130,412 research outputs found
Mechanisms of action of thioredoxin reductase inhibitors in the context of cancer
No full textThe increased understanding of the role of redox homeostasis in cancer survival and progression has placed a spotlight on studying the perturbations in redox signaling as cancer vulnerabilities. These vulnerabilities are in part under the control of antioxidant systems such as the thioredoxin system, with its main effector, the selenoprotein thioredoxin reductase (TXNRD). The selenocysteine- containing (Sec) active site of TXNRD is highly susceptible to alkylation by electrophiles and this has in fact been shown to be a part of the mechanism of action of a range of anticancer compounds in the clinic and in trials, including cisplatin and auranofin. Discovering and developing compounds with a focused target profile on TXNRD has been a major aim of the Arner group, so as to limit the side effects seen with drugs with broader target profiles and to study the precise downstream effects of TXNRD inhibition on redox signaling in cancer. These efforts led to the discovery of thioredoxin reductase inhibitor 1 (TRi-1), a highly selective TXNRD inhibitor with good antitumoral activity in mouse models. This thesis has focused on further characterizing the effects of TRi-1 in cancer cells and better understanding the role of TXNRD as a cancer vulnerability.Paper I further confirmed the narrow target profile of TRi-1 in comparison to auranofin on a proteomics scale by combining thermal proteome profiling, protein expression and redox proteomics approaches. It also established that TRi-1 does not result in a stable downregulation of cellular TXNRD activity, but instead causes rapid inhibition followed by a compensatory increase.In Paper II, we explored the activities of TRi-1 analogs with functionalizations allowing for increased mitochondrial uptake or differential electrophilicity of the selenocysteine-interacting moiety, both against cytosolic and mitochondrial TXNRD isoforms. We arrived at a diverse collection of novel compounds with a range of efficacies in recombinant systems and cancer cell lines, including scaffolds with improved activity compared to TRi-1.Paper III identified surprising connections between TXNRD and ferroptosis by confirming ferroptosis inducers as inhibitors of TXNRD and by establishing that TRi-1-induced cell death cannot be classified as ferroptosis and indeed cannot be rescued by any of the most common death inhibitors. We also reported differential glutathione peroxidase 4 migration patterns in response to ferroptosis inducing TXNRD1 inhibitors and TRi-1, hinting their effects on antioxidant systems in recombinant and cellular contexts are more complex than previously anticipated.Paper IV characterized in detail the kinetics of cellular events taking place after TRi-1 and thereby comprehensively portrayed the mechanisms of action of this compound in cancer cells. We established that short term exposure of the cells, in the order of one hour, to the compound is in every way equivalent to a continuous exposure and showed the kinetics of TRi-1 derivatization of the TXNRD selenopeptide in cells. The anticancer effects were predominantly caused by an arrest in cell cycle progression characterized by a downregulation of CDK1/2. Cells experienced peroxiredoxin dimerization and overoxidation, suggestive of increased oxidative stress, but without major perturbations in protein or nucleotide homeostasis.Paper V established the efficacy of TRi-1 in parasite TXNRD isoforms with unusual structural domains, suggesting that a broader application of this compound to pathologies beyond cancer may be possible, much like the broader indications for using the more promiscuous auranofin.Overall, the papers comprising this thesis have focused on exploring different aspects of the mechanism of action of TRi-1 as a TXNRD inhibitor and have painted a multifaceted picture of the compound's activities extending far beyond its target engagement.List of scientific papersI. Pierre Sabatier, Christian M. Beusch, Radosveta Gencheva, Qing Cheng, Roman Zubarev, Elias S.J. Arnér. Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin. Redox Biol. 2021 Nov 11;48:102184. https://doi.org/10.1016/j.redox.2021.102184II. Miloš Jović#, Radosveta Gencheva #, Qing Cheng, Karoline C. Scholzen, Života Selaković, Elias S.J. Arnér, Igor M. Opsenica. Development of novel analogs of the TRi-1 and TRi-2 selenoprotein thioredoxin reductase inhibitors with initial assessment of their cytotoxicity profiles. [Submitted]III. Dorian M. Cheff, Chuying Huang, Karoline C. Scholzen, Radosveta Gencheva, Michael H. Ronzetti, Qing Cheng, Matthew D. Hall, Elias S. J. Arnér. The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD. Redox Biol. 2023 Jun;62:102703. https://doi.org/10.1016/j.redox.2023.102703IV. Radosveta Gencheva, Giovanni Chiappetta, Karoline C. Scholzen, Praveen Pandey, Zhao Wenchao, Lucia Coppo, Qing Cheng, Joelle Vinh, Andrei Chabes, Elias S.J. Arnér. Insights into the kinetics of thioredoxin reductase derivatization and associated cancer cell death by the small molecule inhibitor TRi-1. [Manuscript]V. Francesca Fata#, Radosveta Gencheva #, Qing Cheng, Rachel Lullo, Matteo Ardini, Ilaria Silvestri, Federica Gabriele, Rodolfo Ippoliti, Christina A. Bulman, Judy A. Sakanari, David L. Williams, Elias S.J. Arnér, Francesco Angelucci. Biochemical and structural characterizations of thioredoxin reductase selenoproteins of the parasitic filarial nematodes Brugia malayi and Onchocerca volvulus. Redox Biol. 2022 May;51:102278. https://doi.org/10.1016/j.redox.2022.102278</p
