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6. Expression of Interest for Evolution of the Mu2e Experiment

Author

Abusalma, F., Ambrose, D., Artikov, A., Bernstein, R., Blazey, G. C., Bloise, C., Boi, S., Bolton, T., Bono, J., Bonventre, R., Bowring, D., Brown, D., Byrum, K., Campbell, M., Caron, J. -F., Cervelli, F., Chokheli, D., Ciampa, K., Ciolini, R., Coleman, R., Cronin-Hennessy, D., Culbertson, R., Cummings, M. A., Daniel, A., Davydov, Y., Demers, S., Denisov, D., Denisov, S., Di Falco, S., Diociaiuti, E., Djilkibaev, R., Donati, S., Donghia, R., Drake, G., Dukes, E. C., Echenard, B., Edmonds, A., Ehrlich, R., Evdokimov, V., Fabbricatore, P., Ferrari, A., Frank, M., Gaponenko, A., Gatto, C., Giorgio, Z., Giovannella, S., Giusti, V., Glass, H., Glenzinski, D., Goodenough, L., Group, C., Happacher, F., Harkness-Brennan, L., Hedin, D., Heller, K., Hitlin, D., Hocker, A., Hooper, R., Horton-Smith, G., Hu, C., Hung, P. Q., Hungerford, E., Jenkins, M., Jones, M., Kargiantoulakis, M., Khaw, K. S., Kiburg, B., Kolomensky, Y., Kozminski, J., Kutschke, R., Lancaster, M., Lin, D., Logashenko, I., Lombardo, V., Luca, A., Lukicov, G., Lynch, K., Martini, M., Mazzacane, A., Miller, J., Miscetti, S., Morescalchi, L., Mott, J., Mueller, S. E., Murat, P., Nagaslaev, V., Neuffer, D., Oksuzian, Y., Pasciuto, D., Pedreschi, E., Pezzullo, G., Pla-Dalmau, A., Pollack, B., Popov, A., Popp, J., Porter, F., Prebys, E., Pronskikh, V., Pushka, D., Quirk, J., Rakness, G., Ray, R., Ricci, M., Röhrken, M., Rusu, V., Saputi, A., Sarra, I., Schmitt, M., Spinella, F., Stratakis, D., Strauss, T., Talaga, R., Tereshchenko, V., Tran, N., Tschirhart, R., Usubov, Z., Velasco, M., Wagner, R., Wang, Y., Werkema, S., Whitmore, J., Winter, P., Xia, L., Zhang, L., Zhu, R. -Y., Zutshi, V., and Zwaska, R.

Subjects
Physics - Instrumentation and Detectors, High Energy Physics - Experiment
Abstract

We propose an evolution of the Mu2e experiment, called Mu2e-II, that would leverage advances in detector technology and utilize the increased proton intensity provided by the Fermilab PIP-II upgrade to improve the sensitivity for neutrinoless muon-to-electron conversion by one order of magnitude beyond the Mu2e experiment, providing the deepest probe of charged lepton flavor violation in the foreseeable future. Mu2e-II will use as much of the Mu2e infrastructure as possible, providing, where required, improvements to the Mu2e apparatus to accommodate the increased beam intensity and cope with the accompanying increase in backgrounds., Comment: 17 pages, 4 figures, 1 table; Submitted to the Fermilab Physics Advisory Committee

Published
2018

12. Novel PP2A-Activating Compounds in Neuroblastoma.

Author

Nazam, Nazia, Bownes, Laura V., Julson, Janet R., Quinn, Colin H., Erwin, Michael H., Marayati, Raoud, Markert, Hooper R., Shirley, Sorina, Stewart, Jerry E., Yoon, Karina J., Aye, Jamie, Ohlmeyer, Michael, and Beierle, Elizabeth A.

Subjects
PHOSPHORYLATION, PHENOMENOLOGICAL biology, ANTINEOPLASTIC agents, CELL proliferation, PHOSPHATASES, XENOGRAFTS, CELL motility, IN vivo studies, BIOCHEMISTRY, CELLULAR signal transduction, ESTERASES, CELL lines, GENE expression, ONCOGENES, SULFONAMIDES, CELL survival, NEUROBLASTOMA, PHARMACODYNAMICS
Abstract

Simple Summary: Neuroblastoma is the third most common type of childhood cancer but is responsible for over 15% of all pediatric cancer deaths. Children with advanced disease have less than a 50% survival rate and are in desperate need of new treatment options. Protein phosphatase 2A (PP2A) is a protein that inhibits tumors, but it is turned off in neuroblastoma. We have previously shown that we can activate PP2A in neuroblastoma with certain drugs and decrease tumor growth, but these drugs also affect the function of the immune system. We now have new small molecules that activate PP2A without upsetting the immune system. We observed a decrease in tumor growth, proliferation, and motility with our novel PP2A activators. We feel that a better understanding of how activating PP2A inhibits neuroblastoma will lead to better treatments for these children. Background: Neuroblastoma (NB) remains one of the deadliest pediatric solid tumors. Recent advancements aimed at improving outcomes have been insufficient, and patients with high-risk NB continue to have a poor prognosis. Protein phosphatase 2A (PP2A) is a tumor suppressor protein downregulated in many cancers, including NB. PP2A activation has been shown to affect the malignant phenotype in other solid tumors. The present studies aim to investigate the effects of two novel PP2A activators as a NB therapeutic. Methods: Four established NB cell lines and a patient-derived xenoline were utilized to study the effect on cell viability, proliferation, motility, and in vivo tumor growth using two novel tricyclic sulfonamide PP2A activators, ATUX-3364 and ATUX-8385. Results: ATUX-3364 and ATUX-8385 increased PP2A activity. These PP2A activators led to decreased viability, proliferation, and motility of NB cells. Treatment of animals bearing NB tumors with ATUX-3364 or ATUX-8385 resulted in decreased tumor growth in MYCN-amplified SK-N-BE(2) tumors. At the molecular level, PP2A-based reactivation led to dephosphorylation of MYCN-S62 and decreased MYCN protein expression. Conclusions: PP2A activators decreased NB cell viability, proliferation, and motility. In vivo experiments show that PP2A activators have more significant effects on tumorigenesis in MYCN-amplified tumors. Finally, phosphorylation of MYCN protein was decreased following treatment with novel sulfonamide PP2A activators. These data and mechanistic insights may be useful for developing new PP2A-based therapies that target MYCN for the treatment of NB. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Mu2e Technical Design Report

