bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 90: In vitro functional evaluation of immuno-oncology drug candidates in customized bioassays
Authors: Vlaming Martijn , Sidot Emmanuelle , Lefèvre Jezabel , Boelen Ellen , Pattyn Sofie 
Published: March 2024

Abstract
Increased understanding of the complex tumor microenvironment and its interactors has boosted therapeutic interest and highlighted the importance of the development of innovative in vitro bioassays to represent all the players of the cancer immune response and thereby potentially provide pivotal information on the functional dynamics of candidate therapeutics. Regulatory T cells play an important role by downregulating the anti-tumor response. Their regulation mechanisms constitute an important target for new therapeutics. To study these mechanisms in a human model, suppressive Treg bioassays, mimicking the suppressive action of these cells, were developed and optimized. We further highlight the study of neutrophil function in vitro using flow-cytometry or the Incucyte® live imaging system to monitor neutrophil functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), Neutrophil Extracellular Traps (NETs) formation and the release of Reactive Oxygen Species (ROS). Additionally, multiplex cytokine and peroxidase enzyme analysis after activation and stimulation of neutrophils can be evaluated using ELISA or Luminex technology. Moreover, to refine/reduce non-human primate (NHP) usage, we aimed to develop cost-effective NHP in vitro assays with predictive value for in vivo studies. We isolated Cynomolgus Macaque monocytes and successfully differentiated/polarized them into M0- and M2-like macrophages with a cell surface phenotype comparable to that of their human counterparts. We further developed a Cynomolgus Macaque PBMC x human dendritic cell (DC) mixed lymphocyte reaction (MLR) assay for functional evaluation of test compounds, effectively generated Cynomolgus Macaque immature DCs and implemented Cynomolgus Macaque cytokine release assays.Using high quality primary human immune cells from our own biobank, in vitro bioassays have been developed with superior robustness and reproducibility to screen candidate Immuno-Oncology therapeutics.
Citation Format: Martijn Vlaming, Emmanuelle Sidot, Jezabel Lefèvre, Ellen Boelen, Sofie Pattyn. In vitro functional evaluation of immuno-oncology drug candidates in customized bioassays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 90.
Abstract 91: Comprehensive 27-marker standard panel for immune monitoring of pre-clinical tumor mouse models using spectral analyzer technology
Authors: Hummel Jonas F. , Metzger Philipp , Sonntag Roland , Borrero-Wolff Dennis , Obodozie Cynthia , Weber Holger 
Published: March 2024

Abstract
Within the last decade, major technological advances in flow cytometry and (single cell) RNA-sequencing have deepened our understanding of complex anti-tumoral immune responses. This allows a comprehensive immune monitoring of novel therapies in pre-clinical models.
Conventional flow cytometry is reaching its technical limitation. The emitted fluorescence signal of the target population stained with antibodies is evaluated with simple bandpass filters, which leads to spectral overlap and thus the number of parameters that can be analyzed simultaneously is limited. The spectral analyzer technology combines both methods, providing great flexibility in evaluating different immune cell populations. This provides the opportunity to obtain target information by measuring the entire fluorescence spectrum measuring each wavelength individually and thus evaluating the true signal of each fluorochrome unaffected by autofluorescence or spillover.
Our standard all-in-one flow cytometry panel uses the full capacity of a conventional BD Fortessa flow cytometer and enables the differentiation of important immune cell populations in tumors, such as T cells (CD4+, CD8+, regulatory T cells), B and NK cells as well as macrophages (M1/M2), MDSCs (granulocytes and monocytes) and dendritic cells. However, it would be of great advantage to gain further insights into activation and effector functions of the immune cells using markers like CD44 & CD62L, CD69, PD-1, Lag-3, Tim-3 and PDL-1, CD80, CD86, CD40 and Ki-67. The Sony ID7000 spectral analyzer enables the simultaneous assessment of 27 markers to evaluate immune phenotypes, with the ability to include up to 4 individual target antibodies.
Flow cytometry data from various tumor models are presented, demonstrating the enormous utility and potential of the spectral analyzer, especially with limited and precious tumor sample material, by evaluating different immune cell populations simultaneously without reaching its technical limits. The spectral analyzer technology enables us to mechanistically investigate differences in tumor therapies such as PD-1 treatment or other immune cell modulators not only phenotypically but also with regard to activation and differentiation of immune cell populations.
Citation Format: Jonas F. Hummel, Philipp Metzger, Roland Sonntag, Dennis Borrero-Wolff, Cynthia Obodozie, Holger Weber. Comprehensive 27-marker standard panel for immune monitoring of pre-clinical tumor mouse models using spectral analyzer technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 91.
Abstract 92: Assessment of an in vitro potency assay for evaluation of immune cell-mediated cytotoxicity using the Omni Pro 12 automated imaging platform
Authors: Sullivan Denise , Stemkens Lieke , Thijssen Inge , Meiler Svenja , Califano Danielle , Chvatal Stacie , Millard Daniel 
Published: March 2024

