bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual Scene Graph Convolutional Network for Motivation Prediction
Authors: Wanyan Yuyang , Yang Xiaoshan , Ma Xuan , Xu Changsheng
Published: December 2022

Humans can easily infer the motivations behind human actions from only visual data by comprehensively analyzing the complex context information and utilizing abundant life experiences. Inspired by humans’ reasoning ability, existing motivation prediction methods have improved image-based deep classification models using the commonsense knowledge learned by pre-trained language models. However, the knowledge learned from public text corpora is probably incompatible with the task-specific data of the motivation prediction, which may impact the model performance. To address this problem, this paper proposes a
dual scene graph convolutional network (dual-SGCN)
to comprehensively explore the complex visual information and semantic context prior from the image data for motivation prediction. The proposed dual-SGCN has a visual branch and a semantic branch. For the visual branch, we build a visual graph based on scene graph where object nodes and relation edges are represented by visual features. For the semantic branch, we build a semantic graph where nodes and edges are directly represented by the word embeddings of the object and relation labels. In each branch, node-oriented and edge-oriented message passing is adopted to propagate interaction information between different nodes and edges. Besides, a multi-modal interactive attention mechanism is adopted to cooperatively attend and fuse the visual and semantic information. The proposed dual-SGCN is learned in an end-to-end form by a multi-task co-training scheme. In the inference stage, Total Direct Effect is adopted to alleviate the bias caused by the semantic context prior. Extensive experiments demonstrate that the proposed method achieves state-of-the-art performance.
Revisiting Graph-based Recommender Systems from the Perspective of Variational Auto-Encoder
Authors: Zhang Yi , Zhang Yiwen , Yan Dengcheng , Deng Shuiguang , Yang Yun
Published: December 2022

Graph-based recommender system has attracted widespread attention and produced a series of research results. Because of the powerful high-order connection modeling capabilities of the Graph Neural Network, the performance of these graph-based recommender systems are far superior to those of traditional neural network-based collaborative filtering models. However, from both analytical and empirical perspectives, the apparent performance improvement is accompanied with a significant time overhead, which is noticeable in large-scale graph topologies. More importantly, the intrinsic data-sparsity problem substantially limits the performance of graph-based recommender systems, which compelled us to revisit graph-based recommendation from a novel perspective. In this article, we focus on analyzing the time complexity of graph-based recommender systems to make it more suitable for real large-scale application scenarios. We propose a novel end-to-end graph recommendation model called the Collaborative Variational Graph Auto-Encoder (CVGA), which uses the information propagation and aggregation paradigms to encode user–item collaborative relationships on the user–item interaction bipartite graph. These relationships are utilized to infer the probability distribution of user behavior for parameter estimation rather than learning user or item embeddings. By doing so, we reconstruct the whole user–item interaction graph according to the known probability distribution in a feasible and elegant manner. From the perspective of the graph auto-encoder, we convert the graph recommendation task into a graph generation problem and are able to do it with approximately linear time complexity. Extensive experiments on four real-world benchmark datasets demonstrate that CVGA can be trained at a faster speed while maintaining comparable performance over state-of-the-art baselines for graph-based recommendation tasks. Further analysis shows that CVGA can effectively mitigate the data sparsity problem and performs equally well on large-scale datasets.
Sex-based comparisons of muscle cellular adaptations after 10 weeks of progressive resistance training in middle-aged adults
Authors: Binet Emileigh R. , McKenna Colleen F. , Salvador Amadeo F. , Martinez Isabel G. , Alamilla Rafael A. , Collao Nicolas , Bodnariuc Giana , Khan Naiman A. , Paluska Scott A. , Burd Nicholas A. , De Lisio Michael
Published: December 2022

We demonstrate that resistance training-induced increases in fiber hypertrophy, FAP content, and capillarization are similar between middle-aged males and females.
Load carriage aerobic exercise stimulates a transient rise in biochemical markers of bone formation and resorption
Authors: Staab Jeffery S. , Lutz Laura J. , Foulis Stephen A. , Gaffney-Stomberg Erin , Hughes Julie M.
Published: December 2022

In this study, we demonstrated evidence for increases in both bone formation and resorption in the first 4 h after a bout of load carriage exercise. However, these changes largely disappear by 24 h after exercise. Acute formation and resorption of bone following exercise may reflect distinct physiological mechanoadaptive responses. Future work is needed to identify ways to promote acute post-exercise bone formation and minimize post-exercise resorption to optimize bone adaptation to exercise.
Upregulation of SERPINE2 Results in Poor Prognosis of Hepatoblastoma via Promoting Invasion Abilities
Authors: Zou Guoyou , Lv Yong , Kong Meng , Xiang Bo , Chen Jing
Published: December 2022

