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Vera, Hernán, und Andrew Gordon. „On How to Dissolve Racial Taboos“. Contexts 4, Nr. 4 (November 2005): 68–69. http://dx.doi.org/10.1525/ctx.2005.4.4.68.
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du Pré, Athena. „Applied Health Communication. Kevin B. Wright and Scott D. Moore [Editors]“. Health Communication 23, Nr. 5 (08.10.2008): 492–94. http://dx.doi.org/10.1080/10410230802342184.
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Renick, Timothy M. „At Variance: the Church's Argument Against Homosexual Conduct – Kevin F. Scott“. Religious Studies Review 32, Nr. 2 (April 2006): 114–15. http://dx.doi.org/10.1111/j.1748-0922.2006.00061_2.x.
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Smith, Katherine Clegg. „Applied Health Communication - Edited by Kevin B. Wright & Scott D. Moore“. Journal of Communication 59, Nr. 3 (September 2009): E21—E23. http://dx.doi.org/10.1111/j.1460-2466.2009.01450.x.
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Smith, Katherine Clegg. „Applied Health Communication - Edited by Kevin B. Wright and Scott D. Moore“. Journal of Communication 59, Nr. 4 (Dezember 2009): E28—E30. http://dx.doi.org/10.1111/j.1460-2466.2009.01466.x.
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Scott, Yvonne. „Stephen Loughman, The Lake, Yvonne Scott, Kevin Kavanagh Gallery, Dublin, February - March 2006“. Circa, Nr. 116 (2006): 82. http://dx.doi.org/10.2307/25564443.
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Heintz, Michael. „Piercing the Clouds: Lectio Divina and Preparation for Ministry ed. by Kevin Zilverberg and Scott Carl“. Antiphon: A Journal for Liturgical Renewal 26, Nr. 1 (2022): 101–4. http://dx.doi.org/10.1353/atp.2022.0010.
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Medley-Rath, Stephanie R. „Postindustrial Peasants: The Illusion of Middle-Class Prosperity - by Kevin T. Leicht and Scott T. Fitzgerald“. Sociological Inquiry 78, Nr. 1 (18.01.2008): 141–43. http://dx.doi.org/10.1111/j.1475-682x.2008.00225.x.
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Raab, Christian. „Piercing the Clouds : Lectio Divina and Preparation for Ministry ed. by Kevin Zilverberg, Scott Carl (review)“. American Benedictine Review 73, Nr. 3 (September 2022): 343–45. http://dx.doi.org/10.1353/ben.2022.a923866.
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Maxile, Horace J. „Ulysses Kay: Works for Chamber Orchestra. Metropolitan Philharmonic Orchestra, Kevin Scott, conductor. Albany Records, TROY 961, 2007.“ Journal of the Society for American Music 3, Nr. 3 (August 2009): 388–90. http://dx.doi.org/10.1017/s1752196309990022.
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Coulton, Alexander, Irene Lobon, Lavinia Spain, Andrew Rowan, Desiree Shnidrig, Scott Shepherd, Ben Shum et al. „Abstract A012: Advanced melanoma exhibits a diversity of evolutionary routes to lethality“. Cancer Research 82, Nr. 10_Supplement (15.05.2022): A012. http://dx.doi.org/10.1158/1538-7445.evodyn22-a012.
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Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR002) of the Conference Proceedings. Citation Format: Alexander Coulton, Irene Lobon, Lavinia Spain, Andrew Rowan, Desiree Shnidrig, Scott Shepherd, Ben Shum, Fiona Byrne, Lewis Au, Kim Edmonds, Ellie Carlyle, Alexandra Renn, Christina Messiou, Charlotte Spencer, Andreas M. Schmidt, Zayd Tippu, Aljosja Rogiers, Max Emmerich, Camille Gerard, Husayn Pallikonda, Cristina Naceur-Lombardelli, Floris Foijer, Hilda van den Bos, René Wardenaar, Diana Spierings, Kate Young, Lisa Pickering, Andrew Furness, Elaine Borg, Miriam Mitchison, David Moore, Mary Falzon, Ian Proctor, Ruby Stewart, Ula Mahadeva, Anna Green, James Larkin, Charles Swanton, Mariam Jamal-Hanjani, Kevin Litchfield, Samra Turajlic. Advanced melanoma exhibits a diversity of evolutionary routes to lethality [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A012.
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شيحا, زياد. „اللجوء إلى التعاون الدولي لاسترداد العائدات المتحصلة من جرائم الفساد“. Arab Researcher 2, Nr. 3 (01.10.2021): 267–88. http://dx.doi.org/10.57072/ar.v2i3.75.
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تتطلب ملفات الفساد وغسيل الأموال – الأكثر تعقيداً – بشكل عام جهوداً مضنية لإسترداد العائدات والأصول التي تعبر الحدود الوطنية. إذ من المتصور – في ظل التطور التكنولوجى وتطور وسائل الاتصال، وسهولة انتقال الأموال باستخدام عمليات التحويل التي تتم بواسطة الحاسوب المتنقل والهواتف المحمولة – أن تُرتكَب عناصر الجريمة في دول مختلفة. فعلى سبيل المثال قد تكون إحدى الشركات التي دفعت مبالغ مالية كرشوة للحصول على عقد في صالحها مقرها الرئيسي في بلد غير الذي دُفعت فيه الرشاوى، أو أن يكون الموظفون العموميون الذين قبضوا هذه المبالغ قادرون على غسل تلك الأموال في دولة ثالثة. هذا بالإضافة إلى أن القطاع المالي الدولي يشكل البيئة الخصبة إلى من يتطلع إلى غسل تلك الأموال غير المشروعة ووضع العراقيل التي تحول دون تعقبها. وقد يلعب المحامون والمحاسبون دور الوسيط بين المجرمون الذين يتطلعون لغسل الأموال المتحصلة من جرائم الفساد وبين القطاع المالي من أجل إخفاء تورطهم في صفقات معينة أو ملكيتهم لبعض الأموال[1].
[1] Jean-Pierre Brun, Larissa Gray, Kevin Stephenson, et Clive Scott, avec la participation de Nina Gidwaney Manuel de Recouvrement des Biens Mal Acquis, Un Guide pour les Praticiens, p 143.
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McLean, Roger. „The Geomorphology of the Great Barrier Reef: Development, Diversity and Change- by David Hopley, Scott G. Smithers and Kevin E. Parnell“. Geographical Research 47, Nr. 1 (März 2009): 87–89. http://dx.doi.org/10.1111/j.1745-5871.2008.00566.x.
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C. Zielinska, Anna. „David Plunkett, Scott J. Shapiro et Kevin Toh (dir.), Dimensions of normativity : new essays on metaethics and jurisprudence, Oxford, Oxford University Press, 2019.“ Revue de métaphysique et de morale N° 117, Nr. 1 (31.01.2023): 144–47. http://dx.doi.org/10.3917/rmm.231.0144.
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Waye, PhD, Laurie. „Acknowledgements“. Arbutus Review 4, Nr. 1 (01.11.2013): i—ii. http://dx.doi.org/10.18357/tar41201312705.
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Publishing a journal is the work of many people. The people listed below have been integral to the creation and production of The Arbutus Review.Teresa Dawson, Director of the Learning and Teaching Centre, who created the JournalInba Kehoe, Scholarly Communications and Copyright Officer of the Library, who shepherds the online portion of the JournalLaurie Waye, Managing Editor of the Journal and Manager of the Writing CentreMichael Lukas, Guest editor of the JournalShu-min Huang, Journal Designer and Coordinator of the Writing CentreAll submissions are reviewed blind by at least two readers. These readers are graduate students, researchers, staff, and alumni from the University of Victoria. We thank them for their valuable contributions to The Arbutus Review.Akina Umemoto Helen KennedyAnirban Kar Ilijc AlbaneseBehn Skovgaard Andersen Jennifer SmithBethany Coulthard Jonathan SchmidBrendan Boyd Judy WalshBrian Coleman Julia Serena ReadyBrian Vatne Leslie BraggCarrie Hill Linnea Gay PerryChristina Suzanne Marion SelfridgeClarise Lim Scott KouriConstance Sobsey Sheri GitelsonEmma Hughes Stephanie FieldHeike LettariWe also thank the instructors who supported their students’ submissions. Their weaving together of research into the undergraduate experience has enriched their students’ education.Dr. Alexandra D’Arcy, Department of LinguisticsDr. Charlotte Schallié, Department of Germanic and Slavic StudiesDr. Daniella Constantinescu, Department of Mechanical EngineeringDr. Jillianne Code, Faculty of EducationDr. Kevin Walby, Department of SociologyDr. Laura Cowen, Department of Mathematics and StatisticsDr. Martin Adams, Department of Pacific and Asian StudiesDr. Rustom Bhiladvala, Department of Mechanical EngineeringDr. Valerie Irvine, Faculty of Education
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Borthakur, S., P. Mande, D. Rios, P. Halvey, A. Boisvert, M. Rowe, A. Agrawal et al. „AB0019 TREATMENT OF AUTOIMMUNE AND INFLAMMATORY SKIN DISEASES USING SKIN-TARGETING BIFUNCTIONAL ANTIBODIES: A LOCALIZED IMMUNOMODULATION APPROACH“. Annals of the Rheumatic Diseases 80, Suppl 1 (19.05.2021): 1043.3–1044. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1665.
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Background:Current treatment approaches for autoimmune conditions comprise primarily of systemic immunosuppressants or cytokine blockade. The concentration of therapeutic molecules to the tissues that are the sites of autoimmune and inflammatory diseases is a promising approach with the potential to induce therapeutic benefit and avert risks associated with systemic immunotherapies. Pandion Therapeutics is developing a bifunctional antibody platform that can drive localized immune modulation by combining a “tether antibody” that targets a tissue of choice and “an effector end” that activates specific regulatory immune pathways to restore immune-homeostasis.Objectives:Here we report the engineering of a skin-tethered PD-1 agonist and a skin-tethered CD39 that inhibit T cell activation and function and deplete local ATP, respectively, modulating different arms of the immune system in a tissue specific manner.Methods:Biophysical assays were performed to characterize Skin-tethered immune effectors for drug-like properties and in vitro and in vivo assays for target binding, cellular activity and tissue specific-localization. Moreover, these bifunctionals were tested in pathway-relevant preclinical models such as Vitiligo and Contact Hypersensitivity.Results:Biophysical characterization of the bifunctional molecules showed desired drug like properties including specificity, stability, and manufacturability. The skin tethered bifunctionals showed effector activity in in vitro assays and selectively localized to the skin. Skin localization strikingly correlated with a tether-dependent efficacy compared to a non-tether control.Conclusion:We believe that this therapeutic approach has the potential to drive the resolution of cutaneous inflammation, providing an opportunity for developing new targeted therapies for autoimmune and inflammatory skin diseases.Disclosure of Interests:Susmita Borthakur Shareholder of: Pandion Therapeutics Inc., Employee of: Pandion therapeutics Inc., Purvi Mande: None declared, Daniel Rios: None declared, Patrick Halvey: None declared, Angela Boisvert: None declared, MIchael Rowe: None declared, Anisha Agrawal: None declared, Minasri Borah: None declared, Mike Cianci: None declared, Joanne L. Viney Shareholder of: Pandion therapeutics Inc., Consultant of: Harpoon, Finch, Quench, HotSpot, Employee of: Pandion Therapeutics Inc., Katalin Kis-Toth: None declared, Kevin L. Otipoby Shareholder of: Pandion Therapeutics Inc., Employee of: Pandion Therapeutics Inc., Ivan Mascanfroni: None declared, Nathan Higginson-Scott Shareholder of: Pandion Therapeutics Inc., Consultant of: Mediar Tx, Employee of: Pandion Therapeutics Inc.
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Goodfield, Laura L., Johanna Lahdenranta, Heather Scott, Tamera Ashworth, Lia Luus, Anna F. Licht, Kevin McDonnell, Phil Brandish und Nicholas Keen. „Abstract 4230: Modeling the cDC1 ex vivo and in vitro: Development and comparison of a conventional dendritic cell culture system for industry“. Cancer Research 82, Nr. 12_Supplement (15.06.2022): 4230. http://dx.doi.org/10.1158/1538-7445.am2022-4230.
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Abstract Conventional dendritic cells (cDC) are innate immune cells specialized in antigen sampling and subsequent cross-presentation to immune cells and are critical for an effective anti-tumor immune response. While crucial to immunity against intracellular pathogens, viruses, and tumors, cDC type I (cDC1) are a relatively rare population and constitute about 0.05% of cells in the blood. Using these rare cells in screening assays can be a challenge, as very small proportions are found in peripheral human blood and since they are difficult to isolate with high viability and purity. Existing methods to generate acceptable numbers of cDC1s require a feeder cell line, which is not accessible to many laboratories. Using a systematic approach, we developed a scalable differentiation system to generate a mixed culture containing cDC1 cells from CD34+ hematopoietic stem cells isolated from cord blood that does not require feeder cells. This culture of cells has been phenotypically and functionally characterized to express high levels of CD141 and Clec9a, as well as responsiveness to various activating stimuli including poly (I:C). Cells derived from this culture method express similar levels of CD141 and Clec9a compared to those observed in peripheral blood of healthy donors. Our effort to find a less laborious, more efficient system includes comparison to cDC1 responses from an in vitro differentiation system to cDC1s isolated from humanized mouse bone marrow, with evaluation of both surface marker phenotype and responsiveness to activating stimuli. We also compared the responses of these cells to monocyte derived dendritic cells that express CD141 and Clec9a. These data demonstrate that the HSC-derived cDC1 cultures provide a comparison of unique dendritic cells that may be utilized for screening assays in an industry setting. Citation Format: Laura L. Goodfield, Johanna Lahdenranta, Heather Scott, Tamera Ashworth, Lia Luus, Anna F. Licht, Kevin McDonnell, Phil Brandish, Nicholas Keen. Modeling the cDC1 ex vivo and in vitro: Development and comparison of a conventional dendritic cell culture system for industry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4230.
