bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB179: Identification of the highly potent and orally available ER-targeting PROTAC degrader HP568 for the treatment of breast cancer
Authors: Du Wu , Tu Zhilin , Qin Dekun , Li Haibo , Duan Jingyi , Liu Shijuan , Zhang Meng , Nie Zhenyan , Yuan Zhihui , Li Jing , Li Xinghai 
Published: April 2024

Abstract
Breast cancer remains an unmet medical need. It has become the most occurring and deadliest cancer for women globally. Estrogen receptor (ER) is expressed in 75% of breast cancers and has the key role in tumorigenesis and progression of ER+ breast cancers. Endocrine treatments that target ER are the mainstay therapies for the ER+ breast cancers, yet drug resistance unavoidably develops due to mutations in the ER gene. The ER-targeting proteolysis targeting chimera (PROTAC) degrader is an emerging new modality that interrupts the ER signaling through degradation of ER and offers unprecedented potential for solving the endocrine resistance. We have discovered HP568, an ER-targeting PROTAC that is highly potent against both the wild-type ER and ER mutants. HP568 has a favorable ADME profile that is superior to known competitor ER-targeting PROTAC. In the head-to-head comparison efficacy studies, HP568 has demonstrated the dose-dependent and superior efficacy that is well consistent with the drug exposure profile and PD biomarkers. HP568 also shows a synergetic effect in combination with a CDK4/6 inhibitor. HP568 is clean in the secondary pharmacology profiling, and well tolerated in animal tox studies. HP568 is under the preclinical development and has the potential to be the best-in-class ER-targeting degrader. HP568 structure will not be disclosed.
Citation Format: Wu Du, Zhilin Tu, Dekun Qin, Haibo Li, Jingyi Duan, Shijuan Liu, Meng Zhang, Zhenyan Nie, Zhihui Yuan, Jing Li, Xinghai Li. Identification of the highly potent and orally available ER-targeting PROTAC degrader HP568 for the treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB179.
Abstract LB212: Transcriptional dosage of oncogenic KRAS drives lung adenocarcinoma cell states, progression and metastasis
Authors: Serresi Michela , Kertalli Sonia , Dramaretska Yuliia , Schmitt Matthias Jürgen , Naumann Heike , Zschummel Maria , Gargiulo Gaetano 
Published: April 2024

Abstract
Metastasis is the endpoint of tumorigenesis and is generally diagnosed at an untreatable stage. The molecular mechanisms underlying metastasis and biomarkers for early intervention are largely unknown. Here, combining a mouse model of aggressive Kras-driven non-small-cell lung cancer with in vivo fate mapping and CRISPR activation screens, we show that transcriptional amplification of oncogenic Kras promotes orthotopic lung cancer lesions growth as well as oligoclonal and polyclonal metastasis to distal organs. Mild Kras transcriptional up-regulation by CRISPRa is sufficient to fuel competitive advantage in vitro and in vivo. Parallel CRISPR activation and transcriptome sequencing show that KrasG12D amplification cooperates with sterile inflammation to drive tumor progression and with the TGFß pathway to promote metastasis. Chromatin profiling of Kras-amplifying cells uncovers transcriptional regulators potentially collaborating with oncogenic Kras to drive lung cancer and metastasis in vivo. Transcriptional modulation of KRAS dosage in mouse cell and pharmacological inhibition in human PDXs affect cell stress and differentiation programs. These observations are corroborated by bulk and single-cell RNA-seq analysis in patients. Collectively, our data on a model oncogene advance our current understanding of how KRAS drives tumor evolution, with implications for prognosis and treatment of patients.
Citation Format: Michela Serresi, Sonia Kertalli, Yuliia Dramaretska, Matthias Jürgen Schmitt, Heike Naumann, Maria Zschummel, Gaetano Gargiulo. Transcriptional dosage of oncogenic KRAS drives lung adenocarcinoma cell states, progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB212.
Abstract LB319: Klf5 acetylation remodels tumor microenvironment to constrain PTEN-deficient prostate tumor growth
Authors: Zhang Baotong , Liu Mingcheng , Mai Fengyi , Xia Siyuan , Dong Jin-Tang 
Published: April 2024

