Bob Van Research Articles

Abstract 418: Elacridar potentiates sunitinib efficacy in colorectal cancer models

Abstract For unresectable metastatic colorectal cancer (mCRC), the main treatment strategy is combination chemotherapy, targeted therapy, or immunotherapy. Long-term treatment benefit of these therapies is limited to a small subgroup of patients. To improve treatment outcome, many tyrosine kinase inhibitors (TKIs) have been clinically tested in patients with mCRC. Most failed already in early-phase clinical trials due to intrinsic resistance. ATP Binding Cassette Transporter (ABC)B1- and ABCG2-transporters are known contributors to treatment resistance in mCRC. Therefore, we evaluated whether inhibition of these transporters could potentiate the efficacy of TKIs in colorectal cancer (CRC) models. CRC cell lines, HT29, COLO320 and CACO2 and newly established patient-derived tumor organoids (PDTOs) from mCRC biopsies were first analyzed for the presence of ABCB1 and ABCG2 expression. Models that expressed ABCB1 or ABCG2 were pre-incubated with a non-toxic dose of elacridar, a potent transporter inhibitor, and exposed to a concertation range of three TKIs; sunitinib, cediranib and osimertinib. Next, we measured intracellular drug concentrations using LC/MS-MS one hour after TKI exposure (20 µM) with or without pre-incubation of elacridar. Using the fluorescent properties of sunitinib, we performed live-cell imaging to compare intracellular sunitinib distribution in cells that were or were not pre-incubated with elacridar. ABCB1 and ABCG2 expression was observed in all CRC models except for HT29 cells, which did not express ABCB1. Pre-incubation with elacridar significantly improved sunitinib efficacy in CRC cells. The IC50 decreased from 2.15 µM to 1.17 µM (p = 0.04), from 1.32 µM to 0.44 µM (p = 0.03), and from 4.94 µM to 3.43 µM (p = 0.03) for HT29, COLO320 and CACO2 cells respectively. This effect was not observed for cediranib and osimertinib. Although not significant, for both PDTO models tested, the IC50 for sunitinib decreased from 8.04 µM to 3.29 µM and from 6.93 µM to 4.16 µM. Intracellular sunitinib concentrations in the tested CRC cell models after sunitinib exposure ranged from 2.46 mM to 4.13 mM without elacridar and from 0.38 mM µM to 1.31 mM when pre-incubated with elacridar (p < 0.01). Live-cell imaging of CRC cells revealed a different pattern of intracellular sunitinib accumulation with and without pre-incubation with elacridar. Inhibition of multi-drug resistance proteins ABCB1 and ABCG2 with the clinically tested selective transporter inhibitor elacridar potentiates sunitinib efficacy in CRC models. Interestingly, this was accompanied with reduced intracellular sunitinib accumulation. Further research in mCRC PDTOs is warranted to confirm whether this mechanism is involved in intrinsic TKI resistance and therefore contribute to the early-phase failure of clinical trials testing TKIs for mCRC. Citation Format: Dennis Poel, Kirti K. Iyer, Bob van Gasteren, Beau Dagniaux, Erik van den Hombergh, Nielka P. van Erp, Daniele V. Tauriello, Henk M. Verheul. Elacridar potentiates sunitinib efficacy in colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 418.

Emily’s Eden: Contemporary Sikh drawings by Emily de Klerk

ABSTRACT During the corona-lockdown, the Dutch Emily de Klerk sat down to digest her Sikh sketches and photographs. Among the results are the 10 drawings included in this essay. While they overall reflect her fascination with Punjab and the Sikhs, they specifically also channelized a feeling of empathy with the farmers protest in New Delhi to which Sikhs play a fundamental role. In the essay, Bob van der Linden embeds Emily's drawings in the light of earlier (colonial) paintings and drawings made of Sikhs by Western artists. Afterwards, an interview provides further context to Emily's work.

