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Published: 10 December 2022

Last updated: 28 January 2023

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1

HaCohen, Ruth. "Sounds of Revelation: Aesthetic-Political Theology in Schoenberg's Moses und Aron." Modernist Cultures 1, no. 2 (October 2005): 110–40. http://dx.doi.org/10.3366/e2041102209000082.

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Ruth HaCohen (Hebrew University) explores Modernism's artistic exploration of its relationship to theology by taking up Schoenberg's late, unfinished opera Moses and Aaron. Reading that opera as a theological-political-aesthetic Tractatus in the tradition of Spinoza, HaCohen draws out the theological implications of Schoenberg's radical rethinking of formal conventions as these organize the relationship between music and text.

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2

Hulick, Jeannette. "Who’s Hungry? by Dean Hacohen." Bulletin of the Center for Children's Books 69, no. 3 (2015): 146–47. http://dx.doi.org/10.1353/bcc.2015.0863.

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3

Loeffler, James. "Ruth HaCohen. The Music Libel against the Jews." American Historical Review 119, no. 4 (October 2014): 1341–42. http://dx.doi.org/10.1093/ahr/119.4.1341.

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4

CMIEL, KENNETH. "TALKING ABOUT TRUTH." Modern Intellectual History 1, no. 2 (August 2004): 293–304. http://dx.doi.org/10.1017/s1479244304000174.

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Malachi Haim Hacohen, Karl Popper – The Formative Years, 1902–1945: Politics and Philosophy in Interwar Vienna (Cambridge: Cambridge University Press, 2000)John Kadvany, Imre Lakatos and the Guises of Reason (Durham, NC: Duke University Press, 2001)Steve Fuller, Thomas Kuhn: A Philosophical History for our Times (Chicago: University of Chicago Press, 2000)

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5

Winther, Judith. "Rabbi Avraham Yizhak HaCohen Kook: between exile and messianic redemption." Nordisk Judaistik/Scandinavian Jewish Studies 9, no. 2 (September 1, 1988): 69–81. http://dx.doi.org/10.30752/nj.69427.

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Until the 19th century and to a certain extent, somewhat into the 20th century, most adherents of traditional, orthodox Judaism were reluctant about, or indifferent towards the active realistic Messianism of Maimonides who averred that only the servitude of the Jews to foreign kings separates this world from the world to come. It follows that important sections of Jewry opposed the budding Zionist idea. Zionism was an abomination in that it would substitute a purely human form of redemption for a redeemer sent by God, and therefore appeared to incite rebellion against God. Rabbi Kook’s teaching was an innovative interpretation of Zionism, not in terms of halakha, Jewish law, but in terms of the Jewish religion as a belief system. He tried to understand the secular Zionist world view, attempted to see redemption as a multi-step process, visualized the Land of Israel as a spiritual centre, and imbued its centrality, although profanely based, with religious significance.

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6

Lapidot, Elad. "Jewish Redemptive Epistemologies, Hegelian Teshuvot: Soloveitchik, Rosenzweig and Kook." Naharaim 14, no. 1 (June 25, 2020): 35–57. http://dx.doi.org/10.1515/naha-2019-0017.

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AbstractThis paper consists in a reflection on the conceptual nerve center of Franz Rosenzweig’s thought and heritage that is the category of redemption as an epistemological category. The reflection is articulated through a comparative study of the redemptive epistemologies of three modern Jewish thinkers: Franz Rosenzweig, Rabbi Yoseph Dov Soloveitchik and HaRav Avraham Yitzchak HaCohen Kook. The comparison arises from a basic feature that this paper identifies as common to all three modern visions of epistemic Jewish redemption: they all feature Hegelian interpretations of the traditional Jewish category of teshuva.

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7

Rosenberg, Jesse. "The Music Libel Against the Jews by Ruth HaCohen (review)." Notes 69, no. 4 (2013): 724–30. http://dx.doi.org/10.1353/not.2013.0056.

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8

Shatz, David. "Rav Avraham Itzhak HaCohen Kook: Between Rationalism and Mysticism. Benjamin Ish-Shalom." Journal of Religion 75, no. 3 (July 1995): 446–47. http://dx.doi.org/10.1086/489658.

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9

Magalhães, Marcos. "Ruth Katz and Ruth HaCohen, Tuning the Mind: Connecting Aesthetics to Cognitive Science." Pragmatics and Cognition 15, no. 2 (June 12, 2007): 387–92. http://dx.doi.org/10.1075/pc.15.2.10mag.

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10

Shafir, Abraham I. ""Az Terem"—A Piyyut by Yochanan Hacohen: A Kedushtha for the Shavuʿot Festival Morning." Hebrew Studies 45, no. 1 (2004): 223–52. http://dx.doi.org/10.1353/hbr.2004.0002.

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11

Kalimi, Isaac. "The Centrality and Interpretation of Psalms in Judaism prior to and during Medieval Times: Approaches, Authorship, Genre, and Polemics." Review of Rabbinic Judaism 23, no. 2 (September 8, 2020): 229–59. http://dx.doi.org/10.1163/15700704-12341371.

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Abstract This study discusses the centrality of the book of Psalms among the Jews and in Judaism. It outlines the seven most important and influential rabbinic exegetical works on Psalms, in the period before and during the medieval age: Targum Psalms and Midrash Psalms Shocher Tov, from some time in the Talmudic period; and five prominent medieval commentaries: Saadia Gaon, Moses haCohen ibn Gikatilla, Rashi, Abraham ibn Ezra, and David Kimchi. I briefly introduce each interpretative work and focus on selected aspects: The commentators’ distinct exegetical methods, their approaches to the questions of the authorship and genre of Psalms, and polemics with inside (e.g., Karaites) and outside (e.g., Christians) opponents. The result is to analysis and synthesis their approaches and to show the various trends that rabbinic Psalms interpretation took in these periods.

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12

Euchner, Walter. "Der Geist des „Roten Wien“ ins 21. Jahrhundert gerettet: Karl Popper Reconsidered by Malachi Haim Hacohen." Politische Vierteljahresschrift 45, no. 1 (March 2004): 116–24. http://dx.doi.org/10.1007/s11615-004-0010-2.

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13

Gensheimer, Cynthia Francis. "To Repair a Broken World: The Life of Henrietta Szold, Founder of Hadassah by Dvora Hacohen." AJS Review: The Journal of the Association for Jewish Studies 46, no. 2 (November 2022): 434–36. http://dx.doi.org/10.1353/ajs.2022.0064.

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14

Nir, Bracha. "Resonance as a resource for stance-taking in narratives." Stance, resonance and the power of engagement 24, no. 1 (August 18, 2017): 94–120. http://dx.doi.org/10.1075/fol.24.1.05nir.

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Abstract This paper traces the recurrence and manipulation of devices in monologic narrative texts produced by university students based on a semi-structured elicitation. It focuses on a detailed analysis of multiple texts produced by different speaker-writers of Hebrew, to illustrate the function of structural resonance of both clauses and combinations of clauses (Clause Packages). The analyses show that while lexical devices reflect a more distanced (less evaluative) discourse stance (Berman 2005), the use of creative resonance (Du Bois 2014) between syntactic structures can either enhance or undermine the narrator’s own explicit perspective on events. Stance is thus not only highlighted by resonance in monologic texts (Sakita this issue); in fact, stance is engaged with in a way that is very similar to what has been illustrated for dialogue (Dori-Hacohen this issue; Dutra this issue; Nir & Zima this issue). It is suggested that the power of this engagement can be fully assessed only if lexical and syntactic resonance are systematically analyzed.

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15

Notturno, Mark A. "Karl Popper: The Formative Years, 1902–1945, Malachi Haim Hacohen. Cambridge University Press, 2000, xiii + 610 pages." Economics and Philosophy 18, no. 2 (October 2002): 351–85. http://dx.doi.org/10.1017/s0266267102252098.

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16

Muhammad Ateeq. "POPPER’S MORAL INDIVIDUALISM AND ITS IMPLICATION FOR REASONABLE DIALOGUE: FOCUS ON HACOHEN’S AND O’HEAR’S INQUIRY OF POPPER’S ETHICS." Journal of Social Sciences and Humanities 54, no. 2 (December 31, 2015): 33–43. http://dx.doi.org/10.46568/jssh.v54i2.113.