Abstract
Prostate cancer is the most common cancer and the second leading cause of cancer-related death in men in the United States. PTEN deficiency is prevalent in patients with prostate cancer. As a tumor suppressor, PTEN is mutated in approximately 20% of primary prostate cancers, and up to 50% of metastatic castration resistant prostate cancer. PTEN inactivation results in high-grade adenocarcinoma with a long latency. The limited tumor progression induced by PTEN deficiency suggests that additional molecular events are activated to constrain tumor progression, and second hits are required. Understanding these secondary genetic hits will provide the rationale for combined therapies in prostate cancer treatment. In this study, we employed a unique genetically knockin mouse model and found that PTEN deficiency induces a KLF5 K369 acetylation-dependent barrier that attenuates FGFR1 signaling and constrains prostate tumor growth. More importantly, we discovered novel microenvironmental crosstalk between prostate cancer cells and cancer associated fibroblasts (CAFs). As suggested by RNA-seq and bioinformatic analyses and further validated by molecular and cellular experiments, we found that interruption of KLF5 acetylation in cancer cells stimulates CAFs to release FGF9 via TNF-α, and FGF9 activating FGFR1 signaling in cancer cells. In addition to this paracrine crosstalk, deacetylated KLF5 induces CX3CR1 and facilitates FGFR1 activation. Our findings provide a proof of concept for posttranslational modifications as essential molecular events induced by PTEN inactivation to stall prostate cancer progression and demonstrate KLF5 acetylation as a key component in a negative feedback loop by which FGFR1 was suppressed by AKT activation. This study reveals a paracrine reciprocal communication between cancer cells and fibroblasts and provides a clinical rationale for combined therapies using FGFR1 inhibitors (or CX3CR1 inhibitors) and p-AKT inhibitors in PTEN-deficient prostate cancer.
Citation Format: Baotong Zhang, Mingcheng Liu, Fengyi Mai, Siyuan Xia, Jin-Tang Dong. Klf5 acetylation remodels tumor microenvironment to constrain PTEN-deficient prostate tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB319.
Abstract LB339: Transient EZH2 suppression by tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy
Authors: Hou Yingqin , Wu Peng 
Published: April 2024

Abstract
The histone methyltransferase enhancer of zeste homolog 2 (EZH2) plays important roles in T cell differentiation, proliferation and function. Previous studies demonstrated that genetic deletion of EZH2 in CD8+ or total T cells impairs their antiviral and antitumor activity, cytokine production and expansion upon rechallenge. Contrary to the detrimental role of deleting T cell-intrinsic EZH2, here we demonstrate that transient inhibition of EZH2 in T cells prior to the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetostat, delays their dysfunctional progression and preserves T cell stemness and polyfunctionality while having no negative impact on cell proliferation. Tazemetostat induces T-cell epigenetic reprogramming and increases the expression of the self-renewal T cell transcription factor TCF1 by reducing its promoter H3K27 methylation preferentially in rapidly dividing T cells. In a murine melanoma model, T cells depleted of EZH2 induce poor tumor control, whereas T cells pretreated with tazemetostat exhibited superior anti-tumor immunity, especially when used in combination with anti-PD-1 blockade after adoptive transfer. Collectively, these data highlight the potential of transient epigenetic reprogramming by EZH2 inhibition to enhance adoptive T cell immunotherapy.
Citation Format: Yingqin Hou, Peng Wu. Transient EZH2 suppression by tazemetostat during in vitro expansion maintains T cell stemness and improves adoptive T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB339.
Abstract LB388: Super potent and efficacious ALK/ROS1/TRK inhibitor that overcomes multiple drug-resistant mutations
Authors: Xing Li , Wang Jingbing , Zhu Wei 
Published: April 2024

