tbuckley/cabot-search huggingface dataset:
Abstract 57: Ibrutinib improves chimeric antigen receptor T cell control of leukemia by inhibiting myeloid-derived suppressor cells
Authors: Benjamin F. Frost, Olga Shestova, Feng Shen, Chia Sharpe, John C. Byrd, Saar I. Gill
Journal: Cancer Research (2024)

Abstract Background: In patients with chronic lymphocytic leukemia (CLL), we and others have shown that the addition of the BTK inhibitor ibrutinib to CART cells increases the rates of durable complete responses. The mechanism for this remains unknown. Lymphodepletion (LD) is considered critical for CART cell therapy success, yet emergency myelopoiesis during recovery from LD may induce a surge of myeloid-derived suppressor cells (MDSC), particularly in patients with advanced cancer. BTK inhibition has been shown to inhibit MDSC function in vitro. We therefore hypothesized that administration of ibrutinib during and following LD could reduce MDSC-mediated suppression of CART cells and thereby improve CART cell outcomes. Methods: To explore the effects of ibrutinib on human MDSCs, we engineered suppressive monocytes through in vitro culture of CD14+ cells in the presence of IL-6 and GM-CSF. We added ibrutinib to the culture on Days 0-4 and compared the ability of the monocytes to inhibit proliferation of human CAR-T cells. To model CLL treatment with CART in immunocompetent mice, we used the Em-TCL1 adaptive transfer model of CLL. Mice were treated with ibrutinib (I), cyclophosphamide and fludarabine (FC), or ibrutinib + FC (FC+I). MDSCs were isolated from these mice for in vitro function studies. In subsequent experiments mice were also treated with syngeneic CART19 with or without FC or FC+I. Results: In vitro generated human MDSC suppressed CART19 function, and this was prevented by pre-treatment of MDSC with ibrutinib. Myeloid cells from the spleens of CLL-bearing mice inhibited syngeneic CART19 function ex vivo regardless of treatment with FC or I alone, but myeloid cells harvested from CLL-bearing mice treated with FC+I lost suppressive function. Finally, mice treated with CART19 after a LD regimen resembling that in our recently reported clinical trial (FC+I) showed a survival advantage over all other groups. Conclusions: BTK inhibition with ibrutinib prevents myeloid cell suppression of CART cells in vitro in human and murine systems. When combined with lymphodepleting chemotherapy (FC), ibrutinib enhances CART cell control of CLL in vivo, possibly by preventing MDSC-mediated suppression of CART cells. Citation Format: Benjamin F. Frost, Olga Shestova, Feng Shen, Chia Sharpe, John C. Byrd, Saar I. Gill. Ibrutinib improves chimeric antigen receptor T cell control of leukemia by inhibiting myeloid-derived suppressor cells [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 57.
Abstract 5482: Spatial and multi-omic interrogation of the primary and recurrent glioblastoma microenvironment
Authors: Jean R. Clemenceau, Paola Suarez-Meade, Alfredo Quiñones-Hinojosa, Tae Hyun Hwang
Journal: Cancer Research (2024)

Abstract Glioblastoma remains as one of the deadliest malignancies with most cases likely to recur. Recent work has focused on characterizing not only glioma cells, but the tumor microenvironment via single-cell and spatial transcriptomic technologies. This has improved our understanding of the high heterogeneity of this disease and described potential tumor domains. However, there is still a need to further understand the changes that occur between the primary and the recurrent lesion. We propose that a spatial, multi-omic characterization of matched primary and recurrent glioblastoma can yield insights into recurrence mechanisms occurring throughout the tumor microenvironment. We collected 22 IDH-WT glioblastoma samples from 12 patients (11 primary, 11 recurrent, 10 matched pairs) from the Mayo Clinic Neuroscience Biobank. We performed single-nucleus RNA sequencing (15 samples, 10 patients, 5 matched pairs) and proteomics (16 samples, 6 matched pairs) from fresh-frozen tissue, as well as spatial transcriptomics with 10x Visium (14 samples, 8 patients, 6 matched pairs) and 10x Xenium in-situ molecular imaging (6 samples, 2 matched pairs). Using spatial transcriptomics data, we identified regional subsets present in different proportions and distributions between primary and recurrent glioblastoma. These clusters were characterized with gene set and gene ontology analysis, identifying regions enriched with known glioma subtypes and cellular activity. Spatial-based cluster genes were consistent with significantly differentially expressed proteins. We used single-nucleus RNAseq and in-situ molecular imaging data from matched tissue samples to further interrogate relevant cell populations and location in the tumor micro-environment. We identified regions with enriched extra cellular matrix interaction and remodeling signatures to be highly expressed in recurrent glioblastoma. Primary glioblastoma was enriched with oligodendrocyte-like regions with high cell communication and extracellular vesicle signatures. This study will further our understanding of the changes in the mechanisms at play in the complex ecosystem of glioblastoma as it recurs. Citation Format: Jean R. Clemenceau, Paola Suarez-Meade, Alfredo Quiñones-Hinojosa, Tae Hyun Hwang. Spatial and multi-omic interrogation of the primary and recurrent glioblastoma microenvironment [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 5482.
Abstract 559: Investigating DDX3X as a target to improve outcomes in Black and Native American endometrial cancer patients
Authors: James D. Lausen, Doris M. Benbrook
Journal: Cancer Research (2024)