Interview with Technology Startup CEO Bob van Luijt on Value Creation in the Digital Age

Interview with Technology Startup CEO Bob van Luijt on Value Creation in the Digital Age

The Challenge of the Poetic: Criticism in Search of the Real. With a Debt to bOb Van Reeth, 1975–1985

As the 1970s witnessed a growing concern for social issues, which were not addressed by most of post-war modernist projects, architects and intellectuals proposed various approaches to claiming a social engagement in architecture. As these attempts to connect with a social agenda often put the notion of architecture’s autonomy under strain, likewise pleas for a more engaged public debate seemed to question the autonomy of architectural discourse. This paper discusses one particular trajectory in the history of architectural criticism that aimed to resist such an opposition and defended the public merit of an autonomous notion of architecture. It does so by pointing to and interpreting the consequences of an argumentative shift subtending the self-understanding of criticism in Flanders, roughly from the mid-1970s to the mid-1980s. This shift involves the postulate of “the real” as a wilfully and strategically used category and revolved around the understanding that the essence of architecture is inexpressible in language. On the basis of such understanding, “the poetic” then became a model to deal with these limits of language and was presented as the challenge for both architecture and architectural criticism. As this shift is more a shared understanding than an individual affair, this paper focuses on the symbiotic relation of architect bOb Van Reeth (born 1943) and critics Geert Bekaert (1928–2016) and Mil De Kooning (born 1955) to trace the genesis of this postulated category, rather than delimiting the scope by discussing a single critic or journal.

Evaluating the Role of Unit Size in Learning-by-Doing of Energy Technologies

Bart Sweerts worked as a junior researcher at the Energy Transition department of TNO in the Netherlands, where he focused on energy technology development and implementation. During his studies in Earth Science he (co)-authored two peer-reviewed scientific articles published in leading energy journals. Currently, Bart works at Shell, where he focuses on asset optimization. Remko Detz is a scientist at the Energy Transition department of TNO and is a visiting scientist at the Faculty of Science of the University of Amsterdam. His research focuses on energy technology development starting from the early research phase to the analysis of fully integrated systems within society, with a special emphasis on renewable fuels and materials. He received his PhD in Chemistry in 2009 from the University of Amsterdam. He is a (co-)author of several peer-reviewed articles in leading international scientific journals and contributor to several reports. Bob van der Zwaan is a principal scientist at the Energy Transition department of TNO, Professor of Sustainable Energy Technology at the Faculty of Science of the University of Amsterdam, and Adjunct Professor of International Relations at Johns Hopkins University’s School of Advanced International Studies in Bologna. Trained in physics (Utrecht and CERN), economics (Cambridge), and international relations (Geneva), he has held positions at Columbia, Harvard, and Stanford Universities, has been a lead author for the IPCC, serves as co-director of the International Energy Workshop, and researches energy technology and climate change.

Abstract 4804: Multitargeted kinase inhibition (AEE788) alleviates mTOR inhibitor drug resistance in triple-negative breast cancer

Abstract Triple negative breast cancer (TNBC), although accounting for 15-20% of breast cancer, is disproportionally responsible for female cancer death. Despite therapeutic strategies being advanced, the clinical outcome of mTOR-targeted chemotherapy remains poor in the past decades. Recent data have evidenced the interdependence of kinase signaling networks and their involvement in treatment refractory TNBC settings. Thus, a combinatorial therapy targeting multiple components of signaling cascade is urgently needed. We assessed drug response phenotype across 20 TNBC cell lines by profiling the effect of a kinase inhibitor library consisting of >350 different kinase inhibitors (KIs). A panel of TNBC cell lines clustered with resistance phenotype against rapalogues (rapamycin analogues). Rapamycin efficacy on TNBCs was detected by performing proliferation assays and calculating their IC50, respectively. Given the role of the mTOR pathway in translational control, the relationship between rapamycin responses (IC50) and translational factors expression in TNBC cell lines was studied by Pearson analysis. Notably, translation initiation factor EIF2B2, EIF2S3, EIF3S8 and EIF1AX positively correlated with rapamycin response, whereas EIF4EBP2 and EIF2AK2 displayed negative correlation. Next, a rapamycin combination KI library screen was performed to identify kinase inhibitors synergizing with mTOR inhibition. AEE788, a multiple kinase targeting inhibitor, synergistically enhanced inhibitory effect of rapamycin on TNBC cell proliferation. Moreover, AEE788 dose-dependently synergized with mTOR targeted therapy in several TNBC cell lines. The combination treatment significantly decreased phosphorylation level of mTOR and 4EBP1 as well as ERK, indicating downregulation of PI3K/AKT and MAPK pathways. ChEMBL-based cheminformatics analysis indicated that, besides VEGFR and EGFR, a number of other kinases were predicted as the targets of AEE788, including RPS6K1, AKT2 and CDK7. Altogether, our data reveals the essential role of rapamycin-associated translation factors in TNBC, and provides insight in the resistance of TNBC to rapamycin analogues as well as potential therapeutic approaches to alleviate rapamycin resistance. Citation Format: Jichao He, Ronan P. McLaughlin, Vera van der Noord, Gerard van Westen, Yinghui Zhang, Bob van de Water. Multitargeted kinase inhibition (AEE788) alleviates mTOR inhibitor drug resistance in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4804.

