bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficient elimination of primary B-ALL cells in vitro and in vivo using a novel 4-1BB-based CAR targeting a membrane-distal CD22 epitope
Authors: Velasco-Hernandez Talia , Zanetti Samanta Romina , Roca-Ho Heleia , Gutierrez-Aguera Francisco , Petazzi Paolo , Sánchez-Martínez Diego , Molina Oscar , Baroni Matteo Libero , Fuster Jose Luis , Ballerini Paola , Bueno Clara , Fernandez-Fuentes Narcis , Engel Pablo , Menendez Pablo 
Published: August 2020

BackgroundThere are few therapeutic options available for patients with B-cell acute lymphoblastic leukemia (B-ALL) relapsing as CD19– either after chemotherapy or CD19-targeted immunotherapies. CD22-chimeric antigen receptor (CAR) T cells represent an attractive addition to CD19-CAR T cell therapy because they will target both CD22+CD19– B-ALL relapses and CD19– preleukemic cells. However, the immune escape mechanisms from CD22-CAR T cells, and the potential contribution of the epitope binding of the anti-CD22 single-chain variable fragment (scFv) remain understudied.MethodsHere, we have developed and comprehensively characterized a novel CD22-CAR (clone hCD22.7) targeting a membrane-distal CD22 epitope and tested its cytotoxic effects against B-ALL cells both in in vitro and in vivo assays.ResultsConformational epitope mapping, cross-blocking, and molecular docking assays revealed that the hCD22.7 scFv is a high-affinity binding antibody which specifically binds to the ESTKDGKVP sequence, located in the Ig-like V-type domain, the most distal domain of CD22. We observed efficient killing of B-ALL cells in vitro, although the kinetics were dependent on the level of CD22 expression. Importantly, we show an efficient in vivo control of patients with B-ALL derived xenografts with diverse aggressiveness, coupled to long-term hCD22.7-CAR T cell persistence. Remaining leukemic cells at sacrifice maintained full expression of CD22, ruling out CAR pressure-mediated antigen loss. Finally, the immunogenicity capacity of this hCD22.7-scFv was very similar to that of other CD22 scFv previously used in adoptive T cell therapy.ConclusionsWe report a novel, high-affinity hCD22.7 scFv which targets a membrane-distal epitope of CD22. 4-1BB-based hCD22.7-CAR T cells efficiently eliminate clinically relevant B- CD22high and CD22low ALL primary samples in vitro and in vivo. Our study supports the clinical translation of this hCD22.7-CAR as either single or tandem CD22–CD19-CAR for both naive and anti-CD19-resistant patients with B-ALL.
Equilibrium, radial stability and non-adiabatic gravitational collapse of anisotropic neutron stars
Authors: Pretel Juan M. Z. 
Published: August 2020

AbstractIn this work we construct families of anisotropic neutron stars for an equation of state compatible with the constraints of the gravitational-wave event GW170817 and for four anisotropy ansatze. Such stars are subjected to a radial perturbation in order to study their stability against radial oscillations and we develop a dynamical model to describe the non-adiabatic gravitational collapse of the unstable anisotropic configurations whose ultimate fate is the formation of a black hole. We find that the standard criterion for radial stability$$dM/d\rho _c >0$$dM/dρc>0is not always compatible with the calculation of the oscillation frequencies for some anisotropy ansatze, and each anisotropy parameter is constrained taking into account the recent restriction of maximum mass of neutron stars. We further generalize the TOV equations within a non-adiabatic context and we investigate the dynamical behaviour of the equation of state, heat flux, anisotropy factor and mass function as an unstable anisotropic star collapses. After obtaining the evolution equations we recover, as a static limit, the background equations.
Minimal coupling in presence of non-metricity and torsion
Authors: Delhom Adrià 
Published: August 2020

AbstractWe deal with the question of what it means to define a minimal coupling prescription in presence of torsion and/or non-metricity, carefully explaining while the naive substitution$$\partial \rightarrow \nabla $$∂→∇introduces extra couplings between the matter fields and the connection that can be regarded as non-minimal in presence of torsion and/or non-metricity. We will also investigate whether minimal coupling prescriptions at the level of the action (MCPL) or at the level of field equations (MCPF) lead to different dynamics. To that end, we will first write the Euler–Lagrange equations for matter fields in terms of the covariant derivatives of a general non-Riemannian space, and derivate the form of the associated Noether currents and charges. Then we will see that if the minimal coupling prescriptions is applied as we discuss, for spin 0 and 1 fields the results of MCPL and MCPF are equivalent, while for spin 1/2 fields there is a difference if one applies the MCPF or the MCPL, since the former leads to charge violation.
Example-driven virtual cinematography by learning camera behaviors
Authors: Jiang Hongda , Wang Bin , Wang Xi , Christie Marc , Chen Baoquan 
Published: August 2020

