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309 MYC Inhibition Overcomes IMiD Resistance in Heterogeneous Multiple Myeloma Populations
- Lorraine Davis, Zachary J. Walker, Denis Ohlstrom, Brett M. Stevens, Peter A. Forsberg, Tomer M. Mark, Craig T. Jordan, Daniel W. Sherbenou
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- Journal:
- Journal of Clinical and Translational Science / Volume 6 / Issue s1 / April 2022
- Published online by Cambridge University Press:
- 19 April 2022, p. 54
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OBJECTIVES/GOALS: Immunomodulatory drugs (IMiDs) are critical to multiple myeloma (MM) disease control. IMiDs act by inducing Cereblon-dependent degradation of IKZF1 and IKZF3, which leads to IRF4 and MYC downregulation (collectively termed the “Ikaros axis”). We therefore hypothesized that IMiD treatment fails to downregulate the Ikaros axis in IMiD resistant MM. METHODS/STUDY POPULATION: To measure IMiD-induced Ikaros axis downregulation, we designed an intracellular flow cytometry assay that measured relative protein levels of IKZF1, IKZF3, IRF4 and MYC in MM cells following ex vivo treatment with the IMiD Pomalidomide (Pom). We established this assay using Pom-sensitive parental and dose-escalated Pom-resistant MM cell lines before assessing Ikaros axis downregulation in CD38+CD138+ MM cells in patient samples (bone marrow aspirates). To assess the Ikaros axis in the context of MM intratumoral heterogeneity, we used a 35-marker mass cytometry panel to simultaneously characterize MM subpopulations in patient samples. Lastly, we determined ex vivo drug sensitivity in patient samples via flow cytometry. RESULTS/ANTICIPATED RESULTS: Our hypothesis was supported in MM cell lines, as resistant lines showed no IMiD-induced decrease in any Ikaros axis proteins. However, when assessed in patient samples, Pom treatment caused a significant decrease in IKZF1, IKZF3 and IRF4 regardless of IMiD sensitivity. Mass cytometry in patient samples revealed that individual Ikaros axis proteins were differentially expressed between subpopulations. When correlating this with ex vivo Pom sensitivity of MM subpopulations, we observed that low IKZF1 and IKZF3 corresponded to Pom resistance. Interestingly, most of these resistant populations still expressed MYC. We therefore assessed whether IMiD resistant MM was MYC dependent by treating with MYCi975. In 88% (7/8) of patient samples tested, IMiD resistant MM cells were sensitive to MYC inhibition. DISCUSSION/SIGNIFICANCE: While our findings did not support our initial hypothesis, our data suggest a mechanism where MYC expression becomes Ikaros axis independent to drive IMiD resistance, and resistant MM is still dependent on MYC. This suggests targeting MYC directly or indirectly via a mechanism to be determined may be an effective strategy to eradicate IMiD resistant MM.
Characterisation of age and polarity at onset in bipolar disorder
- Janos L. Kalman, Loes M. Olde Loohuis, Annabel Vreeker, Andrew McQuillin, Eli A. Stahl, Douglas Ruderfer, Maria Grigoroiu-Serbanescu, Georgia Panagiotaropoulou, Stephan Ripke, Tim B. Bigdeli, Frederike Stein, Tina Meller, Susanne Meinert, Helena Pelin, Fabian Streit, Sergi Papiol, Mark J. Adams, Rolf Adolfsson, Kristina Adorjan, Ingrid Agartz, Sofie R. Aminoff, Heike Anderson-Schmidt, Ole A. Andreassen, Raffaella Ardau, Jean-Michel Aubry, Ceylan Balaban, Nicholas Bass, Bernhard T. Baune, Frank Bellivier, Antoni Benabarre, Susanne Bengesser, Wade H Berrettini, Marco P. Boks, Evelyn J. Bromet, Katharina Brosch, Monika Budde, William Byerley, Pablo Cervantes, Catina Chillotti, Sven Cichon, Scott R. Clark, Ashley L. Comes, Aiden Corvin, William Coryell, Nick Craddock, David W. Craig, Paul E. Croarkin, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Udo Dannlowski, Franziska Degenhardt, Maria Del Zompo, J. Raymond DePaulo, Srdjan Djurovic, Howard J. Edenberg, Mariam Al Eissa, Torbjørn Elvsåshagen, Bruno Etain, Ayman H. Fanous, Frederike Fellendorf, Alessia Fiorentino, Andreas J. Forstner, Mark A. Frye, Janice M. Fullerton, Katrin Gade, Julie Garnham, Elliot Gershon, Michael Gill, Fernando S. Goes, Katherine Gordon-Smith, Paul Grof, Jose Guzman-Parra, Tim Hahn, Roland Hasler, Maria Heilbronner, Urs Heilbronner, Stephane Jamain, Esther Jimenez, Ian Jones, Lisa Jones, Lina Jonsson, Rene S. Kahn, John R. Kelsoe, James L. Kennedy, Tilo Kircher, George Kirov, Sarah Kittel-Schneider, Farah Klöhn-Saghatolislam, James A. Knowles, Thorsten M. Kranz, Trine Vik Lagerberg, Mikael Landen, William B. Lawson, Marion Leboyer, Qingqin S. Li, Mario Maj, Dolores Malaspina, Mirko Manchia, Fermin Mayoral, Susan L. McElroy, Melvin G. McInnis, Andrew M. McIntosh, Helena Medeiros, Ingrid Melle, Vihra Milanova, Philip B. Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Markus M. Nöthen, Tomas Novak, John I. Nurnberger, Niamh O'Brien, Kevin S. O'Connell, Claire O'Donovan, Michael C. O'Donovan, Nils Opel, Abigail Ortiz, Michael J. Owen, Erik Pålsson, Carlos Pato, Michele T. Pato, Joanna Pawlak, Julia-Katharina Pfarr, Claudia Pisanu, James B. Potash, Mark H Rapaport, Daniela Reich-Erkelenz, Andreas Reif, Eva Reininghaus, Jonathan Repple, Hélène Richard-Lepouriel, Marcella Rietschel, Kai Ringwald, Gloria Roberts, Guy Rouleau, Sabrina Schaupp, William A Scheftner, Simon Schmitt, Peter R. Schofield, K. Oliver Schubert, Eva C. Schulte, Barbara Schweizer, Fanny Senner, Giovanni Severino, Sally Sharp, Claire Slaney, Olav B. Smeland, Janet L. Sobell, Alessio Squassina, Pavla Stopkova, John Strauss, Alfonso Tortorella, Gustavo Turecki, Joanna Twarowska-Hauser, Marin Veldic, Eduard Vieta, John B. Vincent, Wei Xu, Clement C. Zai, Peter P. Zandi, Psychiatric Genomics Consortium (PGC) Bipolar Disorder Working Group, International Consortium on Lithium Genetics (ConLiGen), Colombia-US Cross Disorder Collaboration in Psychiatric Genetics, Arianna Di Florio, Jordan W. Smoller, Joanna M. Biernacka, Francis J. McMahon, Martin Alda, Bertram Müller-Myhsok, Nikolaos Koutsouleris, Peter Falkai, Nelson B. Freimer, Till F.M. Andlauer, Thomas G. Schulze, Roel A. Ophoff
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- Journal:
- The British Journal of Psychiatry / Volume 219 / Issue 6 / December 2021
- Published online by Cambridge University Press:
- 25 August 2021, pp. 659-669
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- December 2021
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Background
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
AimsTo examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
MethodGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
ResultsEarlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
ConclusionsAAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Unexpected circular radio objects at high Galactic latitude
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- Ray P. Norris, Huib T. Intema, Anna D. Kapińska, Bärbel S. Koribalski, Emil Lenc, L. Rudnick, Rami Z. E. Alsaberi, Craig Anderson, G. E. Anderson, E. Crawford, Roland Crocker, Jayanne English, Miroslav D. Filipović, Tim J. Galvin, Andrew M. Hopkins, Natasha Hurley-Walker, Susumu Inoue, Kieran Luken, Peter J. Macgregor, Pero Manojlović, Josh Marvil, Andrew N. O’Brien, Laurence Park, Wasim Raja, Devika Shobhana, Tiziana Venturi, Jordan D. Collier, Catherine Hale, Aidan Hotan, Vanessa Moss, Matthew Whiting
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- Journal:
- Publications of the Astronomical Society of Australia / Volume 38 / 2021
- Published online by Cambridge University Press:
- 18 January 2021, e003
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We have found a class of circular radio objects in the Evolutionary Map of the Universe Pilot Survey, using the Australian Square Kilometre Array Pathfinder telescope. The objects appear in radio images as circular edge-brightened discs, about one arcmin diameter, that are unlike other objects previously reported in the literature. We explore several possible mechanisms that might cause these objects, but none seems to be a compelling explanation.
Long-term treatment leads to reduction of tree-of-heaven (Ailanthus altissima) populations in the Buffalo National River
- Craig C. Young, Jordan C. Bell, Lloyd W. Morrison
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- Journal:
- Invasive Plant Science and Management / Volume 13 / Issue 4 / December 2020
- Published online by Cambridge University Press:
- 14 October 2020, pp. 276-281
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In this case study, we used point mapping data to evaluate long-term treatment of invasive tree-of-heaven [Ailanthus altissima (Mill.) Swingle]. This study at the Buffalo National River included 21 project areas ranging in size from 0.02 to 11.3 ha and spanned 5 to 8 yr depending on the site. The control techniques varied depending on the year and included the application of herbicide, which also varied over the course of the study and included imazapyr, triclopyr, and triclopyr+fluroxypyr. Treatments during the first year reduced local A. altissima populations by an average of 66%. Long-term repeated treatments led to decreases of at least 90% in 70% of the project areas and at least 73% in 95% of the project areas. Only one project area was found to support no plants during the final treatment year. Ailanthus altissima increased at most project areas during an unusually wet year and was more likely to increase than decrease in intervals >1 yr with no treatment. Over the temporal and spatial scales of this case study, we observed high levels of control that will likely meet the specified levels and ecological benefits required in many similar efforts. Land managers must, however, make a long-term commitment of resources to achieve lasting control of this invasive species.