Author

Bartoszek, L., Barnes, E., Miller, J. P., Mott, J., Palladino, A., Quirk, J., Roberts, B. L., Crnkovic, J., Polychronakos, V., Tishchenko, V., Yamin, P., Cheng, C. -h., Echenard, B., Flood, K., Hitlin, D. G., Kim, J. H., Miyashita, T. S., Porter, F. C., Röhrken, M., Trevor, J., Zhu, R. -Y., Heckmaier, E., Kang, T. I., Lim, G., Molzon, W., You, Z., Artikov, A. M., Budagov, J. A., Davydov, Yu. I., Glagolev, V. V., Simonenko, A. V., Usubov, Z. U., Oh, S. H., Wang, C., Ambrosio, G., Andreev, N., Arnold, D., Ball, M., Bernstein, R. H., Bianchi, A., Biery, K., Bossert, R., Bowden, M., Brandt, J., Brown, G., Brown, H., Buehler, M., Campbell, M., Cheban, S., Chen, M., Coghill, J., Coleman, R., Crowley, C., Deshpande, A., Deuerling, G., Dey, J., Dhanaraj, N., Dinnon, M., Dixon, S., Drendel, B., Eddy, N., Evans, R., Evbota, D., Fagan, J., Feher, S., Fellenz, B., Friedsam, H., Gallo, G., Gaponenko, A., Gardner, M., Gaugel, S., Genser, K., Ginther, G., Glass, H., Glenzinski, D., Hahn, D., Hansen, S., Hartsell, B., Hays, S., Hocker, J. A., Huedem, E., Huffman, D., Ibrahim, A., Johnstone, C., Kashikhin, V., Kashikhin, V. V., Kasper, P., Kiper, T., Knapp, D., Knoepfel, K., Kokoska, L., Kozlovsky, M., Krafczyk, G., Kramp, M., Krave, S., Krempetz, K., Kutschke, R. K., Kwarciany, R., Lackowski, T., Lamm, M. J., Larwill, M., Leavell, F., Leeb, D., Leveling, A., Lincoln, D., Logashenko, V., Lombardo, V., Lopes, M. L., Makulski, A., Martinez, A., McArthur, D., McConologue, F., Michelotti, L., Mokhov, N., Morgan, J., Mukherjee, A., Murat, P., Nagaslaev, V., Neuffer, D. V., Nicol, T., Niehoff, J., Nogiec, J., Olson, M., Orris, D., Ostojic, R., Page, T., Park, C., Peterson, T., Pilipenko, R., Pla-Dalmau, A., Poloubotko, V., Popovic, M., Prebys, E., Prieto, P., Pronskikh, V., Pushka, D., Rabehl, R., Ray, R. E., Rechenmacher, R., Rivera, R., Robotham, W., Rubinov, P., Rusu, V. L., Scarpine, V., Schappert, W., Schoo, D., Stefanik, A., Still, D., Tang, Z., Tanovic, N., Tartaglia, M., Tassotto, G., Tinsley, D., Tschirhart, R. S., Vogel, G., Wagner, R., Wands, R., Wang, M., Werkema, S., White Jr., H. B., Whitmore, J., Wielgos, R., Woods, R., Worel, C., Zifko, R., Ciambrone, P., Colao, F., Cordelli, M., Corradi, G., Dane, E., Giovannella, S., Happacher, F., Luca, A., Miscetti, S., Ponzio, B., Pileggi, G., Saputi, A., Sarra, I., Soleti, R. S., Stomaci, V., Martini, M., Fabbricatore, P., Farinon, S., Musenich, R., Alexander, D., Daniel, A., Empl, A., Hungerford, E. V., Lau, K., Gollin, G. D., Huang, C., Roderick, D., Trundy, B., Brown, D. Na., Ding, D., Kolomensky, Yu. G., Lee, M. J., Cascella, M., Grancagnolo, F., Ignatov, F., Innocente, A., L'Erario, A., Miccoli, A., Maffezzoli, A., Mazzotta, P., Onorato, G., Piacentino, G. M., Rella, S., Rossetti, F., Spedicato, M., Tassielli, G., Taurino, A., Zavarise, G., Hooper, R., Brown, D. No., Djilkibaev, R., Matushko, V., Ankenbrandt, C., Boi, S., Dychkant, A., Hedin, D., Hodge, Z., Khalatian, V., Majewski, R., Martin, L., Okafor, U., Pohlman, N., Riddel, R. S., Shellito, A., de Gouvea, A. L., Cervelli, F., Carosi, R., Di Falco, S., Donati, S., Lomtadze, T., Pezzullo, G., Ristori, L., Spinella, F., Jones, M., Corcoran, M. D., Orduna, J., Rivera, D., Bennett, R., Caretta, O., Davenne, T., Densham, C., Loveridge, P., Odell, J., Bomgardner, R., Dukes, E. C., Ehrlich, R., Frank, M., Goadhouse, S., Group, R., Ho, E., Ma, H., Oksuzian, Y., Purvis, J., Wu, Y., Hertzog, D. W., Kammel, P., Lynch, K. R., and Popp, J. L.

Subjects
Physics - Instrumentation and Detectors, High Energy Physics - Experiment
Abstract

The Mu2e experiment at Fermilab will search for charged lepton flavor violation via the coherent conversion process mu- N --> e- N with a sensitivity approximately four orders of magnitude better than the current world's best limits for this process. The experiment's sensitivity offers discovery potential over a wide array of new physics models and probes mass scales well beyond the reach of the LHC. We describe herein the preliminary design of the proposed Mu2e experiment. This document was created in partial fulfillment of the requirements necessary to obtain DOE CD-2 approval., Comment: compressed file, 888 pages, 621 figures, 126 tables; full resolution available at http://mu2e.fnal.gov; corrected typo in background summary, Table 3.4

Published
2015

15. Focal Adhesion Kinase Inhibition Contributes to Tumor Cell Survival and Motility in Neuroblastoma Patient-Derived Xenografts

Author

Laura L. Stafman, Adele P. Williams, Raoud Marayati, Jamie M. Aye, Hooper R. Markert, Evan F. Garner, Colin H. Quinn, Shoeb B. Lallani, Jerry E. Stewart, Karina J. Yoon, Kimberly Whelan, and Elizabeth A. Beierle

Subjects
Medicine, Science
Abstract

Abstract Patient-derived xenografts (PDXs) provide an opportunity to evaluate the effects of therapies in an environment that more closely resembles the human condition than that seen with long-term passage cell lines. In the current studies, we investigated the effects of FAK inhibition on two neuroblastoma PDXs in vitro. Cells were treated with two small molecule inhibitors of FAK, PF-573,228 (PF) and 1,2,4,5-benzentetraamine tetrahydrochloride (Y15). Following FAK inhibition, cell survival and proliferation decreased significantly and cell cycle arrest was seen in both cell lines. Migration and invasion assays were used to determine the effect of FAK inhibition on cell motility, which decreased significantly in both cell lines in the presence of either inhibitor. Finally, tumor cell stemness following FAK inhibition was evaluated with extreme limiting dilution assays as well as with immunoblotting and quantitative real-time PCR for the expression of stem cell markers. FAK inhibition decreased formation of tumorspheres and resulted in a corresponding decrease in established stem cell markers. FAK inhibition decreased many characteristics of the malignant phenotype, including cancer stem cell like features in neuroblastoma PDXs, making FAK a candidate for further investigation as a potential target for neuroblastoma therapy.

Published
2019
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16. Molecular characterisation of NAADP-gated two-pore channels

Author

Hooper, R.