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It is said that the social conflicts and disputes can be resolved by dialogue between opposing groups. Karl popper argues that if social conflicts are resolved with the authoritarian attitude that our arguments are conclusive then this attitude imposes its opinion and hence it cannot provide the ground for reasonable dialogue. Karl Popper rejects authoritarian attitude on the basis of his critique of absolute knowledge. He believes in fallibility of knowledge. He thinks that if disagreementsare resolved with an attitude that our arguments are rational but are not conclusive then this attitude is ready to be convinced by other. Hence it can provide the ground for reasonable dialogue. Popper is of the view that an attitude is moral as it believes in equality of men. Hacohen and O’Hear critically examine Popper’s fallibilism. They identify a problem that fallibilism ultimately leads Popper to anti-foundationalism which makes ethics purely individualistic. In this paper I focus on this problem and workout how Popper’s moral individualism is inadequate for possibility of reasonable dialogue.

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17

Helasvuo, Marja-Liisa. "Searching for motivations for grammatical patternings." Pragmatics. Quarterly Publication of the International Pragmatics Association (IPrA) 24, no. 3 (September 1, 2014): 453–76. http://dx.doi.org/10.1075/prag.24.3.02hel.

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In this article I analyze subject expression in conversational Finnish, identifying the home environments for zero and pronominal subjects in the 1st and 2nd person singular. Based on a syntactically coded database, I show that there is a clear preference, in both 1st and 2nd person, for pronominal subjects over zeros; in other words, double-marking is preferred over single-marking. This clearly contravenes the general preference for minimization or economy in person reference in conversation, as suggested by Sacks and Schegloff (1979) and Levinson (2007; see also Hacohen and Schegloff 2006). The home environments for zero and pronominal subjects are analyzed in terms of the micro-level social actions performed by participants, in order to find motivations for the choice of the form of subject. The analysis of the Finnish data shows that the choice between zero vs. pronominal subject is sensitive to features in the sequential context. It affects turn projection. The article shows that a systematic analysis of the data can provide important insights regarding global patterns. The deeper motivations that lie behind these patternings, however, cannot be understood without close microanalysis of the local contexts of subject expression.

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18

Beller, Steven. "Malachi Haim Hacohen. Jacob & Esau: Jewish European History Between Nation and Empire. Cambridge: Cambridge University Press. Pp. xxi + 733." Austrian History Yearbook 51 (March 27, 2020): 333–35. http://dx.doi.org/10.1017/s0067237820000272.

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19

Stampfer, Shaul. "The Music Libel Against the Jews. By Ruth HaCohen. New Haven, CT: Yale University Press, 2011. Pp. xvi + 507; plates. $38.00." Religious Studies Review 39, no. 4 (December 2013): 283. http://dx.doi.org/10.1111/rsr.12089_8.

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20

Brenner, Michael. "Malachi Haim Hacohen. Jacob & Esau: Jewish European History between Nation and Empire. New York: Cambridge University Press, 2019. 752 pp." AJS Review 44, no. 2 (October 22, 2020): 448–50. http://dx.doi.org/10.1017/s0364009420000306.

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21

Millen, Rochelle L. "Benjamin Ish-Shalom. Rav Avraham Itzhak HaCohen Kook: Between Mysticism and Rationalism. Albany: State University of New York Press, 1993. 329 pp." AJS Review 21, no. 1 (April 1996): 216–19. http://dx.doi.org/10.1017/s0364009400007984.

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22

Sandner, Günther. "Malachi Haim Hacohen. Karl Popper—The Formative Years, 1902—1945: Politics and Philosophy in Interwar Vienna. Cambridge: Cambridge University Press, 2000. Pp. 610." Austrian History Yearbook 33 (January 2002): 299–300. http://dx.doi.org/10.1017/s0067237800014211.

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23

Tirosh-Samuelson, Hava. "Jacob and Esau: Jewish European History between Nation and Empire. By Malachi Haim Hacohen. Cambridge: Cambridge University Press, 2019. Pp. xxii+734. $105.00 (cloth); $34.99 (paper)." Journal of Modern History 92, no. 4 (December 1, 2020): 901–2. http://dx.doi.org/10.1086/711247.

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24

D'Amico, Robert. "Karl Popper—the Formative Years, 1902–1945: Politics and Philosophy in Interwar Vienna. By Malachi Haim Hacohen. Cambridge: Cambridge University Press, 2000. Pp. xiii+610. $54.95." Journal of Modern History 74, no. 4 (December 2002): 897–99. http://dx.doi.org/10.1086/376252.

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25

Ravi, Arvind, Justin Gainor, Monica Arniella, Chip Stewart, Sam Freeman, Mark M. Awad, Patrick Forde, et al. "Abstract 3580: Integrative genomics of checkpoint blockade response in advanced non-small cell lung cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3580. http://dx.doi.org/10.1158/1538-7445.am2022-3580.

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Abstract The introduction of checkpoint blockade therapy, specifically anti-PD-1/PD-L1 agents, has transformed the treatment landscape of advanced Non-Small Cell Lung Cancer (NSCLC). While our understanding of the biology underlying immunotherapy in NSCLC is still incomplete, studies to date have established central roles for Tumor Mutation Burden (TMB) and PD-L1 Tumor Proportion Score (PDL1-TPS). In order to expand our understanding of the molecular features underlying response in NSCLC, we describe here the first joint analysis of the Stand Up 2 Cancer-Mark Foundation (SU2C-MARK) Cohort, a collection of 393 patients with whole exome and/or RNA sequencing along with matched checkpoint blockade response annotation. We identify a number of significant associations between molecular features and response, including: 1) favorable and unfavorable genomic subgroups; 2) distinct immune infiltration signatures associated with wound healing (unfavorable) and immune activated (favorable) microenvironments; and 3) a novel de-differentiated tumor-intrinsic subtype characterized by high TMB, immune activation, and enhanced response rate. Taken together, results from this cohort extend our understanding of NSCLC-specific predictors, providing a rich set of molecular and immunologic hypotheses with which to further our understanding of the biology of checkpoint blockade in NSCLC. Citation Format: Arvind Ravi, Justin Gainor, Monica Arniella, Chip Stewart, Sam Freeman, Mark M. Awad, Patrick Forde, Valsamo Anagnostou, Brian Henick, Jonathan W. Riess, Don Gibbons, Nathan Pennell, Vamisdhar Velcheti, Ignaty Leshchiner, Jaegil Kim, Subba Digumarthy, Mari Mino-Kenudson, John Heymach, Natalie Vokes, Andrew Griffin, Biagio Ricciuti, Naiyer Rizvi, Roy Herbst, Victor Velculescu, Julie Brahmer, Kurt Schalper, Pasi Janne, Jedd Wolchok, Alice Shaw, Nir Hacohen, Gad Getz, Matthew D. Hellmann. Integrative genomics of checkpoint blockade response in advanced non-small cell lung 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 3580.

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26

Mirowski, Philip. "Malachi Haim Hacohen. Karl Popper: The Formative Years, 1902–45: Politics and Philosophy in Interwar Vienna. xiv + 610 pp., bibl., index. Cambridge/New York: Cambridge University Press, 2000. $54.95." Isis 93, no. 2 (June 2002): 324–25. http://dx.doi.org/10.1086/345017.

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27

Tiago, Manoela, Timothy J. Purwin, Mitchell E. Fane, Yash Chhabra, Jessica L. F. Teh, Rama Kadamb, Weijia Cai, et al. "Abstract A005: The aged tumor microenvironment influences tolerance to targeted therapy via NR2F1 overexpression in BRAF-mutant melanoma." Cancer Research 83, no. 2_Supplement_1 (January 15, 2023): A005. http://dx.doi.org/10.1158/1538-7445.agca22-a005.