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Venkatachalam, Annapoorna, Cristina Correia, Cordelia D. Mcgehee, Sarah Finstuen-Magro, Jamison VanBlaricom, Paula A. Schneider, Kevin L. Peterson et al. „Abstract 5058: Impact of dexamethasone on chemotherapy response in ovarian cancer“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 5058. http://dx.doi.org/10.1158/1538-7445.am2023-5058.
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Abstract Background: Ovarian cancer ranks fifth in cancer deaths among women. The gold standard of care for advanced disease includes cytoreductive surgery along with adjuvant or neoadjuvant platinum/taxane-based chemotherapy. Although response to this treatment is high, chemotherapy-induced nausea and vomiting due to platinum agents and allergic reactions due to both agents are common. For nearly half a century, the glucocorticoid (GC) dexamethasone (DEX) has been administered as part of supportive care. However, there have periodically been questions about the possible deleterious effects of DEX on chemotherapy response, especially in solid tumors. Methods: Platinum-sensitive, glucocorticoid receptor (GRα) expressing ovarian cancer cells were exposed to DEX prior to chemotherapy and clonogenic survival was assessed. The effects of DEX on cell cycle and apoptosis were assessed by flow cytometry. Changes in the tumor cell transcriptome after acute DEX treatment were determined by RNA sequencing. Mice bearing orthotopic ovarian cancer patient-derived xenografts (PDXs) were treated with chemotherapy ± DEX to assess changes in chemotherapy response in vivo. Findings: DEX pre-treatment decreased platinum cytotoxicity in ovarian cancer cell lines in vitro and diminished platinum response in some PDXs analyzed for chemotherapy response ex vivo. RNA-seq analysis revealed changes in transcripts encoding proteins involved in platinum detoxification and TNFα pro-survival signaling. In ovarian cancer PDXs, DEX decreased platinum response in one model and had limited impact on both platinum and platinum/taxane chemotherapy in three distinct studies. Interpretation: DEX appears to modulate chemotherapy response in some settings in vitro and ex-vivo. The impact of DEX on chemotherapy response in vivo appears to be limited. However, further investigation of this question in vivo in non-immunosuppressed murine models appears warranted. Citation Format: Annapoorna Venkatachalam, Cristina Correia, Cordelia D. Mcgehee, Sarah Finstuen-Magro, Jamison VanBlaricom, Paula A. Schneider, Kevin L. Peterson, Ethan P. Heinzen, Melissa C. Larson, Xiaonon Hou, Ann L. Oberg, Saravut John Weroha, Scott H. Kaufmann. Impact of dexamethasone on chemotherapy response in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5058.
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Venkatachalam, Annapoorna, Cristina Correia, Cordelia Mcgehee, Sarah Finstuen-Magro, Paula A. Schneider, Rachel Hurley, Kevin L. Peterson et al. „Abstract B098: Impact of dexamethasone on chemotherapy response in ovarian cancer“. Cancer Research 84, Nr. 5_Supplement_2 (04.03.2024): B098. http://dx.doi.org/10.1158/1538-7445.ovarian23-b098.
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Abstract Background: Ovarian cancer ranks fifth in cancer deaths among women. The gold standard of care for advanced disease includes cytoreductive surgery along with adjuvant or neoadjuvant platinum/taxane-based chemotherapy. Although response to this treatment is high, chemotherapy-induced nausea and vomiting due to platinum agents and allergic reactions due to both agents are common. For nearly half a century, the glucocorticoid (GC) dexamethasone (DEX) has been administered as part of supportive care. However, there have periodically been questions about the possible deleterious effects of DEX on chemotherapy response, especially in solid tumors. Methods: Platinum-sensitive, glucocorticoid receptor (GRa) expressing ovarian cancer cells were exposed to DEX prior to chemotherapy and clonogenic survival was assessed. The effects of DEX on cell cycle and apoptosis were assessed by flow cytometry. Changes in the tumor cell transcriptome after acute DEX treatment were determined by RNA sequencing. Mice bearing orthotopic ovarian cancer patient-derived xenografts (PDXs) were treated with chemotherapy ± DEX to assess changes in chemotherapy response in vivo. Findings: DEX pre-treatment decreased platinum cytotoxicity in ovarian cancer cell lines in vitro and diminished platinum response in some PDXs analyzed for chemotherapy response ex vivo. RNA-seq analysis revealed changes in transcripts encoding proteins involved in platinum detoxification and TNFa pro-survival signaling. In ovarian cancer PDXs, DEX decreased platinum response in one model and had limited impact on both platinum and platinum/taxane chemotherapy in three distinct studies. Interpretation: DEX appears to modulate chemotherapy response in some settings in vitro and ex-vivo. The impact of DEX on chemotherapy response in vivo appears to be limited. However, further investigation of this question in vivo in non-immunosuppressed murine models appears warranted. Citation Format: Annapoorna Venkatachalam, Cristina Correia, Cordelia Mcgehee, Sarah Finstuen-Magro, Paula A. Schneider, Rachel Hurley, Kevin L. Peterson, Ethan Heinzen, Melissa C. Larson, Xiaonon Hou, Ann L. Oberg, Saravut Weroha, Scott H. Kaufmann. Impact of dexamethasone on chemotherapy response in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B098.
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Abbaspourtamijani, Ali, Chaoxuan Gu, Qisheng Wu und Yue Qi. „Electrochemical Birch Reduction: A Molecular-Level Venture into the Solvation Structure at the Electrode Interface“. ECS Meeting Abstracts MA2022-01, Nr. 46 (07.07.2022): 1966. http://dx.doi.org/10.1149/ma2022-01461966mtgabs.
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Although selective hydrogenation of aromatics through Birch reduction has long been at the heart of synthetic organic chemistry, its various proposed procedures suffer from monumental challenges. The optimized design of salt, solvent, and additives along with a sacrificial anode material has enabled the recent success of Electrochemically driven Birch reduction (E-Birch) reactions, which are procedurally convenient, safe, and sustainable1. The E-Birch reactions are premised upon the concepts applied in Li-ion battery research regarding the surface protection layer formation, also referred as the solid electrolyte interphase (SEI). However, the impacts of these constituents on the surface layer formation in E-Birch reactions is largely unknown. In this study, we have employed a combination of molecular dynamics (MD) simulations and density functional theory (DFT) calculations to provide insights into the liquid structure and the interactions of these constituents, both in bulk of the solution and at the electrode surface. Specifically, an optimal electrolyte design of LiBr salt in tetrahydrofuran (THF) solvent, with 1,3-dimethylurea (DMU) as the proton donor, and tris(pyrrolidino)phosphoramide (TPPA), as surface protector, has been studied as it promoted high yields of 1,4-diene formation from several aromatic-ring containing molecules with a variety of functional groups. We have found that THF, DMU, and TPPA are all present in the Li+ solvation sheath at the bulk of the solution and at the electrode surface. Since the surface layer is formed by the reduction reactions of solution, the reduction voltage was computed for representative solvation structures. It was found that the reduction voltage and reduction process of THF, DMU, and TPPA were altered by the Li+ coordination and are therefore sensitive to the liquid solution structures. In addition, we have demonstrated that the species in the solvation shell can undergo bond breaking events, which lead to protection layer formation at the electrode surface. The role of salt, solvent, additives, and sacrificial anodes in altering the solution structure and reduction reactions was further discussed. References Peters Byron, K.; Rodriguez Kevin, X.; Reisberg Solomon, H.; Beil Sebastian, B.; Hickey David, P.; Kawamata, Y.; Collins, M.; Starr, J.; Chen, L.; Udyavara, S.; Klunder, K.; Gorey Timothy, J.; Anderson Scott, L.; Neurock, M.; Minteer Shelley, D.; Baran Phil, S., Scalable and safe synthetic organic electroreduction inspired by Li-ion battery chemistry. Science 2019, 363 (6429), 838-845.
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Dufort, Fay J., Christopher J. Leitheiser, Gemma Mudd, Julia Kristensson, Alexandra Rezvaya, Katie Gaynor, Sandra Uhlenbroich et al. „Abstract 4233: Generation of a Bicycle NK-TICA™, a novel NK cell engaging molecule designed to induce targeted tumor cytotoxicity“. Cancer Research 82, Nr. 12_Supplement (15.06.2022): 4233. http://dx.doi.org/10.1158/1538-7445.am2022-4233.
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Abstract The tumor specific activation of natural killer (NK) cells is an area of active investigation in immune oncology, but to date has relied on complex biologic modalities (e.g., antibodies, fusion proteins, or cell therapies). NK cells are highly responsive immune cells that can detect and eliminate tumor cells and bridge innate to adaptive immune responses. Bicycles® are small (ca.1.5kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied the Bicycle platform technology to identify Bicycles® that bind specifically to the key activating receptor, NKp46. When chemically coupled to tumor antigen binding Bicycles, this results in highly potent, antigen-dependent receptor activation and NK cell activation. We term this new class of fully synthetic molecules NK-TICAs and we will describe herein their discovery and evaluation.We demonstrate potent, selective binding of our Bicycles to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function in vitro. With Bicycle’s novel NK-TICA™ compound, we demonstrate the engagement of NK cells, the specific activation and function of NK cells, and enhanced tumor cytotoxicity in a tumor target- and dose-dependent manner.In conclusion, NK-TICAs drive NK cell-mediated tumor cell killing and cytokine production in vitro and as such have the potential to catalyze the development of durable anti-tumor immunity in tumor types not well served by current therapies. We hypothesize that utilization of Bicycle NK-TICA™ as a multifunctional immune cell engager will promote the modulation of NK cells, as well as the infiltration and anti-tumor activity of NK cells in solid tumors. The data presented here provide initial proof of concept for the application of our Bicycle technology to drive NK cell-mediated tumor immunity. Citation Format: Fay J. Dufort, Christopher J. Leitheiser, Gemma Mudd, Julia Kristensson, Alexandra Rezvaya, Katie Gaynor, Sandra Uhlenbroich, Liudvikas Urbonas, Heather Scott, Liuhong Chen, Helen Harrison, Michael Skynner, Kevin McDonnell, Philip E. Brandish, Nicholas Keen. Generation of a Bicycle NK-TICA™, a novel NK cell engaging molecule designed to induce targeted tumor cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4233.
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Chertkow, Howard. „Books Reviews - Principles of Cognitive Neuroscience. 2008. By Dale Purves, Elizabeth M. Brannon, Roberto Cabeza, Scott A. Huettel, Kevin S. LaBar, Michael L. Platt, Marty G. Woldorff. Published by Sinauer Associates Inc, USA. 757 pages. C$105 approx.“ Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 37, Nr. 2 (März 2010): 298. http://dx.doi.org/10.1017/s0317167100118098.
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Woodroffe, Colin D. „The geomorphology of the Great Barrier Reef: development, diversity and change- by David Hopley, Scott G Smithers and Kevin E Parnell andA reef in time: the Great Barrier Reef from beginning to end- by J E N Veron“. Area 40, Nr. 3 (September 2008): 416–17. http://dx.doi.org/10.1111/j.1475-4762.2008.840_4.x.
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Venkatachalam, Annapoorna, Kevin L. Peterson, Cristina Correia, Karen S. Flatten, Xianon Hou, Paula A. Schneider, Emily Balczewski et al. „Abstract 1832: CHK1 inhibitor prexasertib induces NOXA-dependent apoptosis in ovarian cancer“. Cancer Research 82, Nr. 12_Supplement (15.06.2022): 1832. http://dx.doi.org/10.1158/1538-7445.am2022-1832.
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Abstract Background: The kinases ataxia-telangiectasia-mutated-and-Rad3-related (ATR), checkpoint kinase 1 (CHK1) and WEE1 participate in the response to replication stress. Inhibitors of ATR, WEE1 and CHK1 are being tested for antineoplastic activity as monotherapies and in combination with chemotherapy. Although these agents impair cell cycle checkpoints, fork stabilization, origin firing and homologous recombination (HR), little is known about the apoptotic pathways that are engaged and the critical mediators activating cell death mechanisms. The present study utilizes high grade serous ovarian cancer (HGSOC) cell lines and patient derived xenografts (PDXs) to identify the primary mechanism of cell death in ovarian cancer and assess changes involved in the resistance setting after treatment with these inhibitors. Methods: A panel of HGSOC cell lines was examined for responses to ceralasertib (ATRi), prexasertib (CHK1i) or adavosertib (WEE1i) using colony forming assays, immunoblotting and assays for apoptosis. Mechanisms involved in acquired resistance and downstream changes in cell fate were evaluated by generating prexasertib-resistant HGSOC cell lines. Subsequent NGS analysis was performed in the sensitive and resistant pairs. Results: Irrespective of the homologous recombination (HR) status, ovarian cell lines and PDXs underwent cell death during prolonged exposure at clinically achievable concentrations. Treatment of ovarian cancer cell lines with ATRi, CHK1i or WEE1i activated the replication checkpoint, consistent with previously published reports. The subsequent apoptotic response involved PMAIP1 and BCL2L11 upregulation rather than the TNFa-induced death receptor-mediated apoptosis we recently described in acute leukemia (Cancer Res. PMID: 33414171). Additionally, ovarian lines selected for CHK1i resistance failed to die in response to either ATRi or WEE1i. Conclusions: Prexasertib, ceralasertib, and adavosertib exhibit monotherapy activity in both HR deficient and proficient HGSOC cell lines and PDX models. Unlike AML, death receptor mediated apoptosis was not observed; instead, the primary mechanism of cell killing in HGSOC lines involves activation of the mitochondrial apoptotic pathway. Cross-resistance of these DNA damage repair modulators is likely multifactorial and mainly involves diminished replication stress response. Citation Format: Annapoorna Venkatachalam, Kevin L. Peterson, Cristina Correia, Karen S. Flatten, Xianon Hou, Paula A. Schneider, Emily Balczewski, Cordelia McGehee, Rachel M. Hurley, Xue W. Meng, Chance Sine, Rameen Shah, Nicole Vincelettte, Husheng Ding, Hu Li, Saravut (John) Weroha, Scott H. Kaufmann. CHK1 inhibitor prexasertib induces NOXA-dependent apoptosis in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1832.