Subjects
570
Abstract

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent intracellular calcium (Ca2+)-mobilising second messenger implicated in a variety of physiological processes. Unusually, NAADP mediates Ca2+ release from acidic organelles, such as the lysosome, and not the endoplasmic reticulum. Recently, members of the voltagegated ion channel super-family, the two-pore channels (TPCs), have been identified as molecular targets of NAADP. The aim of this thesis is to investigate the molecular properties of these poorly characterised ion channels. In this study, I present the cloning of a novel TPC isoform from the sea urchin, an extensively used model organism for NAADP signalling, and the subsequent characterisation of the complete ancestral sea urchin TPC family. Sea urchin TPCs appeared to be Nglycosylated in an isoform-specific manner, displayed anomalous migration upon fractionation, similar to endogenous NAADP-binding proteins, and localised to the endo-lysosomal system. To characterise the properties of human TPCs, antibodies suitable for Western blot and immunocytochemistry analyses were identified. The topology of human TPCs was examined using in silico prediction methods, combined with fluorescence protease protection assays and the mapping of TPC antibody epitopes and N-glycosylation sites. Human TPCs conformed to a twelve transmembrane region model with cytosolic termini. The quaternary structure of TPCs was investigated using FRET analysis, sucrose density gradients, gel filtration, co-immunoprecipitation, and chemical cross-linking of both full-length TPCs and individual hydrophobic domains. TPCs likely assemble as dimers possibly within a high molecular weight protein complex. Finally, I show that the N-terminus of TPC1 regulates NAADP-mediated Ca2+ release and identify a potential physiological role for TPC2 in pigmentation.

Published
2011

17. The responsibility to implement 'The Responsibility to Protect'

Author

Hooper, R. S.

Subjects
327
Abstract

The Responsibility to Protect offers a morally based policy that places a new responsibility on the international community to protect populations from extremes of harm caused by governments. From the policy’s text, the reason for action seems to lie, most fundamentally, in an expression of ‘our common humanity’. However, The Responsibility to Protect does not offer any justification for its proposals. It responds to the question ‘what ought to be done?’ but answers the question ‘what can be done?’ leaving in between a gap in the moral credibility of action. The thesis explores what this lack of philosophical underpinning means to the persuasive power of the policy. The thesis then examines the claim of sovereignty as responsibility and finds it confused and incomplete and lacking the detail necessary for coherent implementation. It uses the Aristotelian square of opposition to investigate the tripartite nature of the new responsibilities to prevent and rebuild. Finally, the thesis investigates the policy’s apparent assumption that an ethically based policy of humanitarian intervention can be appropriately guided by the ethical rules of war. It asks if war and humanitarian intervention are the same thing and finds that they are not. It then explores the incoherence created by using the Just War Tradition for guide R2P. If The Responsibility to Protect offers no greater generation of will and effective action to humanitarian intervention than the current ad hoc process does, its establishment as UN policy becomes a pyrrhic victory. It will result in further anomalies in response by the UN, and consequent damage to the reputation and credibility of the UN as the guardian of international peace and security.

Published
2010

18. Development of techniques for the study of protein systems

Author

Hooper, R. J.

Subjects
572.8
Abstract

This dissertation descries work undertaken to investigate protein systems on nano- and micro-levels. The principal objective was the application of fluid dynamic gauging with simultaneous direct imaging of the changes in microstructure occurring during the cleaning of whey protein foulants. Laser confocal microscopy allowed images of the internal microstructure, on the micron and tens-of-microns scales, to be matched against the changing macro-properties of a whey protein film during cleaning, as measured by the gauge on the tens-of-microns scale. This work constitutes proof of concept; the successful capture of gauging and microscopy data displaying consistent, complementary phenomena proved the efficacy of the experimental concept. Achievement of this goal required first establishing the operating range within which use of the gauge caused minimal interference with the film being studied and, secondly, the development of a whey protein foulant that reproduced behavioural characteristics of fouling layers studied by previous researchers while also being suitable for microscopy. Both these objectives were achieved. That minimal interference range was established by comparing gauging cleaning profiles of particular deposits within duct flows against alternative cleaning profiles obtained by measuring the changing thermal resistances of the deposits. It was shown that the suitability of the operating regime was dependent on the capacity of the deposit to resist the suction pressure of the gauge. Stresses that exceed the cohesive and adhesive strengths of a deposit were used to explore in more detail the adhesive properties of foulant layers, using dried tomato purée as a model system. A quasi-stagnant system was used, in which the only flow present was that through the gauge. Thus the gauge was the source of all stresses imposed on the deposit by flow; this enabled accurate inference of the imposed normal stress.

Published
2006

20. Using 3D-bioprinted models to study pediatric neural crest-derived tumors

Author

Colin H. Quinn, Andee M. Beierle, Janet R. Julson, Michael E. Erwin, Hasan Alrefai, Hooper R. Markert, Jerry E. Stewart, Sara Claire Hutchins, Laura V. Bownes, Jamie M. Aye, Elizabeth Mroczek-Musulman, Patricia H. Hicks, Karina J. Yoon, Christopher D. Willey, and Elizabeth A. Beierle

Subjects
Materials Science (miscellaneous), Industrial and Manufacturing Engineering, Biotechnology
Abstract

The use of three-dimensional (3D) bioprinting has remained at the forefront of tissue engineering and has recently been employed for generating bioprinted solid tumors to be used as cancer models to test therapeutics. In pediatrics, neural crest-derived tumors are the most common type of extracranial solid tumors. There are only a few tumor-specific therapies that directly target these tumors, and the lack of new therapies remains detrimental to improving the outcomes for these patients. The absence of more efficacious therapies for pediatric solid tumors, in general, may be due to the inability of the currently employed preclinical models to recapitulate the solid tumor phenotype. In this study, we utilized 3D bioprinting to generate neural crest-derived solid tumors. The bioprinted tumors consisted of cells from established cell lines and patient-derived xenograft tumors mixed with a 6% gelatin/1% sodium alginate bioink. The viability and morphology of the bioprints were analyzed via bioluminescence and immunohisto chemistry, respectively. We compared the bioprints to traditional two-dimensional (2D) cell culture under conditions such as hypoxia and therapeutics. We successfully produced viable neural crest-derived tumors that retained the histology and immunostaining characteristics of the original parent tumors. The bioprinted tumors propagated in culture and grew in orthotopic murine models. Furthermore, compared to cells grown in traditional 2D culture, the bioprinted tumors were resistant to hypoxia and chemotherapeutics, suggesting that the bioprints exhibited a phenotype that is consistent with that seen clinically in solid tumors, thus potentially making this model superior to traditional 2D culture for preclinical investigations. Future applications of this technology entail the potential to rapidly print pediatric solid tumors for use in high-throughput drug studies, expediting the identification of novel, individualized therapies.

Published
2023
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22. Rapid Characterization of Solid Tumors Using Resonant Sensors

Author

Beierle, Andee M., primary, Quinn, Colin H., additional, Markert, Hooper R., additional, Carr, Adam, additional, Marayati, Raoud, additional, Bownes, Laura V., additional, Hutchins, Sara Claire, additional, Stewart, Jerry E., additional, Hill, Benjamin, additional, Ohlmeyer, Michael, additional, Reuel, Nigel F., additional, and Beierle, Elizabeth A., additional

Published
2022
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25. Rapid Characterization of Solid Tumors Using Resonant Sensors

Author

Andee M. Beierle, Colin H. Quinn, Hooper R. Markert, Adam Carr, Raoud Marayati, Laura V. Bownes, Sara Claire Hutchins, Jerry E. Stewart, Benjamin Hill, Michael Ohlmeyer, Nigel F. Reuel, and Elizabeth A. Beierle

Subjects
General Chemical Engineering, General Chemistry
Abstract

Cancer continues to be a significant cause of non-traumatic pediatric mortality. Diagnosis of pediatric solid tumors is paramount to prescribing the correct treatment regimen. Recent efforts have focused on non-invasive methods to obtain tumor tissues, but one of the challenges encountered is the ability to obtain an adequate amount of viable tissue. In this study, a wireless, inductor-capacitor (LC) sensor was employed to detect relative permittivity of pediatric tumor tissues. There is a comparison of resonant frequencies of tumor tissues between live versus dead tissues, the primary tumor tissue versus tissue from the organs of origin or metastasis, and treated versus untreated tumors. The results show significant shifts in resonant frequencies between the comparison groups. Dead tissues demonstrated a significant shift in resonant frequencies compared to alive tissues. There were significant differences between the resonant frequencies of normal tissues versus tumor tissues. Resonant frequencies were also significantly different between primary tumors compared to their respective metastases. These data indicate that there are potential clinical applications of LC technology in the detection and diagnosis of pediatric solid tumors.