Abstract 1527: Splicing factors determine breast cancer cell mitosis through control of sister chromatid cohesion

Abstract Breast cancer is the mostly diagnosed cancer in women worldwide and is also the leading cause of death from cancer in women, mainly due to metastasis formation. Accumulating evidence suggests that RNA splicing is critical in breast cancer progression. To investigate the role of every single component of the splicing machinery (the spliceosome) in this process, we systematically evaluated the effect of siRNA-mediated knockdown of 244 splicing factors on proliferation in two highly proliferative breast cancer cell lines MDA-MB-231 and Hs578T. Hits of the primary screen were validated with single siRNAs and separated based on their effects on migration and proliferation respectively. Knockdown of nine validated proliferation hits, amongst which was SF3B1, a known breast cancer driver gene, resulted for all nine hits in a distinct poly-lobed nuclear phenotype in both cell types, accompanied by increased DNA content and higher number of cells in G1-S transition. Increased levels of phospho-Histone H3 and lack of metaphase alignment suggested a defect in mitosis, which was confirmed by decreased RNA expression of sister chromatid cohesion factors MAU2, ESPL1 and SMC1A and interestingly, increased CDCA5 RNA levels. Upon splicing factor knockdown, CDCA5 intron 1 was retained resulting in decreased CDCA5 protein levels, inaccurate metaphase alignment and finally cell death. To identify the direct partners of the splicing factors that control mitosis, we coupled pull-down of GFP fused splicing factors with mass spectrometry. Seven out of the nine splicing factors that were identified in our screen causing poly-lobed nuclear phenotypes, resided in the same protein complex together with proteins involved in snRNP assembly and some mitosis-related factors. In conclusion, we have identified several splicing factors that are critically determining breast cancer cell proliferation through modulating the expression of chromatid cohesion factors and thereby mediating the successful metaphase alignment and ultimate mitosis. Citation Format: Esmee Koedoot, John Martens, Sylvia E. Le Dévédec, Bob van de Water. Splicing factors determine breast cancer cell mitosis through control of sister chromatid cohesion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1527.

Abstract 5179: Uncovering the signaling landscape controlling breast cancer cell migration identifies splicing PRPF4B as a metastasis driver

Abstract Metastasis is the major cause of death in cancer patients and migration of cancer cells from the primary tumor to distant sites is the prerequisite of metastasis formation. Here we applied an imaging-based RNAi phenotypic cell migration screen uing two highly migratory basal breast cancer cell lines (Hs578T and MDA-MB-231 to provide a repository of candidate metastasis drug targets. We screened ~4,200 individual target genes covering most cell signaling components. We discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, of which 45 genes were common denominators of cell migration. Interaction networks of candidate migratory modulators were in common with networks of different clinical breast cancer prognostic and metastasis classifiers. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF were amplified in human primary breast tumors and the expression was associated with metastasis-free survival. Depletion of PRPF4B, BUD31 and BPTF caused primarily downregulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B was essential for TNBC cell migration and critical for breast cancer metastasis formation in vivo, making PRPF4B a candidate for further drug development. Our systematic phenotypic screen provides an important repository for signaling determinants that functionally drive cancer cell migration. Citation Format: Bob van de Water, Erik Danen, Esmee Koedoot, Maria Rogkoti, Michiel Fokkelman, Sylvia Le Devedec, John Martens, Peter Stoilov, John Foekens. Uncovering the signaling landscape controlling breast cancer cell migration identifies splicing PRPF4B as a metastasis driver [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5179.