Abstract
The development of immunotherapies relies on the use of in vitro potency assays—which are key for understanding complex interactions between immune cells and cancer cells. Immune effector T-cells are a promising cancer therapy due to their innate cytotoxicity. In particular, CAR T-cell therapy uses genetically engineered T-cells that express a chimeric antigen receptor that binds to a specific antigen on tumor cells. Assessing the efficacy and potency of CAR T-cell therapies in vitro and at high throughputs is vital for the preclinical development of these promising therapies. Here, we describe an in vitro potency assay that uses an automated imaging platform to quantify immune cell-mediated cytotoxicity of cancer target cells by immune effector cells. A GFP fluorescent and HER-2 expressing lung cancer cell line, A549, was seeded into a 96-well cell culture plate. Then, HER-2 CAR T-cells were added at 24 hours post target cell seeding at various E:T ratios (1:10, 1:5, 1:2, 1:1, and 5:1). Fluorescent images of the target cells were captured every 6 hours by the Omni Pro 12, an automated, high-throughput, live-cell analysis platform designed for continuous multi-well imaging inside an incubator. Automated image analysis was performed using the Confluency Module in the Axion Portal to view attachment and proliferation and quantify cytolysis of fluorescent A549 target cells. Percent cytolysis of the target cells was calculated by comparing the green fluorescent confluency of treated wells to no treatment control wells. A549-GFP cells showed a dose-dependent decrease in confluency over time that correlated with increasing amounts of CAR T-cells. At 92 hours post HER-2 CAR T-cell addition, the 5:1 ET group demonstrated approximately 91.8% +/- 2.0% cytolysis of A549-GFP cells, while the 1:10 group demonstrated approximately 69.2% +/- 3.0% cytolysis. Future work will evaluate differences in CAR T-cell potency when co-cultured with target cells that express different levels of HER-2. Overall, the Omni Pro 12 platform enables continuous quantification of the potency and kinetics of immune cell-mediated cytolysis.
Citation Format: Denise Sullivan, Lieke Stemkens, Inge Thijssen, Svenja Meiler, Danielle Califano, Stacie Chvatal, Daniel Millard. Assessment of an in vitro potency assay for evaluation of immune cell-mediated cytotoxicity using the Omni Pro 12 automated imaging platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 92.
Abstract 933: Single-cell inference and validation of heterogeneous drug sensitivity in cholangiocarcinoma reveals dacinostat as novel therapeutic candidate
Authors: Obradovic Aleksandar , Tomassoni Lorenzo , Yu Daoqi , Drake Charles G. , Dela Cruz FIlemon , Kung Andrew , Califano Andrea 
Published: March 2024