Published
2022

26. PIM3 kinase promotes tumor metastasis in hepatoblastoma by upregulating cell surface expression of chemokine receptor cxcr4

Author

Raoud Marayati, Janet Julson, Laura V. Bownes, Colin H. Quinn, Laura L. Stafman, Andee M. Beierle, Hooper R. Markert, Sara C. Hutchins, Jerry E. Stewart, David K. Crossman, Anita B. Hjelmeland, Elizabeth Mroczek-Musulman, and Elizabeth A. Beierle

Subjects
Hepatoblastoma, Cancer Research, Receptors, CXCR4, Lung Neoplasms, Liver Neoplasms, Cell Membrane, General Medicine, Protein Serine-Threonine Kinases, Chemokine CXCL12, Up-Regulation, Mice, Cell Transformation, Neoplastic, Oncology, Cell Line, Tumor, Animals, Neoplasm Metastasis
Abstract

Patients presenting with metastatic hepatoblastoma have limited treatment options and survival rates as low as 25%. We previously demonstrated that Proviral Integration site in Maloney murine leukemia virus 3 (PIM3) kinase promotes tumorigenesis and cancer cell stemness in hepatoblastoma. In this study, we assessed the role of PIM3 kinase in promoting hepatoblastoma metastasis. We utilized a tail vein injection model of metastasis to evaluate the effect of CRISPR/Cas9-mediated PIM3 knockout, stable overexpression of PIM3, and pharmacologic PIM inhibition on the formation of lung metastasis. In vivo studies revealed PIM3 knockout impaired the formation of lung metastasis: 5 out of 6 mice injected with wild type hepatoblastoma cells developed lung metastasis while none of the 7 mice injected with PIM3 knockout hepatoblastoma cells developed lung metastasis. PIM3 overexpression in hepatoblastoma increased the pulmonary metastatic burden in mice and mechanistically, upregulated the phosphorylation and cell surface expression of CXCR4, a key receptor in the progression of cancer cell metastasis. CXCR4 blockade with AMD3100 decreased the metastatic phenotype of PIM3 overexpressing cells, indicating that CXCR4 contributed to PIM3's promotion of hepatoblastoma metastasis. Clinically, PIM3 expression correlated positively with CXCR4 expression in primary hepatoblastoma tissues. In conclusion, we have shown PIM3 kinase promotes the metastatic phenotype of hepatoblastoma cells through upregulation of CXCR4 cell surface expression and these findings suggest that targeting PIM3 kinase may provide a novel therapeutic strategy for metastatic hepatoblastoma.

Published
2022

28. Surgery for constipation: systematic review and clinical guidance: Paper 1: Introduction & Methods

Author

Knowles, C. H., Grossi, U., Horrocks, E. J., Pares, D., Vollebregt, P. F., Chapman, M., Brown, S. R., Mercer‐Jones, M., Williams, A. B., Hooper, R. J., Stevens, N., Mason, J., Campbell, Kenneth, Clarke, Andrew, Cruickshank, Neil, Dixon, Anthony, Emmett, Christopher, Lacy‐Colson, Jon, Lindsey, Ian, Miller, Andrew, Pilkington, Sophie, Smart, Neil, Tincello, Douglas, Telford, Karen, Yiannakou, Yan, Altomare, Donato, Boenicke, Lars, Buntzen, Steen, Campbell, Ken, Christensen, Peter, DʼHoore, Andre, Espin, Eloy, Jayne, David, Jones, Oliver, Knapp, Jens‐Christian, Laurberg, Soren, Lehur, Paul, Matzel, Klaus, OʼConnell, Ronan, Prudʼhomme, Michel, Ratto, Carlo, Trompetto, Mario, and Vaizey, Caroline

Published
2017
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29. Surgery for constipation: systematic review and practice recommendations: Graded practice and future research recommendations

Author

Knowles, C. H., Grossi, U., Horrocks, E. J., Pares, D., Vollebregt, P. F., Chapman, M., Brown, S., Mercer‐Jones, M., Williams, A. B., Yiannakou, Y., Hooper, R. J., Stevens, N., Mason, J., Campbell, Kenneth, Clarke, Andrew, Cruickshank, Neil, Dixon, Anthony, Emmett, Christopher, Lacy‐Colson, Jon, Lindsey, Ian, Miller, Andrew, Pilkington, Sophie, Smart, Neil, Tincello, Douglas, Telford, Karen, Altomare, Donato, Boenicke, Lars, Buntzen, Steen, Campbell, Ken, Christensen, Peter, DʼHoore, Andre, Espin, Eloy, Jayne, David, Jones, Oliver, Knapp, Jens‐Christian, Laurberg, Soren, Lehur, Paul, Matzel, Klaus, OʼConnell, Ronan, Prudhomme, Michel, Ratto, Carlo, Trompetto, Mario, and Vaizey, Carolynne

Published
2017
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30. The batched stepped wedge design: A design robust to delays in cluster recruitment

Author

Kasza, J, Bowden, R, Hooper, R, Forbes, AB, Kasza, J, Bowden, R, Hooper, R, and Forbes, AB

Abstract

Stepped wedge designs are an increasingly popular variant of longitudinal cluster randomized trial designs, and roll out interventions across clusters in a randomized, but step-wise fashion. In the standard stepped wedge design, assumptions regarding the effect of time on outcomes may require that all clusters start and end trial participation at the same time. This would require ethics approvals and data collection procedures to be in place in all clusters before a stepped wedge trial can start in any cluster. Hence, although stepped wedge designs are useful for testing the impacts of many cluster-based interventions on outcomes, there can be lengthy delays before a trial can commence. In this article, we introduce "batched" stepped wedge designs. Batched stepped wedge designs allow clusters to commence the study in batches, instead of all at once, allowing for staggered cluster recruitment. Like the stepped wedge, the batched stepped wedge rolls out the intervention to all clusters in a randomized and step-wise fashion: a series of self-contained stepped wedge designs. Provided that separate period effects are included for each batch, software for standard stepped wedge sample size calculations can be used. With this time parameterization, in many situations including when linear models are assumed, sample size calculations reduce to the setting of a single stepped wedge design with multiple clusters per sequence. In these situations, sample size calculations will not depend on the delays between the commencement of batches. Hence, the power of batched stepped wedge designs is robust to unexpected delays between batches.