Abstract A023: Cell migration is a stronger predictor of patient survival in breast cancer than cell proliferation

Abstract Significance: The efficacy of anticancer drugs has been conventionally estimated in the laboratory by measuring post-treatment in vitro proliferation rates of cancer cell lines. The results of such in vitro measurements, however, rarely translate to human trials, thus posing a significant translational challenge. Additional cellular phenotypes have hence been studied in recent years, examining cell migration and invasion. Understanding how each of these in vitro measured phenotypes contributes to the patient response and survival is hence an important open challenge. Here, mining thousands of breast cancer tumors and cell-line experiments, we explore this relationship and delineate the individual contributions of these phenotypes, in predicting patient survival and response. Methods: Migration and proliferation was measured for 43 different breast cancer cell lines. Integrating these measurements with the cell lines' transcriptomics, we built gene expression-based predictors of each of these phenotypes in cell lines and in tumors. The predicted phenotypes were then used to study their contribution to patient survival. Results: Analyzing the transcriptomics of these cell lines, we identified specific gene-expression signatures of breast cancer migration and proliferation, that are highly predictive of these phenotypes (using cross validation). Subsequently, we applied these signatures to a collection of more than 2800 breast cancer tumors in the TCGA and METABRIC collection, to predict their proliferation and migration rates. Our analysis shows that both laboratory-measured proliferation and migration signatures are predictive of breast cancer stage, grade, subtypes, and finally, of patient survival. Notably, we find that the predicted migration rates of tumors are stronger predictors of patient survival than their predicted proliferation rates. This finding is further reinforced via analyzing migration and proliferation signatures that we derive from in vitro shRNA knockout experiments. We also find that patients whose tumors have high predicted migration rates specifically benefited from cytoskeletal drug treatments. Finally, we find that the predicted migration rates are associated with response of checkpoint inhibitor in patients. We are further extensively validating this by collecting tumor biopsies from patients post immunotherapy. Conclusions: Taken together, these results testify to the superiority of migration- over proliferation-based transcriptomic signatures in predicting breast cancer tumor phenotypes and patients’ survival. This suggests that in vitro migration measurements of drug response may significantly increase the translational value of cellular phenotypic measurements in predicting drug efficacy in patients. Finally, because tumor migration rates are predictive of cancer immunotherapy, they may provide a viable biomarker for immunotherapy response in patients. Citation Format: Nishanth U. Nair, Avinash Das, Joo Sang Lee, Sridhar Hannenhalli, Sylvia Le Dévédec, Bob van de Water, Eytan Ruppin. Cell migration is a stronger predictor of patient survival in breast cancer than cell proliferation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A023.

Music and Empire in Britain and India: Identity, Internationalism, and Cross-Cultural Communication by Bob van der Linden

Music and Empire in Britain and India: Identity, Internationalism, and Cross-Cultural Communication by Bob van der Linden

Abstract 893: Systematic assessment of spliceosome components as drivers of breast cancer progression

Abstract Accumulating evidence indicates that RNA splicing is involved in different steps of carcinogenesis. Although the critical role of a limited number of splicing factors has been demonstrated in several cancer studies, the function of many spliceosome components is still unknown. In breast cancer samples higher expression levels of a subset of spliceosome components consistently correlated with more aggressive tumor types in patient microarray as well as RNA sequencing data from The Cancer Genome Atlas (TCGA). We further systematically evaluated the effect of siRNA-mediated knockdown of 244 individual splicing factors on both cell migration and proliferation in two aggressive breast cancer cell lines MDA-MB-231 and Hs578T using high throughput microscopy. Primary candidates were validated with four single siRNAs and classified based on their effects on migration and proliferation. Knockdown of validated spliceosome factors such as SNRPG and SNRPA1 affected the levels of small nuclear RNAs, the main catalyzers of the spliceosome. Moreover, high expression of these key candidate hits is associated with poor breast cancer metastasis free survival. To investigate the downstream mechanisms and splicing patterns controlled by our candidate genes we performed RNA sequencing on both control and siRNA mediated knockdown cells. Interestingly, knockdown of our hits affect extracellular matrix pathways that are essential in tumor cell migration and invasion. Altogether our data indicate a key role for spliceosome factors in the control of breast cancer progression which provide new leads for future therapeutic intervention. Citation Format: Esmee Koedoot, Sylvia Le Dévédec, Bob van de Water. Systematic assessment of spliceosome components as drivers of breast cancer progression [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 893. doi:10.1158/1538-7445.AM2017-893

Abstract 103: Blockage of Cdc7/CDK9 signaling sensitizes triple negative breast cancer to EGFR-targeted therapy

