bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 548: The microRNA-10b targeted therapeutic, TTX-MC138, is effective in preclinical pancreatic adenocarcinoma
Authors: Ghosh Subrata , Lazarus Douglas , Robertson Neil , Crosier Edward , Liu Peter , Medarova Zdravka 
Published: June 2023

Abstract
Non-coding RNAs, such as miRNAs, represent promising targets for cancer therapy, given their role as critical players in oncogenic processes, including tumor initiation and progression, metastasis and therapeutic resistance. We and others demonstrated that miRNA-10b is a critical driver of tumor cell viability, especially in the metastatic setting. Based on this discovery, it became feasible to treat established metastatic cancer by inhibiting miR-10b. This was accomplished using a therapeutic, termed TTX-MC138, composed of antagomirs against miR-10b, conjugated to dextran-coated iron oxide nanoparticles. In our previous studies in murine models of metastatic breast cancer, we demonstrated the effectiveness of TTX-MC138 at preventing and eliminating existing metastases. Here, we describe the application of TTX-MC138 for the treatment of pancreatic adenocarcinoma. TTX-MC138 was administered weekly via intravenous injection into mice bearing orthotopic xenografts derived from human pancreatic adenocarcinoma cells. Tumor burden was measured by in vivo bioluminescence imaging. Animal survival, body weight, and tumor and metastatic burden at necropsy were also analyzed. Serum and tumor miR-10b expression, as well as global gene expression using RNA-seq were assessed to provide insight into target engagement and molecular function. Animals treated with vehicle or gemcitabine served as controls. Tumor growth rate was found to be significantly lower in animals treated with TTX-MC138 vs controls (p &lt; 0.0001 for TTX-MC138 vs. PBS and vs. gemcitabine). Importantly, 40% of the animals treated with TTX-MC138 regressed their tumors completely as measured by bioluminescence imaging. Treatment continued for 10 weeks, after which the responding mice were monitored for disease recurrence without treatment for an additional 10 weeks. The animals showed evidence of continued weight gain and durable survival. They were sacrificed 10 weeks after treatment was discontinued, despite no evidence of morbidity, to perform necropsy. No tumors or metastases were found at the time of sacrifice. Gene expression analysis confirmed target engagement and molecular mechanism of action. Against the background of our earlier work, these studies provide further evidence of the potential of TTX-MC138 for cancer therapy and expand its relevance beyond metastatic breast cancer to also include pancreatic adenocarcinoma.
Citation Format: Subrata Ghosh, Douglas Lazarus, Neil Robertson, Edward Crosier, Peter Liu, Zdravka Medarova. The microRNA-10b targeted therapeutic, TTX-MC138, is effective in preclinical pancreatic adenocarcinoma [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 548.
Abstract 5672: Comparative mouse pharmacokinetics of matched- and unmatched-isotype anti-PD-L1 antibodies
Authors: Demestichas Breanna , Kleeman Sam , Chvasta Matthew , Janowitz Tobias 
Published: June 2023