Published
2022

32. Targeting High-Risk Neuroblastoma Patient-Derived Xenografts with Oncolytic Virotherapy

Author

Colin H. Quinn, Andee M. Beierle, Sara Claire Hutchins, Raoud Marayati, Laura V. Bownes, Jerry E. Stewart, Hooper R. Markert, Michael H. Erwin, Jamie M. Aye, Karina J. Yoon, Gregory K. Friedman, Christopher D. Willey, James M. Markert, and Elizabeth A. Beierle

Subjects
Cancer Research, neuroblastoma, Oncology, oncolytic viruses, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, immunotherapy, three-dimensional printing, patient-derived xenografts, RC254-282
Abstract

Cancer is the leading cause of death by disease in children, and over 15% of pediatric cancer-related mortalities are due to neuroblastoma. Current treatment options for neuroblastoma remain suboptimal as they often have significant toxicities, are associated with long-term side effects, and result in disease relapse in over half of children with high-risk disease. There is a dire need for new therapies, and oncolytic viruses may represent an effective solution. Oncolytic viruses attack tumor cells in two ways: direct infection of tumor cells leading to cytolysis, and production of a debris field that stimulates an anti-tumor immune response. Our group has previously shown that M002, an oncolytic herpes simplex virus (oHSV), genetically engineered to express murine interleukin-12 (mIL-12), was effective at targeting and killing long term passage tumor cell lines. In the current study, we investigated M002 in three neuroblastoma patient-derived xenografts (PDXs). PDXs better recapitulate the human condition, and these studies were designed to gather robust data for translation to a clinical trial. We found that all three PDXs expressed viral entry receptors, and that the virus actively replicated in the cells. M002 caused significant tumor cell death in 2D culture and 3D bioprinted tumor models. Finally, the PDXs displayed variable susceptibility to M002, with a more profound effect on high-risk neuroblastoma PDXs compared to low-risk PDX. These findings validate the importance of incorporating PDXs for preclinical testing of oncolytic viral therapeutics and showcase a novel technique, 3D bioprinting, to test therapies in PDXs. Collectively, our data indicate that oHSVs effectively target high-risk neuroblastoma, and support the advancement of this therapy to the clinical setting.

Published
2022
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33. Metastatic human hepatoblastoma cells exhibit enhanced tumorigenicity, invasiveness and a stem cell-like phenotype

Author

Raoud Marayati, Janet R. Julson, Laura V. Bownes, Colin H. Quinn, Sara C. Hutchins, Adele P. Williams, Hooper R. Markert, Andee M. Beierle, Jerry E. Stewart, Anita B. Hjelmeland, Elizabeth Mroczek-Musulman, and Elizabeth A. Beierle

Subjects
Hepatoblastoma, Mice, Phenotype, Cell Line, Tumor, Stem Cells, Pediatrics, Perinatology and Child Health, Liver Neoplasms, Animals, Humans, Surgery, General Medicine, Article
Abstract

BACKGROUND/PURPOSE: Metastatic hepatoblastoma continues to pose a significant treatment challenge, primarily because the precise mechanisms involved in metastasis are not fully understood, making cell lines and preclinical models that depict the progression of disease and metastasis-related biology paramount. We aimed to generate and characterize a metastatic hepatoblastoma cell line to create a model for investigation of the molecular mechanisms associated with metastasis. MATERIALS/METHODS: Using a murine model of serial tail vein injections of the human hepatoblastoma HuH6 cell line, non-invasive bioluminescence imaging, and dissociation of metastatic pulmonary lesions, we successfully established and characterized the metastatic human hepatoblastoma cell line, HLM_3. RESULTS: The HLM_3 cells exhibited enhanced tumorigenicity and invasiveness, both in vitro and in vivo compared to the parent HuH6 cell line. Moreover, HLM_3 metastatic hepatoblastoma cells exhibited a stem cell-like phenotype and were more resistant to the standard chemotherapeutic cisplatin. CONCLUSION: This newly described metastatic hepatoblastoma cell line offers a novel tool to study mechanisms of tumor metastasis and evaluate new therapeutic strategies for metastatic hepatoblastoma.

Published
2022

35. Meta‐analysis of individual‐patient data from EVAR‐1, DREAM, OVER and ACE trials comparing outcomes of endovascular or open repair for abdominal aortic aneurysm over 5 years