Designing a camera motion controller that has the capacity to move a virtual camera automatically in relation with contents of a 3D animation, in a cinematographic and principled way, is a complex and challenging task. Many cinematographic rules exist, yet practice shows there are significant stylistic variations in how these can be applied.
In this paper, we propose an example-driven camera controller which can extract camera behaviors from an example film clip and re-apply the extracted behaviors to a 3D animation, through learning from a collection of camera motions. Our first technical contribution is the design of a low-dimensional cinematic feature space that captures the essence of a film's cinematic characteristics (camera angle and distance, screen composition and character configurations) and which is coupled with a neural network to automatically extract these cinematic characteristics from real film clips. Our second technical contribution is the design of a cascaded deep-learning architecture trained to (i) recognize a variety of camera motion behaviors from the extracted cinematic features, and (ii) predict the future motion of a virtual camera given a character 3D animation. We propose to rely on a Mixture of Experts (MoE) gating+prediction mechanism to ensure that distinct camera behaviors can be learned while ensuring generalization.
We demonstrate the features of our approach through experiments that highlight (i) the quality of our cinematic feature extractor (ii) the capacity to learn a range of behaviors through the gating mechanism, and (iii) the ability to generate a variety of camera motions by applying different behaviors extracted from film clips. Such an example-driven approach offers a high level of controllability which opens new possibilities toward a deeper understanding of cinematographic style and enhanced possibilities in exploiting real film data in virtual environments.
Abstract A18: Characterization of checkpoint inhibitors in the tumor microenvironment (TME) and peripheral blood in endemic Burkitt Lymphoma
Authors: Saikumar-Lakshmi Priya , Oduor Cliff , Forconi Catherine , Marsh Patrick , Ong’echa John Michael , Bailey Jeffrey , Moormann Ann 
Published: August 2020

Abstract
Introduction: The tumor microenvironment and the interaction between immune checkpoint inhibitors (ICIs) and tumor cells are essential to understand for designing future immunotherapy strategies. In this study, we aim to characterize the tumor microenvironment (TME) in children diagnosed with endemic Burkitt lymphoma (eBL), the most common pediatric cancer in Africa. A history of chronic malaria (Plasmodium falciparum) and Epstein-Barr virus (EBV) coinfections are both risk factors in the etiology of eBL.
Methods: Using multicolor flow cytometry and single-cell RNA sequencing, we analyzed the expression of immune checkpoint inhibitors in T cells from the tumor microenvironment and from peripheral blood mononuclear cells (PBMC) of eBL patients, along with age-matched controls with different malaria exposure. Additionally, CD8 T-cell infiltration was confirmed by immunohistochemistry.
Results: PD-1+ CD4 T cells from eBL PBMCs were increased in number compared to healthy controls from the malaria-endemic area (p=0.03). Both CD4 and CD8 T cells from eBL PBMCs reveal higher frequency of TIGIT expressers compared to healthy controls (non-malaria endemic) (p=0.002, p=0.007 respectively). PD1+ TIGIT+ IFNG- memory CD4 T cells phenotype from eBL PBMCs was increased upon short stimulation with PMA/ionomycin, as well as “naive-like” CD95+ PD1high TIGIT+ CTLA4+ IFNG+ CD8T cells. Tumor samples from 4 eBL patient were used on single-cell analysis; we observed activated T-cells profile that highly upregulated TIGIT within the tumor microenvironment. We also noticed relatively low expression of other ICIs such as PD1, TIM3, LAG3, and CTLA4. Base on all these data, we calculated an exhaustion score that was higher than the cytotoxicity score in our eBL-derived tumor-infiltrating lymphocytes (TILs). In addition, we use immunohistochemistry staining to confirm CD8 T-cell infiltration and ICI expression in eBL tumor fine needle aspirates. Our future directions will employ TIGIT blockade inhibitor studies of CD8 T cells, in order to increase expansion and function of CD8 TILs. Our results will help support future development of ICI therapies in endemic Burkitt lymphoma.
Citation Format: Priya Saikumar-Lakshmi, Cliff Oduor, Catherine Forconi, Patrick Marsh, John Michael Ong’echa, Jeffrey Bailey, Ann Moormann. Characterization of checkpoint inhibitors in the tumor microenvironment (TME) and peripheral blood in endemic Burkitt Lymphoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A18.
Abstract A21: Time-to-event Bayesian optimal interval design to accelerate phase I pediatric oncology trials
Authors: Yuan Ying , Lin Ruitao , Li Daniel , Nie Lei , Warren Katherine 
Published: August 2020