4353 The Role of BCL2 Mediated Calcium Signaling on Leukemia Stem Cell Metabolism
- Anagha Inguva, Shanshan Pei, Maria Amaya, Brett Stevens, Courtney Jones, Daniel Pollyea, Craig Jordan
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- Journal:
- Journal of Clinical and Translational Science / Volume 4 / Issue s1 / June 2020
- Published online by Cambridge University Press:
- 29 July 2020, p. 19
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OBJECTIVES/GOALS: The objective of this study is to define the molecular mechanisms that control survival of malignant stem cells in acute myeloid leukemia (AML). Leukemia stem cells (LSCs) are not effectively eradicated by standard treatment and lead to resistance and relapse, which contribute to poor survival rates. METHODS/STUDY POPULATION: The recently FDA approved venetoclax, a BCL2 inhibitor, with azacitidine, a hypomethylating agent leads to a 70% response rate in AML patients. Analysis of patients treated with this regimen showed direct targeting of LSCs. BCL2 has a non-canonical function in regulation of intracellular calcium. To determine how BCL2 mediated calcium signaling plays a role in LSC biology, we used LSCs isolated from venetoclax/azacitidine (ven/aza) sensitive and resistant patient samples to measure expression of calcium channels via RNA seq. BIO-ID, siRNA, flow cytometry, seahorse assays, calcium measurements and colony assays were used to determine the effects of calcium channel perturbation on LSC biology. RESULTS/ANTICIPATED RESULTS: BCL2 inhibition leads to decreased OXPHOS activity in primary AML specimens. BIO-ID studies revealed cation/metal ion transporters, ER membrane proteins and ER membrane organization as top enriched pathways interacting with BCL2. RNA-seq data showed increased expression of genes involved in calcium influx into the ER in ven/aza sensitive LSCs and increased expression of genes involved in calcium efflux from the ER in ven/aza resistant samples. Ven/Aza resistant LSCs have increased mitochondrial calcium content, consistent with their increased OXPHOS activity as calcium is required for OXPHOS. Perturbation of these channels leads to decreased OXPHOS activity and decreased viability in LSCs. DISCUSSION/SIGNIFICANCE OF IMPACT: We postulate that a deeper understanding of the mechanisms behind ven/aza targeting of LSCs will lead to the development of novel therapies for patients who do not respond to ven/aza. Our data show targeting intracellular calcium signaling could be a viable therapeutic strategy for AML patients.
A National Spinal Muscular Atrophy Registry for Real-World Evidence
- Victoria L. Hodgkinson, Maryam Oskoui, Joshua Lounsberry, Saïd M’Dahoma, Emily Butler, Craig Campbell, Alex MacKenzie, Hugh J. McMillan, Louise Simard, Jiri Vajsar, Bernard Brais, Kristine M. Chapman, Nicolas Chrestian, Meghan Crone, Peter Dobrowolski, Susan Dojeiji, James J. Dowling, Nicolas Dupré, Angela Genge, Hernan Gonorazky, Simona Hasal, Aaron Izenberg, Wendy Johnston, Edward Leung, Hanns Lochmüller, Jean K. Mah, Alier Marerro, Rami Massie, Laura McAdam, Anna McCormick, Michel Melanson, Michelle M. Mezei, Cam-Tu E. Nguyen, Colleen O’Connell, Erin K. O’Ferrall, Gerald Pfeffer, Cecile Phan, Stephanie Plamondon, Chantal Poulin, Xavier Rodrigue, Kerri L. Schellenberg, Kathy Selby, Jordan Sheriko, Christen Shoesmith, Garth Smith, Monique Taillon, Sean Taylor, Jodi Warman Chardon, Scott Worley, Lawrence Korngut
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- Journal:
- Canadian Journal of Neurological Sciences / Volume 47 / Issue 6 / November 2020
- Published online by Cambridge University Press:
- 04 June 2020, pp. 810-815
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Background:
Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population.
Methods:The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials.
Results:The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner.
Conclusion:Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.
Investigating the function of prehistoric stone bowls and griddle stones in the Aleutian Islands by lipid residue analysis – CORRIGENDUM
- Marjolein Admiraal, Alexandre Lucquin, Matthew von Tersch, Peter D. Jordan, Oliver E. Craig
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- Quaternary Research / Volume 91 / Issue 3 / May 2019
- Published online by Cambridge University Press:
- 04 October 2018, p. 1075
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Investigating the function of prehistoric stone bowls and griddle stones in the Aleutian Islands by lipid residue analysis
- Marjolein Admiraal, Alexandre Lucquin, Matthew von Tersch, Peter D. Jordan, Oliver E. Craig
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- Quaternary Research / Volume 91 / Issue 3 / May 2019
- Published online by Cambridge University Press:
- 04 June 2018, pp. 1003-1015
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The earliest durable cooking technologies found in Alaska are stone bowls and griddle stones recovered from the Aleutian Islands. This article aims to identify the function of these artefacts. Molecular and chemical analyses of carbonised residues found on their surfaces confirm that these artefacts were used to process marine resources. Both artefacts have high lipid content and C:N ratios, suggesting they were used to process oily substances. Stable isotope results of individual lipids suggest that they were used to process different sets of resources within the aquatic spectrum as griddle stones have slightly more 13C-depleted lipids than stone bowls, possibly indicating more variable use. Integration of these results with archaeological and ethnographic data leads us to infer that griddle stones were used for cooking a diversity of aquatic resources, possibly with the addition of plant foods, whereas stone bowls were specifically used to render marine mammal fats. We further hypothesize that a sudden peak in stone bowl frequencies at 4000–3000 cal yr BP was connected to a Neoglacial cold spell bringing sea ice conditions to the Aleutian Islands. This may have led to new subsistence strategies in which the rendering of marine mammal fats played a central role.