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Abstract Despite the clinical success of targeted inhibitors, tumor responses to these agents are transient, and drug-tolerant residual cells seed resistance. Understanding the role of tumor-intrinsic mechanisms and effects of the tumor microenvironment in mediating drug tolerance will guide and optimize targeted therapies. Given similarities between drug tolerance and cellular dormancy, we studied the role of nuclear receptor subfamily 2 group F member 1 (NR2F1) in response to targeted therapy. We used BRAF-mutant cutaneous melanoma models treated with BRAF and MEK inhibitors (BRAFi + MEKi) since patients treated with this combination typically develop resistance. The aged tumor microenvironment has been shown to increase therapy resistance, and we find that melanoma cells in aged mice express higher levels of NR2F1 than when the same cells are injected into young animals. Transcriptomic analysis of melanoma patient samples treated with BRAFi + MEKi showed increased expression of NR2F1 post-treatment. Similarly, NR2F1 was highly expressed in minimal residual disease collected on BRAFi + MEKi treatment in patient- and xenograft-derived tumors. High expression of NR2F1 promotes tumor survival and invasion in the presence of BRAFi + MEKi in vitro leading to tolerance to BRAFi + MEKi efficacy in vivo. Depletion of NR2F1 in YUMM1.7 allografts grown in aged mice improved response to the combination therapy. Altogether, our findings suggest that NR2F1 promotes drug tolerance leading to minimal residual disease in melanoma and that NR2F1-high cells may be targeted with CDK4/6 inhibitors to improve targeted therapy outcomes in melanoma patients. Citation Format: Manoela Tiago, Timothy J. Purwin, Mitchell E. Fane, Yash Chhabra, Jessica L. F. Teh, Rama Kadamb, Weijia Cai, Inna Chervoneva, Sheera Rosenbaum, Vivian Chua, Nir Hacohen, Michael A. Davies, Jessie Villanieva, Ashani T. Weeraratna, Claudia Capparelli, Julio A. Aguirre-Ghiso, Andrew E. Aplin. The aged tumor microenvironment influences tolerance to targeted therapy via NR2F1 overexpression in BRAF-mutant melanoma [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A005.

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28

Fuller, Steve. "MALACHI HAIM HACOHEN, Karl Popper – The Formative Years, 1902–1945: Politics and Philosophy in Interwar Vienna. Cambridge: Cambridge University Press, 2001. Pp. xiii+610. ISBN 0-521-47053-6. £35.00, $54.95 (hardback)." British Journal for the History of Science 34, no. 3 (September 2001): 341–73. http://dx.doi.org/10.1017/s0007087401224455.

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29

Janik, Allan. "Karl Popper — The Formative Years, 1902-1945: Politics and Philosophy in Interwar Vienna. By Malachi Haim Hacohen. Cambridge, UK: Cambridge University Press. 2000. Pp. xiv + 610. $54.95. ISBN 0-521-47053-6." Central European History 35, no. 4 (December 2002): 613–16. http://dx.doi.org/10.1017/s0008938900001977.

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30

Gattei, Stefano. "Malachi H. Hacohen, Karl Popper—The Formative Years, 1902–1945: Politics and Philosophy in Interwar Vienna. New York: Cambridge University Press, 2000, cloth £35/US$54.95, hardback. ISBN 0-521-47053-6 (hardback)." British Journal for the Philosophy of Science 52, no. 4 (December 1, 2001): 815–25. http://dx.doi.org/10.1093/bjps/52.4.815.

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31

Mehta, Arnav, Lynn Bi, Aziz Al'Khafaji, Martin Jankowiak, Milan Parikh, Mehrtash Babadi, Alex Bloemendal, et al. "Abstract B016: Quantifying and dissecting pancreatic cancer cell phenotypic plasticity using lineage tracing, single-cell multiomics and CRISPR perturbations reveals novel regulators of plastic states." Cancer Research 82, no. 22_Supplement (November 15, 2022): B016. http://dx.doi.org/10.1158/1538-7445.panca22-b016.

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Abstract Pancreatic cancer is a lethal disease in part because tumor cells exist in distinct transcriptional phenotypes (e.g. basal and classical states), each with a selective ability to evade current chemotherapy regimens. Two major mechanisms have been suggested for treatment evasion: 1) intrinsic resistance of certain phenotypes to particular chemotherapy regimens and 2) plasticity of treatment sensitive phenotypes to adopt more resistant phenotypes. However, the relative contribution of these mechanisms to treatment resistance is still poorly understood. Whereas previous work has described the redistribution of tumor cell states under selective treatment pressure, there is no direct evidence that tumor cells exhibit phenotypic plasticity at steady state or with treatment. By leveraging technological advancements in single-cell methods, lineage tracing and functional genomics, we have now shown direct evidence of phenotypic state switching in human pancreatic cancer cell lines. By performing single-cell RNA-seq on 5 barcoded PDAC cell lines over a steady state timecourse and under chemotherapy selective pressure (>600k cells total), we identify unique plasticity phenotypes within these cell lines and infer regulators of these plastic states. We validate the role of several of these regulators using bulk phenotypic CRISPRi screens in these cell lines. We next perform CRISPRi perturbations along with lineage tracing and single-cell multiomics (>300k cells) to dissect the regulatory relationships that underlie these cell states. We identify several novel epithelial and mesenchymal biasing factors, including those with unique roles in the most plastic clones. Collectively, we nominate several regulators that bias PDAC cell states thus posing a paradigm whereby perturbations may be used to homogenize tumor populations towards treatment-sensitive phenotypes. We believe this approach combined with current chemotherapy regimens could benefit pancreatic cancer patients by targeting residual, resistant tumor cells in the localized and metastatic disease settings to improve patient survival. Citation Format: Arnav Mehta, Lynn Bi, Aziz Al'Khafaji, Martin Jankowiak, Milan Parikh, Mehrtash Babadi, Alex Bloemendal, Marc Schwartz, Glen Munson, Joeseph Chan, Cassandra Burdziak, Elisa Donnard, Ryan Park, Chen Lu, Philippe Rigollet, Andrew Aguirre, Vidya Subramanian, Ray Jones, Eric S. Lander, David T. Ting, Dana Pe'er, Nir Hacohen. Quantifying and dissecting pancreatic cancer cell phenotypic plasticity using lineage tracing, single-cell multiomics and CRISPR perturbations reveals novel regulators of plastic states [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B016.

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Tian, Jun, Jonathan H. Chen, Sherry X. Chao, Karin Pelka, Vjola Jorgji, Islam Baiev, William B. Bradford, et al. "Abstract LB003: Combined BRAF, MEK, and PD-1 inhibition in BRAFV600E colorectal cancer patients: Correlative studies from a phase 2 trial." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB003. http://dx.doi.org/10.1158/1538-7445.am2022-lb003.

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Abstract Background: Although BRAF inhibitors combined with EGFR and/or MEK inhibitors have improved efficacy in BRAFV600E colorectal cancer (CRC), response rates remain low and clinical benefit is not durable. Preclinical studies suggest that BRAF-targeted therapy in combination with immune checkpoint blockade could enhance anti-tumor activity. We have previously reported on the efficacy from an ongoing phase 2 clinical trial of anti-PD-1 antibody spartalizumab in combination with BRAF inhibitor dabrafenib and MEK inhibitor trametinib in BRAFV600E CRC patients. Of 26 patients, overall response rate (ORR) was 38% (10/26) and compares favorably to the historical controls in BRAFV600E CRC, yet the mechanisms of patient response in this trial need further investigation. Methods: Single-cell RNA-seq (scRNA-seq) was performed on 23 paired baseline and day 15 tumor biopsies. Patient-derived organoids (PDOs) were generated from baseline tumor biopsies. Results: scRNA-seq of paired biopsies revealed increased CD8+ T cell infiltration after treatment in patients with better clinical outcome (PFS > 6 months, n=11). From the on- versus pre-treatment differentially expression analysis and gene set enrichment analysis in the tumor epithelial compartment, we observed greater induction and enrichment of immune gene signatures such as antigen processing and presentation, type I and II interferon response, chemokine activity, as well as superior MAPK pathway inhibition with therapy in patients with PFS > 6 months. In comparison, patients with PFS < 6 months (n=12) showed less immune gene upregulation and MAPK pathway inhibition in tumor cells. PDOs treated with dabrafenib and trametinib exhibited gene expression changes that mirrored the changes observed in scRNA-seq of tumor cells in the same patients from which they were derived. BRAF/ERKi treatment in PDOs produced greater MAPK pathway inhibition and immune genes induction than BRAF/MEKi. Conclusion: Correlative studies of combined anti-PD-1 and BRAF/MEK inhibition suggest that the tumor-intrinsic immune response induced by MAPK pathway inhibition might underlie cooperativity between BRAF-targeted therapy and immune checkpoint blockade. A greater degree of immune gene induction in tumor cells could be enhanced by superior MAPK pathway inhibition, which provides rationale for further clinical studies. Citation Format: Jun Tian, Jonathan H. Chen, Sherry X. Chao, Karin Pelka, Vjola Jorgji, Islam Baiev, William B. Bradford, Edmond Wong, Princy Sindurakar, Tomonori Oka, Shadmehr Demehri, Nir Hacohen, Ryan B. Corcoran. Combined BRAF, MEK, and PD-1 inhibition in BRAFV600E colorectal cancer patients: Correlative studies from a phase 2 trial [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 LB003.