Abstract
Late-onset toxicity is common for novel molecularly targeted agents and immunotherapy. It causes major logistic difficulty for existing adaptive phase I trial designs, which require the observance of toxicity early enough to apply dose escalation rules for new patients. The same logistic difficulty arises when the accrual is rapid. We propose the time-to-event Bayesian optimal interval (TITE-BOIN) design to accelerate phase I trials by allowing for real-time dose assignment decisions for new patients while some enrolled patients’ toxicity data are still pending. Similar to the rolling six design, the TITE-BOIN dose escalation/de-escalation rule can be tabulated before the trial begins, making it transparent and simple to implement, but is more flexible in choosing the target DLT rate and has higher accuracy to identify the MTD. Compared to the more complicated model-based time-to-event continuous reassessment method (TITE-CRM), the TITE-BOIN has comparable accuracy to identify the MTD but is simpler to implement with substantially better overdose control. A numerical study shows that the TITE-BOIN design supports continuous accrual, without sacrificing patient safety or the accuracy of identifying the MTD, and therefore has great potential to accelerate early-phase drug development.
Note: This abstract was not presented at the conference.
Citation Format: Ying Yuan, Ruitao Lin, Daniel Li, Lei Nie, Katherine Warren. Time-to-event Bayesian optimal interval design to accelerate phase I pediatric oncology trials [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A21.
Abstract A32: Selective inhibition of AuroraA by LY3295668 erbumine in neuroblastoma models induces apoptosis through a combination of S-phase DNA damage and mitotic arrest
Authors: Dowless Michele , Kremer Jill , Lowery Caitlin , Gong Xueqian , Klahn Joseph , Stephens Jennifer , Hui Yu-Hua , Blosser Wayne , Martinez Ricardo , Du Jian , Stancato Louis 
Published: August 2020

Abstract
Aurora kinase A (AuroraA) is a serine/threonine protein kinase critical for centrosome maturation, mitotic spindle formation, and spindle checkpoint activation. Aberrant expression of AuroraA promotes tumor initiation and disease progression, making it a promising therapeutic target in several cancer types. However, recent clinical trials of purported selective AuroraA inhibitors failed due to lack of efficacy and/or hematologic toxicity, likely due to concurrent inhibition of Aurora kinase B (AuroraB). Selective AuroraA inhibition leads to mitotic arrest and apoptosis, while AuroraB inhibition causes persistent DNA endoreduplication and polyploidy leading to genomic instability. LY3295668 erbumine (LY3295668) is a selective AuroraA inhibitor with preclinical activity in multiple models of cancer including neuroblastoma (NBL). High-risk NBL, a devastating pediatric cancer with few effective treatment options, is mainly stratified by MYCN amplification status. In NBL, AuroraA stabilizes N-MYC post-transcriptionally; moreover, AuroraA also controls N-MYC-dependent transcription during S-phase. Here, we evaluated LY3295668 in multiple NBL cell lines and in vivo mouse models where treatment resulted in apoptosis and tumor regressions, respectively. We compared LY3295668 to alisertib (a dual AuroraA/B inhibitor) in multiple cell-based assays that differentiate AuroraA activity from that of AuroraB and showed that LY3295668 has a distinct pharmacologic profile from alisertib. In addition, we determined the mechanism of action for LY3295668 includes DNA damage prior to mitotic block. Our results further support that AuroraA controls MYC-dependent transcription in S-phase and selective inhibition of AuroraA with LY3295668 promotes transcription-replication conflicts leading to DNA damage. In addition to AuroraA-mediated mitotic arrest, this DNA damage may contribute to the hypersensitivity of MYC-driven tumors such as NBL. In summary, LY3295668 is a selective AuroraA inhibitor with a dual mechanism of action in NBL involving DNA damage in S-phase and a cell cycle block in mitosis. These combined activities contribute to sensitivity of preclinical NBL models.
Citation Format: Michele Dowless, Jill Kremer, Caitlin Lowery, Xueqian Gong, Joseph Klahn, Jennifer Stephens, Yu-Hua Hui, Wayne Blosser, Ricardo Martinez, Jian Du, Louis Stancato. Selective inhibition of AuroraA by LY3295668 erbumine in neuroblastoma models induces apoptosis through a combination of S-phase DNA damage and mitotic arrest [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A32.
Abstract A51: Advances in the etiology and therapeutics of a lethal childhood cancer, fibrolamellar hepatocellular carcinoma
Authors: Lalazar Gadi , Jarmel Melissa , Wang Ruisi , Tomasini Michael , Requena David , Ng Denise , Simon Sanford M. 
Published: August 2020