Abstract
Abnormal activation of ALK, ROS1 and TRK is implicated in tumorigenesis, progression, invasion, and metastasis of malignancies through various mechanisms. The first generation TRK inhibitors including larotrectinib and entrectinib have limited applications due to acquired resistance in clinical settings. Multiple on-target mutations occur at the solvent-front, gatekeeper, and xDFG motif inside the ATP binding pocket of the TRK kinase domain. While some candidates under current clinical development aim to address the solvent-front mutation, they are ineffective against the xDFG mutations (e.g.NTRK1.G667X). There is strong unmet medical needs for next generation TRK inhibitors that can address resistance mutations. We employ the synergistic advantages of domain expertise and modern technology to accelerate early stage drug discovery. On our deep learning (DL) centric AI platform, extensive scientific computing supports large scale virtual screening, generative design, drug property prediction and multi-objective lead optimization. Only the optimized candidate compounds are passed along for synthesis and testing to save time and cost. In Ba/F3-TPM3 cellular assays, LB-2159 showed superior potencies that are hundreds to thousands of fold higher than larotrectinib and/or entrectinib, with IC50 values of 0.02 nM for NTRK1.WT, 0.3 nM for NTRK1.G595R and 0.88 nM for NTRK1.G667C. Similar cellular potencies were demonstrated for ALK and ROS1. In xenograft models LB-2159 at 10 mg/kg bid resulted in complete tumor regression in Ba/F3-TPM3-NTRK1-WT tumors, 96% TGI in Ba/F3-TPM3-NTRK1-G595R tumors, 84% TGI and 100% survival in mice bearing Ba/F3-TPM3-NTRK1-G667C tumors. The pharmacokinetic profiles of LB-2159 are overall favorable, demonstrating extended stability and half life. In vitro safety screens yielded clean profiles without any DDI signal or hERG liability. Preclinical safety evaluations exhibited good tolerance in rats. In multiple dose escalation studies LB-2159 was well tolerated at 50 mg/kg/day and beyond. Empowered by our proprietary AI platform, we have discovered the novel ALK/ROS1/TRK inhibitors that overcome clinically known resistance mutations. Our drug candidate exhibited good tolerance in animals in preclinical safety evaluations. In xenograft models that are resistant to current treatments the compound demonstrates strong tumor suppression efficacy. LB-2159 is advancing through IND enabling studies, and its preclinical profiles support the potential for best-in-class treatment for NTRK fusion-positive solid tumors.
Citation Format: Li Xing, Jingbing Wang, Wei Zhu. Super potent and efficacious ALK/ROS1/TRK inhibitor that overcomes multiple drug-resistant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB388.
Abstract LB445: USP24 suppresses T cell anti-tumor activity by enhancing the stability of the PD-1 protein
Authors: Hsieh Hung-Chia , Hung Jan-Jong , Wang Yi-Ching 
Published: April 2024