Abstract Introduction: The goal of this project was to identify and test a new molecular target that will help reduce the worse outcomes of endometrial cancer, especially in Black and Native American patients. Endometrial cancer is rapidly on the rise in the developed world. It has overtaken many other types of cancer in both incidence and mortality. Black populations are disproportionately impacted by endometrial cancer, both in Oklahoma and across the United States. In Oklahoma specifically, Native Americans are the most heavily impacted group. Methods: Machine learning techniques were used to analyze comprehensive metabolic panel (CMP) data from electronic medical record of patients in the University of Oklahoma (OU) network of hospitals and clinics. This data was broken down by endometrial cancer status, race, and age. Plasma samples of endometrial cancer patients were collected from the OU Health Sciences Center Biobank. These samples were analyzed by mass spectrometry. Endometrial cancer cell lines Ishikawa (low-grade) and ARK-1 and ARK-4 (high grade) were cultured in EMEM. For treating the cells, we used RK-33, a small molecule inhibitor of DDX3X. MTT assays were performed in 96-well plates at increasing concentrations of RK-33 for 48 hours. Western blots were used to determine effect of the drug on cellular DDX3X and yH2AX protein levels. Results: Machine learning analysis EMR data revealed a difference between races in albumin levels of women with endometrial cancer. Black and Native American patients had lower albumin, which is known to correlate to worse outcomes. IPA analysis of plasma proteomics revealed several proteins that were differentially expressed between races. Among these was DDX3X, the X-linked form of DDX3, a DEAD-box RNA helicase which is involved in DNA damage repair. Patient data indicated that patients with high DDX3X expression tended to have lower survival rates. MTT analysis determined that Ishikawa has a lower IC50 than the high-grade cell lines, but all responded. Western blotting confirmed that treatment with RK-33 reduced the amount of DDX3X in the cells and increased y-H2AX, indicating more DNA damage. Conclusions: This study demonstrates that DDX3X is a valid molecular target in endometrial cancer. The differential expression across race groups indicates that Black and Native Americans may stand to benefit the most from a novel drug targeting this difference. Because DDX3X is involved in DNA damage repair, combining the treatment with a DNA-damaging drug may increase response to the drug as well. Citation Format: James D. Lausen, Doris M. Benbrook. Investigating DDX3X as a target to improve outcomes in Black and Native American endometrial cancer patients [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 559.
Abstract 5389: Development of T-cell exclusion in melanoma
Authors: Ha-Ram Park, Hee Won Yang, Minah Kim
Journal: Cancer Research (2024)

