94 results on '"Shanks, E."'
Search Results
2. CONSTRUCTION: BEST PRACTICE FOR CONTROL OF TODAY'S NOISE AND HAND-ARM VIBRATION EXPOSURES
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Shanks, E, primary
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- 2020
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3. Longitudinal changes in EEG power, sleep cycles and behaviour in a tau model of neurodegeneration
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Holton, C. M., primary, Hanley, N., additional, Shanks, E., additional, Oxley, P., additional, McCarthy, A., additional, Eastwood, B. J., additional, Murray, T. K., additional, Nickerson, A., additional, and Wafford, K. A., additional
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- 2020
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4. S124 IDENTIFICATION OF THE DOPAMINE AND SEROTONIN TRANSPORTERS SLC6A3 AND SLC6A4 AS NOVEL SURVIVAL FACTORS IN LEUKEMIC STEM CELLS IN CHRONIC MYELOID LEUKAEMIA
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Aldosari, A., primary, Ritchie, J., additional, Calvo-Sánchez, J., additional, Hewit, K., additional, James, D., additional, Dunn, K., additional, Copland, M., additional, Holyoake, T., additional, Shanks, E., additional, Scott, M., additional, and Vetrie, D., additional
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- 2019
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5. Repurposing of mebendazole as a potential synergistic therapy with docetaxel in castration resistant prostate cancer
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Rushworth, L., primary, Patel, R., additional, Hewit, K., additional, Munnings-Tomes, S., additional, Straube, A., additional, James, D., additional, Shanks, E., additional, and Leung, H., additional
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- 2018
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6. The ERBB network facilitates KRAS-driven lung tumorigenesis
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Neidler, S., primary, Hedley, A., additional, Kruspig, B., additional, Monteverde, T., additional, Hewit, K., additional, Neiswandt, B., additional, Rosenwald, A., additional, Shanks, E., additional, Dick, C., additional, and Murphy, D., additional
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- 2016
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7. Historical occurrence of alien arthropods and pathogens on trees in Canada
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Nealis, V.G., DeMerchant, I., Langor, D., Noseworthy, M.K., Pohl, G., Porter, K., Shanks, E., Turnquist, R., and Waring, V.
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Trees -- Diseases and pests -- Forecasts and trends ,Fungi, Phytopathogenic -- Forecasts and trends ,Arthropoda -- Forecasts and trends ,Earth sciences ,Market trend/market analysis ,Diseases and pests ,Forecasts and trends - Abstract
The Canadian Forest Invasive Alien Species (CanFIAS) database provides point records of alien arthropod (insects and mites) and pathogen (fungi) species found on trees in Canada extracted from more than 100 years of national surveys. Each record includes a species identification, location, year of observation, and host association and is linked electronically to its original source. More than 175 000 records of 329 alien arthropod species and 11 plant pathogens are available. Historical rates of detection, as indicated by first records, were greatest in the decades following the two world wars. The overall rate has been approximately three species per year since 1900. Richness of alien species is greatest in the Coastal and Great Lakes- St. Lawrence forest ecozones and lowest in the Subalpine and Tundra ecozones. The alien species most significant in terms of extent of invasion and damage to trees are tree-host specialists, feeding on or infecting mostly one or two genera in a single plant family. Important commercial trees including pine, spruce, poplar, and birch and amenity genera including willow, cherry, and maple host the greatest diversity of alien species. Sap-feeding insects are the most speciose feeding group, but foliage- feeding and wood-boring insects and plant pathogens cause the most damage. Key words: alien invasive species, insects, pathogens, survey. La base de donnees sur les especes exotiques envahissantes forestieres au Canada (EEEFCan) fournit des rapports ponctuels au sujet des especes exotiques d'arthropodes (insectes et acariens) et de champignons pathogenes observees sur les arbres. Ces rapports sont extraits des releves nationaux qui remontent a plus d'une centaine d'annees. Chaque rapport inclut l'identification de l'espece, la localisation, l'annee d'observation ainsi que l'hote associe et est relie electroniquement a sa source originelle. Plus de 175 000 rapports de 329 especes exotiques d'arthropodes et de 11 phytopathogenes sont disponibles. Comme l'indiquent les premiers rapports, les taux historiques de detection etaient plus eleves au cours de decennies qui ont suivi les deux guerres mondiales. Globalement, le taux est d'environ trois especes par annee depuis 1900. La richesse en especes exotiques est la plus elevee dans les ecozones forestieres cotiere et des Grands Lacs et du Saint-Laurent et la plus faible dans les ecozones subalpine et de toundra. Les especes exotiques les plus importantes en termes d'ampleur de l'invasion et des dommages aux arbres sont celles qui ont developpe une specificite pour leurs hotes; la plupart du temps elles se nourrissent sur ou infectent un ou deux genres d'une meme famille de plantes. Des arbres importants du point de vue commercial incluant le pin, l'epicea, le peuplier et le bouleau et des genres d'agrement incluant le saule, le cerisier et l'erable servent d'hotes a la plus grande diversite d'especes exotiques. Parmi les phytophages, le groupe des insectes succivores compte le plus d'especes mais les insectes qui se nourrissent du feuillage (phyllophages) et ceux qui creusent des galeries dans le bois (xylophages) ainsi que les phytopathogenes causent le plus de dommages. [Traduit par la Redaction] Mots-cles : especes exotiques envahissantes, insectes, pathogenes, releve., Introduction Organisms have been introduced outside their native ranges for as long as people have colonized new territory and long before the notions of 'invasive' and 'alien' entered our consciousness [...]
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- 2016
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8. Cone beam (CBCT) imaging in cochlear implantation practice
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Stapleton, Emma, primary, Shanks, E Mary, additional, Allen, Agnes, additional, and Wardrop, Peter, additional
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- 2016
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9. Convergence of Series with Positive Terms
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Shanks, E. Baylis
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- 1957
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10. Iterated Sums of Powers of the Binomial Coefficients
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Shanks, E. B.