Author

Powell, J. T., Sweeting, M. J., Ulug, P., Blankensteijn, J. D., Lederle, F. A., Becquemin, J.‐P., Greenhalgh, R. M., Greenhalgh, R. M., Beard, J. D., Buxton, M. J., Brown, L. C., Harris, P. L., Powell, J. T., Rose, J. D. G., Russell, I. T., Sculpher, M. J., Thompson, S. G., Lilford, R.J., Bell, P. R. F., Greenhalgh, R. M., Whitaker, S.C., Poole‐Wilson, the late P.A., Ruckley, C. V., Campbell, W. B., Dean, M. R. E., Ruttley, M. S. T., Coles, E. C., Powell, J. T., Halliday, A., Gibbs, S. J., Brown, L. C., Epstein, D., Sculpher, M. J., Thompson, S. G., Hannon, R. J., Johnston, L., Bradbury, A. W., Henderson, M. J., Parvin, S. D., Shepherd, D. F. C., Greenhalgh, R. M., Mitchell, A. W., Edwards, P. R., Abbott, G. T., Higman, D. J., Vohra, A., Ashley, S., Robottom, C., Wyatt, M. G., Rose, J. D. G., Byrne, D., Edwards, R., Leiberman, D. P., McCarter, D. H., Taylor, P. R., Reidy, J. F., Wilkinson, A. R., Ettles, D. F., Clason, A. E., Leen, G. L. S., Wilson, N. V., Downes, M., Walker, S. R., Lavelle, J. M., Gough, M. J., McPherson, S., Scott, D. J. A., Kessell, D. O., Naylor, R., Sayers, R., Fishwick, N. G., Harris, P. L., Gould, D. A., Walker, M. G., Chalmers, N. C., Garnham, A., Collins, M. A., Beard, J. D., Gaines, P. A., Ashour, M. Y., Uberoi, R., Braithwaite, B., Whitaker, S. C., Davies, J. N., Travis, S., Hamilton, G., Platts, A., Shandall, A., Sullivan, B. A., Sobeh, M., Matson, M., Fox, A. D., Orme, R., Yusef, W., Doyle, T., Horrocks, M., Hardman, J., Blair, P. H. B., Ellis, P. K., Morris, G., Odurny, A., Vohra, R., Duddy, M., Thompson, M., Loosemore, T. M. L., Belli, A. M., Morgan, R., Adiseshiah, M., Brookes, J. A. S., McCollum, C. N., Ashleigh, R., Aukett, M., Baker, S., Barbe, E., Batson, N., Bell, J., Blundell, J., Boardley, D., Boyes, S., Brown, O., Bryce, J., Carmichael, M., Chance, T., Coleman, J., Cosgrove, C., Curran, G., Dennison, T., Devine, C., Dewhirst, N., Errington, B., Farrell, H., Fisher, C., Fulford, P., Gough, M., Graham, C., Hooper, R., Horne, G., Horrocks, L., Hughes, B., Hutchings, T., Ireland, M., Judge, C., Kelly, L., Kemp, J., Kite, A., Kivela, M., Lapworth, M., Lee, C., Linekar, L., Mahmood, A., March, L., Martin, J., Matharu, N., McGuigen, K., Morris‐Vincent, P., Murray, S., Murtagh, A., Owen, G., Ramoutar, V., Rippin, C., Rowley, J., Sinclair, J., Spencer, S., Taylor, V., Tomlinson, C., Ward, S., Wealleans, V., West, J., White, K., Williams, J., Wilson, L., Grobbee, D. E., Blankensteijn, J. D., Bak, A. A. A., Buth, J., Pattynama, P. M., Verhoeven, E. L. G., van Voorthuisen, A. E., Blankensteijn, J. D., Balm, R., Buth, J., Cuypers, P. W. M., Grobbee, D. E., Prinssen, M., van Sambeek, M. R. H. M., Verhoeven, E. L. G., Baas, A. F., Hunink, M. G., van Engelshoven, J. M., Jacobs, M. J. H. M., de Mol, B. A. J. M., van Bockel, J. H., Balm, R., Reekers, J., Tielbeek, X., Verhoeven, E. L. G., Wisselink, W., Boekema, N., Heuveling, L. M., Sikking, I., Prinssen, M., Balm, R., Blankensteijn, J. D., Buth, J., Cuypers, P. W. M., van Sambeek, M. R. H. M., Verhoeven, E. L. G., de Bruin, J. L., Baas, A. F., Blankensteijn, J. D., Prinssen, M., Buth, J., Tielbeek, A.V., Blankensteijn, J. D., Balm, R., Reekers, J. A., van Sambeek, M. R. H. M., Pattynama, P., Verhoeven, E. L. G., Prins, T., van der Ham, A. C., van der Velden, J. J. I. M., van Sterkenburg, S. M. M., ten Haken, G. B., Bruijninckx, C. M. A., van Overhagen, H., Tutein Nolthenius, R. P., Hendriksz, T. R., Teijink, J. A. W., Odink, H. F., de Smet, A. A. E. A., Vroegindeweij, D., van Loenhout, R. M. M., Rutten, M. J., Hamming, J. F., Lampmann, L. E. H., Bender, M. H. M., Pasmans, H., Vahl, A. C., de Vries, C., Mackaay, A. J. C., van Dortmont, L. M. C., van der Vliet, A. J., Schultze Kool, L. J., Boomsma, J. H. B., van Dop, H. R., de Mol van Otterloo, J. C. A., de Rooij, T. P. W., Smits, T. M., Yilmaz, E. N., Wisselink, W., van den Berg, F. G., Visser, M. J. T., van der Linden, E., Schurink, G. W. H., de Haan, M., Smeets, H. J., Stabel, P., van Elst, F., Poniewierski, J., Vermassen, F. E. G., Lederle, F. A., Freischlag, J. A., Kohler, T. R., Latts, E., Matsumura, J., Padberg, F. T., Jr, Kyriakides, T. C., Swanson, K. M., Guarino, P., Peduzzi, P., Antonelli, M., Cushing, C., Davis, E., Durant, L., Joyner, S., Kossack, the late A., Kyriakides, T. C., LeGwin, Mary, McBride, V., OʼConnor, T., Poulton, J., Stratton, the late S., Zellner, S., Snodgrass, A. J., Thornton, J., Swanson, K. M., Haakenson, C. M., Stroupe, K.T., Jonk, Y., Hallett, J. W., Hertzer, N., Towne, J., Katz, D. A., Karrison, T., Matts, J. P., Marottoli, R., Kasl, S., Mehta, R., Feldman, R., Farrell, W., Allore, H., Perry, E., Niederman, J., Randall, F., Zeman, M., Beckwith, the late D., OʼLeary, T. J., Huang, G. D., Latts, E., Bader, M., Ketteler, E. R., Kingsley, D. D., Marek, J. M., Massen, R. J., Matteson, B. D., Pitcher, J. D., Langsfeld, M., Corson, J. D., Goff, J. M., Jr, Kasirajan, K., Paap, C., Robertson, D. C., Salam, A., Veeraswamy, R., Milner, R., Kasirajan, K., Guidot, J., Lal, B. K., Busuttil, S. J., Lilly, M. P., Braganza, M., Ellis, K., Patterson, M. A., Jordan, W. D., Whitley, D., Taylor, S., Passman, M., Kerns, D., Inman, C., Poirier, J., Ebaugh, J., Raffetto, J., Chew, D., Lathi, S., Owens, C., Hickson, K., Dosluoglu, H. H., Eschberger, K., Kibbe, M. R., Baraniewski, H. M., Matsumura, J., Endo, M., Busman, A., Meadows, W., Evans, M., Giglia, J. S., El Sayed, H., Reed, A. B., Ruf, M., Ross, S., Jean‐Claude, J. M., Pinault, G., Kang, P., White, N., Eiseman, M., Jones, the late R., Timaran, C. H., Modrall, J. G., Welborn, M. B., III, Lopez, J., Nguyen, T., Chacko, J. K. Y., Granke, K., Vouyouka, A. G., Olgren, E., Chand, P., Allende, B., Ranella, M., Yales, C., Whitehill, T. A., Krupski, the late W. C., Nehler, M. R., Johnson, S. P., Jones, D. N., Strecker, P., Bhola, M. A., Shortell, C. K., Gray, J. L., Lawson, J. H., McCann, R., Sebastian, M.W., Kistler Tetterton, J., Blackwell, C., Prinzo, P. A., Lee, N., Padberg, F. T., Jr, Cerveira, J. J., Lal, B. K., Zickler, R. W., Hauck, K. A., Berceli, S. A., Lee, W. A., Ozaki, C. K., Nelson, P. R., Irwin, A. S., Baum, R., Aulivola, B., Rodriguez, H., Littooy, F. N., Greisler, H., OʼSullivan, M. T., Kougias, P., Lin, P. H., Bush, R. L., Guinn, G., Bechara, C., Cagiannos, C., Pisimisis, G., Barshes, N., Pillack, S., Guillory, B., Cikrit, D., Lalka, S. G., Lemmon, G., Nachreiner, R., Rusomaroff, M., OʼBrien, E., Cullen, J. J., Hoballah, J., Sharp, W. J., McCandless, J. L., Beach, V., Minion, D., Schwarcz, T. H., Kimbrough, J., Ashe, L., Rockich, A., Warner‐Carpenter, J., Moursi, M., Eidt, J. F., Brock, S., Bianchi, C., Bishop, V., Gordon, I. L., Fujitani, R., Kubaska, S. M., III, Behdad, M., Azadegan, R., Ma Agas, C., Zalecki, K., Hoch, J. R., Carr, S. C., Acher, C., Schwarze, M., Tefera, G., Mell, M., Dunlap, B., Rieder, J., Stuart, J. M., Weiman, D. S., Abul‐Khoudoud, O., Garrett, H. E., Walsh, S. M., Wilson, K. L., Seabrook, G. R., Cambria, R. A., Brown, K. R., Lewis, B. D., Framberg, S., Kallio, C., Barke, R. A., Santilli, S. M., dʼAudiffret, A. C., Oberle, N., Proebstle, C., Johnson, L. L., Jacobowitz, G. R., Cayne, N., Rockman, C., Adelman, M., Gagne, P., Nalbandian, M., Caropolo, L. J., Pipinos, I. I., Johanning, J., Lynch, T., DeSpiegelaere, H., Purviance, G., Zhou, W., Dalman, R., Lee, J. T., Safadi, B., Coogan, S. M., Wren, S. M., Bahmani, D. D., Maples, D., Thunen, S., Golden, M. A., Mitchell, M. E., Fairman, R., Reinhardt, S., Wilson, M. A., Tzeng, E., Muluk, S., Peterson, N. M., Foster, M., Edwards, J., Moneta, G. L., Landry, G., Taylor, L., Yeager, R., Cannady, E., Treiman, G., Hatton‐Ward, S., Salabsky, the late B., Kansal, N., Owens, E., Estes, M., Forbes, B. A., Sobotta, C., Rapp, J. H., Reilly, L. M., Perez, S. L., Yan, K., Sarkar, R., Dwyer, S. S., Perez, S., Chong, K., Kohler, T. R., Hatsukami, T. S., Glickerman, D. G., Sobel, M., Burdick, T. S., Pedersen, K., Cleary, P., Back, M., Bandyk, D., Johnson, B., Shames, M., Reinhard, R. L., Thomas, S. C., Hunter, G. C., Leon, L. R., Jr, Westerband, A., Guerra, R. J., Riveros, M., Mills, J. L., Sr, Hughes, J. D., Escalante, A. M., Psalms, S. B., Day, N. N., Macsata, R., Sidawy, A., Weiswasser, J., Arora, S., Jasper, B. J., Dardik, A., Gahtan, V., Muhs, B. E., Sumpio, B. E., Gusberg, R. J., Spector, M., Pollak, J., Aruny, J., Kelly, E. L., Wong, J., Vasilas, P., Joncas, C., Gelabert, H. A., DeVirgillio, C., Rigberg, D. A., Cole, L., Becquemin, J.‐P., Marzelle, J., Becquemin, J.‐P., Sapoval, M., Becquemin, J.‐P., Favre, J.‐P., Watelet, J., Lermusiaux, P., Sapoval, M., Lepage, E., Hemery, F., Dolbeau, G., Hawajry, N., Cunin, P., Harris, P., Stockx, L., Chatellier, G., Mialhe, C., Fiessinger, J.‐N., Pagny, L., Kobeiter, H., Boissier, C., Lacroix, P., Ledru, F., Pinot, J.‐J., Deux, J.‐F., Tzvetkov, B., Duvaldestin, P., Watelet, J., Jourdain, C., David, V., Enouf, D., Ady, N., Krimi, A., Boudjema, N., Jousset, Y., Enon, B., Blin, V., Picquet, J., LʼHoste, P., Thouveny, F., Borie, H., Kowarski, S., Pernes, J.‐M., Auguste, M., Becquemin, J.‐P., Desgranges, P., Allaire, E., Marzelle, J., Kobeiter, H., Meaulle, P.‐Y., Chaix, D., Juliae, P., Fabiani, J. N., Chevalier, P., Combes, M., Seguin, A., Belhomme, D., Sapoval, M., Baque, J., Pellerin, O., Favre, J. P., Barral, X., Veyret, C., Watelet, J., Peillon, C., Plissonier, D., Thomas, P., Clavier, E., Lermusiaux, P., Martinez, R., Bleuet, F., C, Dupreix, Verhoye, J. P., Langanay, T., Heautot, J. F., Koussa, M., Haulon, S., Halna, P., Destrieux, L., Lions, C., Wiloteaux, S., Beregi, J. P., Bergeron, P., Pinot, J.‐J., Patra, P., Costargent, A., Chaillou, P., DʼAlicourt, A., Goueffic, Y., Cheysson, E., Parrot, A., Garance, P., Demon, A., Tyazi, A., Pillet, J.‐C., Lescalie, F., Tilly, G., Steinmetz, E., Favier, C., Brenot, R., Krause, D., Cercueil, J. P., Vahdat, O., Sauer, M., Soula, P., Querian, A., Garcia, O., Levade, M., Colombier, D., Cardon, J.‐M., Joyeux, A., Borrelly, P., Dogas, G., Magnan, P.‐É., Branchereau, A., Bartoli, J.‐M., Hassen‐Khodja, R., Batt, M., Planchard, P.‐F., Bouillanne, P.‐J., Haudebourg, P., Bayne, J., Gouny, P., Badra, A., Braesco, J., Nonent, M., Lucas, A., Cardon, A., Kerdiles, Y., Rolland, Y., Kassab, M., Brillu, C., Goubault, F., Tailboux, L., Darrieux, H., Briand, O., Maillard, J.‐C., Varty, K., and Cousins, C.