Exploring the emergence of an ‘Aquatic’ Neolithic in the Russian Far East: organic residue analysis of early hunter-gatherer pottery from Sakhalin Island
- Kevin Gibbs, Sven Isaksson, Oliver E. Craig, Alexandre Lucquin, Vyacheslav A. Grishchenko, Tom F.G. Farrell, Anu Thompson, Hirofumi Kato, Alexander A. Vasilevski, Peter D. Jordan
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The Neolithic in north-east Asia is defined by the presence of ceramic containers, rather than agriculture, among hunter-gatherer communities. The role of pottery in such groups has, however, hitherto been unclear. This article presents the results of organic residue analysis of Neolithic pottery from Sakhalin Island in the Russian Far East. Results indicate that early pottery on Sakhalin was used for the processing of aquatic species, and that its adoption formed part of a wider Neolithic transition involving the reorientation of local lifeways towards the exploitation of marine resources.
Point Mapping Integrates Data Collection and Weed Control Operations
- Craig C. Young, Jordan C. Bell, Chad S. Gross, Lloyd W. Morrison, Jennifer L. Haack-Gaynor
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- Invasive Plant Science and Management / Volume 10 / Issue 1 / March 2017
- Published online by Cambridge University Press:
- 27 April 2017, pp. 33-43
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In this case study, we evaluated a point-mapping method for simultaneously collecting data while controlling three invasive woody plant species: black locust, Chinese privet, and hardy orange. The study in Arkansas Post National Memorial included seven project areas ranging in size from 2.7 to 27.3 ha and spanned six field seasons (2010 to 2015). The control techniques varied depending on plant size and always included the application of herbicide, which also varied over the course of the study to include glyphosate, imazapyr, and triclopyr. Each person responsible for controlling plants simultaneously collected global positioning system point data to estimate the foliar cover of the plants treated. The resulting data demonstrated evidence of decreases in all three plant species in most project areas during the 6-yr period. Initial increases in area treated for some species–area combinations reflected differences in the preliminary efforts required to control invasive plants in entire project areas, but by 2012 six of seven project areas were treated in their entirety. Despite a high level of reduction, in some cases, the plants persisted at low levels even during the sixth year of the project. Our findings support the ability of this method to granularly detect changes in plant abundance while simultaneously controlling invasive plants. With several acknowledged limitations, this streamlined project-based monitoring approach provides data that allow managers to assess the effectiveness of weed control treatments.
Contributors
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- By Mitchell Aboulafia, Frederick Adams, Marilyn McCord Adams, Robert M. Adams, Laird Addis, James W. Allard, David Allison, William P. Alston, Karl Ameriks, C. Anthony Anderson, David Leech Anderson, Lanier Anderson, Roger Ariew, David Armstrong, Denis G. Arnold, E. J. Ashworth, Margaret Atherton, Robin Attfield, Bruce Aune, Edward Wilson Averill, Jody Azzouni, Kent Bach, Andrew Bailey, Lynne Rudder Baker, Thomas R. Baldwin, Jon Barwise, George Bealer, William Bechtel, Lawrence C. Becker, Mark A. Bedau, Ernst Behler, José A. Benardete, Ermanno Bencivenga, Jan Berg, Michael Bergmann, Robert L. Bernasconi, Sven Bernecker, Bernard Berofsky, Rod Bertolet, Charles J. Beyer, Christian Beyer, Joseph Bien, Joseph Bien, Peg Birmingham, Ivan Boh, James Bohman, Daniel Bonevac, Laurence BonJour, William J. Bouwsma, Raymond D. Bradley, Myles Brand, Richard B. Brandt, Michael E. Bratman, Stephen E. Braude, Daniel Breazeale, Angela Breitenbach, Jason Bridges, David O. Brink, Gordon G. Brittan, Justin Broackes, Dan W. Brock, Aaron Bronfman, Jeffrey E. Brower, Bartosz Brozek, Anthony Brueckner, Jeffrey Bub, Lara Buchak, Otavio Bueno, Ann E. Bumpus, Robert W. Burch, John Burgess, Arthur W. Burks, Panayot Butchvarov, Robert E. Butts, Marina Bykova, Patrick Byrne, David Carr, Noël Carroll, Edward S. Casey, Victor