Abstract Immune checkpoint inhibitors (ICIs), which prevent immune cell exhaustion and boost an antitumor response, have shown remarkable treatment efficacy in patients with advanced melanoma. However, its efficacy is limited by the emergence of resistance associated with an immunosuppressive tumor microenvironment (TME). The contribution of abnormal tumor vasculature to limited immune cell infiltration into the tumor core has been reported but the mechanisms of its development are still elusive. We analyzed how tumor angiogenesis affects the immune cell exclusion at different time points of primary melanoma using syngeneic murine melanomas. The spatial distribution of various immune cell populations and vascular integrity were analyzed in whole tumor cross-sections via multiplex immunofluorescence staining. We found that the exclusion pattern of CD8+ T cells was less evident with a balanced distribution across the whole tumor regions at the early stage. However, as the tumor grows, there is a pronounced accumulation of CD8+ T cells at the tumor periphery with a conspicuous absence in the core. Tumor blood vessels were structurally uniform and functionally stable in the early developmental tumor but became unstable and leaky as the tumor progressed, which was associated with the development of CD8+ T-cell exclusion. To understand the mechanism underlying vascular regulation of immune exclusion during tumor progression, we will investigate the expression of genes related to tumor angiogenesis using spatial transcriptomic analysis and RNA sequencing of endothelial cells (CD45+CD31-) sorted from the murine melanomas. These results highlight the contribution of spatial tumor vascular destabilization to the T-cell exclusion development, implying the potential of targeting tumor vasculature to enhance immune activation and the therapeutic efficacy of ICI in melanoma. Citation Format: Ha-Ram Park, Hee Won Yang, Minah Kim. Development of T-cell exclusion in melanoma [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 5389.
Development of a SARS‐CoV‐2 neutralization assay based on a pseudotyped virus using a HIV system
Authors: Ziteng Liang, Jincheng Tong, Xi Wu, Shuo Liu, Jiajing Wu, Yuanling Yu, Li Zhang, Chenyan Zhao, Qiong Lu, Jianhui Nie, Weijin Huang, Youchun Wang
Journal: MedComm (2024)

Abstract Regarding the extensive global attention to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) that constitutes an international public health emergency, pseudovirus neutralization assays have been widely applied due to their advantages of being able to be conducted in biosafety level 2 laboratories and having a high safety factor. In this study, by adding a blue fluorescent protein (AmCyan) gene to the HIV system pSG3‐△env backbone plasmid Hpa I and truncating the C‐terminal 21 amino acids of the SARS‐CoV‐2 spike protein (S), high‐titer SARS‐CoV‐2‐Sdel21‐AmCyan fluorescent pseudovirus was successfully packaged. The fluorescent pseudovirus was used to establish a neutralization assay in a 96‐well plate using 293T cells stably transfected with the AF cells. Then, parameters such as the ratio of backbone and membrane plasmid, sensitive cells, inoculation of cells and virus, as well as incubation and detection time were optimized. The pseudovirus neutralization assay demonstrated high accuracy, sensitivity, repeatability, and a strong correlation with the luminescent pseudovirus neutralization assay. Additionally, we scaled up the neutralizing antibody determination method by increasing the plate size from 96 wells to 384 wells. We have established a robust fluorescent pseudotyped virus neutralization assay for SARS‐CoV‐2 using the HIV system, providing a foundation for serum neutralization antibody detection, monoclonal antibody screening, and vaccine development.
Author Correction: Oesophageal atresia
Authors: Marinde van Lennep, Maartje M. J. Singendonk, Luigi Dall’Oglio, Fréderic Gottrand, Usha Krishnan, Suzanne W. J. Terheggen-Lagro, Taher I. Omari, Marc A. Benninga, Michiel P. van Wijk
Journal: Nature Reviews Disease Primers (2024)
Comment on ‘Association of systemic inflammatory markers and tertiary lymphoid structure with pathological complete response in gastric cancer patients receiving preoperative treatment: a retrospective cohort study’
Authors: Shanshan Xie, Yong Zhi, Changming Shao, Binfang Zeng
Journal: International Journal of Surgery (2024)

Xie, Shanshan MD; Zhi, Yong MD; Shao, Changming MD; Zeng, Binfang MD Author Information
Left atrial reservoir strain is a superior discriminator of cardioembolism in ischaemic stroke
Authors: Aditya Bhat, Gary C H Gan, Henry H L Chen, Shaun Khanna, Vipul Mahajan, Arnav Gupta, Camelia Burdusel, Nigel Wolfe, Lina Lee, Maria Carmo P Nunes, Cesar Augusto Taconeli, José Luiz Padilha da Silva, Timothy C Tan
Journal:  (2024)