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Dubrot, Juan, Peter P. Du, Sarah Kate Lane-Reticker, Emily A. Kessler, Audrey J. Muscato, Arnav Mehta, Samuel S. Freeman, et al. "Abstract 3610: In vivo CRISPR screens reveal the landscape of immune evasion pathways across cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3610. http://dx.doi.org/10.1158/1538-7445.am2022-3610.

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Abstract The immune system can eliminate tumors, but checkpoints enable tumors to escape immune destruction. Here, we report the systematic identification of immune evasion mechanisms using genome-scale in vivo CRISPR screens in eight murine cancer models treated with immune checkpoint blockade (ICB). We identify and validate previously unreported immune evasion genes and identify key immune inhibitory checkpoints that have a conserved role across several cancer models, such as the non-classical MHC-I molecule Qa-1b/HLA-E, which scores as the top overall sensitizing hit across all screens. Surprisingly, we find that loss of IFNγ signaling by tumor cells sensitizes 6 of 8 cancer models to ICB. While IFN-mediated inflammation has been associated with response to ICB, there have also been reports of ICB-resistance driven by IFN sensing. However, several divergent mechanisms have been proposed to explain the inhibitory effect of tumor IFN sensing, leading to uncertainty about how this key immune signaling pathway is regulating anti-tumor immunity in different contexts. Using in vivo screening data, transcriptional profiling, and genetic interaction studies, we reveal that the immune-inhibitory effects of tumor IFN sensing are the direct result of tumor upregulation of classical and non-classical MHC-I genes. The interferon-MHC-I axis can inhibit anti-tumor immunity through two mechanisms: first, upregulation of classical MHC-I inhibits the cytotoxicity of natural killer cells, which are activated by ICB. Second, IFN-mediated upregulation of Qa-1b directly inhibits cytotoxicity by effector CD8+ T cells via the NKG2A/CD94 receptor, which is induced on CD8+ T cells by ICB. Finally, we show that high interferon-stimulated gene expression in patients is associated with decreased survival in RCC and poor response to ICB in melanoma. Our study establishes a unifying mechanism to explain the inhibitory role of tumor IFN sensing, revealing that IFN-mediated upregulation of classical and non-classical MHC-I inhibitory checkpoints can facilitate immune escape. Citation Format: Juan Dubrot, Peter P. Du, Sarah Kate Lane-Reticker, Emily A. Kessler, Audrey J. Muscato, Arnav Mehta, Samuel S. Freeman, Peter M. Allen, Kira E. Olander, Kyle M. Ockerman, Clara H. Wolfe, Fabius Wiesmann, Nelson H. Knudsen, Hsiao-Wei Tsao, Arvin Iracheta-Vellve, Emily M. Schneider, Andrea N. Rivera-Rosario, Ian C. Kohnle, Hans W. Pope, Austin Ayer, Gargi Mishra, Margaret D. Zimmer, Sarah Y. Kim, Animesh Mahapatra, Hakimeh Ebrahimi-Nik, Dennie T. Frederick, Genevieve M. Boland, W. Nicholas Haining, David E. Root, John G. Doench, Nir Hacohen, Kathleen B. Yates, Robert T. Manguso. In vivo CRISPR screens reveal the landscape of immune evasion pathways across 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 3610.

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Price, Colles, Jonathan H. Chen, Karin Pelka, Sherry Chao, Michael Therrien, Timothy Wiggin, Nicolas Fernandez, et al. "Abstract 2030: A single-cell spatially resolved map of colorectal cancer identifies novel spatial relationships between cancer cells and the microenvironment." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2030. http://dx.doi.org/10.1158/1538-7445.am2022-2030.

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Abstract Understanding the tumor microenvironment (TME) requires more than just a catalog of cell types and gene programs. It is critical to see the spatial organization of the cells are and where they form multicellular interaction networks. Here we present a single-cell spatially resolved transcriptomic analysis of human mismatch repair deficient (MMRd) and proficient (MMRp) colorectal cancer (CRC) specimens. High tumor mutational burden MMRd tumors are known to have an immune response characterized by higher cytolytic T cell infiltrates compared to MMRp tumors, making them an ideal system for spatial single-cell profiling and understanding how the immune-driven programs differ between these tumors. MERFISH is a massively multiplexed single molecule imaging technology which can simultaneously capture and measure the quantity and distribution of hundreds to thousands of RNA species within single cells across a tissue1. We designed a MERFISH library of over 450 genes including genes important to proliferation, apoptosis, immune signaling, immune cell type pathways and other critical pathways in CRC. Patient samples, obtained commercially or through MGH, were hybridized with the designed MERFISH library and stained with a cell boundary marker to delineate cells across the tissue. We performed unsupervised clustering to identify cell types and we calculated spatial statistics to characterize how the cell type distribution varied between MMRd and MMRp tumors. We identified the cellular composition of each tumor, including immune and stromal cells, and the spatial distribution of these cell types. We were able to readily identify all cell types and states previously discovered by single-cell RNA sequencing2 in intact patient specimens, thus providing an accurate map of the cellular composition and spatial organization of these cells in the tumor microenvironment. We transformed these cell types into neighborhoods and discovered a highly organized spatial distribution of most cell types throughout the tumor. While spatial organization was observed in both MMRp and MMRd CRC we saw a significant shift in spatial organization between these tumor classifications notably in the immune population. Further, previously predicted multicellular interaction networks2 appeared as spatially organized structures in the tissue and were distinct in MMRd versus MMRp tumor specimens. Our data provide a richness of concrete hypotheses about which cells are working together, how these cells function cooperatively, and where these cells are located which will be critical in advancing therapy in these immunologically distinct types of colorectal cancer. These cancer maps are critical to truly understand the biology of CRC as well as identify avenues for the development of future therapies for CRC patients. Citation Format: Colles Price, Jonathan H. Chen, Karin Pelka, Sherry Chao, Michael Therrien, Timothy Wiggin, Nicolas Fernandez, Jiang He, George Emanuel, Genevieve Boland, Nir Hacohen. A single-cell spatially resolved map of colorectal cancer identifies novel spatial relationships between cancer cells and the microenvironment [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 2030.

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Mehta, Arnav, Aparna Parikh, Milan Parikh, Ryan Park, Moshe Sade-Feldman, Lynn Bi, Nicole Carzo, et al. "Abstract C012: Dissecting the reorganization of pancreatic tumor microenvironments after radiation and immunotherapy reveals insights into immunotherapy resistance." Cancer Research 82, no. 22_Supplement (November 15, 2022): C012. http://dx.doi.org/10.1158/1538-7445.panca22-c012.