Abstract
Persistent programmed cell death-1 (PD-1)/PD-L1 inhibitory signaling disrupts T cell cytotoxic function, leading to T cell exhaustion—a phenomenon strongly associated with advanced cancer progression and immunotherapy failure. Deciphering the mechanisms behind dysregulated PD-1 expression and reactivating tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) is crucial. Our previous research established that tumor-associated macrophage-derived IL-6 promotes STAT3-dependent PD-1 transcriptional activity and immunotherapy resistance. The current study further explores whether IL-6 abundance in the TME contributes to PD-1 protein stability. Results indicate that IL-6 extended PD-1 protein half-life in T cells, suggesting its role in modulating PD-1 protein stability. Furthermore, analysis of the GEO database showed a positive correlation between the expression of ubiquitin-specific-processing protease (USP) family enzymes and PD-1 in non-responding patients receiving anti-PD-1 therapy. Knockdown experiments revealed that USP24 strongly downregulated PD-1 protein expression and stability. USP24 depletion reversed IL-6-induced PD-1 expression and stability, with USP24 colocalizing with PD-1 at the plasma membrane upon IL-6 stimulation. Immunoprecipitation-Western blot assays confirmed that USP24 directly interacted with PD-1 and countered E3 ligase c-Cbl-mediated ubiquitination. Depleting USP24 suppressed PD-1-mediated immunosuppression both in vitro and in vivo. In lung-specific EGFRL858R/USP24C1698A functional knockout mice, tumor progression was slower, and exhausted tumor-infiltrating PD-1+ TIM-3+ CD8+ T cells reduced compared to EGFRL858R mice. Inhibiting PD-1 stability with an IL-6 neutralizing antibody or the novel inhibitor USP24-i-101 decreased tumor volume and increased activated cytotoxic T cell infiltration in vivo. Moreover, USP24-i-101 enhanced therapeutic effects in combination with anti-CTLA4 immunotherapy. Clinically, our in-house cohort revealed elevated USP24 expression in tumor-infiltrating lymphocytes or peripheral T cells, correlating with worse clinical outcomes and unfavorable responses to immunotherapy in lung cancer patients. This study uncovers USP24 as a novel PD-1 regulator, deubiquitinating PD-1 to enhance protein stability and suppress T cell function. In conclusion, USP24 emerges as a potential target for enhancing anti-tumor immunity and as a biomarker predicting clinical responses to immunotherapy in lung cancer.
Citation Format: Hung-Chia Hsieh, Jan-Jong Hung, Yi-Ching Wang. USP24 suppresses T cell anti-tumor activity by enhancing the stability of the PD-1 protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB445.
Abstract ND11: Chemoproteomic-enabled discovery of VVD-214, a synthetic lethal allosteric inhibitor of WRN helicase
Authors: Kikuchi Shota , Pettazzoni Piergiorgio , Baltgalvis Kristen A. , Lamb Kelsey N. , Symons Kent T. , Wu Chu-Chiao , Hoffman Melissa A. , Snead Aaron N. , Song Xiaodan , Glaza Thomas , Green Jason C. , Rogness Donald C. , Lam Betty , Rodriguez-Aguirre Maria E. , Woody David R. , Eissler Christie L. , Rodiles Socorro , Negron Seth M. , Bernard Steffen M. , Tran Eileen , Pollock Jonathan , Tabatabaei Ali , Contreras Victor , Williams Heather N. , Pastuszka Martha K. , Sigler John J. , Rudolph Markus G. , Classen Moritz , Brugger Doris , Claiborne Christopher , Plancher Jean-Marc , Cuartas Isabel , Seoane Joan , Burgess Laurence E. , Abraham Robert T. , Weinstein David S. , Simon Gabriel M. , Patricelli Matthew P. , Kinsella Todd M. 
Published: April 2024

Abstract
WRN helicase is a promising target for treating cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms. Currently, there are no approved drugs directly targeting human DNA or RNA helicases, in part due to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemical proteomic-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN. The clinical lead, VVD-214, covalently engages cysteine 727 of WRN in a nucleotide cooperative manner and inhibits ATP hydrolysis and helicase activity, resulting in widespread double-stranded DNA breaks, nuclear swelling, and cell death in MSI-high, but not microsatellite stable cells. VVD-214 provided robust tumor regression in multiple MSI-high colorectal cancer cell lines and patient derived xenograft models, including models derived from patients progressing on immune checkpoint therapies. VVD-214 was exceptionally well tolerated, and constitutes a promising oral drug candidate for patients with MSI-high cancers.
Citation Format: Shota Kikuchi, Piergiorgio Pettazzoni, Kristen A. Baltgalvis, Kelsey N. Lamb, Kent T. Symons, Chu-Chiao Wu, Melissa A. Hoffman, Aaron N. Snead, Xiaodan Song, Thomas Glaza, Jason C. Green, Donald C. Rogness, Betty Lam, Maria E. Rodriguez-Aguirre, David R. Woody, Christie L. Eissler, Socorro Rodiles, Seth M. Negron, Steffen M. Bernard, Eileen Tran, Jonathan Pollock, Ali Tabatabaei, Victor Contreras, Heather N. Williams, Martha K. Pastuszka, John J. Sigler, Markus G. Rudolph, Moritz Classen, Doris Brugger, Christopher Claiborne, Jean-Marc Plancher, Isabel Cuartas, Joan Seoane, Laurence E. Burgess, Robert T. Abraham, David S. Weinstein, Gabriel M. Simon, Matthew P. Patricelli, Todd M. Kinsella. Chemoproteomic-enabled discovery of VVD-214, a synthetic lethal allosteric inhibitor of WRN helicase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND11.
Hybrid optimal feature selection approach for internet of things based medical data analysis for prognosis
Authors: Bel Felcia , Selvaraj Sabeen 
Published: April 2024