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KITLV, Redactie. „Book reviews“. Bijdragen tot de taal-, land- en volkenkunde / Journal of the Humanities and Social Sciences of Southeast Asia 166, Nr. 2-3 (2010): 331–80. http://dx.doi.org/10.1163/22134379-90003622.
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Edward Aspinall, Islam and nation; Separatist rebellion in Aceh, Indonesia. (Gerry van Klinken) Greg Bankoff and Sandra Swart (with Peter Boomgaard, William Clarence-Smith, Bernice de Jong Boers and Dhiravat na Pombejra), Breeds of empire; The ‘invention’ of the horse in Southeast Asia and Southern Africa 1500–1950. (Susie Protschky) Peter Boomgaard, Dick Kooiman and Henk Schulte Nordholt (eds), Linking destinies; Trade, towns and kin in Asian history. (Hans Hägerdal) Carstens, Sharon A. Histories, cultures, identities; Studies in Malaysian Chinese worlds. (Kwee Hui Kian) T.P. Tunjanan; m.m.v. J. Veenman, Molukse jongeren en onderwijs: quick scan 2008. Germen Boelens, Een doel in mijn achterhoofd; Een verkennend onderzoek onder Molukse jongeren in het middelbaar beroepsonderwijs. E. Rinsampessy (ed.), Tussen adat en integratie; Vijf generaties Molukkers worstelen en dansen op de Nederlandse aarde. (Fridus Steijlen) Isaäc Groneman, The Javanese kris. (Dick van der Meij) Michael C. Howard, A world between the warps; Southeast Asia’s supplementary warp textiles. (Sandra Niessen) W.R. Hugenholtz, Het geheim van Paleis Kneuterdijk; De wekelijkse gesprekken van koning Willem II met zijn minister J.C. Baud over het koloniale beleid en de herziening van de grondwet 1841-1848. (Vincent Houben) J. Thomas Lindblad, Bridges to new business; The economic decolonization of Indonesia. (Shakila Yacob) Julian Millie, Splashed by the saint; Ritual reading and Islamic sanctity in West Java. (Suryadi) Graham Gerard Ong-Webb (ed.), Piracy, maritime terrorism and securing the Malacca Straits. (Karl Hack) Natasha Reichle, Violence and serenity; Late Buddhist sculpture from Indonesia. (Claudine Bautze-Picron, Arlo Griffiths) Garry Rodan, Kevin Hewison and Richard Robison (eds), The political economy of South-East Asia; Markets, power and contestation. (David Henley) James C. Scott, The art of not being governed; An anarchist history of upland Southeast Asia. (Guido Sprenger) Guido Sprenger, Die Männer, die den Geldbaum fällten; Konzepte von Austausch und Gesellschaft bei den Rmeet von Takheung, Laos. (Oliver Tappe) Review Essay Two books on East Timor. Carolyn Hughes, Dependent communities; Aid and politics in Cambodia and East Timor. David Mearns (ed.), Democratic governance in Timor-Leste; Reconciling the local and the national. (Helene van Klinken) Review Essay Two books on Islamic terror Zachary Abuza, Political Islam and violence in Indonesia. Noorhaidi Hasan, Laskar jihad; Islam, militancy, and the quest for identity in post-New Order Indonesia. (Gerry van Klinken) Korte Signaleringen Janneke van Dijk, Jaap de Jonge en Nico de Klerk, J.C. Lamster, een vroege filmer in Nederlands-Indië. Griselda Molemans en Armando Ello, Zwarte huid, oranje hart; Afrikaanse KNIL-nazaten in de diaspora. Reisgids Indonesië; Oorlogsplekken 1942-1949. Hilde Janssen, Schaamte en onschuld; Het verdrongen oorlogsverleden van troostmeisjes in Indonesië. Jan Banning, Comfort women/Troostmeisjes. (Harry Poeze)
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Venkatachalam, Annapoorna, Cristina Correia, Kevin L. Peterson, Xiaonan Hou, Annabella R. Strathman, Paula A. Schneider, Karen S. Flatten et al. „Abstract B012: Transcriptomic insights reveal role of BCL2 proteins in replication checkpoint inhibitor response“. Cancer Research 84, Nr. 5_Supplement_2 (04.03.2024): B012. http://dx.doi.org/10.1158/1538-7445.ovarian23-b012.
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Abstract Background: The kinases ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR), checkpoint kinase 1 (CHK1) and WEE1 participate in the response to replication stress. Inhibitors of ATR, WEE1, and CHK1 are being tested for antineoplastic activity as monotherapies and in combination with chemotherapy. Although these agents impair cell cycle checkpoints, fork stabilization, origin firing, and HR, little is known about the apoptotic pathways that are engaged and the critical mediators activating cell death mechanisms. The present study utilizes high-grade serous ovarian cancer (HGSOC) cell lines and patient-derived xenografts (PDXs) to understand the predominant apoptotic players and assess changes involved in the resistance setting after treatment with these inhibitors. Methods: HGSOC cell lines were examined for responses to ceralasertib (ATRi), prexasertib (CHK1i), or adavosertib (WEE1i) using colony forming assays, immunoblotting, and assays for apoptosis. To characterize the cell death networks after prexasertib treatment, RNA-seq analysis was performed in two representative cell lines. Mechanisms involved in acquired resistance and downstream changes in cell fate were evaluated by generating prexasertib- resistant HGSOC cell lines. Results: Irrespective of the homologous recombination (HR) status, ovarian cell lines, and PDXs underwent cell death during prolonged exposure at clinically achievable concentrations. CDC25A-CDK2 signaling was predictive of responsiveness in vitro and in vivo. The subsequent apoptotic response was c-Jun N-terminal kinases (JNK) dependent and involved engagement of mitochondrial pathways rather than the TNFa-induced death receptor-mediated apoptosis we recently described in acute leukemia (H. Ding, N. Vincelette, et al., Cancer Res. 81:2666-2678, 2021). Additionally, ovarian lines selected for CHK1i resistance failed to die in response to either ATRi or WEE1i but were sensitive to front-line therapy options, including carboplatin and PARP inhibitor. Conclusions: Unlike AML, death receptor-mediated apoptosis was not observed; instead, the primary mechanism of cell killing in HGSOC lines involves activation of the mitochondrial apoptotic pathway. Our findings identify the key cell death-initiating events that serve as measures of response to replication checkpoint inhibitors in ovarian cancer. Acquired resistance to these therapies is multifactorial and mainly involves failure to exacerbate the replication stress response. Citation Format: Annapoorna Venkatachalam, Cristina Correia, Kevin L. Peterson, Xiaonan Hou, Annabella R. Strathman, Paula A Schneider, Karen S. Flatten, Laura N. Duffield, Cordelia D. McGehee, Melissa C. Larson, Xue Meng, Nicole D Vincelette, Ann L. Oberg, Hu Li, John Weroha, Scott H Kaufmann. Transcriptomic insights reveal role of BCL2 proteins in replication checkpoint inhibitor response [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B012.
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Zhang, Zeda, Xin Fang, Yu-jui Ho, Sascha Haubner, Friederike Kogel, Clemens Hinterleitner, Stella Paffenholz et al. „Abstract 115: Developing uPAR CAR T Cells for High-Grade Serous Ovarian Cancer“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 115. http://dx.doi.org/10.1158/1538-7445.am2024-115.
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Abstract Chimeric Antigen Receptor (CAR) T cells are a modality of immunotherapy that act to eliminate cancer cells by redirecting the cytolytic activity through targeting a protein overexpressed on the surface of the cancer cell. In contrast to move conventional cancer therapies, their anti-cancer activity does not depend on a cancer-specific molecular vulnerability but rather the differential expression of the target antigen on tumor cells compared to normal tissues. We have developed CAR T cells targeting the urokinase plasminogen activator receptor (uPAR), which is overexpressed on senescent cells but not expressed highly in vital organs, to selectively target senescent cells in a range of tissue damage pathologies where they are known to be pathogenic. uPAR is also highly overexpressed in a wide range of cancer types, including pancreatic, kidney, bladder, brain and ovarian carcinomas, respectively, raising the possibility that CAR T cells targeting uPAR may also be effective against cancer. Indeed, leveraging an electroporation-based genetically-engineered mouse model of ovarian cancer, we demonstrate the robust anti-tumor efficacy of murine uPAR CAR T cells in immunocompetent syngeneic mice. Moreover, through an exhaustive functional screening of 37 distinct human uPAR single-chain fragment variants (scFVs), we have successfully identified lead scFVs exhibiting subnanomolar affinity to membrane-anchored uPAR. Significantly, these human uPAR CAR T cells exhibit the capability to eliminate both orthotopic and metastatic human HGSOC xenograft tumors without inducing severe adverse effects. Ongoing efforts encompass the assessment of the long-term safety and toxicity profiles of uPAR CAR T cells utilizing a humanized mouse model platform. Our results provide a strong rationale for developing uPAR CAR T cells as an anticancer strategy relevant to a broad range of tumor types, and provide an avenue for safety profiling of uPAR CAR T cells prior to clinical testing in non-cancer patients harboring senescence-related pathologies. Citation Format: Zeda Zhang, Xin Fang, Yu-jui Ho, Sascha Haubner, Friederike Kogel, Clemens Hinterleitner, Stella Paffenholz, Kevin Chen, Wei Luan, Amanda Kulick, Gertrude Gunset, Andreina Garcia Angus, Jing Zhang, Zijian Xu, Adam Wang, Qingwen Jiang, Elisa de Stanchina, Britta Weigelt, Dmitriy Zamarin, Aveline Filliol, Judith Feucht, Jorge Mansilla-Soto, Corina Amor, Michel Sadelain, Scott Lowe. Developing uPAR CAR T Cells for High-Grade Serous Ovarian Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 115.
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Castro, Jennifer, Matthew H. Daniels, Chuang Lu, David Brennan, Deepali Gotur, Young-Tae Lee, Kevin Knockenhauer et al. „Abstract 1136: Targeting DHX9 inhibition as a novel therapeutic modality in microsatellite instable colorectal cancer“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 1136. http://dx.doi.org/10.1158/1538-7445.am2023-1136.
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Abstract DHX9 is a multifunctional DEAH-box ATP-independent RNA helicase which has been reported to play important roles in replication, transcription, translation, RNA splicing and RNA processing which contribute to DHX9’s role in maintenance of genomic stability. Functionally, DHX9’s role involves binding to as well as unwinding and/or resolving double-stranded and single-stranded DNA/RNA, DNA/RNA hybrids (R-loops), circular RNA and DNA/RNA G quadraplexes. Overexpression of DHX9 is evident in multiple cancer types, including colorectal cancer (CRC) and lung cancer. In addition, microsatellite instable (MSI) tumors exhibiting defective mismatch repair (dMMR) show a strong dependence on DHX9, making this helicase an attractive target for oncology drug discovery. Here we describe data supporting targeting DHX9 in MSI CRC as a novel therapeutic, and the first identification of potent and selective in vitro and in vivo small molecule inhibitors of DHX9. We demonstrate that DHX9 inhibition in MSI CRC, delivered either through siRNA knockdown or compound treatment, leads to an increase in RNA/DNA secondary structures such as R-loops and circRNA (i.e. circBRIP1) inducing replication stress. Cell lines that are dMMR (i.e. MSI) are unable to resolve this replication stress, resulting in prevention of DNA replication in S phase and later onset of apoptosis. We were able to confirm this selective dependency in a panel of 20 CRC cell lines; anti-proliferative effects mediated by DHX9 inhibition were dependent on cell line dMMR status in a 10-day proliferation assay. Furthermore, compound 1, an orally bioavailable DHX9 inhibitor was used to investigate in vivo efficacy in MSI CRC (LS411N) and MSS CRC (SW480) xenograft models. Compound 1 was well tolerated across the 28-day treatment period with robust and durable tumor regression (TGI = 105 %) observed in the LS411N tumor xenograft model only. In addition, following cessation of treatment, minimal tumor regrowth was observed in a 28-day post treatment window. Tumor and plasma concentrations of compound 1 and changes in pharmacodynamic markers of DHX9 inhibition, such as circBRIP1 mRNA, were measured and resulting PK and PD data were highly correlated. Together, these preclinical data validate DHX9 as a tractable new target with potential utility as a novel treatment for patients with MSI CRC. Citation Format: Jennifer Castro, Matthew H. Daniels, Chuang Lu, David Brennan, Deepali Gotur, Young-Tae Lee, Kevin Knockenhauer, April Case, Jie Wu, Shane M. Buker, Julie Liu, Brian A. Sparling, E. Allen Sickmier, Stephen J. Blakemore, P. Ann Boriack-Sjodin, Kenneth W. Duncan, Scott Ribich, Robert A. Copeland. Targeting DHX9 inhibition as a novel therapeutic modality in microsatellite instable colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1136.
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Nair, Praveen, Sarah Kolitz, Jason Funt, Peter J. King, Kevin D. Fowler, Anna Travesa, Ian Rose et al. „Abstract 4265: Humanized 3D tumor models that are mutationally aligned with AACR GENIE patients predict IMM-1-104 activity in RAS-addicted tumors“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 4265. http://dx.doi.org/10.1158/1538-7445.am2023-4265.