Abstract The treatment of Triple-Negative Breast Cancer (TNBC) still represents a profound clinical challenge, the disease being disproportionately responsible for breast cancer-associated deaths. As a consequence, the identification of targeted agents, which synergize with current therapeutic options, is paramount. Resistance to EGFR-tyrosine kinase inhibitors (TKIs), despite frequent EGFR overexpression and reliance on downstream signalling pathways in TNBC, remains endemic. Recent data has also suggested that kinase-inhibition of EGFR in itself is insufficient, given the kinase-independent functions of the protein in transcriptional regulation and DNA-repair may permit prolonged EGFR-mediated signalling in the presence of inhibitors. We performed a kinase inhibitor drug screen (378 kinase inhibitors targeting ~40 different cancer-related kinases) to identify synergistic activity with EGFR inhibition in TNBC. We demonstrate that the dual cdc7/CDK9 inhibitor PHA-767491 synergizes with multiple EGFR-TKIs (Erlotinib, Gefitinib and Lapatinib) in vitro to overcome resistance to EGFR-targeted therapy in various TNBC cell lines. Combined inhibition of EGFR and cdc7/CDK9 resulted in reduced cell proliferation, accompanied by induction of apoptosis and G2-M cell cycle-arrest. Combination therapy inhibited crucial components of the DNA-replicative machinery and also proteins involved in CDK9-mediated transcriptional elongation. Moreover, higher expression of cdc7 and POLR2A was found to be significantly correlated with poorer survival rates in breast cancer patients. Additionally, this synergistic combination effectively inhibited the growth of cells isolated from patient-derived TNBC xenografts under ex vivo culture conditions, highlighting the utility of targeting common transcriptional nodes in cancers addicted to growth factor-mediated signalling pathways. Citation Format: Ronan P. McLaughlin, Jichao He, Vera van der Noord, Jevin Redel, Marcel Smid, Lambert Dorssers, John Martens, John Foekens, Yinghui Zhang, Bob van de Water. Blockage of Cdc7/CDK9 signaling sensitizes triple negative breast cancer to EGFR-targeted therapy [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 103. doi:10.1158/1538-7445.AM2017-103

Resonances of the Raj: India in the English Musical Imagination, 1897–1947 by Nalini Ghuman (review)

Reviewed by: Resonances of the Raj: India in the English Musical Imagination, 1897–1947 by Nalini Ghuman Laurie J. Sampsel Resonances of the Raj: India in the English Musical Imagination, 1897–1947. By Nalini Ghuman. New York: Oxford University Press, 2014. [xv, 345 p. ISBN 9780199314898 (hardcover), $49.95; (e-book), various.] Music examples, illustrations, bibliography, index, companion Web site: http://global.oup.com/us/companion.websites/9780199314898/. In Resonances of the Raj, Nalini Ghuman examines the role of English rule in India as it influenced musicians during its final fifty years. To that end, she includes six chapters spanning the period, which need not be read in order. She includes a broad range of musicians: Maud MacCarthy (1882–1967), Edward Elgar (1857–1934), Gustav Holst (1874–1934), Amy Woodforde-Finden (1860–1919), Kaikhosru Shapurji Sorabji (1892–1988), and John Foulds (1880– 1939). Ghuman includes a short introduction, but no conclusion. She explains “I have chosen to focus on musical case studies involving six figures who, I believe, are both representative of the era and significant in their own right” (p. 3). Resonances of the Raj is a welcome addition to a growing body of literature on oriental influences on British music. Other recent books include Music and Orientalism in the British Empire, 1780s–1940s, edited by Martin Clayton and Bennett Zon (Aldershot, Hampshire, Eng.: Ashgate, 2007), and Bob van der Linden’s Music and Empire in Britain and India (New York: Palgrave Macmillan, 2013). Each has a chapter about the musicians Ghuman includes in her book. Four of the six chapters are revisions of Ghuman’s 2003 dissertation from the University of California, Berkeley (Anna Nalini Gwynne, “India in the English Musical Imagination, 1890–1940” [Ph.D. diss., University of California, Berkeley, 2003]). The two new chapters on Maud MacCarthy and John Foulds, the first and last, respectively, are among the strongest of the book. Little has been written about MacCarthy as an individual or on her collaborations with her husband, Foulds. For example, there is no entry in Grove Music Online on MacCarthy, and she is only mentioned in the article about her husband. Ghuman’s contribution in the first chapter focuses on MacCarthy’s work as an ethnomusicologist [End Page 369] in India from 1907–9 (before she met Foulds) and her lecture recitals on Indian music presented in England and Paris from 1910 to 1930. In the last chapter of her book, Ghuman focuses on the final years of Foulds’s life (1935–39) when he lived in India and worked as Director of European Music at All India Radio in Delhi. The compositions considered include Gandharva-Music, Three Mantras, Essays in the Modes, and pieces written for his Indo–European Orchestra. Ghuman outlines Foulds’s struggles in getting his music published, performed, and broadcast; his motivation for moving to India; his untimely death from cholera in 1939; and his possible influence on later musician Ravi Shankar. Previous work on the couple includes a chapter in Bob van der Linden’s Music and Empire in Britain and India, which focuses on theosophy as an influence on MacCarthy and Foulds. Perhaps the strongest chapter of the book is dedicated to Amy Woodforde-Finden’s Four Indian Love Lyrics (London: Boosey & Hawkes, 1902). Here Ghuman studies both the music and the texts by Violet Nicolson (written under the pseudonym Laurence Hope). The Indian influence is in Nicolson’s texts and the illustrations on the early editions, more so than in the music itself. The Indian Love Lyrics were popular in 1902 and remain so today, especially “Kashmiri Song,” with its tale of forbidden love on the banks of the Shalimar. Ghuman also examines “The Temple Bells” and “Less than the Dust,” but not “Till I Wake.” Comparisons are drawn between the Eastern elements in Cyril Scott’s Lotus Land and Liza Lehmann’s “The Snake-Charmer” from the Golden Threshold, both of which were composed a few years later. As a scholar of Cyril Scott and his music, I must say I disagree that Scott’s Lotus Land was inspired by his impression of India. Hopefully, however, Ghuman’s chapter will encourage more scholarship devoted to Woodforde-Finden...