Background. Hepatoblastoma (HB) is the most common malignant liver tumor in children. High-risk patients, especially those with tumor metastasis, have poor prognosis. Serpin family E member 2 (SERPINE2) is overexpressed in a variety of tumors, especially adenocarcinoma, and promotes tumor invasion and metastasis. The function and mechanism of SERPINE2 in HB are still unclear. The purpose of this study was to investigate the potential clinical prognostic value and molecular mechanism of SERPINE2 in HB. Methods. We performed bioinformatics analyses on HB microarray data GSE131329 to study the role of SERPINE2. The expression level of SERPINE2 in HB and its clinical significance were further analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemistry. After constructing the SERPINE2 overexpression and knockdown in HepG2 and HUH6 cells, the 5-ethynyl-29-deoxyuridine (EdU) assay, wound healing assay, Transwell experiment, and apoptosis assay were performed to explore the role of SERPINE2 in HB progress. Results. Upregulation of SERPINE2 was found in HB tissues and was associated with a poor prognosis. Moreover, the SERPINE2 expression was related to tumor size, vascular invasion, and tumor metastasis. The Cox regressions show that high SERPINE2 expression is an independent risk factor for HB. SERPINE2 overexpression remarkably enhanced HB cell migration and invasion and suppressed apoptosis, while knockdown of SERPINE2 exerted the opposite effect. In addition, SERPINE2 facilitated the epithelial to mesenchymal transformation (EMT) phenotype of HB cells in vitro. Conclusion. Our findings indicated that SERPINE2 accelerates HB progression, suggesting that SERPINE2 may be a potential prognostic biomarker and an underlying therapeutic target for HB.
Learning Condition-Invariant Scene Representations for Place Recognition across the Seasons Using Auto-Encoder and ICA
Authors: Islam Tariqul , Rabiul Islam Sheikh , Rahman Mahbubur
Published: December 2022

To localize the position and perfect autonomous navigation, building up a map is essential for mobile robots. The map becomes very important when the weather is not appropriate for the robot. However, the map becomes inconsistent when the robot moves in the environment and detects errors with emotional accuracy. The loop-closure detection is the process through which a robot can acknowledge the location visited previously, which can identify the ultimate solution to the previous problem. The robot faced difficulty identifying its previously visited path when the environment underwent an extreme change. The main motive of our work is to promote a model capable of understanding the scenes that are presented robustly. Moreover, during seasonal changes, this model provides an appropriate loop-closure detection result. Independent component analysis (ICA) and auto-encoder are proposed to complete our research work. ICA is a powerful tool to describe invariant images perfectly. Especially, when the robot moves through a changing environment, ICA provided more accurate outcomes than the other algorithm (baseline algorithm). On the other hand, the auto-encoder can distinguish between two features of scene variant condition and invariant condition. The encoder takes our work’s next steps by discovering possible routes. To analyze the performance, this work uses the baseline method with a precision-recall curve and a fraction of correct matches. The proposed algorithm ICA showed a 91.05% accuracy rate, which is better than the baseline algorithms, and the appropriate route-finding rate using an auto-encoder is also acceptable.
Remote Sensing Image Reconstruction Based on Improved Adaptive Tensor Nuclear Norm Minimization
Authors: Li Jinliang , Yang Yang , Sun Shuai , Lv Chao , Liu Peng , Qu Xiaohai , Lei Sai
Published: December 2022

Incomplete remote sensing image observation data require proper processing to restore the original data. Nevertheless, the lack of information, due to noise and dead pixels, along with the quality of the acquired images that may be severely degraded, limits the accuracy of later processing. Therefore, this paper proposes a remote sensing image restoration scheme that employs the low-rank structure of the Bayesian probability tensor latent space and a new tensor completion method, which has strong robustness for the model selection process of the following remote sensing image data analysis. Considering the data space, we incorporate an adaptive nuclear norm regularization into the processing of latent factors that performs singular value decomposition on a more accurate scale. The proposed model adopts two algorithms: Augmented Lagrange Multiplier (ALM) and Alternating Least Squares (ALS). Several synthetic and real-data-based experiments illustrate the inherent ability of our method in restoring original information and preventing overfitting problems, even when a vast number of items are missing. In addition, the combination of adaptive nuclear norm regularization and tensor decomposition is stable, settling a high sensitivity of rank selection and low computational efficiency in traditional tensor reconstruction methods.
Inclusive Technology Performance Evaluation in the Production of Teff (Eragrostis tef (Zucc.) Trotter)
Authors: Mihiretu Ademe , Asresu Melaku
Published: December 2022

Different management practices likely to enhance teff production are used in Ethiopia, however, evidence on their relative performance is little studied or unavailable. This on-farm experiment was conducted to assess the performance of different management practices for teff productivity, profitability, and acceptability in subtropical districts of North East Amhara. Four trial treatments (viz., IKIM, IBIM, LBIM, and LBFM) were laid out in an unreplicated simple block considering farmers as replication during the main cropping seasons of 2019 and 2020. Tukey’s (HSD) test following one-way ANOVA, partial budget analysis, and weighted matrix ranking were used to explain the significance level, profitability, and preference traits, respectively. Results presented a significant (