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Abstract Introduction: IMM-1-104, with pan-RAS activity through deep cyclic inhibition MEK, was evaluated in humanized 3D preclinical tumor models displaying diverse MAPK pathway activation events. Based on drug-response, sensitivity and resistance profiles, a biomarker signature for IMM-1-104 was developed in order to project potential therapeutic response of cancer patients found in the AACR Project GENIE (GENIE) database. Experimental Procedures: Humanized 3D preclinical models better predict in vivo tumor responses versus 2D culture and more accurately replicate biology of human tumors. Therefore, the antitumor activity of IMM-1-104 was evaluated in over 130 tumor models spanning 12 distinct histologies in the humanized 3D tumor growth assay (3D-TGA). Cell-based whole exome sequencing readouts were combined with 3D-TGA results to build a pharmacogenomic response algorithm. When applied to the GENIE patient database, resultant tumor-specific response landscapes helped to inform an early pan-RAS clinical trial design for IMM-1-104. Summary of New Data: A machine learning model was developed to predict IMM-1-104 sensitivity using response-associated genes and signaling networks that were identified using 3D-TGA pharmacogenomics data. This model was used to estimate GENIE patient IMM-1-104 response profiles across key solid tumor indications. In addition, mutation constellations from GENIE were compared with those observed in cell lines to identify preclinical models that best resemble real-world patients. This effort was designed to further enrich the translational fidelity of specific tumor models with the goal of translationally identifying patient populations most likely to benefit from IMM-1-104 treatment. Conclusions: The depth of response to IMM-1-104 was evaluated across a panel of diverse 3D-TGA tumor models and led to identification of a biomarker signature for therapeutically addressable MAPK pathway addiction. To translate these findings into a relevant clinical application, a response algorithm was developed and applied to the GENIE database, which has cataloged the molecular profiles of over 100,000 cancer patients. Mutational landscapes of patients within GENIE helped identify preclinical models that better represent patient profiles likely to be encountered in the clinic. This approach could, as a general principle, be applied as a tool for improving biomarker discovery and clinical translation of oncology drugs. Citation Format: Praveen Nair, Sarah Kolitz, Jason Funt, Peter J. King, Kevin D. Fowler, Anna Travesa, Ian Rose, John Brothers, Amy Axel, Scott Barrett, Benjamin J. Zeskind, Brett M. Hall. Humanized 3D tumor models that are mutationally aligned with AACR GENIE patients predict IMM-1-104 activity in RAS-addicted tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4265.
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Bamdad, Cynthia Carol, Benoit S. Smagghe, Scott T. Moe, Mark G. Carter, Trevor J. Grant, Kevin R. Yi, Michael J. Nash et al. „Abstract 6351: MUC1*-ADCs are effective against heterogeneous solid tumor cancers“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 6351. http://dx.doi.org/10.1158/1538-7445.am2024-6351.
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Abstract Purpose: To develop a MUC1*-ADC for the treatment of over 75% of solid tumor cancers. Methods: MUC1* (muk 1 star) is a growth factor receptor created after cleavage and release of the N-terminal portion of MUC1. The targeting antibody, huMNC2, has already demonstrated safety and cancer selectivity in a 1st-in-human CAR-T clinical trial for treatment of metastatic breast cancers. MNC2 is an IgG1 antibody that only recognizes the conformational epitope created when MUC1 is cleaved by specific tumor-associated enzymes. Confocal microscopy and pHlourin2 were employed to measure antibody internalization as a function of time. We conjugated MNC2 to MMAE, MMAF, Dxd and exatecan via several different linkers. MUC1*-ADCs with DARs ranging from 4-8 were tested in vitro and in vivo for efficacy against a panel of solid tumor cancers. Heterogenous MUC1* tumors were made by mixing different ratios of mCherry wild-type cancer cells with GFP MUC1* overexpressed cancer cells. Resulting H scores ranged from 10-280 (max 300). Results: Cancer cells internalized the MUC1* MNC2 antibody within 2 hours. In vitro, MUC1*-ADC IC50s ranged from 1.3nM to 20.0nM, depending on the linker-payload and cancer subtype, wherein the majority had an IC50 of about 10nM. In general, efficacy in animals was seen across multiple cancer sub-types treated with multiple MUC1*-ADCs. Efficacy in animals xenografted with heterogeneous MUC1* tumors showed a dependence on antigen density. Greatest efficacy was observed for breast cancer xenografts with an H Score >10 treated with MNC2-Deruxtecan. However, only pancreatic tumors with higher H Scores were completely eliminated by MNC2-MMAE, MNC2-Deruxtecan and MNC2-exatecan. MNC2-ADC and MNC2-CAR share the same antibody. No off-tumor toxicity was observed in animals treated with MNC2-ADC, which mimicked lack of off-target toxicities for MNC2-CAR T cells in humans. Conclusions: These data, combined with MNC2-CAR T data from our 1st-in-human trial for metastatic breast cancer, supports a conclusion that the MUC1* antibody MNC2 is safe and could have high therapeutic value as a MUC1*-ADC for multiple solid tumors with both high and low antigen density. Citation Format: Cynthia Carol Bamdad, Benoit S. Smagghe, Scott T. Moe, Mark G. Carter, Trevor J. Grant, Kevin R. Yi, Michael J. Nash, Jacy P. Marquez, Natalie K. Miller, Jac-Leen S. Nash, Dan S. Miller, Danica M. Walkley, Andrew K. Stewart. MUC1*-ADCs are effective against heterogeneous solid tumor cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6351.
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Jensen, Owen, Shubhanshi Trivedi, Jackson G. Cacioppo, Kelin Li, Jeffrey Aubé, J. Scott Hale, Edward T. Ryan und Daniel T. Leung. „Erratum to: Use of a MAIT Activating Ligand, 5-OP-RU, as a Mucosal Adjuvant in a Murine Model of Vibrio cholerae O1 Vaccination“. Pathogens and Immunity 7, Nr. 1 (13.09.2022): 145–46. http://dx.doi.org/10.20411/pai.v7i1.541.
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ERRATUM TO: USE OF A MAIT ACTIVATING LIGAND, 5-OP-RU, AS A MUCOSAL ADJUVANT IN A MURINE MODEL OF VIBRIO CHOLERAE O1 VACCINATION DOI: 10.20411/pai.v7i1.525 Reason: The authors sincerely regret the inadvertent omission of Jackson G. Cacioppo as coauthor of this work. He has no additional conflicts of interest. Corrected version: Owen Jensen1,2, Shubhanshi Trivedi1, Jackson G. Cacioppo3, Kelin Li3, Jeffrey Aubé3, J. Scott Hale2, Edward T. Ryan4,5,6, Daniel T. Leung1, 2*
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Cani, Andi K., Emily M. Dolce, Elizabeth P. Darga, Kevin Hu, Chia-Jen Liu, James M. Rae, Daffyd G. Thomas et al. „Abstract 1700: Serial monitoring of single-cell circulating tumor cell genomics in metastatic lobular breast cancer to identify precision and immuno-oncology biomarkers with therapeutic implications“. Cancer Research 82, Nr. 12_Supplement (15.06.2022): 1700. http://dx.doi.org/10.1158/1538-7445.am2022-1700.
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Abstract Clinical decisions for precision and immuno-oncology therapies are based on predictive biomarkers commonly obtained from a single metastatic biopsy, or from archived primary tumor material. Circulating genomic biomarkers present a minimally invasive way to monitor the intra-patient tumor heterogeneity and its fluctuations in order to provide a real-time evaluation of the changing clonal architecture with potential therapeutic implications. Single-cell DNA next generation sequencing (scNGS) of circulating tumor cells (CTC) is a particularly well-suited method of unraveling and monitoring that heterogeneity to complement biomarker information obtained from tissue and cell-free circulating tumor DNA (ctDNA). In this proof-of-concept study we analyzed 123 CTC, 15 white blood cells (WBC), and ctDNA from 15 CTC-positive lobular breast cancer patients, five of whom had CTC available at both metastatic baseline and after progression on a variety of therapies chosen at their physician’s discretion. CTC were enriched with the CellSearch® system and isolated as single cells with the DEPArray™ system. Whole genome amplified CTC DNA underwent scNGS with the Oncomine Comprehensive Assay covering ~500 genes and 1.1Mb of genomic space to detect mutations, copy number alterations, tumor mutation burden (TMB) and microsatellite instability (MSI). 99.1% of cells were informative, with a mean sequencing depth of 664x. Using our previously developed, CTC-based precision medicine reporting platform, MI-CTCSeq, multiple CTC in seven of 15 patients (47%) had mutations that were actionable by FDA-approved targeted therapies including in the oncogenes PIK3CA (alpelisib) and FGFR2 (erdafitinib). 13 patients (87%) displayed intra-patient, inter-CTC genomic heterogeneity of putative driver mutations. Two of five (40%) patients with CTC at both baseline and progression displayed fluctuations in their CTC subclonal makeup between timepoints. One of the two harbored a baseline ESR1 (estrogen receptor α) p.D538G activating mutation that largely disappeared at progression and was replaced by a CTC subclone with a different ESR1 activating mutation, p.Y537S. Intriguingly, this patient’s CTC also harbored an FGFR2 p.K659M mutation in an actionable “hotspot” at progression, which was absent at baseline, suggesting potential utility of serial monitoring by CTC scNGS. TMB scores and MSI status in CTC were highly concordant with those measured in clinical tissue biopsies. Taken together, these data suggest the non-invasive interrogation of the CTC genomic landscape and its serial monitoring to inform precision and immuno-oncology treatments in real time. Citation Format: Andi K. Cani, Emily M. Dolce, Elizabeth P. Darga, Kevin Hu, Chia-Jen Liu, James M. Rae, Daffyd G. Thomas, Scott A. Tomlins, Arul M. Chinnaiyan, Aaron M. Udager, Costanza Paoletti, Erin F. Cobain, Daniel F. Hayes. Serial monitoring of single-cell circulating tumor cell genomics in metastatic lobular breast cancer to identify precision and immuno-oncology biomarkers with therapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1700.
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Guo, Jimmy A., Daniel Zhao, Scott P. Ginebaugh, Steven Wang, Ananya D. Jambhale, Patrick Z. Yu, Westley W. Wu et al. „Abstract PR-006: Integrative genomic characterization of therapeutic targets for pancreatic cancer“. Cancer Research 81, Nr. 22_Supplement (15.11.2021): PR—006—PR—006. http://dx.doi.org/10.1158/1538-7445.panca21-pr-006.
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Abstract Targeted therapies for molecularly-defined subtypes have led to immense clinical benefit for many cancer types but have generally not been successful for pancreatic cancer. Given that the mainstay of treatment remains multi-agent chemotherapy with FOLFIRINOX or gemcitabine/nab-paclitaxel, there remains an urgent need to identify novel actionable vulnerabilities for subsets of PDAC patients. Toward this end, we conducted an integrative, genome-scale examination of genetic dependencies and cell surface targets for PDAC by leveraging CRISPR and RNAi screening data from The Cancer Dependency Map Project, genomic data of bulk patient tumors from The Cancer Genome Atlas, and custom single-nucleus RNA-seq of a 43-patient cohort comprised of untreated and treated specimens. Our results re-affirm the prominence of Ras/MAPK signaling and a synthetically-lethal interaction between VPS4A/B, but also reveal recurrent susceptibilities to genes within the fatty acid metabolism, vesicular transport and exocytosis, and nucleobase synthesis pathways that otherwise have minor to moderate depleting effects on the majority of cell lines. Aberrations in frequent tumor suppressor genes and chromosomal arm-level variations appear to modify the strength of dependencies, including that of KRAS, CCND1, and GPX4, and may serve as predictive biomarkers of response. In addition, we leveraged mRNA profiling of bulk primary tumors as well as metastatic organoid models to conduct a genome-wide search for cell surface targets that are highly-expressed in tumors while lowly or not expressed in other toxicity-prone, non-malignant tissues. These putative drug targets do not need to be cancer dependencies and can be compatible with antibody-based therapeutic strategies that leverage alternative modes of cellular toxicity. Our approach identifies MSLN, NECTIN4, TROP2, and other antigens which have previously been shown to be largely tumor-specific but also reveals the expression of multiple putative targets within the CEACAM, claudin, and tetraspanin families. Finally, molecular subtyping efforts over the past decade have yielded classical and basal-like as consensus subtypes with variations therein, but genetic dependencies and cell surface expression patterns unique to either are insufficiently understood. We identified CLDN18, CEACAM5, and CEACAM6 as cell surface antigens for the classical subtype and MSLN, AQP5, and SLC6A14 for basal-like. Dependency on TLK2 and CCND1 is associated with the basal-like and classical subtype, respectively. Taken together, our integrative genomic approach may provide a precision medicine blueprint for stratifying and targeting pancreatic cancer. Citation Format: Jimmy A. Guo, Daniel Zhao, Scott P. Ginebaugh, Steven Wang, Ananya D. Jambhale, Patrick Z. Yu, Westley W. Wu, Peter Chen, Maryann Zhao, Kristen E. Lowder, Kevin S. Kapner, Hannah I. Hoffman, Stephanie W. Cheng, Daniel Y. Kim, Rebecca Boiarsky, Francois Aguet, Brenton Paolella, John M. Krill-Burger, James M. McFarland, Tobiloba Oni, Tyler Jacks, Aviv Regev, Gad Getz, William L. Hwang, Harshabad Singh, Andrew J. Aguirre. Integrative genomic characterization of therapeutic targets for pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PR-006.
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Flick, Matthew, Taylor Weiskittel, Kevin Meng-Lin, Fulvio D'Angelo, Francesca Caruso, Shannon Ensign, Mylan Blomquist et al. „Abstract 5621: Multi-parametric MRI maps regional heterogeneity of high grade glioma phenotypes“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 5621. http://dx.doi.org/10.1158/1538-7445.am2023-5621.