Abstract Aims Echocardiographic measures of left heart size and function have long been associated with cardioembolic mechanisms of stroke development, however, the diagnostic performance and comparison of measures of atrial function in this context has not been well studied. We sought to evaluate the diagnostic performance of left atrial reservoir strain (LASr) in identification of cardioembolism in the ischaemic stroke population relative to traditional measures of left heart size and function. Methods and results Consecutive patients admitted to our institution with ischaemic stroke or transient ischaemic attack were recruited and underwent comprehensive transthoracic echocardiography. Strokes were classified by aetiology with comparison undertaken between cardioembolic and non-cardioembolic types. Four hundred and eighteen consecutive stroke patients with a cardioembolic (n = 229) or non-cardioembolic (n = 189) stroke aetiology were analysed. LASr was impaired in cardioembolic compared with non-cardioembolic strokes (16.7 ± 8.2% vs. 26.0 ± 5.5%, P &amp;lt; 0.01) and provided greatest discrimination [area under the curve (AUC) 0.813, 95%CI 0.773–0.858] in differentiating stroke subtypes when compared with LVEF (AUC difference 0.150, P &amp;lt; 0.01), LAVI (AUC difference 0.083, P &amp;lt; 0.01), and E/e’ (AUC difference 0.163, P &amp;lt; 0.01). Inclusion of LASr in a model with conventional left heart echocardiographic factors improved model performance with a net reclassification improvement of 1.083 (95%CI 0.945–1.220, P &amp;lt; 0.01). Further, a proposed user-defined model-based clinical algorithm with LASr demonstrated improved diagnostic accuracy of the identification of cardioembolic stroke subtypes which was best appreciated in patients without atrial fibrillation. Conclusion LASr may provide enhanced diagnostic accuracy beyond conventional echocardiographic measures to discriminate cardioembolic from non-cardioembolic stroke mechanisms, in particular amongst those without comorbid atrial fibrillation.
Evaluation of a delayed liver transplantation strategy for patients with HCC receiving bridging therapy: the DELTA-HCC study
Authors: Catherine Lamarque, Lauriane Segaux, Philippe Bachellier, Benjamin Buchard, Faiza Chermak, Filomena Conti, Thomas Decaens, Sébastien Dharancy, Vincent Di Martino, Jérôme Dumortier, Claire Francoz-Caudron, Jean Gugenheim, Jean Hardwigsen, Fabrice Muscari, Sylvie Radenne, Ephrem Salamé, Thomas Uguen, José Ursic-Bedoya, Corinne Antoine, Aurélie Deshayes, Christian Jacquelinet, Pierre-André Natella, Vincent Leroy, Daniel Cherqui, Nadia Oubaya, Christophe Duvoux
Journal: Journal of Hepatology (2024)

To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy (DS) was adopted in France in 2015 in patients listed for any single HCC treated with resection or thermal ablation during the waiting phase. The DS involves postponing LT until recurrence. The purpose of this study was to evaluate the DS to make sure that it did not hamper pre- and post-LT outcomes.
Pyroptotic T cell-derived active IL-16 has a driving function in ovarian endometriosis development
Authors: Jinghe Zhang, Weidong Zhao, Yonggang Zhou, Shengdi Xi, Xiuxiu Xu, Xianghui Du, Xiaohu Zheng, Weiping Hu, Rui Sun, Zhigang Tian, Binqing Fu, Haiming Wei
Journal: Cell Reports Medicine (2024)

Endometriosis, affecting 6%–10% of women, often leads to pain and infertility and its underlying inflammatory mechanisms are poorly understood. We established endometriosis models in wild-type and IL16KO mice, revealing the driver function of IL-16 in initiating endometriosis-related inflammation. Using an in vitro system, we confirmed iron overload-induced GSDME-mediated pyroptosis as a key trigger for IL-16 activation and release. In addition, our research led to the development of Z30702029, a compound inhibiting GSDME-NTD-mediated pyroptosis, which shows promise as a therapeutic intervention for endometriosis. Importantly, our findings extend beyond endometriosis, highlighting GSDME-mediated pyroptosis as a broader pathway for IL-16 release and offering insights into potential treatments for various inflammatory conditions.
Domain generalization across tumor types, laboratories, and species — Insights from the 2022 edition of the Mitosis Domain Generalization Challenge
Authors: Marc Aubreville, Nikolas Stathonikos, Taryn A. Donovan, Robert Klopfleisch, Jonas Ammeling, Jonathan Ganz, Frauke Wilm, Mitko Veta, Samir Jabari, Markus Eckstein, Jonas Annuscheit, Christian Krumnow, Engin Bozaba, Sercan Çayır, Hongyan Gu, Xiang ‘Anthony’ Chen, Mostafa Jahanifar, Adam Shephard, Satoshi Kondo, Satoshi Kasai, Sujatha Kotte, V.G. Saipradeep, Maxime W. Lafarge, Viktor H. Koelzer, Ziyue Wang, Yongbing Zhang, Sen Yang, Xiyue Wang, Katharina Breininger, Christof A. Bertram
Journal: Medical Image Analysis (2024)