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- 1951
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11. Solutions of Differential Equations by Evaluations of Functions
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Shanks, E. Baylis
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- 1966
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12. Stereological estimation of eye volume using the Pappus method
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Reed, M. G., primary, Shanks, E., additional, Beech, D. J., additional, Barlow, L., additional, and Howard, C. V., additional
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- 2001
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13. Scottish data on intrapartum related deaths are in same direction as Welsh data
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Chalmers, J. W T, primary, Shanks, E., additional, Paterson, S., additional, McInneny, K., additional, Baird, D., additional, and Penney, G., additional
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- 1998
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14. Geographical inequality in the provision of carotid endarterectomy in Scotland
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Adam, D J, primary, Bain, M, additional, Shanks, E, additional, and Bradbury, A W, additional
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- 1998
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15. Geographical inequality in the provision of carotid endarterectomy in Scotland
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Andrew W. Bradbury, Donald J. Adam, M. Bain, and Shanks E
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education.field_of_study ,Inequality ,business.industry ,media_common.quotation_subject ,medicine.medical_treatment ,Population ,Audit ,Carotid endarterectomy ,Asymptomatic ,Stroke prevention ,Medicine ,Surgery ,Residence ,Internal carotid artery stenosis ,medicine.symptom ,business ,education ,media_common ,Demography - Abstract
Background Carotid endarterectomy (CEA) is a proven method of stroke prevention in patients with symptomatic and asymptomatic high-grade internal carotid artery stenosis. This study examined whether site of residence affects access to CEA in Scotland. Methods Scottish Morbidity Record hospital discharge data were collected by the Information and Statistics Division of the National Health Service in Scotland and analysed for the interval 1 January 1989 to 31 December 1995. The number of CEAs performed in the hospitals of each of the 15 regional Health Boards, and CEA rate per 100 000 population resident in each Health Board region, were determined. Results In 1989, 65 CEAs were performed in the hospitals of five Health Boards and in 1995, 431 CEAs were performed in nine Health Boards. In 1989, the CEA rate per 100 000 resident population varied between 0 (four regions) and 4 (one region), with one region significantly different from Scotland as a whole (P Conclusion Despite a sixfold increase in the number of CEAs being performed, and a rise in the number of centres performing CEA, there is increasing geographical inequality in the provision of CEA in Scotland.
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- 1998
16. LETTERS.
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SHANKS, E. CHAT., JOHNSTON, THOMAS P., BRADLEY, S. M., HART, WILLIAM L., KLOPSTEG, PAUL E., GRUMAN, A. P., COULTER, DOUGLAS, ALLISON, W. F., MOLONEY, STEPHEN J., and CORCORAN, ANN
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ATTACK on Pearl Harbor (Hawaii), 1941 ,AMERICAN veterans - Published
- 1945
17. Mathematical Notes
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Shanks, E. Baylis, primary, Krall, H. L., additional, Danese, Arthur E., additional, Shia, Wen-Hou, additional, Seebeck, C. L., additional, Hoelzer, H., additional, Rudin, Mary Ellen, additional, and Steinberg, R., additional
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- 1957
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18. Mathematical Notes
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Shanks, E. B., primary, Utz, W. R., additional, and Fort, M. K., additional
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- 1951
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19. Homothetic correspondences between Riemannian spaces
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Shanks, E. Baylis, primary
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- 1950
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20. Study of non-linear optimization techniques
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Shanks, E. B
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Computers - Abstract
Nonlinear optimization techniques in dynamic programming and solution of ordinary nonlinear differential equations by Runge-Kutta method
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- 1971
21. Numerical integration of second order differential equations
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Shanks, E. B
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Mathematics And Information Sciences - Abstract
Performance characteristics of higher order approximations of Runge-Kutta type are analyzed, and performance predictors for time required on machine and for error size are developed. Technique is useful in evaluating system performance, analyzing material characteristics, and designing inertial guidance and nuclear instrumentation and materials.
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- 1971
22. Solutions of differential equations by evaluations of functions.
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Shanks, E. B
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Mathematics - Abstract
Runge-Kutta fourth order formula used to obtain approximate solution to differential equations
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- 1966
23. Higher order approximations of runge-kutta type
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Shanks, E. B
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Mathematics - Abstract
Runge-Kutta integration for higher order differential equation solution
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- 1965
24. A MATHEMATICAL TREATMENT OF THE PROBLEM OF DETERMINING THE EIGENVALUES ASSOCIATED WITH A PARTITION FUNCTION OF AN ATOM IN THE INTERIOR OF A PLASMA
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Shanks, E. B
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Physics, Atomic, Molecular, And Nuclear - Abstract
Eigenvalues associated with partition function of atoms in interior of plasmas - mathematical treatment of ionization
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- 1963
25. A RECURSION RELATION ASSOCIATED WITH A CERTAIN SPECIAL TYPE DETERMINANT
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Shanks, E. B
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Meteorology - Abstract
Recursion relation developed from certain determinants, computational routine to evaluate such determinants
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- 1963
26. Performance characteristics of higher order approximations of runge-kutta type
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Shanks, E. B
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Mathematics - Abstract
Performance characteristics of higher order approximations of Runge-Kutta type
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- 1963
27. Stage-related combined modality treatment of retinoblastoma. Results of a prospective study.
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Howarth, Cathryn, Meyer, David, Hustu, H. Omar, Johnson, Warren W., Shanks, Ellen, Pratt, Charles, Howarth, C, Meyer, D, Hustu, H O, Johnson, W W, Shanks, E, and Pratt, C
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- 1980
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28. Adjuvant multiple drug chemotherapy for osteosarcoma of the extremity.
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Pratt, Charles, Shanks, Ellen, Hustu, Omar, Rivera, Gaston, Smith, John, Kumar, A. P. Mahesh, Pratt, C, Shanks, E, Hustu, O, Rivera, G, Smith, J, and Kumar, A P
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- 1977
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29. A REVERIE.
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SHANKS, E. C.
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- 1869
30. O-17 - Repurposing of mebendazole as a potential synergistic therapy with docetaxel in castration resistant prostate cancer.
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Rushworth, L., Patel, R., Hewit, K., Munnings-Tomes, S., Straube, A., James, D., Shanks, E., and Leung, H.