Abstract 3780: Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in osteosarcoma cells

Abstract Osteosarcoma is the most common primary bone malignancy with relatively high incidence in young people. Here, we found that expression of Aven was inversely correlated with metastasis-free survival in osteosarcoma patients and is increased in metastases compared to primary osteosarcoma biopsies. Also in chondrosarcoma, the second most common bone sarcoma, expression correlated with increased histological grade. Aven is an adaptor protein that has been implicated in anti-apoptotic signaling and serves as an oncoprotein in acute lymphoblastic leukemia. In human osteosarcoma cells, silencing Aven triggered a G2 cell cycle arrest. Chk1 protein levels were attenuated and ATR-Chk1 DNA damage response signaling in response to chemotherapy was abolished in Aven-depleted osteosarcoma cells while ATM, Chk2, and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven-controlled ATR-Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix-embedded cultures Chk1 inhibition effectively sensitized human osteosarcoma cells to chemotherapy. Together, these findings implicate Aven in ATR-Chk1 signaling and point towards Chk1 inhibition as a strategy to sensitize osteosarcomas to chemotherapy. Citation Format: Zuzanna Baranski, Tijmen T.H. Booij, Yvonne de Jong, Jolieke van Oosterwijk, Anne-Marie Cleton, Leo Price, Bob van de Water, Judith V.M.G. Bovée, Pancras C.W. Hogendoorn, Erik Danen. Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in osteosarcoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3780. doi:10.1158/1538-7445.AM2015-3780

Abstract 4021: A kinome screen identifies SRPK1 to mediate breast cancer metastasis

Abstract Tumor cell migration plays key role in cancer cell dissemination and metastasis and is controlled by signaling-mediated cytoskeletal and cell-matrix adhesion remodeling. Using a phagokinetic track (PKT) assay with migratory H1299 cells, we performed a siRNA screen of almost 1,500 genes encoding kinases/phosphatases, adhesome-related and migration-related proteins, with the aim of identifying genes that determine tumor cell migration speed, and persistence. Thirty candidate genes, showing significant effect were validated in live tumor cell migration assays, and eight of those had a significant association with metastasis free survival in breast cancer patients, ITGB3BP, MAP3K8, NEK2, SHC1 and SRPK1 being most significant . Further examination indicated that the expression of SRPK1, the most interesting gene identified in this screen , was highest in basal-like breast cancer and its expression level was correlated with poor disease outcome and preferred metastasis to the lungs and brain. In two independent breast tumor metastasis models, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver and spleen and inhibited focal adhesion reorganization. We provide here a comprehensive information resource on the molecular determinants of tumor cell migration and identify SRPK1 as a potential candidate drug target associated with breast cancer metastasis. Citation Format: Bob van de Water, Wies van Roosmalen, Sylvia Le Devedec, John Meerman, John Foekens, John Martens, Benny Geiger. A kinome screen identifies SRPK1 to mediate breast cancer metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4021. doi:10.1158/1538-7445.AM2014-4021

Abstract 4349: Genome-wide kinase and phosphatase siRNA screen identifies clinically relevant targets in IGF1R signaling-mediated antiestrogen resistance in breast cancer.