Recognition of mitotic figures in histologic tumor specimens is highly relevant to patient outcome assessment. This task is challenging for algorithms and human experts alike, with deterioration of algorithmic performance under shifts in image representations. Considerable covariate shifts occur when assessment is performed on different tumor types, images are acquired using different digitization devices, or specimens are produced in different laboratories. This observation motivated the inception of the 2022 challenge on MItosis Domain Generalization (MIDOG 2022). The challenge provided annotated histologic tumor images from six different domains and evaluated the algorithmic approaches for mitotic figure detection provided by nine challenge participants on ten independent domains. Ground truth for mitotic figure detection was established in two ways: a three-expert majority vote and an independent, immunohistochemistry-assisted set of labels. This work represents an overview of the challenge tasks, the algorithmic strategies employed by the participants, and potential factors contributing to their success. With an F1 score of 0.764 for the top-performing team, we summarize that domain generalization across various tumor domains is possible with today's deep learning-based recognition pipelines. However, we also found that domain characteristics not present in the training set (feline as new species, spindle cell shape as new morphology and a new scanner) led to small but significant decreases in performance. When assessed against the immunohistochemistry-assisted reference standard, all methods resulted in reduced recall scores, with only minor changes in the order of participants in the ranking.
Engineered human osteoarthritic cartilage organoids
Authors: Laura Dönges, Atharva Damle, Andrea Mainardi, Thomas Bock, Monica Schönenberger, Ivan Martin, Andrea Barbero
Journal: Biomaterials (2024)

The availability of human cell-based models capturing molecular processes of cartilage degeneration can facilitate development of disease-modifying therapies for osteoarthritis (Acevedo Rua et al., 2021) [1], a currently unmet clinical need. Here, by imposing specific inflammatory challenges upon mesenchymal stromal cells at a defined stage of chondrogenesis, we engineered a human organotypic model which recapitulates main OA pathological traits such as chondrocyte hypertrophy, cartilage matrix mineralization, enhanced catabolism and mechanical stiffening. To exemplify the utility of the model, we exposed the engineered OA cartilage organoids to factors known to attenuate pathological features, including IL-1Ra, and carried out mass spectrometry-based proteomics. We identified that IL-1Ra strongly reduced production of the transcription factor CCAAT/enhancer-binding protein beta (Hirata et al., 2012) [2] and demonstrated that inhibition of the C/EBPβ-activating kinases could revert the degradative processes. Human OA cartilage organoids thus represent a relevant tool towards the discovery of new molecular drivers of cartilage degeneration and the assessment of therapeutics targeting associated pathways.
Biomaterial-mediated intracellular control of macrophages for cell therapy in pro-inflammatory and pro-fibrotic conditions
Authors: Tina Tylek, Joanna Wong, Andrew E. Vaughan, Kara L. Spiller
Journal: Biomaterials (2024)

Macrophages are key modulators of all inflammatory diseases and essential for their resolution, making macrophage cell therapy a promising strategy for regenerative medicine. However, since macrophages change rapidly in response to microenvironmental cues, their phenotype must be controlled post-administration. We present a tunable biomaterial-based strategy to control macrophages intracellularly via small molecule-releasing microparticles. Poly(lactic-co-glycolic acid) microparticles encapsulating the anti-inflammatory and anti-fibrotic drug dexamethasone were administered to macrophages in vitro, with uptake rates controlled by different loading regimes. Microparticle dose and dexamethasone content directly affected macrophage phenotype and phagocytic capacity, independent of particle content per cell, leading to an overall pro-reparative, anti-inflammatory, anti-fibrotic phenotype with increased phagocytic and ECM degrading functionality. Intracellularly controlled macrophages partially maintained this phenotype in vivo in a murine pulmonary fibrosis model, with more prominent effects in a pro-fibrotic environment compared to pro-inflammatory. These results suggest that intracellular control using biomaterials has the potential to control macrophage phenotype post-administration, which is essential for successful macrophage cell therapy.