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PROSTATE cancer , *CLINICAL trials , *MEBENDAZOLE , *DOCETAXEL , *CANCER chemotherapy - Published
- 2018
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31. 450 - The ERBB network facilitates KRAS-driven lung tumorigenesis.
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Neidler, S., Hedley, A., Kruspig, B., Monteverde, T., Hewit, K., Neiswandt, B., Rosenwald, A., Shanks, E., Dick, C., and Murphy, D.
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- 2016
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32. A MATHEMATICAL TREATMENT OF THE PROBLEM OF DETERMINING THE EIGENVALUES ASSOCIATED WITH A PARTITION FUNCTION OF AN ATOM IN THE INTERIOR OF A PLASMA
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Shanks, E
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- 1963
33. Phenotypic profiling of solute carriers characterizes serine transport in cancer.
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Papalazarou V, Newman AC, Huerta-Uribe A, Legrave NM, Falcone M, Zhang T, McGarry L, Athineos D, Shanks E, Blyth K, Vousden KH, and Maddocks ODK
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- Animals, Biological Transport, Amino Acids metabolism, Serine metabolism, Mammals metabolism, Membrane Transport Proteins metabolism, Colorectal Neoplasms genetics
- Abstract
Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling., (© 2023. The Author(s).)
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- 2023
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34. The Dopamine D1 Receptor Positive Allosteric Modulator Mevidalen (LY3154207) Enhances Wakefulness in the Humanized D1 Mouse and in Sleep-Deprived Healthy Male Volunteers.
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McCarthy AP, Svensson KA, Shanks E, Brittain C, Eastwood BJ, Kielbasa W, Biglan KM, and Wafford KA
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- Animals, Healthy Volunteers, Humans, Isoquinolines, Male, Mice, Receptors, Dopamine D1, Sleep physiology, Neuroprotective Agents pharmacology, Wakefulness
- Abstract
Dopamine (DA) plays a key role in several central functions including cognition, motor activity, and wakefulness. Although efforts to develop dopamine receptor 1 (D1) agonists have been challenging, a positive allosteric modulator represents an attractive approach with potential better drug-like properties. Our previous study demonstrated an acceptable safety and tolerability profile of the dopamine receptor 1 positive allosteric modulator (D1PAM) mevidalen (LY3154207) in single and multiple ascending dose studies in healthy volunteers (Wilbraham et al., 2021). Herein, we describe the effects of mevidalen on sleep and wakefulness in humanized dopamine receptor 1 (hD1) mice and in sleep-deprived healthy male volunteers. Mevidalen enhanced wakefulness (latency to fall asleep) in the hD1 mouse in a dose dependent [3-100 mg/kg, orally (PO)] fashion when measured during the light (zeitgeber time 5) and predominantly inactive phase. Mevidalen promoted wakefulness in mice after prior sleep deprivation and delayed sleep onset by 5.5- and 15.2-fold compared with vehicle-treated animals, after the 20 and 60 mg/kg PO doses, respectively, when compared with vehicle-treated animals. In humans, mevidalen demonstrated a dose-dependent increase in latency to sleep onset as measured by the multiple sleep latency test and all doses (15, 30, and 75 mg) separated from placebo at the first 2-hour postdose time point with a circadian effect at the 6-hour postdose time point. Sleep wakefulness should be considered a translational biomarker for the dopamine receptor 1 positive allosteric modulator mechanism. SIGNIFICANCE STATEMENT: This is the first translational study describing the effects of a selective dopamine receptor 1 positive allosteric modulator (D1PAM) on sleep and wakefulness in the human dopamine receptor 1 mouse and in sleep-deprived healthy male volunteers. In both species, drug exposure correlated with sleep latency, supporting the use of sleep-wake activity as a translational central biomarker for D1PAM. Wake-promoting effects of D1PAMs may offer therapeutic opportunities in several conditions, including sleep disorders and excessive daytime sleepiness related to neurodegenerative disorders., (Copyright © 2022 The Author(s).)
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- 2022
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35. An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism.
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Nacke M, Sandilands E, Nikolatou K, Román-Fernández Á, Mason S, Patel R, Lilla S, Yelland T, Galbraith LCA, Freckmann EC, McGarry L, Morton JP, Shanks E, Leung HY, Markert E, Ismail S, Zanivan S, Blyth K, and Bryant DM
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- ADP-Ribosylation Factor 6, ADP-Ribosylation Factors metabolism, Animals, Carcinogenesis genetics, Carcinogenesis metabolism, Cell Line, Tumor, Guanine Nucleotide Exchange Factors genetics, Heterografts, Humans, Low Density Lipoprotein Receptor-Related Protein-1 metabolism, Male, Mice, Mice, Nude, Neoplasms metabolism, Proto-Oncogene Proteins c-akt metabolism, Guanine Nucleotide Exchange Factors metabolism, Neoplasm Metastasis genetics, Phosphatidylinositols metabolism, Signal Transduction
- Abstract
The signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. Here, we report development of 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that alternate variants of IQSEC1, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by controlling phosphoinositide metabolism. All IQSEC1 variants activate ARF5- and ARF6-dependent PIP5-kinase to promote PI(3,4,5)P
3 -AKT signalling and growth. In contrast, select pro-invasive IQSEC1 variants promote PI(3,4,5)P3 production to form invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion in vitro and metastasis in vivo. Induction of pro-invasive IQSEC1 variants and elevated IQSEC1 expression occurs in a number of tumour types and is associated with higher-grade metastatic cancer, activation of PI(3,4,5)P3 signalling, and predicts long-term poor outcome across multiple cancers. IQSEC1-regulated phosphoinositide metabolism therefore is a switch to induce invasion over growth in response to the same external signal. Targeting IQSEC1 as the central regulator of this switch may represent a therapeutic vulnerability to stop metastasis.- Published
- 2021
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36. Benign versus malignant Parkinson disease: the unexpected silver lining of motor complications.