Caston, Victor Caston, Albert Casullo, Robert L. Causey, Alan K. L. Chan, Ruth Chang, Deen K. Chatterjee, Andrew Chignell, Roderick M. Chisholm, Kelly J. Clark, E. J. Coffman, Robin Collins, Brian P. Copenhaver, John Corcoran, John Cottingham, Roger Crisp, Frederick J. Crosson, Antonio S. Cua, Phillip D. Cummins, Martin Curd, Adam Cureton, Andrew Cutrofello, Stephen Darwall, Paul Sheldon Davies, Wayne A. Davis, Timothy Joseph Day, Claudio de Almeida, Mario De Caro, Mario De Caro, John Deigh, C. F. Delaney, Daniel C. Dennett, Michael R. DePaul, Michael Detlefsen, Daniel Trent Devereux, Philip E. Devine, John M. Dillon, Martin C. Dillon, Robert DiSalle, Mary Domski, Alan Donagan, Paul Draper, Fred Dretske, Mircea Dumitru, Wilhelm Dupré, Gerald Dworkin, John Earman, Ellery Eells, Catherine Z. Elgin, Berent Enç, Ronald P. Endicott, Edward Erwin, John Etchemendy, C. Stephen Evans, Susan L. Feagin, Solomon Feferman, Richard Feldman, Arthur Fine, Maurice A. Finocchiaro, William FitzPatrick, Richard E. Flathman, Gvozden Flego, Richard Foley, Graeme Forbes, Rainer Forst, Malcolm R. Forster, Daniel Fouke, Patrick Francken, Samuel Freeman, Elizabeth Fricker, Miranda Fricker, Michael Friedman, Michael Fuerstein, Richard A. Fumerton, Alan Gabbey, Pieranna Garavaso, Daniel Garber, Jorge L. A. Garcia, Robert K. Garcia, Don Garrett, Philip Gasper, Gerald Gaus, Berys Gaut, Bernard Gert, Roger F. Gibson, Cody Gilmore, Carl Ginet, Alan H. Goldman, Alvin I. Goldman, Alfonso Gömez-Lobo, Lenn E. Goodman, Robert M. Gordon, Stefan Gosepath, Jorge J. E. Gracia, Daniel W. Graham, George A. Graham, Peter J. Graham, Richard E. Grandy, I. Grattan-Guinness, John Greco, Philip T. Grier, Nicholas Griffin, Nicholas Griffin, David A. Griffiths, Paul J. Griffiths, Stephen R. Grimm, Charles L. Griswold, Charles B. Guignon, Pete A. Y. Gunter, Dimitri Gutas, Gary Gutting, Paul Guyer, Kwame Gyekye, Oscar A. Haac, Raul Hakli, Raul Hakli, Michael Hallett, Edward C. Halper, Jean Hampton, R. James Hankinson, K. R. Hanley, Russell Hardin, Robert M. Harnish, William Harper, David Harrah, Kevin Hart, Ali Hasan, William Hasker, John Haugeland, Roger Hausheer, William Heald, Peter Heath, Richard Heck, John F. Heil, Vincent F. Hendricks, Stephen Hetherington, Francis Heylighen, Kathleen Marie Higgins, Risto Hilpinen, Harold T. Hodes, Joshua Hoffman, Alan Holland, Robert L. Holmes, Richard Holton, Brad W. Hooker, Terence E. Horgan, Tamara Horowitz, Paul Horwich, Vittorio Hösle, Paul Hoβfeld, Daniel Howard-Snyder, Frances Howard-Snyder, Anne Hudson, Deal W. Hudson, Carl A. Huffman, David L. Hull, Patricia Huntington, Thomas Hurka, Paul Hurley, Rosalind Hursthouse, Guillermo Hurtado, Ronald E. Hustwit, Sarah Hutton, Jonathan Jenkins Ichikawa, Harry A. Ide, David Ingram, Philip J. Ivanhoe, Alfred L. Ivry, Frank Jackson, Dale Jacquette, Joseph Jedwab, Richard Jeffrey, David Alan Johnson, Edward Johnson, Mark D. Jordan, Richard Joyce, Hwa Yol Jung, Robert Hillary Kane, Tomis Kapitan, Jacquelyn Ann K. Kegley, James A. Keller, Ralph Kennedy, Sergei Khoruzhii, Jaegwon Kim, Yersu Kim, Nathan L. King, Patricia Kitcher, Peter D. Klein, E. D. Klemke, Virginia Klenk, George L. Kline, Christian Klotz, Simo Knuuttila, Joseph J. Kockelmans, Konstantin Kolenda, Sebastian Tomasz Kołodziejczyk, Isaac Kramnick, Richard Kraut, Fred Kroon, Manfred Kuehn, Steven T. Kuhn, Henry E. Kyburg, John Lachs, Jennifer Lackey, Stephen E. Lahey, Andrea Lavazza, Thomas H. Leahey, Joo Heung Lee, Keith Lehrer, Dorothy Leland, Noah M. Lemos, Ernest LePore, Sarah-Jane Leslie, Isaac Levi, Andrew Levine, Alan E. Lewis, Daniel E. Little, Shu-hsien Liu, Shu-hsien Liu, Alan K. L. Chan, Brian Loar, Lawrence B. Lombard, John Longeway, Dominic McIver Lopes, Michael J. Loux, E. J. Lowe, Steven Luper, Eugene C. Luschei, William G. Lycan, David Lyons, David Macarthur, Danielle Macbeth, Scott MacDonald, Jacob L. Mackey, Louis H. Mackey, Penelope Mackie, Edward H. Madden, Penelope Maddy, G. B. Madison, Bernd Magnus, Pekka Mäkelä, Rudolf A. Makkreel, David Manley, William E. Mann (W.E.M.), Vladimir Marchenkov, Peter Markie, Jean-Pierre Marquis, Ausonio Marras, Mike W. Martin, A. P. Martinich, William L. McBride, David McCabe, Storrs McCall, Hugh J. McCann, Robert N. McCauley, John J. McDermott, Sarah McGrath, Ralph McInerny, Daniel J. McKaughan, Thomas