Abstract Antiestrogen resistance of breast cancer has been linked to increased growth factor receptor signaling such as invoked by the insulin-like growth factor 1 (IGF-1) receptor (IGF1R). We have previously shown that increased IGF1R signaling by ectopic IGF1R overexpression in MCF7 cells (MCF7-IGF1R) directly drives an estrogen receptor (ER)-independent cell proliferation in MCF7 cells that leads to antiestrogen resistance. To identify components of the downstream IGF1R signaling pathways that mediate antiestrogen resistance, we have performed a human genome-wide kinase and phosphatase siRNA screen under tamoxifen resistance condition (1 μM 4-OH-tamoxifen, 1 nM estradiol, and 100 ng/ml IGF-1) in MCF7-IGF1R cells. We identified 174 kinases and phosphatases that increased or decreased tamoxifen resistance. Of these, 14 significantly correlated with the time to disease progression of metastatic breast cancer patients treated with first-line tamoxifen monotherapy, including ADRA1B, BMPR1B, CDK10, CDK5, EIF2AK1 and MAP2K5. Low expression of these six genes in patients correlated with short time to disease progression and silencing of these genes in MCF7-IGF1R cells further increased proliferation under tamoxifen resistance condition. Low expression of the other eight genes in patients correlated with longer time the time to disease progression and silencing of these genes in MCF7-IGF1R cells decreased proliferation under tamoxifen resistance condition Therefore, these latter genes may represent novel drug targets that may be useful to restore tamoxifen sensitivity in breast cancer. Knockdown of two of these genes suppressed IGF1R-mediated effects and restored the anti-proliferative effect of tamoxifen in a dose dependent manner, suggesting synthetic lethality between the knockdowns and tamoxifen. Further study of one of these genes revealed that stable knockdown inhibits proliferation and three-dimensional growth under tamoxifen resistance condition, accompanied with an increase in G1/G0 arrest and mild induction of apoptosis. These effects are independent of PI3K/AKT and MAPK/ERK signaling pathways, and suggest that an as yet unknown pathway plays a decisive role in tamoxifen resistance induced by IGF1R signaling. Citation Format: John H. Meerman, Yinghui Zhang, Maurice P. Jansen, Ramakrishnaiah Siddapa, Sreenivasa Ramaiahgari, Leo Price, Erik Danen, Els M. Berns, John Foekens, Bob van de Water. Genome-wide kinase and phosphatase siRNA screen identifies clinically relevant targets in IGF1R signaling-mediated antiestrogen resistance in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4349. doi:10.1158/1538-7445.AM2013-4349

Schoonebeek Heavy-Oil Redevelopment Requires Complex Chemistry Management

This article, written by Editorial Manager Adam Wilson, contains highlights of paper SPE 150635, ’Integrated Production Chemistry Management of the Schoonebeek Heavy Oil Redevelopment in the Netherlands: From Project to Startup and Steady State Production,’ by Andrew G. Shepherd, SPE, Stuart Mcgregor, and Ruud Trompert, Nederlandse Aardolie Maatschappij, and Sen Ubbels, Bob van de Gender, SPE, Theo van Ommen, SPE, and Sjoerd van der Knoop, SPE, Champion Technologies. The production chemistry management process undertaken during the design, commissioning, and startup of the Schoonebeek redevelopment faced challenging separation issues, saline water, and a multitude of other process conditions that resulted in a complex application portfolio. Chemical selection was conducted in adherence to health, safety, security, and environment (HSSE) directives and focused on unique produced fluid properties. Since startup, the success of chemical performance has come from the availability of chemical treatment programs and surveillance/sampling plans. So far, no contingency chemicals have been needed at the facilities. Introduction The Schoonebeek oil field was discovered in 1943 and operated until the late 1990s. A number of enhanced oil recovery methods were used in this field, including high- and low-pressure steam-floods, hot waterfloods, and in-situ combustion. The field is now being redeveloped, using low-pressure steam-flood with horizontal wells. Superheated steam, supplied by a combined heat and power (CHP) plant, will be injected into the reservoir through 25 wells adjacent to the production wells in 17 locations. Gross production will be evacuated from the reservoir through 44 horizontal wells in 18 locations using artificial lift pumps, with a casing vapor recovery (CVR) system included to improve the gross lifting capability. Production from each wellsite will be routed through a gross gathering system to the central treating facilities (CTF). The CTF will include the required facilities to separate the oil, water, and associated gas and treat the respective streams to export quality. Production Chemistry Management Compliance toward European chemical regulations (REACH) was one of main drivers for the short-listing of products to be applied in the Schoonebeek redevelopment. Schoonebeek crude oil has a relatively high API weight. Nevertheless, the crude oil is quite acidic, as seen in high total acid number and naphthenic acid values. Most (>90 wt%) of the naphthenic acids are in salt form, which means that they may affect oil/water separation. The crude oil also has very particular wax properties. A high cloud point and pour point indicate that wax precipitation and gelling in the facilities may become a problem during normal operations if not controlled. Furthermore, wax particles contribute to crude oil viscosity and also may affect separation. Fig. 1 presents an overview of the main chemical applications selected for treatment between the wellsites and the CTF and at the CTF itself, together with the main process vessels and streams.