MeSH term explosion and author rank improve expert recommendations
No full textInformation overload is an often-cited phenomenon that reduces the productivity, efficiency and efficacy of scientists. One challenge for scientists is to find appropriate collaborators in their research. The literature describes various solutions to the problem of expertise location, but most current approaches do not appear to be very suitable for expert recommendations in biomedical research. In this study, we present the development and initial evaluation of a vector space model-based algorithm to calculate researcher similarity using four inputs: 1) MeSH terms of publications; 2) MeSH terms and author rank; 3) exploded MeSH terms; and 4) exploded MeSH terms and author rank. We developed and evaluated the algorithm using a data set of 17,525 authors and their 22,542 papers. On average, our algorithms correctly predicted 2.5 of the top 5/10 coauthors of individual scientists. Exploded MeSH and author rank outperformed all other algorithms in accuracy, followed closely by MeSH and author rank. Our results show that the accuracy of MeSH term-based matching can be enhanced with other metadata such as author rank
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe 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
"Closing the R&D Gap, Evaluating the Sources of R&D Spending"
No full textBoth spending and tax policies have been implemented in the United States with the goal of stimulating private sector research and development (R&D). Karier questions whether current R&D policy, especially the research and experimentation tax credit, can contribute to closing the gap between nondefense expenditures on R&D in the United States and such expenditures in other countries, such as Japan and Germany. He also explores possible changes to our current R&D policy to make it more effective.
Dispelling the Myths Behind First-author Citation Counts
No full textWe 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
Scholarly Communication and Publishing Lunch and Learn Talk #11: The ULS Open Access Author Fee Fund
No full textAt the May 2014 talk, you will learn about the ULS Open Access Author Fee Fund--what it is, why we do it, how it works, and how the program is going so far
The R&D Tax Incentives
No full textThis article sets out some background information and reflections of the author on the R&D tax incentive schemes included in the Common Corporate Tax Base (CCTB) Proposal. In particular the author analyzes the stimulus to private R&D through ad hoc tax incentives included in the CCTB Proposal and dives into the actual provisions included in the Proposal highlighting the most relevant issues connected with their design and interpretation. Moreover, the author explores the interaction between the CCTB Proposal and the granting by Member States of domestic R&D tax incentives
Morphologic and functional correlates of synaptic pathology in the cathepsin D knockout mouse model of congenital neuronal ceroid lipofuscinosis
No full textMutations in the cathepsin D (CTSD) gene cause an aggressive neurodegenerative disease (congenital neuronal ceroid lipofuscinosis) that leads to early death. Recent evidence suggests that presynaptic abnormalities play a major role in the pathogenesis of CTSD deficiencies. To identify the early events that lead to synaptic alterations, we investigated synaptic ultrastructure and function in presymptomatic CTSD knockout (Ctsd) mice. Electron microscopy revealed that there were significantly greater numbers of readily releasable synaptic vesicles present in Ctsd mice than in wild-type control mice as early as postnatal day 16. The size of this synaptic vesicle pool continued to increase with disease progression in the hippocampus and thalamus of the Ctsd mice. Electrophysiology revealed a markedly decreased frequency of miniature excitatory postsynaptic currents (mEPSCs) with no effect on paired-pulse modulation of the evoked excitatory post synaptic potentials in the hippocampus of Ctsd mice. The reduced mEPSCs frequency was observed before the appearance of epilepsy or any morphologic sign of synaptic degeneration. Taken together, these data indicate that CTSD is required for normal synaptic function and that a failure in synaptic trafficking or recycling may bean early and important pathologic mechanism in Ctsd mice; these presynaptic abnormalities may initiate synaptic degeneration in advance of subsequent neuronal loss
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