Abstract
Introduction: Fibrolamellar hepatocellular carcinoma (FLC) is a liver cancer affecting adolescents and young adults without underlying liver disease. Patients with FLC are often diagnosed with advanced-stage disease and have a poor 5-year survival. Recently we have made advances in both understanding the etiology of FLC as well as developing therapeutics. We have found that the bulk of the genome lacks recurrent single-nucleotide or structural variants (inversions, amplifications) with the exception of a deletion in one copy of chromosome 19. This results in a fusion of the first exon of the heat shock protein, DNAJB1, with the 2nd through 10th exons of PRKACA, the catalytic subunit of protein kinase A. Expression of this fusion in the livers of mice, either by CRISPR or transposon, is sufficient to phenocopy the disease. The kinase activity of the fusion protein is essential for transformation, but equivalent expression of the native kinase is not sufficient.
Results: Etiology: We have tested the ability of the native kinase and fusion oncokinase to phosphorylate potential substrates in human liver. We have found a discrete set of substrates that are phosphorylated in human liver for which we are now testing, which are critical for the pathogenesis of this cancer. Therapeutics: We have purified the fusion oncokinase without a tag and used a high-throughput screen to find inhibitors. We have found inhibitors in the nanomolar range for which we are using structural analysis to inform our medicinal chemistry. Additionally, we have developed several “never-in-plastic” patient-derived xenograft (PDX) models that retain expression of the driver, histology, transcriptome, and proteome of the original human tumor. We have also screened for compounds that induce tumor cell death and tumor regression in FLC PDXs.
Conclusion: Subtle changes in the kinase substrate profile of the fusion kinase provide new leads for therapeutics for FLC. The ability to find inhibitors of the kinase in the nanomolar range, as well as the ability to screen for inhibitors of the PDX, offers the first hope for treatment against this lethal tumor.
Citation Format: Gadi Lalazar, Melissa Jarmel, Ruisi Wang, Michael Tomasini, David Requena, Denise Ng, Sanford M. Simon. Advances in the etiology and therapeutics of a lethal childhood cancer, fibrolamellar hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A51.
Abstract A63: Overcoming challenges in health care with machine learning: Innovation from retinoblastoma
Authors: Janusonis Isabella , Truong Tran , Liu Justin , Chen Mei , Gallie Brenda 
Published: August 2020

Abstract
Introduction: As retinoblastoma is a rare pediatric cancer (1/17,000 live births) with little evidence to justify treatment choices, we built a cloud-based retinoblastoma-specific electronic health record database for point-of-care data to support clinical and research collaboration and provide a quantitative analysis of prescribed treatments.
Methods: Disease-specific Electronic Patient Illustrated Clinical Timeline (DEPICT HEALTH) is online, cloud-based, interactive, with point-of-care timelines and corresponding retinal/tumor drawings, with standardized scoring of tumor number, size, and locations.
Results: DEPICT HEALTH records are contributed by the entire care team and used in quantitative treatment analyses. DEPICT HEALTH effectively communicates disease and treatment information to the patients’ circle of care and their parents, independent of language. The Retinoblastoma Activity Index (RAI) quantifies the active tumor (colored yellow) by counting the yellow pixels in the DEPICT HEALTH digital drawings. The drawings represent tumor at every encounter based on the collective opinion of the care team, and the RAI will quantitate tumor response to treatment. Two clinical trials were initiated using DEPICT HEALTH and RAI for eligibility and short- and long-term outcomes.
Conclusion: Using RAI to score tumor response provides RECIST (response evaluation criteria in solid tumors) for retinoblastoma research, a standard of measurement that has never before been available. Machine learning methods will ultimately analyze point-of-care data to predict patient outcomes and assist with clinical decision making. DEPICT HEALTH provides an unbiased view of the efficacy of treatments, with potential to allow global point-of-care data to be widely available for research, essentially an “n” of “ALL.”
Citation Format: Isabella Janusonis, Tran Truong, Justin Liu, Mei Chen, Brenda Gallie. Overcoming challenges in health care with machine learning: Innovation from retinoblastoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A63.
Abstract A75: Mithramycin evicts SWI/SNF from chromatin to induce epigenetic reprogramming in rhabdoid tumor
Authors: Chasse Maggie H. , Johnson Benjamin K. , Boguslawski Elissa A. , Sorensen Katie M. , Beddows Ian , Madaj Zachary , Foxa Gabrielle E. , Rybski Kristin J. , Kitchen-Goosen Susan M. , Williams Bart O. , Triche Timothy J. , Grohar Patrick J. 
Published: August 2020

Abstract
The text of this abstract has not been printed at the request of the authors due to intellectual property matters.
Citation Format: Maggie H. Chasse, Benjamin K. Johnson, Elissa A. Boguslawski, Katie M. Sorensen, Ian Beddows, Zachary Madaj, Gabrielle E. Foxa, Kristin J. Rybski, Susan M. Kitchen-Goosen, Bart O. Williams, Timothy J. Triche Jr., Patrick J. Grohar. Mithramycin evicts SWI/SNF from chromatin to induce epigenetic reprogramming in rhabdoid tumor [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A75.