Abstract
Immune checkpoint inhibitors (ICI) are highly effective for a minority of patients with cancer. Pre-clinical research into mechanisms of ICI resistance is reliant upon anti-PD-1 or anti-PD-L1 antibody treatment in mouse models of cancer. Common approaches utilize commercially-available rat isotype anti-PD-L1 antibodies given by intraperitoneal (IP) injection at relatively high doses (5mg/kg every 2-3 days), often for extended periods. However, there has been limited investigation into the pharmacokinetics of these antibodies with single and repeat dosing, which could inform rational dose scheduling. Non-species-matched antibodies are known to induce accelerated anti-drug immune responses, compared to species-matched antibodies. As a result, we hypothesized that matched-isotype anti-PD-L1 (based on the grafting of atezolizumab variable regions onto a mouse IgG2a scaffold) and unmatched-isotype rat IgG2b anti-PD-L1 would be associated with distinct pharmacokinetics on single and repeated dosing. We first confirmed that both matched and unmatched antibodies have nanomolar-range affinity for mouse PD-L1 by surface plasmon resonance (0.85nM and 0.37nM, respectively). Using a single IP injection in 8-week-old male C57BL/6J mice followed by repeated tail-vein plasma sampling and an indirect anti-PD-L1 ELISA, we detected a trend towards prolonged median half-life for the matched (n=17 mice) versus unmatched (n=19) antibody (91.5 versus 39.0 hours). We detected a particularly wide range of half-life measurements for matched antibody experiments (19.8 to 337.7 hours), suggesting that antibody clearance can be highly heterogeneous. Using repeated IP injection (2 doses, 14 days apart), we identified markedly accelerated antibody clearance for both antibodies resulting in comparable antibody half-lives after dose 2 (11.9 versus 12.5 hours, n=13 and n=8 mice, respectively), suggestive of a time-dependent anti-drug adaptive immune response. These findings have significant implications for in vivo antibody treatment experiments, demonstrating that repeat dosing is associated with rapid antibody clearance, irrespective of the antibody species. These data should be taken into consideration when planning longer-term antagonism of PD-1/PD-L1 signaling with antibodies in mice and strengthen the basis for short term window studies that examine the intratumoral immune biology. Furthermore, the high variability in antibody half-life suggests that antibody pharmacokinetics could confound ICI treatment response studies in vivo.
Citation Format: Breanna Demestichas, Sam Kleeman, Matthew Chvasta, Tobias Janowitz. Comparative mouse pharmacokinetics of matched- and unmatched-isotype anti-PD-L1 antibodies. [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 5672.
Abstract 625: PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance
Authors: Wong Chun Wai , Evangelou Christos , Sefton Kieran N. , Leshem Rotem , Sergiou Kleita , Carro Macarena Lucia Fernandez , Uzuner Erez , Mole Holly , Telfer Brian A. , Wilcock Daniel J. , Smith Michael P. , Kunii Kaiko , Perl Nicholas R. , Lorigan Paul , Williams Kaye J. , Rao Patricia E. , Nagaraju Raghavendar T. , Niepel Mario , Hurlstone Adam F. 
Published: June 2023

Abstract
Adaptive resistance limits immune checkpoint blockade therapy (ICBT) response duration and magnitude. Interferon γ (IFNγ), a critical cytokine that promotes cellular immunity, also induces adaptive resistance to ICBT. Using syngeneic mouse tumor models, we confirmed that chronic IFNγ exposure confers resistance to anti-Programmed cell death protein 1 (α-PD-1) therapy. We identified consistent upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in both chronic IFNγ-treated cancer cells and patient melanoma with elevated IFNG expression. Knockdown or pharmacological inhibition of PARP14 increased effector T cell infiltration into tumors derived from cells pre-treated with IFNγ and decreased the presence of regulatory T cells, leading to restoration of α-PD-1 sensitivity. Finally, we determined that tumors which spontaneously relapsed following α-PD-1 therapy could be re-sensitized upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance.
Citation Format: Chun Wai Wong, Christos Evangelou, Kieran N. Sefton, Rotem Leshem, Kleita Sergiou, Macarena Lucia Fernandez Carro, Erez Uzuner, Holly Mole, Brian A. Telfer, Daniel J. Wilcock, Michael P. Smith, Kaiko Kunii, Nicholas R. Perl, Paul Lorigan, Kaye J. Williams, Patricia E. Rao, Raghavendar T. Nagaraju, Mario Niepel, Adam F. Hurlstone. PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance [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 625.
Abstract 6288: Discovery and characterization of potent, selective CBP degraders
Authors: La Bonte Laura , Sappal Darshan 
Published: June 2023

Abstract
CREB binding protein (CBP) and E1A binding protein (p300) are paralog histone acetyltransferases involved in many cellular processes via their activity as transcription factor co-activators. Dysregulation of one or both proteins has been implicated in a variety of cancers. Due to the high homology between CBP and p300, identification of selective chemical matter that specifically and directly targets CBP has proven challenging. Here, we describe a potent, highly selective CBP heterobifunctional degrader with selective biological activity in CBP dependent cancer lines.
Citation Format: Laura La Bonte, Darshan Sappal. Discovery and characterization of potent, selective CBP degraders [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 6288.
Abstract 6301: Post-translational modifications regulate sensitivity to Polatuzumab Vedotin in DLBCL
Authors: Corcoran Sean R. , Staudt Louis M. , Hodson Daniel 
Published: June 2023