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Abstract Immune checkpoint blockade (ICB) has revolutionized the treatment of many cancers but has been ineffective for the treatment of microsatellite stable (MSS) PDAC. The lack of efficacy of immunotherapies in PDAC is due to: 1) a desmoplastic tumor microenvironment (TME); 2) the presence of suppressive cells, including myeloid derived suppressor cells and regulatory T cells; and 3) the lack of antigen-presenting dendritic cells (DCs) that are important in priming an effective immune response to generate functionally effective tumor antigen-specific T cells. We recently completed a pilot study of dual ICB (Ipilumamab and Nivolumab) with radiation therapy (SBRT 8Gy for 3 fractions) in a cohort of 25 metastatic PDAC patients that had progressed on conventional chemotherapy; this combination conferred an impressive 18% ORR and 29% disease control rate measured on non-irradiated lesions (historical 0% ORR with ICB in PDAC). This led to a phase 2 study in 30 metastatic PDAC patients using this dual modality treatment paradigm. To understand the role of radiation and ICB in altering the PDAC tumor microenvironment we performed single-cell RNA-sequencing and TCR-sequencing (>180k cells), and single-nucleus RNA-sequencing (>300k cells) on 36 tumor biopsies (23 pre-treatment, 13 paired on-treatment between day 10 and 21) from patients undergoing treatment in our phase 2 study. Tumor tissue was taken from distinct tissue sites, including primary tumors in the pancreas, and liver and abdominal wall metastases. We identified distinct tumor cell state distributions within different tissues, and a redistribution of cells from basal/mesenchymal states to classical states after radiation. We identified several state-specific interferon stimulated gene programs thus cataloging distinct responses of epithelial cells with different transcriptional states. Importantly, we found a redistribution of T cells states towards proliferating and exhausted T cells with unique clonality after radiation. Additionally, the myeloid compartment after radiation was enriched for C1QC+ and MHCII+ macrophage subsets, as well as infiltrating CD16/CD16 monocytes and CD14 monocytes, each showing induction of unique sets of interferon stimulated genes (ISGs). We next sought to better understand immunotherapy resistance mechanisms within these PDAC patients despite finding strong ISG induction in several subsets. We analyzed covarying gene programs and identified multicellular communities of cells before and after radiation that underlie interaction networks associated with radiation. Together our data provides the most comprehensive single-cell atlas of paired biopsies to study tumor and immune cell states in the context of radiation and ICB response. Citation Format: Arnav Mehta, Aparna Parikh, Milan Parikh, Ryan Park, Moshe Sade-Feldman, Lynn Bi, Nicole Carzo, Tarin M. Grillo, Islam Baiev, Olanike Asupoto, Irena Gushterova, Tom LaSalle, Anna Gonye, Emily Blaum, Sebastien Vigneau, Ronan Chaligne, Ana Lako, Thomas Lila, David Nelson, Caroline Porter, Orr Ashenberg, Karthik Jagadesh, William L. Hwang, Christopher Smillie, David P. Ryan, David T. Ting, Theodore Hong, Dana Pe'er, Nir Hacohen. Dissecting the reorganization of pancreatic tumor microenvironments after radiation and immunotherapy reveals insights into immunotherapy resistance [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C012.

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Urbinati, Stefano. "Divisorial Models of Normal Varieties." Proceedings of the Edinburgh Mathematical Society 60, no. 4 (January 31, 2017): 1053–64. http://dx.doi.org/10.1017/s0013091516000614.

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AbstractWe prove that the canonical ring of a canonical variety in the sense of de Fernex and Hacon is finitely generated. We prove that canonical varieties are Kawamata log terminal (klt) if and only if is finitely generated. We introduce a notion of nefness for non-ℚ-Gorenstein varieties and study some of its properties. We then focus on these properties for non-ℚ-Gorenstein toric varieties.

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Hidy, Samantha, and David Weaver. "230 Single cell PIK3 gene expression patterns support duvelisib (PI3K-delta, gamma inhibitor) treatment of melanoma and other tumors after checkpoint inhibitor therapy." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A248. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0230.

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BackgroundDuvelisib, an FDA-approved oral phosphoinositide 3-kinase (PI3K)-δ,γ inhibitor, targets tumor cells of B/T cell malignancies, but may modulate non-malignant immune cells in the tumor microenvironment (TME) of many cancers. PI3K–δ and PI3K–γ downmodulate immunosuppressive Tregs and myeloid cells in solid tumors.1, 2, 3 We used single-cell RNA analysis of PIK3CD and PIK3CG to explore resistance mechanisms to checkpoint inhibitors (CPI).MethodsSingle-cell melanoma (SKCM) RNAseq datasets: GSE120575;4 CD45+ cells from 48 CPI responders and non-responder tumors, and GSE115978;5 33 treatment-naïve and CPI-progressing (resistant) tumors. Cancer cells and CD45+ TME subpopulations, specified by gene expression signatures and tSNE plots, had PI3K gene expressions profiled. Differential gene expression (DE) was gated in MAST/Seurat. Fishers test Odds Ratio (OR) was calculated for ‘high’ expression.ResultsPIK3CD expression is higher in SKCM than most cancers (10.8 median RSEM log 2).7 By single-cell analysis, PIK3CD (> 0.3 log2 TPM) occurs in 68.2% of cancer cells, with PIK3CB, PIK3CA, and PIK3CG expressed in 32.3%, 12.0%, and 7.2% respectively. PIK3CD-high cancer cells (>4 log2 TPM) have a 711-gene DE gene signature mostly related to immune processes. A higher proportion of cancer cells in CPI resistant tumors express PIK3CD, than untreated tumors (OR 2.02, 95% CI 1.65–2.48, p=3.04 × 10–12), as do PIK3CD+PIK3CG-expressing cancer cells (OR 2.14, 95% CI 1.47–3.13, p=4.2 × 10-5). Additionally, in PI3K–δ or PI3K–γ high melanoma cell lines duvelisib inhibited proliferation, p-AKT and c-myc.7 PIK3CD and PIK3CG are prominently expressed in many SKCM CD45+ TME cells (84.5% and 31.7% CD45+ respectively). PIK3CD (>0.3 log2 TPM) occurs in a high fraction of T (85.7%), CD8+ T (86.3%), CD4+ T (86.9%), B (78.5%), macrophages (88%), and NK (85%). PIK3CG is highest in B, dendritic, cycling lymphocytes and plasma cells. Strikingly, a significantly higher proportion of PIK3CD+ cells occur in resistant tumors compared to untreated for all CD45+ cells, (OR 1.64, 95% CI 1.40–1.94, p=4.79 × 10-10), CD8+ T (OR 2.15, 95% CI 1.61–2.86, p=6.5 × 10-8), and an exhausted C8+ T subpopulation (OR 3.17, 95% CI 1.89–5.37, p=2.95 × 10-6). PIK3CD+PIK3CG-expressing CD45+ cells are significantly increased in CPI-resistant tumors (OR 1.22, 95% CI 1.07–1.39, p=0.002).ConclusionsThese findings support a mechanism where CPI therapies may contribute to modulation of PI3Kδ expression in cancer cells and the immune TME. The PI3K-δ,γ inhibitor duvelisib is being investigated in combination with CPI and evaluated in the context of CPI resistance in clinical trials: pembrolizumab (HNSC, NCT04193293), and nivolumab (Richter’s Syndrome, NCT03892044).ReferencesAli K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, Bouabe H, Scudamore CL, Hancox T, Maecker H, Friedman L, Turner M, Okkenhaug K, Vanhaesebroeck B. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer Nature 2014; 510(7505):407–411.Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S, Woo G, Nguyen AV, Figueiredo CC, Foubert P, Schmid MC, Pink M, Winkler DG, Rausch M, Palombella VJ, Kutok J, McGovern K, Frazer KA, Wu X, Karin M, Sasik R, Cohen EE, Varner JA. PI3Kγ is a molecular switch that controls immune suppression. Nature 2016; 539(7629):437–442.De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, Budhu S, Ghosh A, Pink M, Tchaicha J, Douglas M, Tibbitts T, Sharma S, Proctor J, Kosmider N, White K, Stern H, Soglia J, Adams J, Palombella VJ, McGovern K, Kutok JL, Wolchok JD, Merghoub T. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature 2016; 539(7629):443–447.Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins RW, Lieb DJ, Chen JH, Frederick DT, Barzily-Rokni M, Freeman SS, Reuben A, Hoover PJ, Villani AC, Ivanova E, Portell A, Lizotte PH, Aref AR, Eliane JP, Hammond MR, Vitzthum H, Blackmon SM, Li B, Gopalakrishnan V, Reddy SM, Cooper ZA, Paweletz CP, Barbie DA, Stemmer-Rachamimov A, Flaherty KT, Wargo JA, Boland GM, Sullivan RJ, Getz G, Hacohen N. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 2018; 175: 998–1013.Jerby-Arnon L, Shah P, Cuoco MS, Rodman C, Su MJ, Melms JC, Leeson R, Kanodia A, Mei S, Lin JR, Wang S, Rabasha B, Liu D, Zhang G, Margolais C, Ashenberg O, Ott PA, Buchbinder EI, Haq R, Hodi FS, Boland GM, Sullivan RJ, Frederick DT, Miao B, Moll T, Flaherty KT, Herlyn M, Jenkins RW, Thummalapalli R, Kowalczyk MS, Cañadas I, Schilling B, Cartwright ANR, Luoma AM, Malu S2, Hwu P, Bernatchez C, Forget MA, Barbie DA, Shalek AK, Tirosh I, Sorger PK, Wucherpfennig K, Van Allen EM, Schadendorf D, Johnson BE, Rotem A, Rozenblatt-Rosen O, Garraway LA, Yoon CH, Izar B, Regev A. A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade. Cell 2018; 175: 984–997.Firebrowse Gene Expression Viewerhttp://firebrowse.org/viewGene.html.Coma S, Weaver DT, Pachter JA. [Poster #663] The dual PI3K-δ/PI3K-γ inhibitor duvelisib inhibits signaling and proliferation of solid tumor cells expressing PI3K-δ and/or PI3K-γ. AACR. 2020.

