receptor (CD89). Neutrophils are abundant in the body and can be activated to strongly induce antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis, which lead to the destruction of cancer cells. However, IgA antibodies face challenges such as complex glycosylation, complicating large-scale production, and a shorter half-life compared to IgG. To address these challenges, we have modified IgA antibodies to improve their stability and production feasibility. This modified version, named IgA3.0, has shown promising results. In both in vitro experiments and mouse models, IgA3.0 antibodies demonstrated strong anti-tumor responses by effectively activating neutrophils upon binding to tumor antigens. Furthermore, we explored the optimal conditions for IgA therapy, revealing that IgA's effectiveness is highly dependent on the level of tumor antigens. A system allowing for the controlled expression of antigens on tumor cells indicated that higher antigen levels are necessary for IgA to be effective compared to IgG. This specificity could potentially lead to fewer side effects, as healthy cells with lower antigen levels would be less likely to be targeted. To address the limitation of IgA's shorter half-life, we investigated methods to extend it. We attached albumin or its DIII domain to IgA, leveraging albumin's ability to bind to the neonatal Fc receptor (FcRn) and undergo recycling, thus protecting the antibody from degradation. This modification successfully extended IgA's half-life without compromising its effectiveness. Furthermore, checkpoint molecules like CD47 on tumor cells inhibit immune responses by binding to SIRPα on myeloid cells, including neutrophils. Blocking this interaction can enhance the efficacy of IgA. Our research showed that combining IgA therapy with CD47 blockade significantly improved anti-tumor responses in vitro and in mouse models. This combination increased neutrophil infiltration and activity in the tumor microenvironment, leading to better tumor control. In conclusion, this thesis demonstrates that IgA antibodies can effectively recruit and activate neutrophils against cancer cells, offering a viable alternative to IgG-based therapies. By optimizing IgA and understanding which cancer types benefit most from neutrophil activation, this research aims to improve outcomes for patients who do not respond to existing treatments
Proteolytic regulation of Notch1 receptor activity in cancer
No full textThe Notch receptor is part of a highly conserved signaling pathway essential in development and disease in embryos and adults. Notch proteins coordinate cell-cell communication through receptor-ligand interactions between adjacent cells. First Notch is cleaved in the Golgi by furin at Site-1 (S1) resulting in cell surface expression of heterodimeric transmembrane receptors. Subsequent ligand binding induces conformational changes of Notch allowing ADAM metalloproteases to cleave Site-2 (S2). Consequently, Notch is cleaved intramembranously at Site-3 (S3) by gamma-secretase, liberating Notch intracellular domain (NICD) which translocates to the nucleus and participates in a co-activator complex starting transcription of target genes. We investigated S2 cleavage by determining the exact metalloprotease involved in Notch1 activation. Using genetic and biochemical methods we demonstrated ADAM10, but not the previously reported ADAM17, plays an essential role in executing ligand-induced S2 cleavage in mammalian cells. Genetic or pharmacological metalloprotease inhibition still allowed extracellular cleavage of Notch1, indicating unknown proteases are present able to cleave at S2. Notch1 gain-of-function mutations identified in human cancers map to the negative control region alleviating the requirement for ligand binding for extracellular cleavage to occur. The serine protease Granzyme B (GrB) activates caspases triggering apoptosis to kill virus-infected and tumor cells. A caspase-independent substrate of GrB is Notch1. We examined in detail Notch cleavage by GrB, and demonstrated GrB cleaved the Notch1 intracellular domain at two distinct aspartic acids, D1860 and D1961. GrB cleavage of Notch1 occurs in all subcellular compartments; during Notch transport, at the membrane, and nucleus. Cleavage of Notch1 by GrB results in loss of transcriptional activity, disabling Notch1 function, likely resulting in a block of cellular proliferation and stimulating cell death. Notch is often deregulated in cancers and activating mutations in NOTCH1 are associated with acute T-cell leukemia (T-ALL). Overexpression of Notch1 in bone marrow of mice leads to T-ALL. Although gamma-secretase inhibitors (GSI) are often used to block Notch activation in T-ALL, a significant number of T-ALL become resistant to GSI treatment. Currently no drugs are available that effectively overcome GSI resistance in T-ALL. We employed 2D-DIGE to identify novel proteins involved in GSI resistance by comparing proteomes of GSI treated resistant and sensitive T-ALL lines. Validation by Western and qPCR resulted in identification of ERM protein Ezrin that is differentially expressed upon GSI treatment. Currently, its exact role in mediating resistance needs to be addressed. Although Notch is involved in a broad variety of cancers, good mouse models are lacking. Current models express constitutive, non-physiological levels of Notch1 from exogenous promoters. Improved models are needed where expression and activity of cancer-associated Notch1 mutant proteins can be regulated in a tissue-specific and temporal manner, but still require enzymatic processing. Such a model would be amendable to therapeutic intervention using drugs intervening with Notch1 processing. To achieve this, we engineered an oncogenic Notch1 Knock-In allele, expressed from ROSA26 locus which enables tissue-specific activation by Cre-recombinase and tetracycline controlled gene expression of mutant Notch1. Currently, characterization of our in vivo mouse model is ongoing
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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