Published
2017
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36. External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis

Author

Snell, K, Allotey, J, Smuk, M, Hooper, R, Chan, C, Ahmed, A, Chappell, L, Von Dadelszen, P, Green, M, Kenny, L, Khalil, A, Khan, K, Mol, B, Myers, J, Poston, L, Thilaganathan, B, Staff, A, Smith, G, Ganzevoort, W, Laivuori, H, Odibo, A, Arenas Ramirez, J, Kingdom, J, Daskalakis, G, Farrar, D, Baschat, A, Seed, P, Prefumo, F, da Silva Costa, F, Groen, H, Audibert, F, Masse, J, Skrastad, R, Salvesen, K, Haavaldsen, C, Nagata, C, Rumbold, A, Heinonen, S, Askie, L, Smits, L, Vinter, C, Magnus, P, Eero, K, Villa, P, Jenum, A, Andersen, L, Norman, J, Ohkuchi, A, Eskild, A, Bhattacharya, S, Mcauliffe, F, Galindo, A, Herraiz, I, Carbillon, L, Klipstein-Grobusch, K, Yeo, S, Browne, J, Moons, K, Riley, R, Thangaratinam, S, Vergani, P, Snell K. I. E., Allotey J., Smuk M., Hooper R., Chan C., Ahmed A., Chappell L. C., Von Dadelszen P., Green M., Kenny L., Khalil A., Khan K. S., Mol B. W., Myers J., Poston L., Thilaganathan B., Staff A. C., Smith G. C. S., Ganzevoort W., Laivuori H., Odibo A. O., Arenas Ramirez J., Kingdom J., Daskalakis G., Farrar D., Baschat A. A., Seed P. T., Prefumo F., da Silva Costa F., Groen H., Audibert F., Masse J., Skrastad R. B., Salvesen K. A., Haavaldsen C., Nagata C., Rumbold A. R., Heinonen S., Askie L. M., Smits L. J. M., Vinter C. A., Magnus P., Eero K., Villa P. M., Jenum A. K., Andersen L. B., Norman J. E., Ohkuchi A., Eskild A., Bhattacharya S., McAuliffe F. M., Galindo A., Herraiz I., Carbillon L., Klipstein-Grobusch K., Yeo S. A., Browne J. L., Moons K. G. M., Riley R. D., Thangaratinam S., Vergani P., Snell, K, Allotey, J, Smuk, M, Hooper, R, Chan, C, Ahmed, A, Chappell, L, Von Dadelszen, P, Green, M, Kenny, L, Khalil, A, Khan, K, Mol, B, Myers, J, Poston, L, Thilaganathan, B, Staff, A, Smith, G, Ganzevoort, W, Laivuori, H, Odibo, A, Arenas Ramirez, J, Kingdom, J, Daskalakis, G, Farrar, D, Baschat, A, Seed, P, Prefumo, F, da Silva Costa, F, Groen, H, Audibert, F, Masse, J, Skrastad, R, Salvesen, K, Haavaldsen, C, Nagata, C, Rumbold, A, Heinonen, S, Askie, L, Smits, L, Vinter, C, Magnus, P, Eero, K, Villa, P, Jenum, A, Andersen, L, Norman, J, Ohkuchi, A, Eskild, A, Bhattacharya, S, Mcauliffe, F, Galindo, A, Herraiz, I, Carbillon, L, Klipstein-Grobusch, K, Yeo, S, Browne, J, Moons, K, Riley, R, Thangaratinam, S, Vergani, P, Snell K. I. E., Allotey J., Smuk M., Hooper R., Chan C., Ahmed A., Chappell L. C., Von Dadelszen P., Green M., Kenny L., Khalil A., Khan K. S., Mol B. W., Myers J., Poston L., Thilaganathan B., Staff A. C., Smith G. C. S., Ganzevoort W., Laivuori H., Odibo A. O., Arenas Ramirez J., Kingdom J., Daskalakis G., Farrar D., Baschat A. A., Seed P. T., Prefumo F., da Silva Costa F., Groen H., Audibert F., Masse J., Skrastad R. B., Salvesen K. A., Haavaldsen C., Nagata C., Rumbold A. R., Heinonen S., Askie L. M., Smits L. J. M., Vinter C. A., Magnus P., Eero K., Villa P. M., Jenum A. K., Andersen L. B., Norman J. E., Ohkuchi A., Eskild A., Bhattacharya S., McAuliffe F. M., Galindo A., Herraiz I., Carbillon L., Klipstein-Grobusch K., Yeo S. A., Browne J. L., Moons K. G. M., Riley R. D., Thangaratinam S., and Vergani P.