Abstract
Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive malignancy of which one-third of diagnosed patients ultimately relapse and die. New treatment paradigms for relapsed-refractory patients are needed. Most DLBCL tumors are reliant on signaling through their cell surface B-cell receptor (BCR) mediated by ITAMs on CD79A and CD79B to drive anti-apoptotic NF-kB and PI3 kinase signaling. In order to understand how surface BCR is regulated, we performed whole genome CRISPR screens in 9 DLBCL cell lines in which we sorted for high and low surface CD79B or added the CD79B targeted antibody-drug conjugate Polatuzumab-Vedotin (POLA-V). Strikingly, independent of genetic or cell of origin subtype, sgRNAs encoding the entire N-linked glycosylation pathway and specific sugar modification by addition of galactose and sialic acid were found to be enriched in high CD79B fractions and depleted in POLA-V treated samples compared to control. Further testing showed that removing sialic acid by treating with a small molecule inhibitor of sialic acid, genetic perturbation of golgi sugar transporters SLC35A1 and SLC35A2, or the a2,6 sialyltransferase ST6GAL1 resulted in more surface CD79B antibody binding with no significant change in CD79B protein abundance. The specificity of the effect of sialic acid loss on POLA antibody binding was confirmed by removing cell surface sialic acid with exogenous sialidase and observing increased binding of POLA, but not other therapeutic antibodies like Rituximab or CD19 FMC-63. Loss of SLC35A1, SLC35A2, and ST6GAL1 synergized with POLA-V but not the drug conjugate MMAE alone, showing a BCR dependent mechanism of sialic acid loss on POLA-V sensitization. In a further cell of origin subtype analysis of the germinal center B-cell (GCB) DLBCL cell lines, loss of the E3 ligase KLHL6 was found to synergize with POLA-V. Importantly, KLHL6 is heavily mutated across all germinal center derived malignancies, is more highly expressed in germinal center B-cells than other members of the B-cell lineage, and plays an unknown role in the development of autoimmune diseases. Further work will give evidence for the target of KLHL6 mediated ubiquitination and will show how this gene can drive lymphoma and autoimmune disease development in the germinal center.
Citation Format: Sean R. Corcoran, Louis M. Staudt, Daniel Hodson. Post-translational modifications regulate sensitivity to Polatuzumab Vedotin in DLBCL [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 6301.
Abstract 6430: Single-cell transcriptomic and epigenomic landscapes of innate and adaptive immune cells in metastatic melanoma treated with immunotherapy
Authors: Yang Jiekun , Fu Doris , Galani Kyriakitsa , Ho Li-Lun , Robitschek Emily J. , Frederick Dennie T. , Yadav Sandeep K. , Deng Wentao , Singh Anand K. , Burke Kelly P. , Wang Cassia , Sharova Tatyana , Liu David , Rai Kunal , Boland Genevieve M. , Kellis Manolis 
Published: June 2023

Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the care for cancer and extended survival for advanced cancer patients. While ICIs have shown astonishing clinical benefits, less than 50% of patients experience a durable response. To find better biomarkers for ICI response and understand the diverse cellular players in the tumor microenvironment (TME), we performed single-cell RNA sequencing (scRNA; 222,351 cells; 39 samples), single-nucleus transposase-accessible chromatin sequencing (scATAC; 45,478 cells; 15 samples), and bulk RNA sequencing (39 samples) on a metastatic melanoma cohort with rich phenotypic and molecular data. In ICI resistant tumors, we revealed how cell-adhesion and ribosomal activity changes in adaptive immune cells can reflect tumor-level therapeutic failure. We characterized T cell diversity in the TME and discovered an early activated state and a terminally exhausted state. Among the innate immune cells, we detected a mature dendritic cell (DC) state as a strong prognostic predictor of progression-free survival associated with ICI treatment. We studied its differentiation trajectory, transcriptome signatures, epigenome landscape and interactome with T-cells, in comparison to conventional dendritic cell types 1 and 2. We also showed that CRISPR deactivation of the enhancers induced by the mature DC state compromised DCs’ antigen-presentation capabilities and their interactions with antigen-specific T-cells. Lastly, we identified genes and functional modules associated with ICI response (e.g. cell-adhesion) and resistance (e.g. oxidative phosphorylation). Given their functional roles in strengthening immune response to cancer, the molecular and cellular mediators discovered here can help predict ICI regimen efficacy, guide therapeutic development and drug combinations, and pave the path to targeted therapies with long-term effects and new immunotherapies.
Citation Format: Jiekun Yang, Doris Fu, Kyriakitsa Galani, Li-Lun Ho, Emily J. Robitschek, Dennie T. Frederick, Sandeep K. Yadav, Wentao Deng, Anand K. Singh, Kelly P. Burke, Cassia Wang, Tatyana Sharova, David Liu, Kunal Rai, Genevieve M. Boland, Manolis Kellis. Single-cell transcriptomic and epigenomic landscapes of innate and adaptive immune cells in metastatic melanoma treated with immunotherapy. [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 6430.
The Right to Exclude and the Duty to Include: Self-determination, Equal Opportunity, and Immigration
Authors: Kollar Eszter , Banai Ayelet 
Published: June 2023

Abstract
The immigration debate in political theory has produced a series of accounts that justify the state’s right to exclude potential immigrants, where the right of self-determination figures prominently. We challenge two prominent accounts of the self-determination-based right to exclude and defend a circumscribed right to exclude and a corollary duty to admit immigrants, based on our ‘people relationship goods’ account of self-determination. Our conception reconciles the moral claims of global opportunity migrants with the well-being and non-alienation interests of the locals. It therefore provides a principled answer to the philosophical question underlying pressing political conflicts today, namely what is the permissible scope of exclusion by self-determining political communities, in light of weighty global moral demands of inclusion.
The Quadrupole Precipitation Pattern over Eastern China and Its Associated Atmospheric Circulations and Ocean Conditions
Authors: Liu Yuting , Huang Danqing , Zhu Jian , Cheng Chad Shouquan 
Published: June 2023

Abstract
The diversity of summer precipitation regimes over eastern China has raised concerns. Its variations during different warming periods and the relevant mechanisms remain unclear. In this study, the decadal precipitation changes and the associated atmospheric circulations, ocean conditions, and warming over Northern Hemisphere were investigated. The results indicated a quadrupole precipitation pattern over eastern China in the boreal summer, with a significant shift around 1998. From 1985–98 to 1999–2014, two wet anomalies were over North China (NC) and South China (SC), while two dry anomalies were over the Yangtze–Huaihe River basin (YHRB) and northeastern China (NEC). This quadrupole pattern is associated with the circumglobal teleconnection (CGT), the negative phase of the interdecadal Pacific oscillation (“−IPO”), the warming over the high latitudes of North Atlantic (“+HNA”), and the warming rate over the Northern Hemisphere (NWR). The CGT would induce the weakened polar front jet (PJ), southward shift of the PJ, and northward shift of the entire subtropical jet (SJ), which decreased the meridional distance between the PJ and SJ, and therefore resulted in the NC-wet–YHRB-dry–SC-wet variation. As well, the dry NEC was attributed to the enhanced PJ, weakened Iranian Plateau subtropical jet (IPSJ), and northward movement of the PJ and Tibetan Plateau subtropical jet (TPSJ), which were accompanied by −IPO and +HNA. Moreover, the NWR led to the weakened PJ and SJ, as well as the southward shift of PJ, also contributed to the dry YHRB, and wet anomalies over NC and SC. Particularly, the +HNA plays an important role in this quadrupole precipitation variation. Our findings have highlighted the role of jet streams in complex precipitation patterns, which will contribute to understanding the diverse variations in precipitation regimes over eastern China under global warming.