<p>Healthcare is very important application domain in internet of things (IoT). The aim is to provide a novel combined feature selection (FS) methods like univariate (UV) with tree-based methods (TB), recursive feature elimination (RFE) with least absolute shrinkage selection operator (LASSO), mutual information (MI) with genetic algorithm (GA) and embedded methods (EM) with univariate has been applied to internet of medical things (IoMT)based heart disease dataset. The well-suited machine learning algorithms for IoT medical data are logistic regression (LR) and support vector machine (SVM). Each combined method has been applied to the machine learning algorithms to find the best classifier for prognosis. The various performance metrices has been calculated for all the combined feature selection methods for logistic regression and support vector machine and found that for precise classification could be done using recursive elimination feature selection method with LASSO applied to logistic regression achieved a better performance than all other combined methods with high accuracy, sensitivity and high area under curve. Decision has been taken by data analytics that RFE+LASSO using LR feature selection method will provide an overall better performance for IoT based medical heart disease dataset after comparing all other combined methods with LR and SVM classifiers<em>. </em></p>
A Shift in Artistic Practices through Artificial Intelligence
Authors: Tatar Kivanç , Ericson Petter , Cotton Kelsey , Del Prado Paola Torres Núñez , Batlle-Roca Roser , Cabrero-Daniel Beatriz , Ljungblad Sara , Diapoulis Georgios , Hussain Jabbar 
Published: April 2024

Abstract
The explosion of content generated by artificial intelligence (AI) models has initiated a cultural shift in arts, music, and media, whereby roles are changing, values are shifting, and conventions are challenged. The vast, readily available dataset of the Internet has created an environment for AI models to be trained on any content on the Web. With AI models shared openly and used by many globally, how does this new paradigm shift challenge the status quo in artistic practices? What kind of changes will AI technology bring to music, arts, and new media?
Experiential AI: Between Arts and Explainable AI
Authors: Hemment Drew , Murray-Rust Dave , Belle Vaishak , Aylett Ruth , Vidmar Matjaz , Broz Frank 
Published: April 2024

Abstract
Experiential artificial intelligence (AI) is an approach to the design, use, and evaluation of AI in cultural or other real-world settings that foregrounds human experience and context. It combines arts and engineering to support rich and intuitive modes of model interpretation and interaction, making AI tangible and explicit. The ambition is to enable significant cultural works and make AI systems more understandable to nonexperts, thereby strengthening the basis for responsible deployment. This paper discusses limitations and promising directions in explainable AI, contributions the arts offer to enhance and go beyond explainability and methodology to support, deepen, and extend those contributions.
A Comparison of White Matter Brain Differences in Monolingual and Highly Proficient Multilingual Speakers
Authors: Midrigan-Ciochina Ludmila , Vodacek Kayla P. , Sewell Cristina , Corina David P. 
Published: April 2024

Abstract
Language processing relies on the communication between brain regions that is achieved through several white matter tracts, part of the dorsal, ventral, and medial pathways involved in language processing and control (Coggins et al., 2004; Friederici & Gierhan, 2013; Hickok & Poeppel, 2007; Luk et al., 2011). While changes in white matter tract morphology have been reported as a function of second language learning in bilinguals, little is known about changes that may be present in multilanguage users. Here we investigate white matter morphometry in a group of highly proficient multilinguals, (individuals with proficiency in four or more languages), compared to a group of monolinguals. White matter morphometry was quantified using a fixel-based analysis (Raffelt et al., 2015; Raffelt et al., 2017; Tournier et al., 2007). Higher fiber cross-section and lower fiber density values were observed for the multilinguals, in the dorsal pathways (superior longitudinal fasciculus and arcuate fasciculus) and the ventral pathway, including the inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and the uncinate fasciculus. Segments of the corpus callosum, the fornix, and the cortico-spinal tract showed decreases in all three morphometry measures for multilinguals. The findings suggest differential efficiencies in neural communication between domain-specific language regions and domain-general cognitive processes underlying multilingual language use. We discuss the results in relation to the bilingual Anterior to Posterior and Subcortical Shift (BAPSS) hypothesis (Grundy et al., 2017) and the Dynamic Restructuring Model (Pliatsikas, 2020).