McKay, Michael McKinsey, Brian P. McLaughlin, Ernan McMullin, Anthonie Meijers, Jack W. Meiland, William Jason Melanson, Alfred R. Mele, Joseph R. Mendola, Christopher Menzel, Michael J. Meyer, Christian B. Miller, David W. Miller, Peter Millican, Robert N. Minor, Phillip Mitsis, James A. Montmarquet, Michael S. Moore, Tim Moore, Benjamin Morison, Donald R. Morrison, Stephen J. Morse, Paul K. Moser, Alexander P. D. Mourelatos, Ian Mueller, James Bernard Murphy, Mark C. Murphy, Steven Nadler, Jan Narveson, Alan Nelson, Jerome Neu, Samuel Newlands, Kai Nielsen, Ilkka Niiniluoto, Carlos G. Noreña, Calvin G. Normore, David Fate Norton, Nikolaj Nottelmann, Donald Nute, David S. Oderberg, Steve Odin, Michael O’Rourke, Willard G. Oxtoby, Heinz Paetzold, George S. Pappas, Anthony J. Parel, Lydia Patton, R. P. Peerenboom, Francis Jeffry Pelletier, Adriaan T. Peperzak, Derk Pereboom, Jaroslav Peregrin, Glen Pettigrove, Philip Pettit, Edmund L. Pincoffs, Andrew Pinsent, Robert B. Pippin, Alvin Plantinga, Louis P. Pojman, Richard H. Popkin, John F. Post, Carl J. Posy, William J. Prior, Richard Purtill, Michael Quante, Philip L. Quinn, Philip L. Quinn, Elizabeth S. Radcliffe, Diana Raffman, Gerard Raulet, Stephen L. Read, Andrews Reath, Andrew Reisner, Nicholas Rescher, Henry S. Richardson, Robert C. Richardson, Thomas Ricketts, Wayne D. Riggs, Mark Roberts, Robert C. Roberts, Luke Robinson, Alexander Rosenberg, Gary Rosenkranz, Bernice Glatzer Rosenthal, Adina L. Roskies, William L. Rowe, T. M. Rudavsky, Michael Ruse, Bruce Russell, Lilly-Marlene Russow, Dan Ryder, R. M. Sainsbury, Joseph Salerno, Nathan Salmon, Wesley C. Salmon, Constantine Sandis, David H. Sanford, Marco Santambrogio, David Sapire, Ruth A. Saunders, Geoffrey Sayre-McCord, Charles Sayward, James P. Scanlan, Richard Schacht, Tamar Schapiro, Frederick F. Schmitt, Jerome B. Schneewind, Calvin O. Schrag, Alan D. Schrift, George F. Schumm, Jean-Loup Seban, David N. Sedley, Kenneth Seeskin, Krister Segerberg, Charlene Haddock Seigfried, Dennis M. Senchuk, James F. Sennett, William Lad Sessions, Stewart Shapiro, Tommie Shelby, Donald W. Sherburne, Christopher Shields, Roger A. Shiner, Sydney Shoemaker, Robert K. Shope, Kwong-loi Shun, Wilfried Sieg, A. John Simmons, Robert L. Simon, Marcus G. Singer, Georgette Sinkler, Walter Sinnott-Armstrong, Matti T. Sintonen, Lawrence Sklar, Brian Skyrms, Robert C. Sleigh, Michael Anthony Slote, Hans Sluga, Barry Smith, Michael Smith, Robin Smith, Robert Sokolowski, Robert C. Solomon, Marta Soniewicka, Philip Soper, Ernest Sosa, Nicholas Southwood, Paul Vincent Spade, T. L. S. Sprigge, Eric O. Springsted, George J. Stack, Rebecca Stangl, Jason Stanley, Florian Steinberger, Sören Stenlund, Christopher Stephens, James P. Sterba, Josef Stern, Matthias Steup, M. A. Stewart, Leopold Stubenberg, Edith Dudley Sulla, Frederick Suppe, Jere Paul Surber, David George Sussman, Sigrún Svavarsdóttir, Zeno G. Swijtink, Richard Swinburne, Charles C. Taliaferro, Robert B. Talisse, John Tasioulas, Paul Teller, Larry S. Temkin, Mark Textor, H. S. Thayer, Peter Thielke, Alan Thomas, Amie L. Thomasson, Katherine Thomson-Jones, Joshua C. Thurow, Vzalerie Tiberius, Terrence N. Tice, Paul Tidman, Mark C. Timmons, William Tolhurst, James E. Tomberlin, Rosemarie Tong, Lawrence Torcello, Kelly Trogdon, J. D. Trout, Robert E. Tully, Raimo Tuomela, John Turri, Martin M. Tweedale, Thomas Uebel, Jennifer Uleman, James Van Cleve, Harry van der Linden, Peter van Inwagen, Bryan W. Van Norden, René van Woudenberg, Donald Phillip Verene, Samantha Vice, Thomas Vinci, Donald Wayne Viney, Barbara Von Eckardt, Peter B. M. Vranas, Steven J. Wagner, William J. Wainwright, Paul E. Walker, Robert E. Wall, Craig Walton, Douglas Walton, Eric Watkins, Richard A. Watson, Michael V. Wedin, Rudolph H. Weingartner, Paul Weirich, Paul J. Weithman, Carl Wellman, Howard Wettstein, Samuel C. Wheeler, Stephen A. White, Jennifer Whiting, Edward R. Wierenga, Michael Williams, Fred Wilson, W. Kent Wilson, Kenneth P. Winkler, John F. Wippel, Jan Woleński, Allan B. Wolter, Nicholas P. Wolterstorff, Rega Wood, W. Jay Wood, Paul Woodruff, Alison Wylie, Gideon Yaffe, Takashi Yagisawa, Yutaka Yamamoto, Keith E. Yandell, Xiaomei Yang, Dean Zimmerman, Günter Zoller, Catherine Zuckert, Michael Zuckert, Jack A. Zupko (J.A.Z.)