Significance Statement
The purpose of this study is to understand the regime shifts of the East Asian summer monsoon precipitation in different warming periods. We revealed a new precipitation pattern over eastern China as a “+ − + −” precipitation pattern from south to north. The circumglobal teleconnection, the negative phase of the interdecadal Pacific oscillation, the warming over the high-latitude North Atlantic, and the warming over Northern Hemisphere can be used to explain the quadrupole precipitation pattern. These findings could highlight the role of jet streams linking the quadrupole pattern to the teleconnections, dominant decadal ocean variabilities and the warming over Northern Hemisphere. Future work will focus on the role of Arctic rapid warming in summer precipitation over eastern China.
Disentangling Dynamic from Thermodynamic Summer Ice Area Loss from Observations (1979–2021): A Potential Mechanism for a “First-Time” Ice-Free Arctic
Authors: Le Guern-Lepage Alice , Tremblay Bruno L. 
Published: June 2023

Abstract
In recent decades, the Arctic minimum sea ice extent has transitioned from a predominantly thick multiyear ice cover to a thinner seasonal ice cover. We partition the total (observed) Arctic summer area loss into thermodynamic and dynamic (convergence, ridging, and export) sea ice area loss during the satellite era from 1979 to 2021 using a Lagrangian sea ice tracking model driven by satellite-derived sea ice velocities. Results show that the thermodynamic signal dominates the total summer ice area loss and the dynamic signal remains small (∼20%) even in 2007 when dynamic loss was largest. Sea ice loss by compaction (within pack ice convergence) dominates the dynamic area loss, even in years when the export is largest. Results from a simple (Ekman) free-drift sea ice model, supported by results from the Lagrangian model, suggest that nonlinear effects between dynamic and thermodynamic area loss can be important for large negative anomalies in sea ice extent, in accord with previous modeling studies. A detailed analysis of two all-time record minimum years (2007 and 2012)—one with a semipermanent high in the southern Beaufort Sea and the other with a short-lived but extreme storm in the Pacific sector of the Arctic in late summer—shows that compaction by Ekman convergence together with large thermodynamic melt in the marginal ice zone dominated the sea ice area loss in 2007 whereas, in 2012, it was dominated by Ekman divergence amplified by sea–ice albedo feedback—together with an early melt onset. We argue that Ekman divergence from more intense summer storms when the sun is high above the horizon is a more likely mechanism for a “first-time” ice-free Arctic.
Outer Size Distribution of Landfalling Tropical Cyclones over China Changes in the Recent Decades
Authors: Shen Zheng-Qin , Nie Gao-Zhen , Qiu Xin , Gu Jian-Feng , Zhang Yi 
Published: June 2023

Abstract
This study examines the changes in the outer size distribution of landfalling tropical cyclones (TCs) over the Chinese mainland from 1977 to 2020. The period was divided into two epochs: 1977–98 and 1999–2020. The results show that the size distribution of landfalling TCs over South China has no apparent change, while that of landfalling TCs over East China (LTCEC) is narrower in the second epoch, and the difference in the median sizes between East China and South China become more significant. Furthermore, it is found that LTCEC formed over the western part of the western North Pacific (W-WNP) shifted to a larger size range (300–500 km) at landfall, while those formed over the eastern part of the western North Pacific (E-WNP) rarely grew to extremely large size (>500 km). Further investigation revealed that over the W-WNP, the genesis position of LTCEC migrated equatorward during the second epoch, leading to a longer TC lifetime before landfall. Also, the increase of background relative vorticity and moisture associated with the southward migration is conducive to larger initial vortices. For TCs originating from the E-WNP, the change in the active area of TC passages reduced the frequency of TCs affecting the Chinese coast. Moreover, the growth of TC size during the intensification stage was significantly suppressed, lowering the occurrence probability of extremely large TCs. Changes in the large-scale thermodynamic environments between the two epochs were explored. Increased static stability and decreased convective available potential energy are possible factors limiting TC size increase.