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Einat-Nov, Idit. "On the Art of Piyyut: A Reading of Yehezqel Hacohen's "אמרתי לאבנים" (I Said to the Stones)." Hebrew Studies 58, no. 1 (2017): 247–62. http://dx.doi.org/10.1353/hbr.2017.0012.

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Benoist, Olivier. "Exposé Bourbaki 1158 : Réduction stable en dimension supérieure (d'après Kollár, Hacon-Xu, ...)." Astérisque 422 (2020): 291–326. http://dx.doi.org/10.24033/ast.1137.

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Filipazzi, Stefano. "Some remarks on the volume of log varieties." Proceedings of the Edinburgh Mathematical Society 63, no. 2 (December 18, 2019): 314–22. http://dx.doi.org/10.1017/s0013091519000397.

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AbstractIn this note, using methods introduced by Hacon et al. [‘Boundedness of varieties of log general type’, Proceedings of Symposia in Pure Mathematics, Volume 97 (American Mathematical Society, Providence, RI, 2018) 309–348], we study the accumulation points of volumes of varieties of log general type. First, we show that if the set of boundary coefficients Λ satisfies the descending chain condition (DCC), is closed under limits and contains 1, then the corresponding set of volumes satisfies the DCC and is closed under limits. Then, we consider the case of ε-log canonical varieties, for 0 < ε < 1. In this situation, we prove that if Λ is finite, then the corresponding set of volumes is discrete.

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Cohen, Yitshak. "Rabbi Meir Simcha of Dvinsk and His Attitude toward Gentiles." Review of Rabbinic Judaism 17, no. 2 (August 13, 2014): 218–51. http://dx.doi.org/10.1163/15700704-12341269.

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This article examines various issues in R. Meir Simha Hacohen’s (rms) halakhic approach toward gentiles. His approach demonstrates innovation, and it attests mostly to moderation and an effort to reach a compromise with gentiles. We see that his halakhic and judicial approach does not advocate a complete detachment between Jews and gentiles; on the contrary, it encourages increased relations between them. On all the issues examined here, where the Halakhah could be interpreted in a strict manner or leniently, rms follows the approach that facilitates relations between Jews and gentiles. His position is consistent and forms a broad fundamental approach according to which, whenever it is possible to set the laws governing the relations between Jew and gentiles on an even footing, one should make an effort to do so. The article exposes several broad principles in rms’s attitude toward gentiles, for example, the rationale that distinguishes between religious matters and worldly affairs. The laws governing the latter apply to gentiles as well and are identical for gentiles and Jews. The article also shows that rms issued a series of rulings aimed at compromising with gentiles and bringing Jews and gentiles closer together. The article explains rms’s approach of meeting gentiles half way by examining the historical and sociological circumstances within which he acted, including the fact that in Eastern Europe his Jewish circle did not perceive itself as self-referential and conservative. This enabled rms to develop his moderate approach.

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Guzmán Duque, Alba Patricia, Diana Oliveros Contreras, and Edgar Mauricio Mendoza García. "Las competencias científicas a partir de la gestión del conocimiento en Instituciones de Educación Superior." SIGNOS - Investigación en sistemas de gestión 11, no. 2 (June 30, 2019): 23–40. http://dx.doi.org/10.15332/24631140.5080.

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La sociedad exige profesionales competentes para desempeñarse en el mundo laboral mediante la gestión del conocimiento. La investigación es descriptiva y determina cómo los estudiantes (N=189) de una IES de Santander (Colombia) perciben el desarrollo de sus competencias científicas en sus procesos educativos como mecanismo para aportar al mundo laboral. Se utilizó el instrumento Hacoin para medir la competencia científica en estudiantes de pregrados y posgrados, y la técnica estadística Anova para evidenciar las diferencias entre grupos considerando el género y la edad de los participantes. Los resultados evidencian la importancia de los procesos de investigación en la formación y el desarrollo de las competencias científicas a partir de la gestión del conocimiento en los procesos de aprendizaje. Se detecta la mejora en las habilidades interpersonales e intrapersonales, la toma de decisiones y la resolución de problemas, y la adquisición de competencias científicas básicas y especializadas para desarrollar el pensamiento crítico como mecanismo de empleabilidad. Se concluye que el proceso de investigación influye directamente en la adquisición de las competencias que demanda el mundo laboral para mejorar el desempeño de los profesionales en su respectiva área de conocimiento y que la gestión del conocimiento es un proceso clave para el desarrollo de las competencias de los profesionales. Palabras clave: competencias científicas, IES, formación para la investigación, mercado laboral, gestión del conocimiento.

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Akin, Muharrem, Vera Garcheva, Jan-Thorben Sieweke, John Adel, Ulrike Flierl, Johann Bauersachs, and Andreas Schäfer. "Neuromarkers and neurological outcome in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia–experience from the HAnnover COoling REgistry (HACORE)." PLOS ONE 16, no. 1 (January 7, 2021): e0245210. http://dx.doi.org/10.1371/journal.pone.0245210.

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Background Neuron-specific enolase (NSE) and S-100b have been used to assess neurological damage following out-of-hospital cardiac arrest (OHCA). Cut-offs were derived from small normothermic cohorts. Whether similar cut-offs apply to patients treated with hypothermia remained undetermined. Methods We investigated 251 patients with OHCA treated with hypothermia but without routine prognostication. Neuromarkers were determined at day 3, neurological outcome was assessed after hospital discharge by cerebral performance category (CPC). Results Good neurological outcome (CPC≤2) was achieved in 41%. Elevated neuromarkers, older age and absence of ST-segment elevation after ROSC were associated with increased mortality. Poor neurological outcome in survivors was additionally associated with history of cerebrovascular events, sepsis and higher admission lactate. Mean NSE was 33μg/l [16–94] vs. 119μg/l [25–406]; p<0.001, for survivors vs. non-survivors, and 21μg/l [16–29] vs. 40μg/l [23–98], p<0.001 for good vs. poor neurological outcome. S-100b was 0.127μg/l [0.063–0.360] vs. 0.772μg/l [0.121–2.710], p<0.001 and 0.086μg/l [0.061–0.122] vs. 0.138μg/l [0.090–0.271], p = 0.009, respectively. For mortality, thresholds of 36μg/l for NSE and 0.128μg/l for S-100b could be determined; for poor neurological outcome 33μg/l (NSE) and 0.123μg/l (S-100b), respectively. Positive predictive value for NSE was 81% (74–88) and 79% (71–85) for S-100b. Conclusions Thresholds for NSE and S-100b predicting mortality and poor neurological outcome are similar in OHCA patients receiving therapeutic hypothermia as in those reported before the era of hypothermia. However, both biomarkers do not have enough specificity to predict mortality or poor neurological outcome on their own and should only be additively used in clinical decision making.