- Edited by Robert Audi, University of Notre Dame, Indiana
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- Book:
- The Cambridge Dictionary of Philosophy
- Published online:
- 05 August 2015
- Print publication:
- 27 April 2015, pp ix-xxx
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83 - Anti-estrogens and selective estrogen-receptor modulators
- from Part 4 - Pharmacologic targeting of oncogenic pathways
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- By Ping Fan, Vincent T. Lombardi Comprehensive Cancer Center, Georgetown University, DC, USA, V. Craig Jordan, Vincent T. Lombardi Comprehensive Cancer Center, Georgetown University, DC, USA
- Edited by Edward P. Gelmann, Columbia University, New York, Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center, New York, Frank J. Rauscher, III
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- Book:
- Molecular Oncology
- Published online:
- 05 February 2015
- Print publication:
- 19 December 2013, pp 884-892
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Summary
Introduction, definitions and scope
The estrogen receptor (ER), including estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), mediates the biological effects of estrogen for the development and progression of breast cancer, and it serves as an important diagnostic and therapeutic target for prevention and treatment of breast cancer. Targeted estrogen-receptor therapy is the most successful strategy in breast cancer treatment and prevention. These endocrine therapies include aromatase inhibitors (AIs) indirectly targeting the ER that block the synthesis of estrogen from androgen in peripheral tissues and show efficacy in post-menopausal breast cancer patients. Another direct strategy is to use pure anti-estrogens (also called selective estrogen-receptor down-regulators, SERDs), such as fulvestrant, which have no agonist activity and cause degradation of the ER. Fulvestrant has been approved to treat advanced breast cancer after tamoxifen failure. The most widely used therapy for ER-positive breast cancer is selective estrogen receptor modulators (SERMs), which are synthetic molecules that bind to the ER and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the pioneering SERM, is extensively used for targeted therapy of ER-positive breast cancers, and is also approved as the first chemo-preventive agent for lowering breast cancer incidence in high-risk women. The therapeutic and preventive efficacy of tamoxifen was initially proven by a series of experiments in the laboratory that laid the foundation for its clinical use. Unfortunately, use of tamoxifen is associated with de novo and acquired resistance, and some undesirable side effects. The molecular study of resistance provides an opportunity to precisely understand the mechanism of action of SERMs, which may further help in designing new and improved SERMs. Clinical studies demonstrate that another SERM, raloxifene, which is primarily used to treat post-menopausal osteoporosis, is as effective as tamoxifen in preventing breast cancer in post-menopausal women, but with fewer side effects. Overall, these findings open a new horizon for SERMs as a class of drug which can not only be used for therapy and prevention of breast cancer, but also for various other diseases and disorders. We will provide a basic background of anti-estrogens, the current utility of the two pioneering SERMs tamoxifen and raloxifene, discuss in detail the putative mechanism of action of SERMs, and consider progress with new SERMs.
