1,721,004 research outputs found
Abstract 1069: Inhibition of the nuclear import receptor, KpnB1 synergizes with cisplatin toxicity in cervical cancer cells
No full textAbstract
Elevated expression of members of the nuclear transport protein family has been reported in multiple cancers and presents as novel anticancer therapeutic targets. Using a cervical cancer model system, we have previously shown that inhibition of the nuclear import receptor, KpnB1 by siRNA and a novel small molecule, Inhibitor of Nuclear Import (INI-43) resulted in cancer cell death via apoptosis. In this study, we investigated the cancer cell killing effects of KpnB1 inhibition in combination with Cisplatin (CDDP), a first-line chemotherapeutic agent used in the treatment of many cancers. KpnB1 siRNA and INI-43 treatment at sub-lethal concentrations enhanced cancer cells' sensitivity to CDDP. Our data shows that the combination treatment of INI-43 and CDDP significantly decreases CDDP IC50 compared to CDDP treatment alone. Increased PARP-cleavage was observed in combination treated cells and this correlated with increased γH2A.X, indicating increased apoptosis and DNA damage. Furthermore, INI-43 treatment reduced the nuclear import of NFκB, a stress-regulated response transcription factor known to be a KpnB1 cargo protein that promotes cancer cell survival. Decreased levels of downstream pro-survival and DNA-repair targets of NFκB were observed, including cyclinD1, c-Myc and XIAP, which correlated with increased DNA damage and apoptosis. Taken together, results suggest increased Cisplatin sensitivity of cervical cancer cells when nuclear import via KpnB1 is inhibited.
Citation Format: Ru-pin Chi, Wei Wei, Michael Birrer, Virna D. Leaner. Inhibition of the nuclear import receptor, KpnB1 synergizes with cisplatin toxicity in cervical cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1069. doi:10.1158/1538-7445.AM2017-1069</jats:p
Abstract B34: Investigating disruptions in the circadian clock in cancer cells
No full textAbstract
The circadian clock is man's internal time-keeping mechanism; it synchronizes human physiology with the external cycle of day and night. At the molecular level, all cells display a circadian clock driven by core clock proteins that constitute transcription-translation feedback loops, generating oscillating patterns of circadian clock gene expression over time. It is becoming increasingly apparent that disruptions in the circadian clock may contribute to cancer development. This study aimed to investigate the molecular components of the circadian clock in two cancer types prevalent in South Africa: cervical and oesophageal cancer. To our knowledge the circadian clock has not previously been investigated in these cancer types. Microarray and real-time RT-PCR analyses revealed significantly decreased expression of Period 2 (Per2) mRNA in cervical and oesophageal cancer patient tissue compared to normal tissue. Cervical and oesophageal cancer cell lines similarly displayed significantly reduced mRNA and protein levels of certain circadian clock genes, including positive and negative regulators of the circadian clock. Nuclear transport of circadian clock proteins was investigated, since cancer cells display increased nuclear transport rates and circadian clock proteins rely on nucleocytoplasmic shuttling to maintain the correct pace of the circadian clock. Fluorescence recovery after photobleaching (FRAP) analysis was performed and revealed increased nuclear import rates of Bmal1 in cancer compared to normal cells. Altered expression and nuclear import rates of circadian clock proteins in cancer cells suggest these cells might harbor an impaired circadian clock. Luminescence assays are thus currently being employed to determine whether cancer cells display rhythmic expression of core clock genes, as an indication of a functioning circadian clock. A real-time bioluminescence imager is being used to measure Bmal1 and Per2 promoter-luciferase activities in cancer cells over time, after synchronization of circadian oscillators with the glucocorticoid analogue, Dexamethasone. This type of study is relevant to the field of chronotherapy, where elucidating differences in circadian clock functioning in normal and cancer cells could yield better insights into the timing of administration of chemotherapy, ultimately ensuring a better patient response.
Citation Format: Waldo Lexow, Sian-Ailin Da Silva, Virna D. Leaner, Pauline J. van der Watt. Investigating disruptions in the circadian clock in cancer cells [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B34.</jats:p
Abstract B09: KPNB1-mediated nuclear import is required for inflammatory cytokine expression, invasion and survival of cancer cells
No full textAbstract
Karyopherin β1 (KPNB1) is a nuclear transport protein involved in the transport of transcription factors and other proteins containing a nuclear localization sequence (NLS) into the nucleus. Elevated KPNB1 expression has been reported in cancer and transformed cells and is suggested to sustain the increased metabolic and proliferative demands. Transcription factors such as NFκB and AP-1 contain a NLS which is required by KPNB1 for nuclear import. These transcription factors initiate the expression of multiple cytokines and factors associated with inflammation and cancer cell biology. An inflammatory microenvironment, a hallmark of cancer, contributes to factors such as sustained proliferation, invasion and neoangiogenesis. Our study aimed to investigate the effect of inhibiting nuclear import via KPNB1 on cell biology and inflammatory signaling associated with cancer using siRNA and the novel small molecule, Inhibitor of Nuclear Import- 43 (INI-43). Inhibition of KPNB1 lead to reduced migration and invasion of cervical cancer cells while extended inhibition caused decreased proliferation and apoptosis. KPNB1 is essential for the translocation of NFκB into the nucleus as inhibition of nuclear import resulted in its cytoplasmic retention and decreased transcriptional activity of both transcription factors; NFκB and AP-1. DNA-binding studies confirmed a reduced binding-ability or presence of NFκB in the nuclear extract of KPNB1-inhibited cells. Consequently reduced IL-6, IL-1β, TNF-α; and GM-CSF expression, target genes of NFκB and AP-1, was observed. INI-43 significantly inhibited tumor growth in an ectopic xenograft mouse model and histological analysis found the tumor tissue to be less invasive. Immunohistochemical analysis of mice tumors showed reduced overall expression of KPNB1 as well as a shift in cellular localization to be more cytoplasmic following INI-43 treatment. Our study provides evidence that inhibiting KPNB1 has anti-inflammatory and anti-cancer effects and shows promise as a chemotherapeutic target.
Citation Format: Tamara Stelma, Alicia Chi, Anwar Mall, Dhiren Govender, Virna D. Leaner. KPNB1-mediated nuclear import is required for inflammatory cytokine expression, invasion and survival of cancer cells [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B09.</jats:p
KPNB1-mediated nuclear import is required for motility and inflammatory transcription factor activity in cervical cancer cells
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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
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