Abstract
Cholangiocarcinoma is a rare, aggressive malignancy with limited treatment options, due to a paucity of actionable mutations and low response to immune checkpoint inhibitors. Furthermore, its extreme heterogeneity prevents identification of actionable dependencies from bulk-tissue profiles, such that transformed cells themselves represent as little as 10% of cells comprising the complex micro-environment of these tumors. To address these challenges, we introduce a highly generalizable, single-cell framework for the mechanism-based prioritization of drugs to treat rare, heterogeneous tumors. Analysis of tumor cells isolated by single-cell RNA-Sequencing across six patients and two independent data sources using protein activity inference has revealed three molecularly distinct subphenotypes of cholangiocarcinoma cells, present to varying degrees across patients but with highly conserved proteomic signatures, and predicted to be sensitive to four drugs by regulatory network analysis. A seventh independent patient recapitulated these phenotypes, and drug sensitivity predictions at single-cell level for this patient were validated in low-passage, patient-derived xenografts from the same patient, which confirmed tumor growth rate control by two of these drugs (plicamycin and dacinostat) and further validated predicted subpopulation-specific effects, such that dacinostat alone inhibited tumor growth across all three tumor subphenotypes, while plicamycin preferentially inhibited some but not all, allowing the remaining phenotypes to reconstitute a treatment-resistant tumor. This approach suggests dacinostat as a promising candidate for follow-up clinical trials in cholangiocarcinoma, either alone or in combination with current standard-of-care chemotherapies, and is highly generalizable to elucidate complementary dependencies of other aggressive, heterogeneous tumors.
Citation Format: Aleksandar Obradovic, Lorenzo Tomassoni, Daoqi Yu, Charles G. Drake, FIlemon Dela Cruz, Andrew Kung, Andrea Califano. Single-cell inference and validation of heterogeneous drug sensitivity in cholangiocarcinoma reveals dacinostat as novel therapeutic candidate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 933.
Abstract 938: Screening the entire kinase-directed, FDA-approved pharmacopeia against the largest collection of wild-type and mutant kinases reveals many opportunities for drug repurposing and targeted therapy
Authors: Loch Christian M. , Liang Shuguang , Wu Jianghong , Eason Mia , Goupil Alison , Acinapura Anthony , Purcell Jamie , Dominguez Maia 
Published: March 2024

Abstract
We sought to screen all FDA approved, cancer-indicated, kinase targeting drugs using the gold standard radiometric biochemical activity assay (HotSpot) against the largest collection of kinases in the world (&gt;100 drugs against 735 total kinases including 395 wild type and 340 mutants). Virtually every drug examined exhibits polypharmacology inhibiting many kinases. Rarely does the intended target represent the greatest inhibition observed from a drug. Furthermore, most drugs inhibit a select group of mutant kinases, including especially mutants of kinases distinct from the intended target. Within a given kinase, each cancer-identified mutation is often as distinct as the different wild-type kinases are from each other, in terms of inhibition profile. Considering mutants, then, the cancer-relevant druggable kinome is many thousand distinct targets, not 518 “plus a few”. Exposing this reality is a first step towards developing all the therapeutic tools necessary to ultimately defeat cancer. Here, we reveal vast and specific repurposing opportunities among the existing pharmacopeia for tumors that are driven by kinases not previously recognized as targets for certain drugs, and for tumors that have become chemotherapy-resistant through mutation of specific kinases. The most exciting and clinically relevant opportunities were confirmed in cell-based assays, results of which will also be presented.
Citation Format: Christian M. Loch, Shuguang Liang, Jianghong Wu, Mia Eason, Alison Goupil, Anthony Acinapura, Jamie Purcell, Maia Dominguez. Screening the entire kinase-directed, FDA-approved pharmacopeia against the largest collection of wild-type and mutant kinases reveals many opportunities for drug repurposing and targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 938.
Abstract 943: Identification and validation of unusual drug combinations identified from combination databases
Authors: Grant Rainer , Pinheiro Marco , Roska Rachel Weller , Felix Robert 
Published: March 2024