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Merola A, Romagnolo A, Dwivedi AK, Padovani A, Berg D, Garcia-Ruiz PJ, Fabbri M, Artusi CA, Zibetti M, Lopiano L, Pilotto A, Bonacina S, Morgante F, Zeuner K, Griewing C, Schaeffer E, Rodriguez-Porcel F, Kauffman M, Turcano P, de Oliveira LM, Palermo G, Shanks E, Del Sorbo F, Bonvegna S, Savica R, Munhoz RP, Ceravolo R, Cilia R, and Espay AJ
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- Aged, England, Humans, Middle Aged, Prevalence, Retrospective Studies, Parkinson Disease complications, Parkinson Disease epidemiology, REM Sleep Behavior Disorder
- Abstract
Objective: We sought to evaluate demographic, clinical, and habits/occupational variables between phenotypic extremes in Parkinson's disease (PD)., Methods: Databases from nine movement disorders centers across seven countries were retrospectively searched for subjects meeting criteria for very slowly progressive, benign, PD (bPD) and rapidly progressive, malignant, PD (mPD). bPD was defined as Hoehn and Yahr (H&Y) stage ≤ 3, normal cognitive function, and Schwab and England (S&E) score ≥ 70 after ≥ 20 years of PD (≥ 10 years if older than 60 at PD onset); mPD as H&Y > 3, S&E score < 70, and cognitive impairment within 10 years from PD onset. We performed between-group analysis of demographic, habits/occupational, and clinical features at baseline and follow-up and unsupervised data-driven analysis of the clinical homogeneity of bPD and mPD., Results: At onset, bPD subjects (n = 210) were younger, had a single limb affected, lower severity and greater asymmetry of symptoms, and lower prevalence of depression than mPD (n = 155). bPD was associated with active smoking and physical activity, mPD with agricultural occupation. At follow-up, mPD showed higher prevalence of depression, hallucinations, dysautonomia, and REM behaviour disorder. Interestingly, the odds of mPD were significantly reduced by the presence of dyskinesia and wearing-off. Data-driven analysis confirmed the independent clustering of bPD and mPD, with age at onset emerging as a critical discriminant between the two groups (< 46-year-old vs. > 68-year-old)., Conclusions: Phenotypic PD extremes showed distinct demographic, clinical, and habits/occupational factors. Motor complications may be conceived as markers of therapeutic success given their attenuating effects on the odds of mPD.
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- 2020
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37. HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer.
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Brunton H, Caligiuri G, Cunningham R, Upstill-Goddard R, Bailey UM, Garner IM, Nourse C, Dreyer S, Jones M, Moran-Jones K, Wright DW, Paulus-Hock V, Nixon C, Thomson G, Jamieson NB, McGregor GA, Evers L, McKay CJ, Gulati A, Brough R, Bajrami I, Pettitt SJ, Dziubinski ML, Barry ST, Grützmann R, Brown R, Curry E, Pajic M, Musgrove EA, Petersen GM, Shanks E, Ashworth A, Crawford HC, Simeone DM, Froeling FEM, Lord CJ, Mukhopadhyay D, Pilarsky C, Grimmond SE, Morton JP, Sansom OJ, Chang DK, Bailey PJ, and Biankin AV
- Subjects
- Cell Line, Tumor, Humans, Adenocarcinoma genetics, Biomarkers, Tumor metabolism, Carcinoma, Pancreatic Ductal genetics, GATA6 Transcription Factor metabolism, Hepatocyte Nuclear Factor 4 metabolism
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC., Competing Interests: Declaration of Interests A.V.B. receives grant funding from Celgene and AstraZeneca and is a consultant for or on advisory boards of AstraZeneca, Celgene, Elstar Therapeutics, Clovis Oncology, and Roche. S.T.B. is an AstraZeneca employee and shareholder. C.J.L. receives research funding from AstraZeneca, Merck KGaA, and Artios; received consultancy, SAB membership, or honoraria payments from Syncona, Sun Pharma, GLG, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, and Artios; and has stock in Tango and Ovibio. A.A. is co-founder of Tango Therapeutics, Azkarra Therapeutics, and Ovibio Corporation; is a consultant for SPARC, Bluestar, TopoRx, ProLynx, Earli, and Cura; is a member of the SAB of Genentech and GLAdiator; receives grant/research support from SPARC and AstraZeneca; and holds patents on the use of PARP inhibitors held jointly with AstraZeneca, which he has benefitted from financially (and may do so in the future) through the ICR Rewards to Inventors Scheme., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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38. Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment.
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Rushworth LK, Hewit K, Munnings-Tomes S, Somani S, James D, Shanks E, Dufès C, Straube A, Patel R, and Leung HY
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- Animals, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Drug Repositioning methods, Drug Synergism, Humans, Male, Mice, PC-3 Cells, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Docetaxel pharmacology, Drug Screening Assays, Antitumor methods, Mebendazole pharmacology, Prostatic Neoplasms
- Abstract
Background: Docetaxel chemotherapy in prostate cancer has a modest impact on survival. To date, efforts to develop combination therapies have not translated into new treatments. We sought to develop a novel therapeutic strategy to tackle chemoresistant prostate cancer by enhancing the efficacy of docetaxel., Methods: We performed a drug-repurposing screen by using murine-derived prostate cancer cell lines driven by clinically relevant genotypes. Cells were treated with docetaxel alone, or in combination with drugs (n = 857) from repurposing libraries, with cytotoxicity quantified using High Content Imaging Analysis., Results: Mebendazole (an anthelmintic drug that inhibits microtubule assembly) was selected as the lead drug and shown to potently synergise docetaxel-mediated cell killing in vitro and in vivo. Dual targeting of the microtubule structure was associated with increased G2/M mitotic block and enhanced cell death. Strikingly, following combined docetaxel and mebendazole treatment, no cells divided correctly, forming multipolar spindles that resulted in aneuploid daughter cells. Liposomes entrapping docetaxel and mebendazole suppressed in vivo prostate tumour growth and extended progression-free survival., Conclusions: Docetaxel and mebendazole target distinct aspects of the microtubule dynamics, leading to increased apoptosis and reduced tumour growth. Our data support a new concept of combined mebendazole/docetaxel treatment that warrants further clinical evaluation.