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Abstract High grade glioma (HGG) represents a group of devastating diseases with dismal prognosis. Surgical resection of the contrast enhancing (CE) region of HGG remains the mainstay of treatment, but recurrence inevitably arises from the unresected non-contrast enhancing (NE) region, surgically inaccessible due to cancer cell invasion into healthy brain tissue. Due to its critical role in recurrence, understanding of the NE region is central to the improvement of clinical outcomes. We reveal the biological characteristics of this region through image localized multi-regional sampling. We linked microenvironmental characteristics measured by multi-parametric MRI to genomic mutations and transcriptional phenotypes using mixed effect modeling which allowed us to control for individualized patient effects. We first confirmed that T2 is a significant indicator of IDH mutation status in the NE region, being the first description of such a relationship in a HGG cohort. We found the combination of EGFR amplification and CDKN2A homozygous loss was associated with a significantly lower mean diffusivity (MD) compared to double wild type tumors in the NE region, indicating the presence of greater cellular packing and proliferation in EGFR amplification/CDKN2A loss regions. Finally, using single cell pathway based tumor classifications, we showed that nK2, a DSC-MRI metric representing cell size heterogeneity, correlated positively with neuronal signature and negatively with glycolytic/plurimetabolic signature within the NE tumor, indicating that glycolytic/plurimetobolic tumors possessed a high amount of cell size heterogeneity compared to neuronal samples. This hypothesis was supported using digital reference object (DRO) modeling which confirmed that cell size and heterogeneity drove the differential nK2 signal between neuronal and glycolytic/plurimetabolic samples. We identified immune cell infiltrate as one possible mechanism of increased cell size heterogeneity using transcriptomic signature analysis which found more immune cell signatures within glycolytic/plurimetobolic tumors compared to neuronal. Collectively this study demonstrates the central role of multi-parametric MRI as a non-invasive measure of tumor biology and a tool for understanding the clinically critical NE region which can then inform new therapies targeting this region of HGG recurrence. Citation Format: Matthew Flick, Taylor Weiskittel, Kevin Meng-Lin, Fulvio D'Angelo, Francesca Caruso, Shannon Ensign, Mylan Blomquist, Luija Wang, Christopher Sereduk, Gustavo De Leon, Ashley Nespodzany, Javier Urcuyo, Ashlynn Gonzalez, Lee Curtin, Kyle Singleton, Aliya Anil, Natenael Simmineh, Erika Lewis, Teresa Noviello, Reyna Patel, Panwen Wang, Junwen Wang, Jennifer Eschbacher, Andrea Hawkins-Daarud, Pamela Jackson, Kris Smith, Peter Nakaji, Bernard Bendok, Richard Zimmerman, Chandan Krishna, Devi Patra, Naresh Patel, Mark Lyons, Matthew Neal, Kliment Donev, Maciej Mrugala, Alyx Porter, Scott Beeman, Yuxiang Zhou, Leslie Baxter, Christopher Plaisier, Jing Li, Hu Li, Anna Lasorella, Chad Quarles, Kristin Swanson, Michele Ceccarelli, Antonio Iavarone, Nhan Tran, Leland Hu. Multi-parametric MRI maps regional heterogeneity of high grade glioma phenotypes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5621.
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Gong, Dennis, Jimmy A. Guo, Carina Shiau, Ananya D. Jambhale, Steven Wang, Scott Ginebaugh, Patrick Z. Yu et al. „Abstract A117: Molecular stratification of therapeutic targets in pancreatic cancer“. Cancer Research 84, Nr. 2_Supplement (16.01.2024): A117. http://dx.doi.org/10.1158/1538-7445.panca2023-a117.
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Abstract Precision medicine approaches using molecular tumor profiling have resulted in striking clinical benefits in certain patient populations. However, targeted therapy in pancreatic cancer has been unable to displace multi-agent chemotherapy, in part due to lack of actionable biomarkers to anchor stratification. To address this need, we have conducted a biomarker focused analysis of cancer dependencies and cell surface targets to understand specific vulnerabilities present in molecular subgroups. We started by interrogating genome scale CRISPR screening and expression data from The Cancer Dependency Map to identify lineage-enriched, selective dependencies in pancreatic cancer. Our results reveal synthetic lethal interactions such as paralog pairs (e.g., VPS4A/B), dependencies predictable by overexpression (e.g., KLF5), and dependencies predictable by genetic alterations (e.g., RAB10 with SMAD4 deletion). Our results reaffirm the importance of KRAS signaling but also highlight a diversity of downstream essential mechanisms including DOCK5 and RAF1. We also identified vulnerabilities specific to transcriptional subtypes, finding ITGA3 to be a selective dependency of not only the basal-like state in pancreas cancer but also across the spectrum of epithelial malignancies. Given the central role of KRAS mutations in tumorigenesis and the emergence of KRAS inhibitors, we studied predictors of KRAS dependency. GSEA analysis of genes overexpressed in cell lines with lower dependency on KRAS identified gene sets related to focal adhesion, EMT, and neuron development, while lines with high KRAS dependency were enriched in genes related to epithelial differentiation/development and the canonical Hallmark KRAS up signature. These gene signatures also predict resistance and sensitivity to small molecule inhibition of KRAS with a high degree of accuracy (Pearson r = 0.68, 0.94 respectively). In addition to vulnerabilities from intracellular target inhibition, cancer cells may be targeted selectively based on surface proteins using cellular and antibody based therapeutic strategies. We used bulk gene expression data from TCGA and GTEx as well as single cell expression data from The Human Cell Atlas, to calculate enriched genes in pancreas cancer versus critical normal tissues. Our approach captures targets including MSLN, TROP2, MUC1, and CLDN18, which have established tumor specificity, but also identifies PSCA, GPRC5A, and CEACAM5 as additional emerging pancreas tumor specific antigens. We charted interpatient and intratumoral heterogeneity in spatial transcriptomics data using a cohort of 21 treated and untreated pancreatic cancer tissue specimens, identifying MUC1 and GPRC5A as both expressed homogenously across patients and throughout individual tumors while scarcely expressed in normal tissues. Ultimately, these findings may prompt prioritization of new molecularly defined dependencies, and construction of rational combinatorial regimens. Citation Format: Dennis Gong, Jimmy A. Guo, Carina Shiau, Ananya D. Jambhale, Steven Wang, Scott Ginebaugh, Patrick Z. Yu, Kevin S. Kapner, Seema Chugh, Laleh Abbassi, Daniel Zhao, Westley W. Wu, Peter Chen, Harshabad Singh, William L. Hwang, Andrew J. Aguirre. Molecular stratification of therapeutic targets in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A117.
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Bai, Jinlun, David S. Koos, Kayla Stepanian, Kevin Stachelek, Bhavana Bhat, Scott Fraser, Rex Moats und David Cobrinik. „Abstract 236: Modeling multi-step retinoblastoma genesis with cone reporter retinal organoids“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 236. http://dx.doi.org/10.1158/1538-7445.am2024-236.
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Abstract Purpose: This study aims to develop a human retinoblastoma organoid (RBRO) model that recapitulates the cell-of-origin and multi-step retinoblastoma genesis. Background: Retinoblastomas originate from maturing cone photoreceptor precursors with biallelic RB1 inactivation. Rb1 mutant animal models fail to recapitulate retinoblastomagenesis with a cone precursor cell-of-origin, likely due to human-specific cone development features. In explanted fetal retina, pRB-depleted post-mitotic cone precursors proliferate, followed by a 3-5 month premalignant indolence phase before retinoblastoma-like masses emerge at tissue ages similar to retinoblastomas in vivo. However, tissue availability limits research with this disease model. RB1−/- retinal organoids (ROs) provide a potential alternative, as they demonstrate cone proliferation, but they deteriorate before forming indolent premalignant lesions or malignant retinoblastoma foci. Here, we developed methods with which to examine the effects of cone precursor pRB loss in otherwise healthy retinal tissue. Methods: We generated cone-reporter GNAT2-EGFP iPSC lines through CRISPR knock-in of EGFP-P2A at the N-terminus of GNAT2 in WTC11-mTagRFPT-LMNB1. A second round of CRISPR editing produced homozygous RB1 knockout. Chimeric RB1 WT ROs and RB1-null RBROs were generated from cone reporter iPSCs mixed with unedited parental iPSCs. ROs and RBROs were embedded in hydrogel and live-imaged episodically to track EGFP+ cone proliferation dynamics. scRNA-seq was carried out on FACS isolated EGFP+ RB1-null cones at various ages. Results: In RB1 WT ROs, EGFP+ cone precursors appeared at d34 and adopted cone morphology at ~d120, with rapid inner segment growth between ~d120 and ~d150. Immunohistochemistry confirmed cone-specific EGFP expression. In RB1-null RBROs, bi-weekly live confocal imaging revealed initial EGFP+ RB1−/− cone proliferation followed by a pre-malignant indolence phase starting at ~d150. The majority of the initially proliferating cones were Ki67-negative with some adopting mature cone photoreceptor morphology. Nascent retinoblastoma-like foci co-expressing EGFP, cone markers, and Ki67 formed in five of six RBROs after d281, a tissue age that equates to the first post-natal month when early retinoblastomas typically emerge. scRNA-seq of EGFP+ RB1−/− cones from the initial proliferation, indolence, and retinoblastoma-like stages revealed distinct molecular signatures. Conclusions: We generated a human retinoblastoma organoid model that recapitulates the cell-of-origin and timing of multi-step retinoblastomagenesis, with each tumorigenesis stage harboring distinct molecular signatures. This model may enable the identification of epigenetic and transcriptomic changes underlying malignant progression and screening for compounds that efficiently block this process. Citation Format: Jinlun Bai, David S. Koos, Kayla Stepanian, Kevin Stachelek, Bhavana Bhat, Scott Fraser, Rex Moats, David Cobrinik. Modeling multi-step retinoblastoma genesis with cone reporter retinal organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 236.
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Suzuki, Jorge L., Maryam Naghibolhosseini und Mohsen Zayernouri. „A General Return-Mapping Framework for Fractional Visco-Elasto-Plasticity“. Fractal and Fractional 6, Nr. 12 (01.12.2022): 715. http://dx.doi.org/10.3390/fractalfract6120715.
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We develop a fractional return-mapping framework for power-law visco-elasto-plasticity. In our approach, the fractional viscoelasticity is accounted for through canonical combinations of Scott-Blair elements to construct a series of well-known fractional linear viscoelastic models, such as Kelvin–Voigt, Maxwell, Kelvin–Zener, and Poynting–Thomson. We also consider a fractional quasi-linear version of Fung’s model to account for stress/strain nonlinearity. The fractional viscoelastic models are combined with a fractional visco-plastic device, coupled with fractional viscoelastic models involving serial combinations of Scott-Blair elements. We then develop a general return-mapping procedure, which is fully implicit for linear viscoelastic models, and semi-implicit for the quasi-linear case. We find that, in the correction phase, the discrete stress projection and plastic slip have the same form for all the considered models, although with different property and time-step-dependent projection terms. A series of numerical experiments is carried out with analytical and reference solutions to demonstrate the convergence and computational cost of the proposed framework, which is shown to be at least first-order accurate for general loading conditions. Our numerical results demonstrate that the developed framework is more flexible and preserves the numerical accuracy of existing approaches while being more computationally tractable in the visco-plastic range due to a reduction of 50% in CPU time. Our formulation is especially suited for emerging applications of fractional calculus in bio-tissues that present the hallmark of multiple viscoelastic power-laws coupled with visco-plasticity.
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Cani, Andi K., Emily M. Dolce, Kevin Hu, Chia-Jen Liu, Elizabeth P. Darga, Dan Robinson, Yi-Mi Wu et al. „Abstract 5595: Serial monitoring of circulating tumor cells and circulating tumor DNA in metastatic lobular breast cancer identifies intra-tumor heterogeneity and precision and immuno-oncology biomarkers of therapeutic importance“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 5595. http://dx.doi.org/10.1158/1538-7445.am2023-5595.
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Abstract Precision and immuno-oncology clinical decisions are based on predictive biomarkers. Circulating biomarkers offer a minimally invasive approach to monitor intra-patient tumor heterogeneity and detect in real-time the clinically-relevant evolving clonal architecture. Although currently underutilized, single-cell DNA next generation sequencing of circulating tumor cells (CTC) is a particularly suitable method to complement tissue and circulating tumor DNA (ctDNA). Here we analyzed 113 individual CTC, 21 ctDNA, 15 white blood cells (WBC) samples and 15 tissue biopsies, from 15 CTC-positive lobular breast cancer patients. CTC were enriched with the CellSearch® system and isolated as single cells with the DEPArray™ system. CTC, WBC, and ctDNA underwent scNGS with the Oncomine Comprehensive Assay covering ~500 genes and 1.1Mb of genomic space to detect mutations, copy number alterations, tumor mutation burden (TMB) and microsatellite instability (MSI). 99.1% of single cells and 95.2% of ctDNA samples were informative. Our CTC-based precision medicine reporting platform, MI-CTCSeq, detected CTC in 9 of 15 patients (60%) with FDA-approved actionable alterations including in the oncogenes PIK3CA and FGFR2 and HER2. 3 of these 9 (33%) harbored actionable alterations not shared between all 3 analyte types (tissue, CTC and ctDNA) including 3 actionable mutations found in CTC and ctDNA only, 1 in tissue and ctDNA only, and 1 in ctDNA only. Two of those ctDNA mutations were identified near the limit of detection and with a priori knowledge from tissue or CTC. Interestingly, 1 patient with plentiful CTC had no detectable ctDNA. Another patient’s tissue biopsy was inadequate for sequencing while both liquid biopsy analytes were abundant. 13 patients (87%) displayed intra-patient, inter-CTC genomic heterogeneity of driver mutations. 1 of 4 (25%) patients with CTC available in >1 timepoint displayed fluctuations in their CTC subclonal makeup between timepoints. Data from this patient’s 2 tissue biopsies, 4 ctDNA samples, and 27 individual CTC over 6 timepoints, combined to reveal in unprecedented detail inter-metastatic lesion and inter-CTC heterogeneity and evolution in response to endocrine, chemo and immunotherapy selective pressures. In a novel approach we show detection of single-cell CTC TMB and MSI. CTC TMB was highly concordant (R 0.81) with the corresponding tissue biopsies. Further, in a novel observation, we detected intra patient, inter-CTC heterogeneity of TMB and MSI, which has potential implications for immunotherapy response and development of resistance. Taken together, these data support the non-invasive biomarker interrogation and monitoring by liquid biopsy that incorporates CTC to complement tissue in informing treatment approaches. Citation Format: Andi K. Cani, Emily M. Dolce, Kevin Hu, Chia-Jen Liu, Elizabeth P. Darga, Dan Robinson, Yi-Mi Wu, Dafydd G. Thomas, Costanza Paoletti, Scott A. Tomlins, James M. Rae, Aaron M. Udager, Arul M. Chinnaiyan, Erin F. Cobain, Daniel F. Hayes. Serial monitoring of circulating tumor cells and circulating tumor DNA in metastatic lobular breast cancer identifies intra-tumor heterogeneity and precision and immuno-oncology biomarkers of therapeutic importance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5595.