Abstract

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. METHODS: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. RESULTS: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions

Published
2020

40. Targeting High-Risk Neuroblastoma Patient-Derived Xenografts with Oncolytic Virotherapy

Author

Quinn, Colin H., primary, Beierle, Andee M., additional, Hutchins, Sara Claire, additional, Marayati, Raoud, additional, Bownes, Laura V., additional, Stewart, Jerry E., additional, Markert, Hooper R., additional, Erwin, Michael H., additional, Aye, Jamie M., additional, Yoon, Karina J., additional, Friedman, Gregory K., additional, Willey, Christopher D., additional, Markert, James M., additional, and Beierle, Elizabeth A., additional

Published
2022
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44. The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor

Author

Joshua C. Anderson, Caroline D. Goolsby, Kimberly Whelan, Elizabeth Mroczek-Musulman, Jamie M. Aye, Jerry E. Stewart, Raoud Marayati, Elizabeth A. Beierle, Evan F. Garner, Hooper R. Markert, Adele P. Williams, Colin H. Quinn, Christopher D. Willey, Karina J. Yoon, Mary G. Waldrop, Laura L. Stafman, and Smitha Mruthyunjayappa

Subjects
0301 basic medicine, Chemistry, Wilms tumor, Wilms' tumor, medicine.disease, 3. Good health, kinase inhibition, Focal adhesion, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, Growth factor receptor, 030220 oncology & carcinogenesis, medicine, Cancer research, Platelet-Derived Growth Factor Receptor Beta, Phosphorylation, Immunohistochemistry, Viability assay, Tyrosine kinase, Research Paper
Abstract

Aggressive therapies for patients with metastatic Wilms tumor (WT) with subsequent severe late effects warrant the search for novel therapies. The role of focal adhesion kinase (FAK), a non-receptor tyrosine kinase important in pediatric solid tumor development and progression, has not been examined in metastatic WT. Using a novel patient-derived xenograft (PDX) of a primary and matched, isogenic, metastatic WT, the hypothesis of the current study was that FAK would contribute to metastatic WT and small molecule inhibition would decrease tumor growth. Immunohistochemical staining, immunoblotting, cell viability and proliferation assays, cell cycle analysis, and cellular motility and attachment-independent growth assays were performed. FAK was present and phosphorylated in both WT PDXs and in the human samples from which they were derived. FAK inhibition decreased cellular survival, proliferation, and cell cycle progression in both PDXs but only significantly decreased migration, invasion, and attachment-independent growth in the primary WT PDX. Kinomic profiling revealed that platelet-derived growth factor receptor beta (PDGFRβ) may be affected by FAK inhibition in WT. Pharmacologic inhibition of FAK and PDGFRβ was synergistic in primary WT PDX cells. These findings broaden the knowledge of metastatic WT and support further investigations on the potential use of FAK and PDGFRβ inhibitors.

Published
2019
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45. Downregulation of PDGFRß Signaling Overcomes Crizotinib Resistance in a TYRO3 and ALK Mutated Neuroendocrine-Like Tumor

Author

Andee M. Beierle, Colin H. Quinn, Elizabeth Mroczek-Musulman, Jamie M. Aye, David K. Crossman, Adele P. Williams, Hooper R. Markert, Jerry E. Stewart, Raoud Marayati, Karina J. Yoon, Laura V. Bownes, and Elizabeth A. Beierle

Subjects
0301 basic medicine, MAPK/ERK pathway, Cancer Research, medicine.medical_treatment, Receptor expression, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Crizotinib, Neuroendocrine tumor, In vivo, medicine, RC254-282, Original Research, business.industry, Sunitinib, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Drug resistance, Cancer research, business, Patient derived xenoline, TYRO3, medicine.drug
Abstract

Highlights • Rare, high grade neuroendocrine-like pediatric tumor has TYRO3 and ALK mutations. • Crizotinib downregulates STAT3 and ERK1/2 signaling in tumor. • In vivo analysis demonstrated crizotinib resistance. • Crizotinib resistant cells have upregulation of PDGFRß signaling. • PDGFRß inhibition overrides resistance., Patient-derived xenografts provide significant advantages over long-term passage cell lines when investigating efficacy of treatments for solid tumors. Our laboratory encountered a high-grade, metastatic, neuroendocrine-like tumor from a pediatric patient that presented with a unique genetic profile. In particular, mutations in TYRO3 and ALK were identified. We established a human patient-derived xenoline (PDX) of this tumor for use in the current study. We investigated the effect of crizotinib, a chemotherapeutic known to effectively target both TYRO3 and ALK mutations. Crizotinib effectively decreased viability, proliferation, growth, and the metastatic properties of the PDX tumor through downregulation of STAT3 signaling, but expression of PDGFRß was increased. Sunitinib is a small molecule inhibitor of PDGFRß and was studied in this PDX independently and in combination with crizotinib. Sunitinib alone decreased viability, proliferation, and growth in vitro and decreased tumor growth in vivo. In combination, sunitinib was able to overcome potential crizotinib-induced resistance through downregulation of ERK 1/2 activity and PDGFRß receptor expression; consequently, tumor growth was significantly decreased both in vitro and in vivo. Through the use of the PDX, it was possible to identify crizotinib as a less effective therapeutic for this tumor and suggest that targeting PDGFRß would be more effective. These findings may translate to other solid tumors that present with the same genetic mutations.

Published
2021

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