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- 2020
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39. Identification of a Clinically Relevant Signature for Early Progression in KRAS-Driven Lung Adenocarcinoma.
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Neidler S, Kruspig B, Hewit K, Monteverde T, Gyuraszova K, Braun A, Clark W, James D, Hedley A, Nieswandt B, Shanks E, Dick C, and Murphy DJ
- Abstract
Inducible genetically defined mouse models of cancer uniquely facilitate the investigation of early events in cancer progression, however, there are valid concerns about the ability of such models to faithfully recapitulate human disease. We developed an inducible mouse model of progressive lung adenocarcinoma (LuAd) that combines sporadic activation of oncogenic KRas
G12D with modest overexpression of c-MYC (KM model). Histological examination revealed a highly reproducible spontaneous transition from low-grade adenocarcinoma to locally invasive adenocarcinoma within 6 weeks of oncogene activation. Laser-capture microdissection coupled with RNA-SEQ (ribonucleic acid sequencing) was employed to determine transcriptional changes associated with tumour progression. Upregulated genes were triaged for relevance to human LuAd using datasets from Oncomine and cBioportal. Selected genes were validated by RNAi screening in human lung cancer cell lines and examined for association with lung cancer patient overall survival using KMplot.com. Depletion of progression-associated genes resulted in pronounced viability and/or cell migration defects in human lung cancer cells. Progression-associated genes moreover exhibited strong associations with overall survival, specifically in human lung adenocarcinoma, but not in squamous cell carcinoma. The KM mouse model faithfully recapitulates key molecular events in human adenocarcinoma of the lung and is a useful tool for mechanistic interrogation of KRAS-driven LuAd progression., Competing Interests: The authors declare no conflicts of interest.- Published
- 2019
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40. The phospholipid PI(3,4)P 2 is an apical identity determinant.
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Román-Fernández Á, Roignot J, Sandilands E, Nacke M, Mansour MA, McGarry L, Shanks E, Mostov KE, and Bryant DM
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- Animals, Dogs, Endosomes metabolism, Intracellular Membranes metabolism, Madin Darby Canine Kidney Cells, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases metabolism, Phosphatidylinositols metabolism
- Abstract
Apical-basal polarization is essential for epithelial tissue formation, segregating cortical domains to perform distinct physiological functions. Cortical lipid asymmetry has emerged as a determinant of cell polarization. We report a network of phosphatidylinositol phosphate (PIP)-modifying enzymes, some of which are transcriptionally induced upon embedding epithelial cells in extracellular matrix, and that are essential for apical-basal polarization. Unexpectedly, we find that PI(3,4)P
2 localization and function is distinct from the basolateral determinant PI(3,4,5)P3 . PI(3,4)P2 localizes to the apical surface, and Rab11a-positive apical recycling endosomes. PI(3,4)P2 is produced by the 5-phosphatase SHIP1 and Class-II PI3-Kinases to recruit the endocytic regulatory protein SNX9 to basolateral domains that are being remodeled into apical surfaces. Perturbing PI(3,4)P2 levels results in defective polarization through subcortical retention of apically destined vesicles at apical membrane initiation sites. We conclude that PI(3,4)P2 is a determinant of apical membrane identity.- Published
- 2018
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41. A functional genomics screen reveals a strong synergistic effect between docetaxel and the mitotic gene DLGAP5 that is mediated by the androgen receptor.
- Author
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Hewit K, Sandilands E, Martinez RS, James D, Leung HY, Bryant DM, Shanks E, and Markert EK
- Subjects
- Benzamides, Cdc20 Proteins genetics, Cell Cycle Proteins genetics, Cell Proliferation drug effects, Drug Resistance, Neoplasm drug effects, Gene Knockdown Techniques, Humans, Male, Metaphase, Microtubule-Associated Proteins genetics, Nitriles, PC-3 Cells, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin pharmacology, Receptors, Androgen genetics, Transfection, Docetaxel pharmacology, Genomics methods, Neoplasm Proteins genetics, Prostatic Neoplasms genetics, Receptors, Androgen metabolism
- Abstract
Based on a molecular classification of prostate cancer using gene expression pathway signatures, we derived a set of 48 genes in critical pathways that significantly predicts clinical outcome in all tested patient cohorts. We tested these genes in a functional genomics screen in a panel of three prostate cancer cell lines (LNCaP, PC3, DU145), using RNA interference. The screen revealed several genes whose knockdown caused strong growth inhibition in all cell lines. Additionally, we tested the gene set in the presence of docetaxel to see whether any gene exhibited additive or synergistic effects with the drug. We observed a strong synergistic effect between DLGAP5 knockdown and docetaxel in the androgen-sensitive line LNCaP, but not in the two other androgen-independent lines. We then tested whether this effect was connected to androgen pathways and found that knockdown of the androgen receptor by si-RNA attenuated the synergy significantly. Similarly, androgen desensitized LNCaP-AI cells had a higher IC
50 to docetaxel and did not exhibit the synergistic interaction. Short-term exposure to enzalutamide did not significantly alter the behaviour of parental LNCaP cells. An immunofluorescence analysis in LNCaP cells suggests that under the double insult of DLGAP5 knockdown and docetaxel, cells predominantly arrest in metaphase. In contrast, the knockdown of the androgen receptor by siRNA appears to assist cells to progress through metaphase in to anaphase, even in the presence of docetaxel. Our data suggest that DLGAP5 has a unique function in stabilizing spindle formation and surviving microtubule assault from docetaxel, in an androgen-regulated cell cycle system.- Published
- 2018
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42. Investigating the role of mGluR2 versus mGluR3 in antipsychotic-like effects, sleep-wake architecture and network oscillatory activity using novel Han Wistar rats lacking mGluR2 expression.