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Assaad, Majd Al, Hui-Hsuan Kuo, Jones Nauseef, Max F. Levine, Gunes Gundem, Juan S. Medina-Martínez, Jyothi Manohar et al. „Abstract 3437: Whole genome and transcriptome sequencing of a pan cancer cohort unearths novel therapeutic avenues“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 3437. http://dx.doi.org/10.1158/1538-7445.am2023-3437.
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Abstract Whole genome sequencing (WGS) has emerged as a tool to characterize the entire genomic landscape of cancer and capture potential new targets and predictive biomarkers. Using state-of-the-art whole-genome and transcriptome sequencing (WGTS) analysis we interrogated a pan cancer cohort to nominate new treatment options. WGS was performed on 414 tumor/germline pairs from our pan cancer cohort of 355 patients, of which 103 had results of other commercial NGS assays. RNAseq data was available in 96 samples. We employed the Isabl GxT analytic platform and manually curated single base substitution (COSMIC v3) mutational signatures and structural variants (SVs). WGTS results were correlated with available clinico-pathologic data. High throughput drug screening that included PARP inhibitors and functional validation were performed in 61 matched patient-derived tumor organoids (PDTO). We found 5,129 SVs affecting at least one cancer gene in 88% of cases. High-confidence homologous recombination deficiency (HRD), determined by curation of mutational signatures and mutations/SVs affecting oncogenes and tumor suppressor genes, was detected in 8.3% of solid tumors (e.g., prostate, pancreas, ovarian, uterine, breast, gallbladder, and stomach carcinomas). HRD status included tumors with BRCA1/2 wildtype and SVs impacting BRCA1/2, RAD51, ATM and other HRD genes. CDK12-loss associated genomic instability was detected in 7 cases including 3 cases of prostate adenocarcinoma. 93 gene fusions involving cancer genes were detected including known and novel fusions of potential significance (e.g., SLC45A3::ALK in metastatic prostate adenocarcinoma, TMEM106A::BRCA1 in serious ovarian carcinoma, ESR1::EP300 in metastatic breast cancer). Some tumor cohorts demonstrated enrichment of drivers e.g., FGFR1 amplification in male breast cancer, rearrangements at the TERT locus in adrenocortical carcinoma, enrichment for repeat-mediated deletion attributed to mismatch repair (MMR) in gynecological carcinosarcoma, and SVs affecting FHIT in gastric adenocarcinoma. Drug screening of PDTO and functional testing with RAD51 immunofluorescence assay validated high-confidence HRD annotation. One example is a BRCA1/2 wildtype pancreatic adenocarcinoma with increased tandem duplications and SV (inversion) impacting BRCA2, and high-confidence HRD by our novel WGS classifier. Drug screening of the corresponding PDTO showed an enhanced response to Olaparib, in contrast to cases without HRD that did not. We have used state-of-the-art analysis of WGTS to improve the detection of targets and significant biomarkers in a pan cancer cohort, including HRD, CDK12-type genomic instability, pathogenic germline mutations and potential targetable novel fusions. A robust and clinically relevant ex vivo preclinical model allowed us to validate a WGS-based classifier that detects HRD even in cancers with wildtype BRCA1/2. Citation Format: Majd Al Assaad, Hui-Hsuan Kuo, Jones Nauseef, Max F. Levine, Gunes Gundem, Juan S. Medina-Martínez, Jyothi Manohar, Michael Sigouros, Ahmed Elsaeed, David Wilkes, Elli Papaemmanuil, Eloise Chapman, Scott T. Tagawa, Allyson Ocean, Cora N. Sternberg, Eleni Andreopoulou, Manish Shah, Andrea Sboner, Kevin Holcomb, David Nanus, Laura Martin, Olivier Elemento, Juan Miguel Mosquera. Whole genome and transcriptome sequencing of a pan cancer cohort unearths novel therapeutic avenues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3437.
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Johnson, Christian William, Elizabeth M. Terrell, Josh Cook, Bing Shui, Eve O'Donoghue, Shannon Hull, Moon Hee Yang et al. „Abstract 6623: Ala59 mutants of KRAS cooperate with Nf1 loss to enhance colon tumorigenesis“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 6623. http://dx.doi.org/10.1158/1538-7445.am2024-6623.
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Abstract Understanding the role of KRAS allele heterogeneity in tumor development, and its influence on therapeutic efficacy, is critical for the improvement of cancer treatment. The Kirsten rat sarcoma (KRAS) gene is the most frequently mutated oncogene in colorectal cancer (CRC) and patients with CRC tumors positive for KRAS mutations have poorer outcomes and limited treatment options. Extensive work over the past four decades has shown that common oncogenic alleles of KRAS are associated with hyperactivation of the MAPK signaling pathway (i.e. RAF/MEK/ERK), and it is for this reason that patients with KRAS mutant tumors are excluded from targeted therapies against EGFR. Recently, we characterized two alleles of KRAS, KRASA59T and KRASA59E, that paradoxically promote KRAS activation but are impaired in their ability to promote BRAF dimerization (Johnson et al. Mol Cell. 2022. PMID: 35202574). Consistent with these biochemical functions, KRASA59T and KRASA59E are enriched in CRC tumors that already have genetic alterations in genes that regulate MAPK signaling (e.g. EGFR, BRAF, NRAS, NF1). Further, unlike other described oncogenic alleles of KRAS, clinical data suggest that these KRASA59T and KRASA59E may not confer intrinsic resistance to anti-EGFR therapies at all. While KRASA59T and KRASA59E may not promote BRAF dimers, here we show that KRASA59T and KRASA59E does promote dimerization between ARAF and CRAF, and using an unpublished conditional mouse mode of K-Ras (i.e. LSL-K-RasA59E) we tested (1) whether Ala59 alleles are oncogenic or (2) require cooperation with additional MAPK pathway activating mutations, and (3) whether Ala59 alleles can promote intrinsic resistance to EGFR inhibition. Here, we show that endogenous K-RasA59E can disturb colon homeostasis and decrease mouse survival in an autochthonous colon tumor model, demonstrating that A59E alone is an oncogenic allele of KRAS in the colon. Breeding of LSL-K-RasA59E mice with mice harboring a conditional knockout of Nf1 (i.e. Nf1fl/fl), a GTPase activating protein (GAP) that promotes activation of wildtype RAS, show that combined expression of K-RasA59E and wildtype RAS activation cooperatively perturb colon homeostasis and decrease mouse survival. Thus, while KRASA59E may not require a second genetic alteration to activate the MAPK signaling pathway, it can cooperate with these alterations to increase the severity of disease. Finally, using mouse colon derived organoids, we show that endogenous K-RasA59E neither promotes EGF independence of organoid growth nor confers on these organoids a resistance to EGFR inhibition. Thus, our data support a unique role for RAF dimer function in in KRAS mutant tumors of the colon in both development and sensitivity to drugs, as well as argue for the inclusion of KRASA59T and KRASA59E bearing CRC tumors in anti-EGFR therapies. Citation Format: Christian William Johnson, Elizabeth M. Terrell, Josh Cook, Bing Shui, Eve O'Donoghue, Shannon Hull, Moon Hee Yang, Shikha Sheth, Rona Yaeger, Scott Kopetz, Deborah K. Morrison, Kevin Haigis. Ala59 mutants of KRAS cooperate with Nf1 loss to enhance colon tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6623.
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Steele, Maria, Tina Tan, Jason Yokoyama, Allan Wang, Ty Crowl, Jared Hammer, Jerry Chen et al. „Abstract LB070: In vitro modeling of antigen-driven exhaustion in human CAR T cells“. Cancer Research 84, Nr. 7_Supplement (05.04.2024): LB070. http://dx.doi.org/10.1158/1538-7445.am2024-lb070.
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Abstract A major hurdle for chimeric antigen receptor (CAR) T cells to function in solid tumors is chronic antigen exposure leading to terminal lymphocyte exhaustion and impaired anti-tumor activity. Therefore, it is necessary to establish improved in vitro models of antigen-driven CAR T cell exhaustion to evaluate new CAR design candidates prior to validation with costly in vivo studies. Using the human tumor antigen mesothelin (MSLN) and MSLN-targeting CAR T cells as a model, we developed two in vitro assays that drive an exhausted phenotype in human CAR T cells and can be used to predict anti-tumor responses in vivo: 1) a chronic stimulation assay with plate-bound recombinant antigen (MSLN), ICAM-1, and CD58 and 2) a high antigen-expressing 3D tumor spheroid co-culture assay. In the chronic antigen stimulation assay, repetitive exposure to plate-bound MSLN (alongside co-stimulation signals provided by recombinant ICAM-1 and CD58) reprogrammed the transcriptomic profile of MSLN CAR T cells leading to increased surface expression of inhibitory checkpoint molecules and reduced cytokine production. Moreover, chronically stimulated MSLN CAR T cells demonstrated a drastically impaired ability to kill MSLN+ tumor cells compared to their unstimulated or acutely stimulated counterparts. A similar exhausted phenotype was observed in the high-antigen tumor spheroid model: when MSLN CAR T cells were co-cultured with MSLN-high human NCI-H226 spheroids for 7 days in a 96-well plate, expression of inhibitory checkpoint molecules markedly increased on the surface of CAR T cells. This increased expression of exhaustion markers coincided with impairment of NCI-H226 spheroid clearance. By contrast, other tumor spheroid models expressing low to intermediate levels of MSLN (NCI-H1650, NCI-H2052, NCI-H292, and SKOV-3 tumor cells) did not substantially induce expression of inhibitory checkpoint molecules and the spheroids were successfully cleared by MSLN CAR T cells. Importantly, the ability (or inability) of a CAR construct to clear NCI-H226 high-antigen tumor spheroids in vitro accurately predicted CAR T cell performance in in vivo solid tumor studies: the CAR construct that showed effective killing in the in vitro spheroid model was the only condition to provide durable regression of NCI-H1650 tumors in a NSG xenograft mouse model. Additionally, the rank order of CAR efficacy for a series of MSLN CAR binders obtained using the tumor spheroid model mirrored in vivo efficacy. As the CAR T cell field develops novel strategies to combat antigen-driven exhaustion for use in solid tumors, these new antigen-dependent in vitro models of exhaustion can enable more cost-efficient and effective evaluation of those strategies than using in vivo models alone. Citation Format: Maria Steele, Tina Tan, Jason Yokoyama, Allan Wang, Ty Crowl, Jared Hammer, Jerry Chen, Kevin Haworth, Howell Moffett, Aaron Foster, Marc Lajoie, Scott Boyken, Rupesh Amin. In vitro modeling of antigen-driven exhaustion in human CAR T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB070.
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Shepherd, Scott T., Alex Coulton, Cathy D. Vocke, Chris J. Ricketts, Mark Ball, Fiona Byrne, Yuliia Dovga et al. „Abstract 133: Rewinding the tape of life: somatic profiling in Von Hippel-Lindau (VHL) disease reveals evolutionary contingency and constraints“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 133. http://dx.doi.org/10.1158/1538-7445.am2023-133.