Abstract
There is a noted trend in the identification and subsequent approval of rational drug combinations to treat various diseases, particularly cancer. When applied in a clinical setting, synergistic combinations can have significant benefits including improved patient response and avoiding or overcoming drug resistance. Although multiple strategies have been successfully implemented to identify rational drug combinations, extensive validation is initially required to confirm a combination as synergistic. The existence and growing use of web-based repositories containing comprehensive drug combination data is a key resource and can be a valuable starting point for identifying synergistic combinations. However, are synergistic combinations from these datasets expected or rational and can they be validated experimentally? By mining available drug combinations from the DrugCombo database, we wanted to identify unusual drug combinations reported as synergistic and experimentally validate these with dose-response assays. In addition, we set out to establish if cytokines could be used as an inhibition biomarker to easily assess synergy. We found multiple unexpected synergies including a predicted synergy between the JAK1/2 inhibitor Ruxolitinib with Maraviroc, a CCR5 antagonist, or Levetiracetam, an SV2A binding anti-epileptic reported in the lymphoma cell line, L-1236. Experimentally, these predicted synergies could not be validated. In the context of synergistic drug combinations, this work shows that experimental validation is crucial, particularly for combinations with uncertain biological mechanisms.
Citation Format: Rainer Grant, Marco Pinheiro, Rachel Weller Roska, Robert Felix. Identification and validation of unusual drug combinations identified from combination databases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 943.
Abstract 950: Functional characterization of atypical somatic variants in the Gundersen Precision Oncology Cohort
Authors: Feiszt Peter , Kenny Paraic A. 
Published: March 2024

Abstract
The generation and widespread sharing of large somatic mutation datasets has revolutionized our understanding of genetic mechanisms driving cancer initiation and progression. For well-understood mutations, this has created the opportunity for individualized therapeutic intervention in a wide range of malignancies. Beyond these well-characterized mutations, there exists a wide range of alterations that remain poorly understood and which require some kind of functional genomics analysis to determine whether such patients are eligible for the targeted therapy used for more typical mutations in that gene, whether these alterations are passenger mutations that don’t affect throughput on the associated signaling pathway, or reflect another more nuanced phenomenon.
Whether using ectopic overexpression in cell lines or generation of genetically modified mice, addressing this problem at scale using functional genomics approaches is challenging. A key limitation is the absence of the original tissue context in which that variant co-evolved with other genetic alterations as well as data on the clinical response of the patient to successive lines of therapy. This can be addressed, in part, by the banking of tissue from patient cohorts who have had comprehensive genomic profiling as part of their routine clinical care.
The Gundersen Precision Oncology Cohort is a growing dataset of FFPE specimens and longitudinal clinical data from more than 750 patients who have had comprehensive cancer genome profiling using assays from a wide range of diagnostic companies. We use this resource for biomarker discovery and functional classification of many atypical cancer variants. Current subgroups include atypical point mutations in BRAF, ERBB2 and ERBB3, as well as fusions affecting BRAF, PIK3CA and ROS1. We present examples illustrating the value of this approach for classification of variants detected in a range of tumor types.
Citation Format: Peter Feiszt, Paraic A. Kenny. Functional characterization of atypical somatic variants in the Gundersen Precision Oncology Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 950.
O homem dotado de imagem: reempregos críticos segundo Peter Tscherkassky, Jean-Luc Godard, Andrei Ujică e Marylène Negro
Authors: Brenez Nicole 
Published: March 2024

A história das artes (literatura, arquitetura, música, pintura, cinema) é massivamente constituída por reempregos e contrassensos. O século XX viu se desenvolver uma cultura do reemprego de intenção crítica, seja ela de ordem analítica, polêmica ou simplesmente reflexiva. À medida que as imagens se acumularam e as práticas, suportes e modos de difusão se multiplicaram, as iniciativas analíticas e críticas também se desenvolveram.
Sensory modality and information domain contribute jointly to dual-task interference between working memory and perceptual processing
Authors: Fleming Justin T. , Njoroge J. Michelle , Noyce Abigail L. , Perrachione Tyler K. , Shinn-Cunningham Barbara G. 
Published: March 2024