- Author
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Wood CM, Wafford KA, McCarthy AP, Hewes N, Shanks E, Lodge D, and Robinson ESJ
- Subjects
- Amino Acids pharmacology, Amphetamine antagonists & inhibitors, Amphetamine pharmacology, Animals, Bridged Bicyclo Compounds pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cyclohexanes pharmacology, Dose-Response Relationship, Drug, Excitatory Amino Acid Agonists pharmacology, Gamma Rhythm drug effects, Gamma Rhythm physiology, Locomotion drug effects, Locomotion physiology, Male, Motor Activity drug effects, Motor Activity physiology, Mutation, Phencyclidine antagonists & inhibitors, Phencyclidine pharmacology, Rats, Receptors, Metabotropic Glutamate deficiency, Receptors, Metabotropic Glutamate genetics, Sleep drug effects, Theta Rhythm drug effects, Theta Rhythm physiology, Antipsychotic Agents pharmacology, Receptors, Metabotropic Glutamate physiology, Sleep physiology, Wakefulness drug effects, Wakefulness physiology
- Abstract
Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are implicated in a number of psychiatric disorders. They also control sleep-wake architecture and may offer novel therapeutic targets. However, the roles of the mGluR2 versus mGluR3 subtypes are not well understood. Here, we have taken advantage of the recently described mutant strain of Han Wistar rats, which do not express mGluR2 receptors, to investigate behavioural, sleep and EEG responses to mGluR2/3 ligands. The mGluR2/3 agonist, LY354740 (10 mg/kg), reversed amphetamine- and phencyclidine-induced locomotion and rearing behaviours in control Wistar but not in mGluR2 lacking Han Wistar rats. In control Wistar but not in Han Wistar rats the mGluR2/3 agonist LY379268 (3 & 10 mg/kg) induced REM sleep suppression with dose-dependent effects on wake and NREM sleep. By contrast, the mGluR2/3 antagonist LY3020371 (3 & 10 mg/kg) had wake-promoting effects in both rat strains, albeit smaller in the mGluR2-lacking Han Wistar rats, indicating both mGluR2 and mGluR3-mediated effects on wakefulness. LY3020371 enhanced wake cortical oscillations in the theta (4-9 Hz) and gamma (30-80 Hz) range in both Wistar and Han Wistar rat strains, whereas LY379268 reduced theta and gamma oscillations in control Wistar rats, with minimal effects in Han Wistar rats. Together these studies illustrate the significant contribution of mGluR2 to the antipsychotic-like, sleep and EEG effects of drugs acting on group II mGluRs. However, we also provide evidence of a role for mGluR3 activity in the control of sleep and wake cortical theta and gamma oscillations., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
43. Harnessing synthetic lethality to predict the response to cancer treatment.
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Lee JS, Das A, Jerby-Arnon L, Arafeh R, Auslander N, Davidson M, McGarry L, James D, Amzallag A, Park SG, Cheng K, Robinson W, Atias D, Stossel C, Buzhor E, Stein G, Waterfall JJ, Meltzer PS, Golan T, Hannenhalli S, Gottlieb E, Benes CH, Samuels Y, Shanks E, and Ruppin E
- Subjects
- Animals, Biomarkers, Pharmacological, Cell Hypoxia, Cell Line, Tumor, Drug Combinations, Drug Synergism, Humans, Mice, Neoplasms diagnosis, Neoplasms genetics, Neoplasms mortality, Patient Selection, Precision Medicine statistics & numerical data, Xenograft Model Antitumor Assays, Antineoplastic Agents therapeutic use, High-Throughput Screening Assays, Neoplasms drug therapy, Precision Medicine methods, Synthetic Lethal Mutations drug effects
- Abstract
While synthetic lethality (SL) holds promise in developing effective cancer therapies, SL candidates found via experimental screens often have limited translational value. Here we present a data-driven approach, ISLE (identification of clinically relevant synthetic lethality), that mines TCGA cohort to identify the most likely clinically relevant SL interactions (cSLi) from a given candidate set of lab-screened SLi. We first validate ISLE via a benchmark of large-scale drug response screens and by predicting drug efficacy in mouse xenograft models. We then experimentally test a select set of predicted cSLi via new screening experiments, validating their predicted context-specific sensitivity in hypoxic vs normoxic conditions and demonstrating cSLi's utility in predicting synergistic drug combinations. We show that cSLi can successfully predict patients' drug treatment response and provide patient stratification signatures. ISLE thus complements existing actionable mutation-based methods for precision cancer therapy, offering an opportunity to expand its scope to the whole genome.
- Published
- 2018
- Full Text
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44. Targeting BCR-ABL-Independent TKI Resistance in Chronic Myeloid Leukemia by mTOR and Autophagy Inhibition.
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Mitchell R, Hopcroft LEM, Baquero P, Allan EK, Hewit K, James D, Hamilton G, Mukhopadhyay A, O'Prey J, Hair A, Melo JV, Chan E, Ryan KM, Maguer-Satta V, Druker BJ, Clark RE, Mitra S, Herzyk P, Nicolini FE, Salomoni P, Shanks E, Calabretta B, Holyoake TL, and Helgason GV
- Subjects
- Animals, Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Female, Fusion Proteins, bcr-abl genetics, Humans, Imatinib Mesylate administration & dosage, Imidazoles administration & dosage, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Mice, Molecular Targeted Therapy methods, Pyridazines administration & dosage, Pyrimidines administration & dosage, Quinolines administration & dosage, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Autophagy drug effects, Drug Resistance, Neoplasm drug effects, Fusion Proteins, bcr-abl antagonists & inhibitors, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Protein Kinase Inhibitors therapeutic use, TOR Serine-Threonine Kinases antagonists & inhibitors
- Abstract
Background: Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment. By modeling ponatinib resistance and testing samples from these CML patients, it is hoped that an alternative drug target can be identified and inhibited with a novel compound., Methods: Two CML cell lines with acquired BCR-ABL-independent resistance were generated following culture in ponatinib. RNA sequencing and gene ontology (GO) enrichment were used to detect aberrant transcriptional response in ponatinib-resistant cells. A validated oncogene drug library was used to identify US Food and Drug Administration-approved drugs with activity against TKI-resistant cells. Validation was performed using bone marrow (BM)-derived cells from TKI-resistant patients (n = 4) and a human xenograft mouse model (n = 4-6 mice per group). All statistical tests were two-sided., Results: We show that ponatinib-resistant CML cells can acquire BCR-ABL-independent resistance mediated through alternative activation of mTOR. Following transcriptomic analysis and drug screening, we highlight mTOR inhibition as an alternative therapeutic approach in TKI-resistant CML cells. Additionally, we show that catalytic mTOR inhibitors induce autophagy and demonstrate that genetic or pharmacological inhibition of autophagy sensitizes ponatinib-resistant CML cells to death induced by mTOR inhibition in vitro (% number of colonies of control[SD], NVP-BEZ235 vs NVP-BEZ235+HCQ: 45.0[17.9]% vs 24.0[8.4]%, P = .002) and in vivo (median survival of NVP-BEZ235- vs NVP-BEZ235+HCQ-treated mice: 38.5 days vs 47.0 days, P = .04)., Conclusion: Combined mTOR and autophagy inhibition may provide an attractive approach to target BCR-ABL-independent mechanism of resistance.