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Abstract Whether cancer evolution follows a deterministic route prescribed by host factors (germline genetics and/or environment) or proceeds along multiple alternative trajectories due to the stochastic nature of evolution is unknown. Patients with VHL disease have a pathogenic germline mutation in VHL (3p25) and tumorigenesis occurs when the wild-type copy of VHL is lost. Patients develop multiple clonally independent tumors including clear cell renal cell carcinoma (ccRCC), pheochromocytoma or paraganglioma (PPGL) and pancreatic neuroendocrine tumors (pNET), offering an opportunity to test repeatability of evolutionary trajectories between and within patients. We performed deep targeted exome sequencing, in 1520 tumors (993 solid ccRCC; 156 cystic ccRCC; 135 mixed solid/cystic ccRCC; 236 extra-renal) from 130 patients with VHL disease to evaluate somatic variants and copy number alterations, ploidy and chromosomal complexity. Tumor phenotype was evaluated from pathology reports and longitudinal growth kinetics from diagnostic MRI data. Analysis of 889 tumor samples is complete and profiling of the full cohort will be presented at the 2023 AACR meeting. Within clonally independent tumors, we performed two tests to assess for evidence of convergence between tumors from the same patient. First, we tested for parallel events in canonical ccRCC drivers. We found significant enrichment of somatic VHL variants occurring in one patient with a germline whole VHL gene deletion encompassing neighboring BRK1. Contiguous BRK1 loss is associated with less aggressive ccRCC phenotype and our findings suggest a specific constraint in this patient. We next assessed for evidence of convergence by measuring the genetic distance of copy number and mutational profiles between and within patients with resampling and permutation. Similar somatic profiles between tumors were only detected in 1/76 patients whose tumors were characterized by infrequent somatic alterations beyond 3p loss indicating little evidence of convergence. Cystic ccRCCs represent an indolent phenotype not associated with metastasis that may progress to solid tumors over time; we found mixed tumors closely resemble somatic profiles of solid tumors whereas cysts were characterized by infrequent copy number gains and low chromosomal complexity. We also identified cysts with specific losses (chr16, chr17, chr19p) mutually exclusive with 3p LOH suggestive of VHL-loss independent cyst formation. In solid ccRCCs, we found chromosomal complexity and loss of specific chromosomal loci (9p and/or 14q) are associated with diameter potentially reconciling the observation linking risk of metastasis to tumor diameter in VHL-related ccRCC. In summary, within the constrained setting of VHL-related ccRCC, evolution is dominated by chance although specific patient and phenotype specific constraints are observed. Citation Format: Scott T. Shepherd, Alex Coulton, Cathy D. Vocke, Chris J. Ricketts, Mark Ball, Fiona Byrne, Yuliia Dovga, Annika Fendler, Barber Taja, Olga O'Neill, Lina Gerontogianni, Gavin Kelly, Laura S. Schmidt, Daniel R. Crooks, Kirstin Choo, Rabindra Gautam, Zoe Blake, Krista Reynolds, Kevin Litchfield, Maria Merino, Marston W. Linehan, Samra Turajlic. Rewinding the tape of life: somatic profiling in Von Hippel-Lindau (VHL) disease reveals evolutionary contingency and constraints [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 133.
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Banerjee, I., L. Edwards, P. Halvey, S. Alioto, D. Cluckley, C. Mitchell, C. Cox et al. „AB0034 PD-1 AGONISM INHIBITS ACTIVATION OF PLASMACYTOID DENDRITIC CELLS“. Annals of the Rheumatic Diseases 80, Suppl 1 (19.05.2021): 1050.1–1050. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2682.
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Background:T cell function is regulated by complex signaling networks of interconnected activators and inhibitors. Blockade of inhibitory receptors such as programmed death-1 (PD-1) has emerged as a novel treatment for multiple forms of cancer. One of the most common adverse events associated with blockade of the endogenous PD-1/PD-L1 pathway is the induction of autoimmune pathology in multiple tissues, demonstrating that PD-1 activation is necessary for normal immune homeostasis in humans (Kostine, et al., 2018). Given this body of clinical data, we sought to develop a PD-1 agonist antibody as a therapeutic approach to restore immune homeostasis in patients living with autoimmune diseases. PD-1 expression and function has been primarily described on T cells (Ishida, et al., 1992), with additional data available from several other immune cell populations (Ohaegbulam, et al., 2015).Objectives:To study the effect of PD-1 agonism on plasmacytoid dendritic cell (pDC) function.Methods:Human PBMCs stimulated with or without toll-like receptor (TLR)-9 agonist, CpG were analyzed by flow cytometry for PD-1 expression on immune cell subsets. To assess the impact of PD-1 agonist on pDC function human PBMCs were activated by CpG in the presence or absence of PD-1 agonist. Type-I interferon (IFN) levels were quantified using ELISA from culture supernatants. The expression of interferon stimulated genes was analyzed by qPCR as a measure of type-I IFN activation.Results:We have discovered that TLR9 activation can induce PD-1 expression on plasmacytoid dendritic cells, which has not been previously reported. Further, we have demonstrated that PD-1 agonism inhibits TLR9-mediated activation and the effector functions of plasmacytoid dendritic cells.Conclusion:These data suggest the potential of PD-1 as a target for regulating diseases with pathology generated by type-I IFN.References:[1]Ishida, Y., Agata, Y., Shihibahara, K., & Honjo, T. (1992). Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J., 11(11):3887-95.[2]Kostine, M., Rouxel, L., Barnetche, T., Veillon, R., Martin, F., Dutriaux, C., . . . Schaeverbeke, T. (2018). Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study. Annual Rheumatic Disease, 77(3):393-398.[3]Ohaegbulam, K. C., Assal, A., Lazar-Molnar, E., Yao, Y., & Zang, X. (2015). Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends in Molecular Medicine, 21(1); 24-33.Disclosure of Interests:Ishita Banerjee Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Lindsay Edwards Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Patrick Halvey Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Salvatore Alioto Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, David Cluckley Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Caitlin Mitchell Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Christopher Cox Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Emily Lurier Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Michael Cianci Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Soumya Bengeri Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Susmita Borthakur Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Katalin Kis-Toth Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Nathan Higginson-Scott Shareholder of: Pandion Therapeutics, Consultant of: Biotech Companies, Employee of: Pandion Therapeutics, Jo Viney Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics, Kevin L. Otipoby Shareholder of: Pandion Therapeutics, Employee of: Pandion Therapeutics
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Coulton, Alexander, Irene Lobon, Lavinia Spain, Andrew Rowan, Desiree Shnidrig, Scott Shepherd, Ben Shum et al. „Abstract PR002: Advanced melanoma exhibits a diversity of evolutionary routes to lethality“. Cancer Research 82, Nr. 10_Supplement (15.05.2022): PR002. http://dx.doi.org/10.1158/1538-7445.evodyn22-pr002.
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Abstract Despite recent advances in the treatment of advanced melanoma using immune checkpoint inhibitors (ICI), 5-year overall survival remains suboptimal. A clear understanding of the potential evolutionary trajectories of melanoma is needed in order to advance treatment and prognostic options. Here we present the Posthumous Evaluation of Advanced Cancer Environment (PEACE) study of advanced melanoma, revealing a diversity of evolutionary pathways to lethality. This interim analysis of our 50-patient cohort comprises 14 ICI-treated patients with a mixture of phenotypic subtypes, including cutaneous, acral, mucosal and melanoma of unknown primary. The sampling regime encompasses a broad range of visceral metastases from various organ sites, with a total of 573 tumor samples (an average of 40 samples per patient). Our data span a variety of modalities, including exomic, transcriptomic, panel sequencing, single cell sequencing, FISH, and radiological data. Clonal phylogenies of patients were diverse in structure: some followed a linear evolutionary trajectory with little to no branching, whereas others followed a branched evolutionary pattern. We also observed various patterns of metastatic seeding, with both monoclonal and polyclonal cases of seeding. In addition, patients treated with chemotherapy showed higher subclonal mutational burden than those without. As with previous literature, we found extensive copy number alterations in these advanced melanomas. In contrast, however, our data also reveal patients with no incidence of WGD, with previous work finding this to be a ubiquitous feature of advanced melanoma. In cases of WGD, the majority of copy number alterations were losses rather than gains. In terms of treatment resistance, we observed loss of heterozygosity in key genes of the antigen presentation pathway (most notably B2M), and little signal of neoantigen loss via immunoediting, indicating that these tumors develop resistance to ICI regardless of neoantigen burden. A further question of interest was the determination of lesion-level factors influencing response to ICI treatment using radiological data. MYC amplification was significantly associated with non-responding lesions, whilst PBX1, a promoter of natural killer cells, was shown to be significantly amplified in responding lesions. Our single-cell data reveal a case of polyclonal seeding at the level of whole-genome doubling. This has implications for sample-level phylogenies that are inferred from copy-number status, indicating that intra-tumor heterogeneity at the level of copy number could confound these trees. We also find a potentially novel driver of melanoma, PHF3. This gene has previously been associated with UV DNA-damage response, however here it was found in a non-sun damaged melanoma to have a clonal, focal 7n copy number gain in an otherwise diploid cancer, with corresponding upregulation of expression. In summary, our study comprises an extensive intra-patient, multi-lesion analysis of advanced melanoma, with important implications in both technical and clinical settings. Citation Format: Alexander Coulton, Irene Lobon, Lavinia Spain, Andrew Rowan, Desiree Shnidrig, Scott Shepherd, Ben Shum, Fiona Byrne, Lewis Au, Kim Edmonds, Ellie Carlyle, Alexandra Renn, Christina Messiou, Charlotte Spencer, Andreas M. Schmidt, Zayd Tippu, Aljosja Rogiers, Max Emmerich, Camille Gerard, Husayn Pallikonda, Cristina Naceur-Lombardelli, Floris Foijer, Hilda van den Bos, René Wardenaar, Diana Spierings, Kate Young, Lisa Pickering, Andrew Furness, Elaine Borg, Miriam Mitchison, David Moore, Mary Falzon, Ian Proctor, Ruby Stewart, Ula Mahadeva, Anna Green, James Larkin, Charles Swanton, Mariam Jamal-Hanjani, Kevin Litchfield, Samra Turajlic. Advanced melanoma exhibits a diversity of evolutionary routes to lethality [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR002.
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Kolitz, Sarah, Praveen Nair, Mai Johnson, Jason Funt, Peter J. King, Kevin D. Fowler, Anna Travesa et al. „Abstract B021: Pan-RAS IMM-1-104 activity in humanized 3D tumor models is independent of specific amino acid substitution“. Molecular Cancer Research 21, Nr. 5_Supplement (01.05.2023): B021. http://dx.doi.org/10.1158/1557-3125.ras23-b021.
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Abstract Introduction: Novel dual-MEK inhibitor IMM-1-104 is under clinical investigation for use in RAS-addicted solid tumors. Approved KRAS G12C inhibitors are available but cover a limited subset of patients. For example, the KRAS G12C substitution occurs in only 1-3% of pancreatic cancers. We assessed response to IMM-1-104 across RAS mutant preclinical models to determine whether a preference was observed for mutation position, or for specific amino acid substitutions. Experimental Procedures: Response to IMM-1-104 was measured in a humanized 3D tumor growth assay across 133 tumor models. Sixty-nine of these models have a reported RAS mutation, and all models are being mutationally profiled by whole exome sequencing, with the majority (~75%) completed to date. The RAS-mutant panel spans 11 tissue types and includes a subset of 30 confirmed KRAS G12 mutated cell lines drawn from three major indications: 12 pancreatic, 11 lung, and 7 colorectal cancer models. Based on the 3D assay, cell lines were classified into sensitive, intermediate, and resistant to IMM-1-104. The distribution of responses was then assessed across mutation position and amino acid substitutions. Summary of New Data: In the full dataset across 69 RAS-mutant models, at least one model displayed response to IMM-1-104 (sensitive or intermediate) for each observed mutation in K/N/HRAS. That is, no particular mutation position or amino acid substitution was exclusively found to be resistant. Association of response with amino acid identity was further evaluated in a subset of lines for the most frequently altered residue in KRAS, G12. A distribution of responses was observed for each amino acid substitution. The G12 substitutions having at least four cell lines each total across the three indications included G12C (8 lines), D (5 lines), R (4 lines), and V (11 lines). Across cell lines for each of these substitutions, multiple response categories were observed. In each case, half or more lines fell into the intermediate category with the rest falling into one or both of the other response categories. For example, out of the 8 KRAS G12C lines, 6 showed intermediate response, 1 showed resistance, and 1 showed sensitivity. Examining these distributions together, no significant statistical relationship was seen between the amino acid substitution and response categories by Fisher’s exact test. Conclusions: Across 69 RAS-mutated cell lines, each mutation position or amino acid substitution was associated with sensitive or intermediate response in at least one line. Looking at the most commonly mutated position in KRAS, across 30 KRAS G12 mutated cell lines from three cancer indications, no significant preference was observed with respect to response to IMM-1-104 for a particular amino acid at G12. These observations suggest potential relevance of IMM-1-104 to a broad RAS-driven patient population. Citation Format: Sarah Kolitz, Praveen Nair, Mai Johnson, Jason Funt, Peter J. King, Kevin D. Fowler, Anna Travesa, Frank Wang, John Brothers II, Amy Axel, Scott Barrett, Benjamin J. Zeskind, Brett Hall. Pan-RAS IMM-1-104 activity in humanized 3D tumor models is independent of specific amino acid substitution [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B021.
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Abbassi, Laleh, Jullien Dilly, Annan Yang, Giselle Uribe, Branden Parent, Connor Hennessey, Kevin Kapner et al. „Abstract A078: Response and resistance to KRAS inhibition in PDAC mouse models“. Cancer Research 84, Nr. 2_Supplement (16.01.2024): A078. http://dx.doi.org/10.1158/1538-7445.panca2023-a078.