Abstract
Making sense of our environment requires us to extract temporal and spatial information from multiple sensory modalities, particularly audition and vision. Often, we must hold this sensory information in working memory (WM) to guide future actions, while simultaneously processing new sensory inputs as they arise. However, these processes of WM maintenance and perceptual processing can interfere with one another when the tasks rely on similar cognitive resources. fMRI studies have uncovered attention and WM networks that are specialized for either auditory-temporal or visual-spatial processing; the functional specialization of these networks makes specific predictions about patterns of interference between perceptual processing and WM. Specifically, we hypothesized that dual-task interference should increase when the tasks share a common sensory modality, a common information domain (temporal vs. spatial processing), or both. To test these predictions, we asked participants to store temporal or spatial information about auditory or visual stimuli in WM. On some trials, participants also performed an intervening auditory task, which was either temporal or spatial, during WM retention. Errors on WM recall and perceptual judgment tasks both generally increased when the tasks relied on shared modality- and domain-biased resources, with maximal interference when both tasks were auditory-temporal. Pupil dilations were also larger and started earlier when both tasks were auditory-temporal, indicating an increase in cognitive effort to overcome the interference. Event-related potentials (ERPs) and alpha-band oscillatory activity revealed neural signatures of domain-based interference even when the tasks were presented in different sensory modalities, when behavioral differences were masked by ceiling effects. These results demonstrate that sensory modality and information domain jointly affect how task information is represented in WM, consistent with past work demonstrating how tasks engage complementary auditory-temporal and visual-spatial cognitive control networks.
Effect of Sarcopenia on the Prognosis of Clinical Outcomes in Patients With Hepatocellular Carcinoma After Hepatic Resection
Authors: Polvieng Thanatchawan , Hongjinda Sermsak , Thienhiran Anuparp , Burasakarn Pipit , Fuengfoo Pusit 
Published: March 2024

Background We aimed to study the prognostic impact of sarcopenia on overall survival (OS), disease-free survival (DFS), and postoperative outcomes among patients with Hepatocellular carcinoma (HCC) who underwent curative hepatic resection. Methods Data were collected retrospectively from patients with HCC underwent curative hepatic resection and preoperative abdominal computed tomography (CT) at our institution between January 2010 and December 2020. Sarcopenia was evaluated by the skeletal muscle mass at the inferior direction of the third-lumbar-vertebra (L3) cross-sectional area based on preoperative CT imaging using software analysis. Cutoff values for skeletal muscle index (SMI) were 43.75 and 41.10 cm2/m2 for males and females. The patients were classified into sarcopenia and nonsarcopenia groups. The association between preoperative sarcopenia and clinicopathological factors, impact of sarcopenia on survival, and postoperative outcomes were analyzed. Results Sarcopenia was present in 39 of 83 (47.0%) patients who underwent curative hepatic resection for HCC and was significantly correlated with lower SMI, lower serum albumin levels, higher intraoperative blood loss, higher postoperative complications, and longer hospital stay. The 5-year OS was significantly lower in sarcopenic patients than in nonsarcopenic patients (58.2% vs 83.6%; P = .006), but the 5-year DFS was not significantly different between the 2 groups. Multivariate analysis revealed that sarcopenia was a significant risk factor for poor OS (HR 4.728; 95% CI, 1.458-15.329; P = .010). Conclusion Sarcopenia was identified as a prognostic factor for poor OS after hepatic resection, and major postoperative complications were more frequent in sarcopenia. Early sarcopenia detection and management may improve OS and clinical outcomes in postoperative HCC.