- Published
- 2018
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45. Tablet-Based Application for Objective Measurement of Motor Fluctuations in Parkinson Disease.
- Author
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Wissel BD, Mitsi G, Dwivedi AK, Papapetropoulos S, Larkin S, López Castellanos JR, Shanks E, Duker AP, Rodriguez-Porcel F, Vaughan JE, Lovera L, Tsoulos I, Stavrakoudis A, and Espay AJ
- Abstract
Background: The motor subscale of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) has limited applicability for the assessment of motor fluctuations in the home setting., Methods: To assess whether a self-administered, tablet-based application can reliably quantify differences in motor performance using two-target finger tapping and forearm pronation-supination tasks in the ON (maximal dopaminergic medication efficacy) and OFF (reemergence of parkinsonian deficits) medication states, we recruited 11 Parkinson disease (PD) patients (age, 60.6 ± 9.0 years; disease duration, 12.8 ± 4.1 years) and 11 healthy age-matched controls (age, 62.5 ± 10.5 years). The total number of taps, tap interval, tap duration, and tap accuracy were algorithmically calculated by the application, using the more affected side in patients and the dominant hand in healthy controls., Results: Compared to the OFF state, PD patients showed a higher number of taps (84.2 ± 20.3 vs. 54.9 ± 26.9 taps; p = 0.0036) and a shorter tap interval (375.3 ± 97.2 vs. 708.2 ± 412.8 ms; p = 0.0146) but poorer tap accuracy (2,008.4 ± 995.7 vs. 1,111.8 ± 901.3 pixels; p = 0.0055) for the two-target task in the ON state, unaffected by the magnitude of coexistent dyskinesia. Overall, test-retest reliability was high ( r >0.75) and the discriminatory ability between OFF and ON states was good (0.60 ≤ AUC ≤ 0.82). The correlations between tapping data and MDS-UPDRS-III scores were only moderate (-0.55 to 0.55)., Conclusions: A self-administered, tablet-based application can reliably distinguish between OFF and ON states in fluctuating PD patients and may be sensitive to additional motor phenomena, such as accuracy, not captured by the MDS-UPDRS-III., Competing Interests: B.D.W. is supported by the NIH (T32GM063483-14). G.M. is the founder and CEO of Apptomics, Inc. A.K.D. is supported by the NIH as a co-investigator (1R01HL125016-01) and as a collaborator (R21 AI118228). He has also been serving as a statistician in 4 CPRIT grants (PP110156, PP140211, PP150031, and PP130083), Coldwell (co-investigator), and MSA Coalition (collaborator) and as a principal investigator in a TTUHSC ELP mini seed grant. He is a director of biostatistics and epidemiology consulting laboratory at the TTUHSC ELP. S.P. is a full-time employee at TEVA Pharmaceuticals and co-chair of the Task Force on Technology for the International Parkinson and Movement Disorder Society. S.K., J.R.L.C., and E.S. have nothing to disclose. A.P.D. has served as a consultant for Merz Pharma, US WorldMeds, and Auspex Pharmaceuticals and has received honoraria from UCB. F.R.-P., J.V., L.L., I.T., and A.S. have nothing to disclose. A.J.E. is the chair of the Task Force on Technology for the International Parkinson and Movement Disorder Society, is supported by the NIH, and has received grant support from Cleveland Medical Devices Inc./Great Lakes NeuroTechnologies, the Davis Phinney Foundation, and the Michael J. Fox Foundation; personal compensation as a consultant/scientific advisory board member for Solvay, Abbott, Chelsea Therapeutics, TEVA, Impax, Merz, Lundbeck, and Eli Lilly; honoraria from TEVA, UCB, the American Academy of Neurology, and the Movement Disorder Society; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. He has no financial interests in, nor has received compensation from, iMotor or Apptomics, Inc., (Copyright © 2018 by S. Karger AG, Basel.)
- Published
- 2018
- Full Text
- View/download PDF
46. REM sleep homeostasis in the absence of REM sleep: Effects of antidepressants.
- Author
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McCarthy A, Wafford K, Shanks E, Ligocki M, Edgar DM, and Dijk DJ
- Subjects
- Animals, Antidepressive Agents, Tricyclic pharmacology, Male, Rats, Rats, Wistar, Selective Serotonin Reuptake Inhibitors pharmacology, Antidepressive Agents pharmacology, Homeostasis drug effects, Homeostasis physiology, Sleep, REM drug effects, Sleep, REM physiology
- Abstract
Most antidepressants suppress rapid eye movement (REM) sleep, which is thought to be important to brain function, yet the resulting REM sleep restriction is well tolerated. This study investigated the impact of antidepressants with different mechanisms of action, such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCA), on the regulation of REM sleep in rats. REM sleep was first demonstrated to be homeostatically regulated using 5, 8 and 10 h of REM-sleep specific restriction through EEG-triggered arousals, with an average of 91 ± 10% of lost REM sleep recovered following a 26-29 -hour recovery period. Acute treatment with the antidepressants paroxetine, citalopram and imipramine inhibited REM sleep by 84 ± 8, 84 ± 8 and 69 ± 9% respectively relative to vehicle control. The pharmacologically-induced REM sleep deficits by paroxetine and citalopram were not fully recovered, whereas, after imipramine the REM sleep deficit was fully compensated. Given the marked difference between REM sleep recovery following the administration of paroxetine, citalopram, imipramine and REM sleep restriction, the homeostatic response was further examined by pairing REM sleep specific restriction with the three antidepressants. Surprisingly, the physiologically-induced REM sleep deficits incurred prior to suppression of REM sleep by all antidepressants was consistently recovered. The data indicate that REM sleep homeostasis remains operative following subsequent treatment with antidepressants and is unaffected by additional pharmacological inhibition of REM sleep., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
47. Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments.