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Abstract Pancreatic ductal adenocarcinoma (PDAC), among the most lethal cancers with a 5-year survival rate of 11%, is a KRAS-driven disease. Studies have shown that a single glycine (G) to aspartic acid (D) substitution on codon 12 of KRAS protein (known as KRASG12D mutation) appears in 41% of all PDAC cases, highlighting the necessity of targeting KRASG12D as a therapeutic approach. MRTX1133, a recently developed potent, non-covalent, direct, and selective KRASG12D small molecule inhibitor demonstrates a high-affinity interaction with KRASG12D. Previous studies have shown striking efficacy of MRTX1133 on growth inhibition of mouse/human PDAC tumor cells carrying KRASG12D mutation in various in vivo and in vitro models, during short-term treatment. Here in our study, we investigated the efficacy of continuous long-term treatment with MRTX1133 in two different PDAC mouse models: KPC (a genetically engineered mouse model harboring a KRASG12D mutation) and its syngeneic orthotopic model. In both models, tumor sizes were detected by ultrasound imaging and after reaching 100-300 mm3 in volume, mice were enrolled in either MRTX1133 or vehicle treatment (30mg/kg, IP, BID). Tumor sizes were monitored by ultrasound regularly and the treatment continued until mice reached clinical endpoint. At endpoint, mice were sacrificed, and tumors were harvested for a series of downstream experiments. Our results showed that while, in both models, vehicle treated tumors grew aggressively and mice reached endpoint in average 6 days post treatment, drug treated tumors regressed rapidly and survival rate increased significantly to as late as 222 days post treatment in KPC model. However, in both models, drug treated tumors ultimately relapsed, developed resistance to the drug, and resulted in death. Further analysis of KPC mice ultrasound images evidenced that the relapsed tumors occurred at the same sites of the primary tumors. This suggests the possibility of relapsed tumors arising from the regrowth of the dormant residual cells from the primary tumors. Re-implantation of the resistant tumors either in the flank or pancreata of the new wildtype mice resulted in the formation of drug-resistant tumors in hosts. In addition, histopathology analysis of the tumor sections demonstrated a significant increase in the ratio of invasive PDAC to PanIN areas in the drug resistant tumors. Furthermore, multiplex immunofluorescence of both MRTX1133 resistant and vehicle treated tumors from KPC mice demonstrated co-expression of markers representing basal-like and classical PDAC subtypes. Moreover, flow cytometry analysis indicated an increase in the myeloid population of the resistant tumors comparing to the vehicle treated group. In the future directions, through applying a broad range of cellular and molecular experiments we will characterize the kinetics of KRAS inhibitor drug resistance and define possible combination therapy startegies to overcome drug resistance mechanisms. Citation Format: Laleh Abbassi, Jullien Dilly, Annan Yang, Giselle Uribe, Branden Parent, Connor Hennessey, Kevin Kapner, Alexander Jordan, Shatavisha Dasgupta, Micaela Morgado, Taimour Baslan, Li Qiang, Peter Winter, Seema Chugh, Alex Shalek, Ben Stanger, Srivastan Raghavan, Scott Lowe, Brian Wolpin, Stephanie Dougan, Jonathan Nowak, Andrew Aguirre. Response and resistance to KRAS inhibition in PDAC mouse models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A078.
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Nair, Praveen, Sarah Kolitz, Jason Funt, Jan de Jong, Peter King, Amy Yamamura, Mai Johnson et al. „Abstract A134: Predicting activity of IMM-1-104 as single agent and in combination for patients with RAS or RAF mutant tumors“. Molecular Cancer Therapeutics 22, Nr. 12_Supplement (01.12.2023): A134. http://dx.doi.org/10.1158/1535-7163.targ-23-a134.
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Abstract Introduction: Many tumors are addicted to MAPK pathway activation, including the >20% of human tumors with mutations in RAS or RAF1. IMM-1-104 is an oral once-daily treatment currently in Phase 1 in patients with RAS-mutant solid tumors [NCT05585320]. To date, drugs disrupting the MAPK pathway have done so chronically, leading to dose-limiting toxicities (DLTs) and poor response durability. In contrast, IMM-1-104 was designed to provide deep cyclic inhibition (DCI) of the MAPK pathway via a unique pharmacokinetic (PK) profile with high peak plasma drug levels and a near zero drug trough between doses. This promotes pulsatile inhibition of MEK, depriving tumors of sustained signaling of a critical oncogenic pathway while limiting toxicity and durability issues associated with chronic MEK inhibition. In Phase 1a dose escalation, no DLTs were observed, the plasma drug half-life was ~2-hours, and pharmacodynamic (PD) data were consistent with DCI. Phase 1b dose expansion is underway. Translational efforts are focused on identifying MAPK pathway addiction and sensitivity to IMM-1-104. Tumor models displaying patient-aligned genomic profiles against large patient databases such as AACR Project GENIE1 were tested in humanized 3D tumor growth assays (3D-TGA). Computational modeling based on response and in-house genomic data was used to inform identification of patient populations for IMM-1-104 monotherapy and potential combination opportunities. Experimental Procedures: Using cancer-specific, patient-aligned cell lines, IMM-1-104 activity was characterized in the 3D-TGA. Whole exome sequencing was performed to confirm alteration status, and a further subset subjected to RNA sequencing. Pharmacogenomic data were used to generate a model predictive of response to IMM-1-104 and identify biomarker-aligned patient subpopulations. Selected model predictions were then tested in subcutaneous tumor xenograft models in female BALB/c nude mice. Summary of New Data: Assessment of IMM-1-104 across >190 patient-aligned models demonstrated diverse responses across a wide range of MAPK-driven tumor types, including those with RAS or RAF mutations. In addition to RAS, these data suggested additional potential for IMM-1-104 in BRAF-mutant disease. Therefore, IMM-1-104 was tested alone and with encorafenib in the HT-29 colorectal BRAFV600E mutant xenograft model. Monotherapy with either encorafenib or IMM-1-104 displayed superior tumor growth inhibition to binimetinib. IMM-1-104 in combination with encorafenib drove deeper regressions and superior durability of response in a head-to-head in vivo comparison versus binimetinib plus encorafenib. Conclusions: We used an integrated platform of translational experiments and informatics to identify patient-aligned model systems, prioritize factors relevant for response to IMM-1-104’s unique DCI profile, and elucidate combination opportunities to potentially inform clinical development strategies. Citation Format: Praveen Nair, Sarah Kolitz, Jason Funt, Jan de Jong, Peter King, Amy Yamamura, Mai Johnson, Jenny Zhang, Kevin D Fowler, Anna Travesa, Amy Axel, Chris Walker, Scott Barrett, Benjamin J Zeskind, Brett Hall. Predicting activity of IMM-1-104 as single agent and in combination for patients with RAS or RAF mutant tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A134.
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Travesa, Anna, Mai Johnson, Peter King, Praveen Nair, Jason Funt, Sarah Kolitz, Kevin D. Fowler et al. „Abstract A093: Deep Cyclic Inhibition of the MAPK pathway with IMM-6-415, alone and in combination with encorafenib, demonstrates anti-tumor activity and tolerability in RAF mutant tumors in vivo“. Molecular Cancer Therapeutics 22, Nr. 12_Supplement (01.12.2023): A093. http://dx.doi.org/10.1158/1535-7163.targ-23-a093.
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Abstract Introduction: A significant proportion of cancer patients have tumors addicted to uncontrolled MAPK signaling. Activating mutations in RAS or RAF are often directly responsible and have been observed in over 20% of human tumors1. Because MEK is downstream of RAS and RAF, it is an appealing drug target. However, MEK inhibitors have historically suffered from poor clinical durability, high toxicity and a susceptibility to pathway reactivation that has limited monotherapy activity in the RAS mutant setting. Unlike other MEK inhibitors, IMM-1-104 [NCT05585320] and IMM-6-415 are designed with distinctive features including both (1.) a unique target engagement mechanism that helps resist MAPK pathway reactivation and (2.) a pharmacokinetic (PK) profile that enables fast cadence deep cyclic inhibition (DCI). DCI drives pulsatile targeted inhibition that deprives tumor cells of a critical oncogenic pathway while limiting drug-related toxicities by affording normal cells an adequate PK recovery window between drug doses. To our knowledge, IMM-6-415’s preclinical activity is driven by the shortest drug plasma half-life (0.3-hours in mice) of any MEK inhibitor developed to date. Experimental Procedures: IMM-6-415 has already demonstrated promising activity in RAS-mutant xenograft tumor models (SITC 2022). Here, the antitumor activity of IMM-6-415 was evaluated in over 60 humanized 3D tumor growth assays (3D-TGA), which included 30 BRAF class I-mutant tumor models. Additionally, multiple drug-drug combinations have been explored, including vertical drug combinations with BRAF inhibitors. IMM-6-415, binimetinib and encorafenib were tested head-to-head as single agents and in combination with encorafenib in BRAFV600E melanoma and colorectal subcutaneous tumor xenograft models in female BALB/c nude mice. Summary of New Data: As monotherapy, IMM-6-415 demonstrated antitumor activity in over 50% (34 of 66) of the 3D-TGA models tested, including 30 BRAF-mutant preclinical models in which 19 (63%) showed activity. Therefore, we further explored both monotherapy and combination activity of IMM-6-415 in the A-375 (melanoma) and HT-29 (colorectal) BRAF V600E tumor xenograft models. Monotherapy treatment with encorafenib or IMM-6-415 displayed superior tumor growth inhibition (TGI) when compared to binimetinib. Furthermore, the combination of IMM-6-415 plus encorafenib prompted greater TGI with superior durability of response when tested head-to-head against the combination of binimetinib plus encorafenib in vivo at human equivalent doses for registered drugs. Conclusions: IMM-6-415 demonstrated promising activity and tolerability in preclinical models alone and in combination with encorafenib. In combination with encorafenib, IMM-6-415 achieved a greater TGI in vivo than the combination of encorafenib plus binimetinib in BRAFV600E colorectal cancer and melanoma tumor models, suggesting an opportunity for IMM-6-415 as monotherapy or in combination in BRAF mutant tumors. Citation Format: Anna Travesa, Mai Johnson, Peter King, Praveen Nair, Jason Funt, Sarah Kolitz, Kevin D Fowler, John Brothers II, Amy Axel, Scott Barrett, Benjamin J Zeskind, Brett Hall. Deep Cyclic Inhibition of the MAPK pathway with IMM-6-415, alone and in combination with encorafenib, demonstrates anti-tumor activity and tolerability in RAF mutant tumors in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A093.
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Castro, Jennifer, Matthew H. Daniels, David Brennan, Brian T. Johnston, Rishabh Bansal, Monique Laidlaw, Chuang Lu et al. „Abstract C087: DHX9 inhibition as a novel therapeutic modality in microsatellite instable colorectal cancer“. Molecular Cancer Therapeutics 22, Nr. 12_Supplement (01.12.2023): C087. http://dx.doi.org/10.1158/1535-7163.targ-23-c087.
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Abstract Background: DHX9 is a DEAH-box RNA helicase which has been reported to play important roles in replication, transcription, translation and RNA splicing/processing, all of which contribute to DHX9’s role in the maintenance of genomic stability. Functionally, DHX9 unwinds and/or resolves regions of double-stranded DNA and RNA helices but has a greater propensity for secondary structures such as DNA/RNA hybrids (R-loops), circular RNA (circRNA) and DNA/RNA G-quadraplexes. Overexpression of DHX9 is evident in multiple cancer types, including colorectal cancer (CRC) and lung cancer. In particular, microsatellite instable (MSI) tumors exhibiting defective mismatch repair (dMMR) show a strong dependence on DHX9, making this helicase an attractive target for oncology drug discovery. Here, we will demonstrate validation of DHX9 as a novel target for CRC-MSI, and the identification of potent and selective in vitro and in vivo small molecule inhibitors of DHX9. Materials and Methods: DHX9 targeted siRNA or DHX9 small molecule inhibitors were used to assess anti-proliferative activity in multiple different CRC-MSI and CRC-MSS cell lines through either CellTiter-Glo proliferation or colony formation assays. Downstream biological consequences of DHX9 knockdown or inhibition in vitro were determined using immuno-fluorescent imaging, western blot, flow cytometry to measure RNA/DNA secondary structure, cell cycle changes, apoptosis, and qPCR to measure circBRIP1 induction. CRC-MSI and CRC-MSS tumor xenografts were treated with DHX9 inhibitor ATX968 BID orally for 21-28 days. Tumor and plasma samples were collected for pharmacokinetics (PK) and pharmacodynamic (PD) (circBRIP1) measurement. Results: We demonstrate that DHX9 inhibition in CRC-MSI leads to an increase in RNA/DNA secondary structures such as R-loops, G-quadruplexes and Alu mediated circRNA such as circBRIP1, leads to subsequent DNA damage and increased replication stress. Cell lines that exhibit defective DNA repair pathways such as dMMR are unable to resolve this replication stress and demonstrate S-G2 phase cell cycle arrest prior to onset of apoptosis. We confirmed this selective dependency in a panel of cancer cell lines, where anti-proliferative effects mediated by DHX9 inhibition were associated with dMMR status. Furthermore, DHX9 tool compound ATX968 was well tolerated in vivo across a 28-day treatment period with robust and durable tumor regression observed in the MSI CRC tumor xenograft model. Following cessation of treatment, minimal tumor regrowth was observed in a 28-day post treatment window. Tumor and plasma concentrations of ATX968 and changes in PD markers of DHX9 inhibition were measured and resulting PK, PD and efficacy data were highly correlated. Conclusions: Together, these preclinical data validate DHX9 as a tractable new target with potential utility as a novel treatment for patients with CRC-MSI. Conflict of Interests: All authors are current or former employees and shareholders of Accent Therapeutics, Inc. Citation Format: Jennifer Castro, Matthew H Daniels, David Brennan, Brian T Johnston, Rishabh Bansal, Monique Laidlaw, Chuang Lu, Deepali Gotur, Young-Tae Lee, Kevin Knockenhauer, April Case, Jie Wu, Anugraha Raman, Jae Eun Cheong, Julie Liu, Shane M Buker, E. Allen Sickmier, Stephen J Blakemore, P. Ann Boriack-Sjodin, Kenneth W Duncan, Serena J Silver, Scott Ribich, Robert A Copeland. DHX9 inhibition as a novel therapeutic modality in microsatellite instable colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C087.
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Bradley, Colin, Matthew Golden, Faiz Musafere und Josh Havin. „Predicting the behavior of commercially available building foundation isolation materials using a four-parameter fractional Zener model“. INTER-NOISE and NOISE-CON Congress and Conference Proceedings 265, Nr. 1 (01.02.2023): 6208–15. http://dx.doi.org/10.3397/in_2022_0922.
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In this paper we apply a four-parameter fractional Zener model to describe the short and long term creep behavior of a viscoelastic building foundation isolating material currently in use globally in noise and vibration mitigation applications. Building from the classical rheological models composed of springs and dashpots suitably combined (Maxwell, Kelvin-Voight, Zener), we include a fractional derivative component in the form of a Scott-Blair element composed of a Riemann-Liouville derivative of non-integer order. The parameters are identified empirically through measured stress-strain results and hysteresis curves for the material in compression. The model is then compared to the results of a 168h constant load creep test of three commercially available materials.