Abstract C52: Semi-high-throughput whole-animal bioimaging assay identifies novel players in prostate cancer progression

Abstract Although genetic mouse models for cancer and human tumor cell xenotransplantation models in rodents remain essential, such systems are costly, slow, and not amenable to high-throughput assays for cancer drug target discovery. There is a clear need to develop fast, semi-automated in vivo systems for medium to high-throughput screening applications in preclinical target discovery and lead compound identification. In this study, we developed an automated, semi-high throughput, noninvasive and quantitative platform for imaging one critical aspect of cancer progression, namely tumor cell dissemination, in a zebrafish xenotransplantation model. This is the first semi-automated whole organism based bio-imaging assay of tumor progression in a vertebrate. We have used this platform to screen for prostate cancer relevant drug and gene targets, and have identified novel regulators of prostate cancer dissemination. Using 3D in vitro invasion assays, we show a critical role for these molecules in prostate cancer migration strategies. Further validation of these targets is underway in mouse models and human cancer specimens. Citation Format: Veerander Paul Singh Ghotra, Shuning H.E., Hans De Bont, H.P. Spaink, Bob Van de Water, B. Ewa Snaar Jagalska, Erik H.J. Danen. Semi-high-throughput whole-animal bioimaging assay identifies novel players in prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C52.

Dynamics of Arcades in the Netherlands: Developments in Legislation, Policy, and Practice

Gaming Law Review and EconomicsVol. 14, No. 10 ARTICLESDynamics of Arcades in the Netherlands: Developments in Legislation, Policy, and PracticeAd Schreijenberg and Bob van WaverenAd SchreijenbergSearch for more papers by this author and Bob van WaverenSearch for more papers by this authorPublished Online:11 Jan 2011https://doi.org/10.1089/glre.2010.141005AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetails Volume 14Issue 10Dec 2010 Information© 2010 Mary Ann Liebert, Inc.To cite this article:Ad Schreijenberg and Bob van Waveren.Dynamics of Arcades in the Netherlands: Developments in Legislation, Policy, and Practice.Gaming Law Review and Economics.Dec 2010.749-754.http://doi.org/10.1089/glre.2010.141005Published in Volume: 14 Issue 10: January 11, 2011PDF download

Introspective Availability

Philosophy and Phenomenological ResearchVolume 80, Issue 1 p. 208-228 Introspective Availability1 JOHN KULVICKI, JOHN KULVICKI Dartmouth CollegeSearch for more papers by this author JOHN KULVICKI, JOHN KULVICKI Dartmouth CollegeSearch for more papers by this author First published: 27 December 2009 https://doi.org/10.1111/j.1933-1592.2009.00316.x 1 I thank Fred Dretske and Adam Wager for writing up quite useful comments on earlier versions of this paper. Bob Van Gulick invited me to present some of this material at his SPAWN workshop and David Rosenthal invited me to present a version of this paper at the CUNY Cognitive Science Colloquium. I am grateful to them and to the participants at those meetings for their helpful suggestions. Finally I thank the participants at the 2006 Dartmouth/UVM conference. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume80, Issue1January 2010Pages 208-228 RelatedInformation