- Author
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Peck B, Schug ZT, Zhang Q, Dankworth B, Jones DT, Smethurst E, Patel R, Mason S, Jiang M, Saunders R, Howell M, Mitter R, Spencer-Dene B, Stamp G, McGarry L, James D, Shanks E, Aboagye EO, Critchlow SE, Leung HY, Harris AL, Wakelam MJO, Gottlieb E, and Schulze A
- Abstract
Background: Enhanced macromolecule biosynthesis is integral to growth and proliferation of cancer cells. Lipid biosynthesis has been predicted to be an essential process in cancer cells. However, it is unclear which enzymes within this pathway offer the best selectivity for cancer cells and could be suitable therapeutic targets., Results: Using functional genomics, we identified stearoyl-CoA desaturase (SCD), an enzyme that controls synthesis of unsaturated fatty acids, as essential in breast and prostate cancer cells. SCD inhibition altered cellular lipid composition and impeded cell viability in the absence of exogenous lipids. SCD inhibition also altered cardiolipin composition, leading to the release of cytochrome C and induction of apoptosis. Furthermore, SCD was required for the generation of poly-unsaturated lipids in cancer cells grown in spheroid cultures, which resemble those found in tumour tissue. We also found that SCD mRNA and protein expression is elevated in human breast cancers and predicts poor survival in high-grade tumours. Finally, silencing of SCD in prostate orthografts efficiently blocked tumour growth and significantly increased animal survival., Conclusions: Our data implicate lipid desaturation as an essential process for cancer cell survival and suggest that targeting SCD could efficiently limit tumour expansion, especially under the metabolically compromised conditions of the tumour microenvironment.
- Published
- 2016
- Full Text
- View/download PDF
48. LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation.
- Author
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Mardilovich K, Baugh M, Crighton D, Kowalczyk D, Gabrielsen M, Munro J, Croft DR, Lourenco F, James D, Kalna G, McGarry L, Rath O, Shanks E, Garnett MJ, McDermott U, Brookfield J, Charles M, Hammonds T, and Olson MF
- Subjects
- Breast Neoplasms drug therapy, Breast Neoplasms enzymology, Breast Neoplasms pathology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cell Proliferation drug effects, Female, Humans, Lung Neoplasms drug therapy, Lung Neoplasms enzymology, Lung Neoplasms pathology, MCF-7 Cells, Microtubules metabolism, Mitosis physiology, Neoplasms enzymology, Neuroblastoma drug therapy, Neuroblastoma enzymology, Neuroblastoma pathology, Lim Kinases antagonists & inhibitors, Mitosis drug effects, Neoplasms drug therapy, Neoplasms pathology
- Abstract
The actin and microtubule cytoskeletons are critically important for cancer cell proliferation, and drugs that target microtubules are widely-used cancer therapies. However, their utility is compromised by toxicities due to dose and exposure. To overcome these issues, we characterized how inhibition of the actin and microtubule cytoskeleton regulatory LIM kinases could be used in drug combinations to increase efficacy. A previously-described LIMK inhibitor (LIMKi) induced dose-dependent microtubule alterations that resulted in significant mitotic defects, and increased the cytotoxic potency of microtubule polymerization inhibitors. By combining LIMKi with 366 compounds from the GSK Published Kinase Inhibitor Set, effective combinations were identified with kinase inhibitors including EGFR, p38 and Raf. These findings encouraged a drug discovery effort that led to development of CRT0105446 and CRT0105950, which potently block LIMK1 and LIMK2 activity in vitro, and inhibit cofilin phosphorylation and increase αTubulin acetylation in cells. CRT0105446 and CRT0105950 were screened against 656 cancer cell lines, and rhabdomyosarcoma, neuroblastoma and kidney cancer cells were identified as significantly sensitive to both LIMK inhibitors. These large-scale screens have identified effective LIMK inhibitor drug combinations and sensitive cancer types. In addition, the LIMK inhibitory compounds CRT0105446 and CRT0105950 will enable further development of LIMK-targeted cancer therapy.
- Published
- 2015
- Full Text
- View/download PDF
49. Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy.
- Author
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Miller BW, Morton JP, Pinese M, Saturno G, Jamieson NB, McGhee E, Timpson P, Leach J, McGarry L, Shanks E, Bailey P, Chang D, Oien K, Karim S, Au A, Steele C, Carter CR, McKay C, Anderson K, Evans TR, Marais R, Springer C, Biankin A, Erler JT, and Sansom OJ
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Carcinoma, Pancreatic Ductal drug therapy, Deoxycytidine analogs & derivatives, Deoxycytidine therapeutic use, Humans, Hypoxia, Mice, Neoplasm Metastasis prevention & control, Protein-Lysine 6-Oxidase antagonists & inhibitors, Treatment Outcome, Gemcitabine, Carcinoma, Pancreatic Ductal pathology, Pancreatic Neoplasms pathology, Protein-Lysine 6-Oxidase metabolism
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1-Cre Kras(G12D/+) Trp53(R172H/+) (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor-free survival in KPC mice with early-stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease., (© 2015 Cancer Research UK Beatson Institute. Published under the terms of the CC BY 4.0 license.)
- Published
- 2015
- Full Text
- View/download PDF
50. Academic drug discovery within the United Kingdom: a reassessment.
- Author
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Shanks E, Ketteler R, and Ebner D
- Subjects
- Humans, Drug Discovery organization & administration, Universities organization & administration
- Published
- 2015
- Full Text
- View/download PDF
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