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Liu, Sophia, Bryan Iorgulescu, Shuqiang Li, Julia Morriss, Mehdi Borji, Evan Murray, David Braun, Kenneth Livak, Catherine Wu, and Fei Chen. "76 Spatial mapping of T cell receptors and transcriptomes in renal cell carcinoma following immune checkpoint inhibitor therapy." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A84—A85. http://dx.doi.org/10.1136/jitc-2021-sitc2021.076.

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BackgroundBecause conventional single-cell strategies rely on dissociating tissues into suspensions that lose spatial context,1 we developed Slide-TCR-seq to sequence both whole transcriptomes and TCRs with 10µm-spatial resolution, & applied it to renal cell carcinoma (ccRCC) treated with immune checkpoint inhibitors (ICI).MethodsSlide-TCR-seq combines Slide-seqV22 3—a 10µm-resolution spatial approach utilizing mRNA capture and DNA-barcoded beads—with sensitive targeted capture of TCR sequences (rhTCRseq,4 previously developed by our group), thereby enabling amplification of segments extending from upstream of CDR3 to the 3’-end of the TCR transcript (figure 1A). We tested Slide-TCR-seq first on OT-I murine spleen and then applied this methodology to 3 patients‘ pre-αPD-1 ccRCC samples5 and a post-αPD-1 metastasis to investigate the spatial, functional, and clonotypic organization of T cells in relationship to tumor using RCTD,6 spatial enrichment, and spatial expression analyses.ResultsUsing Slide-TCR-seq, we first recapitulated native spatial structure of OT-I mouse spleen (figure 1B-G). TCRα/β CDR3 sequences were detected on 37.1% of beads with Trac/Trbc2 constant sequences—comparable to other scTCRseq methods. Because the clonal and spatial context of TILs have been increasingly implicated in immunotherapy resistance, we used Slide-TCR-seq to analyze a lung ccRCC metastasis following αPD-1 therapy. We employed unsupervised clustering to delineate the tumor, intervening boundary, and lung compartments, and RCTD analyses to spatially map individual cell types; together recapitulating the architecture observed in corresponding histology (figure 2). We identified 1,132 unique clonotypes, with distinct spatial distributions spanning the tissue compartments. Eight clonotypes were significantly enriched in tumor, whereas 5 were depleted (all p<0.05) (figure 3). We then analyzed the relationships between the T cells’ clonotype, gene expression, and tumor infiltration depth among clonotypes. Using a T-cell geneset associated with poor response to ICI,7 we dichotomized T-clonotype beads by geneset expression, and found spatial segregation of this geneset’s expression both within and across clonotypes (figure 4). TCR-4—the most significantly tumor-enriched clonotype—and TCR-2 displayed high expression of the poor ICI response geneset near the tumor’s edge, but low expression deeper in the tumor compartment; indicating that there are transcriptionally distinct subpopulations of these clonotypes, which depended on the extent of their tumor infiltration.Abstract 76 Figure 1Slide-TCR-seq spatially localizes T cell receptors and transcriptome information. a. Schematic of Slide-TCR-seq, in which tissue is placed onto an in situ barcoded bead array. cDNA libraries prepared with Slide-seqV2 are split prior to fragmentation with one portion used for targeted amplification via rhTCRseq optimized for use with Slide-seq libraries. Slide-TCR-seq provides gene expression, cell type, and clonotype information in space. b. Serial sections of the OT-1 mouse spleen with hematoxylin and eosin stain show characteristic architecture of red pulp and white pulp separation. c. Spatial reconstruction of Slide-TCR-seq array for a corresponding section of OT-I mouse spleen, with RCTD immune cell type assignment. NK = natural killer. d. Gene expression gaussian-filtered heatmap for visualizing the spatial distribution of gene markers for marginal zone (Marco), red blood cells (RBCs; Gypa), and CD8 T cells (Cd8a). e and f. Comparing the spatial distribution of constant (left) and variable (right) sequences for TCRα (e) and TCRβ (f), with superimposed density plot. g. The fraction of beads that capture CDR3 variable sequences (y-axis) when constant UMIs are captured (x-axis) for TCRα (left, light blue) and TCRβ (right, dark blue), with the number of corresponding beads along the top axis. All scale bars: 500 µm.Abstract 76 Figure 2Slide-TCR-seq identifies spatial differences between T cell clonotypes in renal cell carcinoma. (a) H&E stain of a ccRCC metastasis to the lung following PD-1 blockade therapy. (b) The compartment assignment of lung (green), immune cell boundary (orange), and tumor (blue) by applying K-nearest neighbors to cell types determined by unsupervised clustering from Slide-TCR-seq of a sequential tissue section. (c) Spatial reconstruction of cell type identifies using RCTD anaysis of the Slide-TCR-seq data. (d) Spatial localization of T cell clonotypes (n=447 clonotypes, colored by clonotype) from the the Slide-TCR-seq data.Abstract 76 Figure 3Top: y-axis Significance of clonotype spatial distributions compared against all other clonotypes with at least ten beads per array from the ccRCC lung metastasis plotted against an x-axis of magnitude of tumor enrichment or depletion (data from n=3 replicate arrays, two one-tailed K-S tests). Bottom: Visualization of selected significant clonotypes, ordered by tumor enrichment, in tissue compartments for a single array (T cells within the tumor compartment are displayed as opaque, T cells within other compartments are displayed as translucent).Abstract 76 Figure 4Spatial and molecular heterogeneity in clonotype gene expression and tumor infiltration. a. The three axes — spatial localization, gene expression, and T cell clonotype — that Slide-TCR-seq can relate. b. Top: distribution of poor response to immune checkpoint inhibitor treatment (’PRI’) geneset7 expression across all clonotypes in the tumor region of the same post-PD1 inhibitor RCC lung metastasis from figures 2–3 (from a single replicate) with kernel density estimation. Yellow = clonotypes with lower than median PRI expression; purple = clonotypes with PRI expression greater than or equal to the median value. Bottom: localization of low (yellow) and high (purple) PRI geneset expression clonotypes within the tumor region (light blue) from the Slide-TCR-seq array shows their distinct spatial separation (light blue = tumor region, orange = boundary region, green = lung region). Scale bar: 500 µm. c. Smoothed histograms comparing the distance infiltrated into tumor by two-tailed K-S test comparing low (yellow) and high (purple) expression clonotypes, as dichotomized by median expression of PRI. d. Comparing distance infiltrated into tumor by two-tailed K-S test between low and high PRI expression T cells across those clonotypes with at least 20 beads (n=7 clonotypes).ConclusionsSlide-TCR-seq effectively integrates spatial transcriptomics with TCR detection at 10µm resolution, thereby relating T cells’ clonality and gene expression to their spatial organization in tumors. Our findings suggest that a clonotype’s T cells may exhibit mixed responses to ICI depending on their spatial localization. The heterogeneity among clonotypes, in both gene expression and organization, underscores the importance of studying the TCR repertoire with spatial resolution.AcknowledgementsWe are grateful to Irving A. Barrera-Lopez, Zoe N. Garcia, and Aziz Al’Khafaji for technical assistance.ReferencesGohil S, Iorgulescu JB, Braun D, Keskin D, Livak K. Applying high-dimensional single-cell technologies to the analysis of cancer immunotherapy. Nat Rev Clin Oncol 2021; 18:244–256.Stickels RR, Murray E, Kumar P, Li J, Marshall JL, Di Bella DJ, Arlotta P, Macosko EZ, Chen F. Highly sensitive spatial transcriptomics at near-cellular resolution with Slide-seqV2. Nat Biotechnol 2021 Mar;39(3):313–319.Rodriques SG, Stickels RR, Goeva A, Martin CA, Murray E, Vanderburg CR, Welch J, Chen LM, Chen F, Macosko EZ. Slide-seq: A scalable technology for measuring genome-wide expression at high spatial resolution. Science 2019 Mar 29;363(6434):1463–1467.Li S, Sun J, Allesøe R, Datta K, Bao Y, Oliveira G, Forman J, Jin R, Olsen LR, Keskin DB, Shukla SA, Wu CJ, Livak KJ. RNase H-dependent PCR-enabled T-cell receptor sequencing for highly specific and efficient targeted sequencing of T-cell receptor mRNA for single-cell and repertoire analysis. Nat Protoc 2019 Aug;14(8):2571–2594.Braun DA, Street K, Burke KP, Cookmeyer DL, Denize T, Pedersen CB, Gohil SH, Schindler N, Pomerance L, Hirsch L, Bakouny Z, Hou Y, Forman J, Huang T, Li S, Cui A, Keskin DB, Steinharter J, Bouchard G, Sun M, Pimenta EM, Xu W, Mahoney KM, McGregor BA, Hirsch MS, Chang SL, Livak KJ, McDermott DF, Shukla SA, Olsen LR, Signoretti S, Sharpe AH, Irizarry RA, Choueiri TK, Wu CJ. Progressive immune dysfunction with advancing disease stage in renal cell carcinoma. Cancer Cell 2021 May 10;39(5):632–648.Cable DM, Murray E, Zou LS, Goeva A, Macosko EZ, Chen F, Irizarry RA. Robust decomposition of cell type mixtures in spatial transcriptomics. Nat Biotechnol 2021 Feb 18. doi: 10.1038/s41587-021-00830-w. Epub ahead of print. PMID: 33603203.Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins RW, Lieb DJ, Chen JH, Frederick DT, Barzily-Rokni M, Freeman SS, Reuben A, Hoover PJ, Villani AC, Ivanova E, Portell A, Lizotte PH, Aref AR, Eliane JP, Hammond MR, Vitzthum H, Blackmon SM, Li B, Gopalakrishnan V, Reddy SM, Cooper ZA, Paweletz CP, Barbie DA, Stemmer-Rachamimov A, Flaherty KT, Wargo JA, Boland GM, Sullivan RJ, Getz G, Hacohen N. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 2018 Nov 1;175(4):998–1013Ethics ApprovalThis study was approved by MGB/DFCI/Broad institution’s Ethics Board; approval number 2019P000017.