List of contributors
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- By Jimmy N. Avari, Joshua Berman, David A. Brent, Benjamin D. Brody, Carolyn Broudy, Gerard E. Bruder, Deborah L. Cabaniss, Megan S. Chesin, Melissa P. DelBello, Davangere P. Devanand, Jordan W. Eipper, Jean Endicott, Eric A. Fertuck, Michael B. First, Benicio N. Frey, Emily Gastelum, Lucas Giner, Barbara L. Gracious, David J. Hellerstein, Aerin M. Hyun, David A. Kahn, Jürgen Kayser, S. Aiden Kelly, James H. Kocsis, Robert A. Kowatch, Gonzalo Laje, Martin J. Lan, Kyle A. B. Lapidus, Frances R. Levin, Sarah H. Lisanby, J. John Mann, Sanjay J. Mathew, Patrick J. McGrath, Francis J. McMahon, Barnett S. Meyers, Luciano Minuzzi, Diana E. Moga, Philip R. Muskin, Edward V. Nunes, Maria A. Oquendo, Ramin V. Parsey, Joan Prudic, Annie E. Rabinovitch, Drew Ramsey, Steven P. Roose, Moacyr A. Rosa, Bret R. Rutherford, Roberto Sassi, Peter A. Shapiro, Margaret G. Spinelli, Barbara H. Stanley, Meir Steiner, Jonathan W. Stewart, M. Elizabeth Sublette, Craig E. Tenke, Jiuan Su Terman, Michael Terman, Michael E. Thase, Helen Verdeli, Myrna M. Weissman
- Edited by J. John Mann, Columbia University, New York
- Edited in association with Patrick J. McGrath, Columbia University, New York, Steven P. Roose, Columbia University, New York
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- Clinical Handbook for the Management of Mood Disorders
- Published online:
- 05 May 2013
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- 09 May 2013, pp vii-x
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6 - Targeting acute myelogenous leukemia stem cells
- from SECTION II - THERAPEUTIC IMPLICATIONS OF CANCER STEM CELLS
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- By Monica L. Guzman, University of Rochester School of Medicine and Dentistry, Gerrit J. Schuurhuis, VU University Medical Center, Craig T. Jordan, University of Rochester Medical Center
- Edited by William L. Farrar
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- Cancer Stem Cells
- Published online:
- 15 December 2009
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- 24 August 2009, pp 93-108
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Multi-epoch Observations of LMXBs in Early-type Galaxies
- Gregory R. Sivakoff, Andrés Jordán, Adrienne M. Juett, Craig L. Sarazin, Jimmy A. Irwin
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- Proceedings of the International Astronomical Union / Volume 1 / Issue S230 / August 2005
- Published online by Cambridge University Press:
- 12 May 2006, pp. 210-214
- Print publication:
- August 2005
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Chandra observations of early-type galaxies have resolved large populations of low-mass X-ray binaries (LMXBs) in early-type galaxies. The majority of these observations have been snapshots on the order of a day or less. In our own Galaxy, LMXBs are known to exhibit a range of luminosity and spectral variability. Multi-epoch observations of early-type galaxies are just beginning to explore the regime of variability on timescales of days to years. We present results for NGC 4365 and NGC 4697, and compare them to the Milky Way.
Clinical Infection Control in Gene Therapy: A Multidisciplinary Conference
- Martin E. Evans, Craig T. Jordan, Stephen M.W. Chang, Carol Conrad, Julie L. Gerberding, Howard L. Kaufman, C. Glen Mayhall, Jan A. Nolta, Anne M. Pilaro, Sean Sullivan, David J. Weber, Nelson A. Wivel
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- Journal:
- Infection Control & Hospital Epidemiology / Volume 21 / Issue 10 / October 2000
- Published online by Cambridge University Press:
- 02 January 2015, pp. 659-673
- Print publication:
- October 2000
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Gene therapy is being studied for the treatment of a variety of acquired and inherited disorders. Retroviruses, adeno-viruses, poxviruses, adeno-associated viruses, herpesviruses, and others are being engineered to transfer genes into humans. Treatment protocols using recombinant viruses are being introduced into clinical settings. Infection control professionals will be involved in reviewing the safety of these agents in their clinics and hospitals. To date, only a limited number of articles have been written on infection control in gene therapy, and no widely available recommendations exist from federal or private organizations to guide infection control professionals. The goals of the conference were to provide a forum where gene therapy experts could share their perspectives and experience with infection control in gene therapy and to provide an opportunity for newcomers to the field to learn about issues specific to infection control in gene therapy. Recommendations for infection control in gene therapy were proposed.
Optimisation of antioestrogen therapy: laboratory and clinical concepts
- V. Craig Jordan
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- Journal:
- Proceedings of the Royal Society of Edinburgh. Section B: Biological Sciences / Volume 95 / 1989
- Published online by Cambridge University Press:
- 05 December 2011, pp. 239-246
- Print publication:
- 1989
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Tamoxifen, a non-steroidal antioestrogen, is the first line endocrine therapy for breast cancer. Laboratory studies during the past decade have provided valuable clues to understand the mode of action of tamoxifen so that the drug can be used to its best advantage in the clinic. Animal models (carcinogen-induced rat mammary carcinoma models, spontaneous mouse mammary tumours, and athymic mice inoculated with hormone-dependent human breast cancer cell lines) all demonstrate that tamoxifen is a tumouristatic agent and long-term or indefinite therapy is required to prevent the appearance of tumours. However, when treatment is stopped, tumours appear spontaneously or can be encouraged to re-appear with oestrogen therapy. These data clearly support the view that adjuvant clinical trials with tamoxifen should employ an indefinite treatment policy or at least until the time of treatment failure. Several clinical trials organisations in Great Britain (CRC and Scottish trial) have recruited a significant number of premenopausal patients. However, unlike postmenopausal patients, long-term tamoxifen therapy of premenopausal women often causes an increase in circulating oestrogen. Since tamoxifen has been shown to be a competitive inhibitor of oestrogen action, strategies to reduce ovarian steroidogenesis (oophorectomy or Zodalex®) may provide an optimal environment to sustain the long-term effectiveness of adjuvant tamoxifen therapy.