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Garcheva, Vera, Muharrem Akin, John Adel, Carolina Sanchez Martinez, Johann Bauersachs, and Andreas Schäfer. "High rate of critical coronary stenosis in comatose patients with Non-ST-elevation out-of-hospital cardiac arrest (NSTE-OHCA) undergoing therapeutic hypothermia—Experience from the HAnnover COoling REgistry (HACORE)." PLOS ONE 16, no. 5 (May 4, 2021): e0251178. http://dx.doi.org/10.1371/journal.pone.0251178.

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Background Myocardial infarction is the most frequent cause for out-of-hospital cardiac arrest (OHCA) in adults. Patients with ST-segment elevations (STE) following return of spontaneous circulation (ROSC) are regularly admitted to the catheterisation laboratory for urgent coronary angiography. Whether patients without obvious STE (NSTE) should receive coronary angiography as part of a standardised diagnostic work-up following OHCA is still debated. Methods We analysed a cohort of 517 subsequent OHCA patients admitted at our institution who received a standardised diagnostic work-up including coronary angiography and therapeutic hypothermia. Patients were 63±14 years old, 76% were male. Overall, 180 (35%) had ST-elevation in the post-ROSC ECG, 317 (61%) had shockable rhythm (ventricular fibrillation or tachycardia) at first ECG. ROSC was achieved after 26±21 minutes. Results Critical coronary stenosis requiring PCI was present in 83% of shockable and 87% of non-shockable STE-OHCA and in 48% of shockable and 22% of non-shockable NSTE-OHCA patients. In-hospital survival was 61% in shockable and 55% in non-shockable STE-OHCA and 60% in shockable and 28% in non-shockable NSTE-OHCA. Conclusion Standardised admission diagnostics in OHCA patients undergoing therapeutic hypothermia with a strict admission protocol incorporating ECG and coronary catheterisation shows a high rate of relevant coronary stenosis in STE-OHCA irrespective of the initial rhythm and in NSTE-OHCA with initial shockable rhythm. Based on the unfavourable outcome and low PCI rate observed in NSTE-OHCA patients with a primary non-shockable ECG rhythm it might be reasonable to restrict routine early coronary angiography to patients with primary shockable rhythms and/or ST-segment elevations after ROSC.

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Rendell, Rebecca A., Jamie Prout, Joseph T. Costello, Heather C. Massey, Michael J. Tipton, John S. Young, and Jo Corbett. "Effects of 10 days of separate heat and hypoxic exposure on heat acclimation and temperate exercise performance." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 313, no. 3 (September 1, 2017): R191—R201. http://dx.doi.org/10.1152/ajpregu.00103.2017.

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Adaptations to heat and hypoxia are typically studied in isolation but are often encountered in combination. Whether the adaptive response to multiple stressors affords the same response as when examined in isolation is unclear. We examined 1) the influence of overnight moderate normobaric hypoxia on the time course and magnitude of adaptation to daily heat exposure and 2) whether heat acclimation (HA) was ergogenic and whether this was influenced by an additional hypoxic stimulus. Eight males [V̇o2max = 58.5 (8.3) ml·kg−1·min−1] undertook two 11-day HA programs (balanced-crossover design), once with overnight normobaric hypoxia (HAHyp): 8 (1) h per night for 10 nights [[Formula: see text] = 0.156; SpO2 = 91 (2)%] and once without (HACon). Days 1, 6, and 11 were exercise-heat stress tests [HST (40°C, 50% relative humidity, RH)]; days 2–5 and 7–10 were isothermal strain [target rectal temperature (Tre) ~38.5°C], exercise-heat sessions. A graded exercise test and 30-min cycle trial were undertaken pre-, post-, and 14 days after HA in temperate normoxia (22°C, 55% RH; FIO2 = 0.209). HA was evident on day 6 (e.g., reduced Tre, mean skin temperature (T̄sk), heart rate, and sweat [Na+], P < 0.05) with additional adaptations on day 11 (further reduced T̄sk and heart rate). HA increased plasma volume [+5.9 (7.3)%] and erythropoietin concentration [+1.8 (2.4) mIU/ml]; total hemoglobin mass was unchanged. Peak power output [+12 (20) W], lactate threshold [+15 (18) W] and work done [+12 (20) kJ] increased following HA. The additional hypoxic stressor did not affect these adaptations. In conclusion, a separate moderate overnight normobaric hypoxic stimulus does not affect the time course or magnitude of HA. Performance may be improved in temperate normoxia following HA, but this is unaffected by an additional hypoxic stressor.

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Litt, David G. "A Guide to the Civil Jurisdiction and Judgments Convention. By Alan Dashwood, Richard Hacon and Robin White. Deventer: Kluwer Law and Taxation Publishers, 1987. Pp. xlii, 604. Index. Dfl.265; £94.50; $129." American Journal of International Law 82, no. 2 (April 1988): 419. http://dx.doi.org/10.2307/2203219.

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Sipkov, Ivan. "A Guide to the Civil Jurisdiction and Judgments Convention. By Alan Dashwood, Richard J. Hacon, and Robin C. A. WHITE. Deventer, The Netherlands, Boston: Kluwer Law and Taxation Publishers, 1986. Pp. xlii, 604, Dfl. 265.00; UK £94.50; U.S. $129.00 (hardcover)." International Journal of Legal Information 16, no. 1 (1988): 44–45. http://dx.doi.org/10.1017/s0731126500021661.

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Hess, Jonathan M. "Ruth HaCohen. The Music Libel Against the Jews." Studies in Christian-Jewish Relations 8, no. 1 (February 7, 2014). http://dx.doi.org/10.6017/scjr.v8i1.5384.

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"Rav Avraham Itzhak HaCohen Kook: between rationalism and mysticism." Choice Reviews Online 31, no. 05 (January 1, 1994): 31–2643. http://dx.doi.org/10.5860/choice.31-2643.

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