p

 ≤ 0.01) treatment difference across districts in days to maturity, grain, and biomass yields. Among treatments, IKIM had short maturity days at Sekota (94), Dehana (105), and Lasta (95) districts. The grain yields were on average 1.75 ton ha−1, 1.45 ton ha−1, and 1.63 ton ha−1 at Sekota, Dehana, and Lasta districts, respectively. The lowest grain yields of 0.70 ton ha−1, 0.58 ton ha−1, and 0.63 ton ha−1 were recorded from LBFM. Despite the higher total variable costs, IKIM was gainful having 51400 ETB, 40579 ETB, and 46928 ETB net benefits at Sekota, Dehana, and Lasta districts, respectively. The MRR showed that a marginal profit of 13.77, 9.76, and 9.23 ETB was gained per each 1.00 ETB investment for shifting the practice (LBFM to IKIM). Therefore, we recommend IKIM as best management practice for consistent teff production in similar agroecological conditions.
Physical Fruit Traits, Proximate Composition, Antioxidant Activity, and Profiling of Fatty Acids and Minerals of Wild Jujube (Ziziphus lotus L. (Desf.)) Fruits from Eleven Moroccan Origins
Authors: Ait Bouzid Hasna , Sakar El Hassan , Bijla Laila , Ibourki Mohamed , Zeroual Ahmed , Gagour Jamila , Koubachi Jamal , Majourhat Khalid , Gharby Saïd
Published: December 2022

This study aimed at investigating the effects of geographical origin on physical fruit traits, proximate composition, fatty acid, and elemental profiling of Moroccan wild jujube (Ziziphus lotus) fruits. Likewise, solvent effects on total phenolic content (TPC), total flavonoid content (TFC), tannin content, and antioxidant activity were also studied. Fruits were sampled from eleven sites where the species grows widely across Morocco (Tafraoute, Taroudant, Zagora, Rhamna, Beni Mellal, Zaouit Cheikh, Khenifra, B-Jaad, Lkhmissat, Sidi Hrazm, and Taounat). Physical fruit traits (length, width, and weight), proximate composition, and minerals were investigated. Fatty acid profiling of extracted oil was also evaluated. TPC and TFC as well as antioxidant activity (ABTS, DPPH, and FRAP) were determined on four different extracts, namely, ethanol extract (EE), methanol extract (ME), acetone extract (AE), and water extract (WE). Our outcomes revealed significant differences (

p
<
0.05

) among different origins for the measured fruit traits including ash (1.69–2.31%), moisture (2.56–5.69%), proteins (2.63–4.64%), oil (1.59–2.91%) and carbohydrates (86.82–89.20%). The most abundant minerals were K (548.93–828.44 mg/100 g) and Ca (137.50–211.78 mg/100 g). Major fatty acids were oleic acid (50.65 –60.25%), palmitic acid (12.03–18.67%), and linoleic acid (12.63–17.21%). Acetone performed better in terms of TPC (12.77–21.67 mg GAE/g DM), TFC (11.00–18.92 mg QE/g DM), and antioxidant activity using ABTS (22.96–29.32 mg TE/g DM), DPPH (27.96–96.64%), and FRAP (8.37–37.59 mg AAE/g DM). In conclusion, Z. lotus fruit could be considered as a source of carbohydrates and minerals and also natural antioxidants.
Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus–Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
Authors: Aggarwal Charu , Saba Nabil F. , Algazi Alain , Sukari Ammar , Seiwert Tanguy Y. , Haigentz Missak , Porosnicu Mercedes , Bonomi Marcelo , Boyer Jean , Esser Mark T. , Cheng Lily I. , Agrawal Sonia , Jennings Emily C. , Durham Nicholas M. , Fraser Karl , Lissa Delphine , Gong Maozhen , Ceaicovscaia Natalia , Gascó Hernández Amaya , Kumar Rakesh
Published: December 2022

Purpose:

Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)–associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18–associated HNSCC.

Patients and Methods:

In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS).

Results:

Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7–47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. <25%). DCR-16 was 44.8% (95% CI, 26.5–64.3). Median PFS was 3.5 months (95% CI, 1.9–9.0); median OS was 29.2 months (15.2–not calculable). Twenty-eight (80.0%) patients had treatment-related adverse events [grade 3: 5 (14.3%); no grade 4/5], resulting in discontinuation in 2 (5.7%) patients. HPV-16/18–specific T cells increased on treatment; 4 of 8 evaluable patients had a >2-fold increase in tumor-infiltrating CD8+ T cells.

Conclusions:

MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.
Abstract A009: ZMYND8 is an epigenetic regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells
Authors: Luo Weibo , Luo Maowu
Published: December 2022

27-hydroxycholesterol (27-HC) is the most abundant oxysterol that increases the risk of breast cancer progression. However, little is known about epigenetic regulation of 27-HC metabolism and its role in breast tumor initiation. Using genetic mouse mammary tumor and human breast cancer models, we showed here that the histone reader ZMYND8 was selectively expressed in breast cancer stem cells (BCSCs) and promoted epithelial-mesenchymal transition (EMT), BCSC maintenance and self-renewal, and oncogenic transformation through its epigenetic functions, leading to breast tumor initiation. Mechanistically, ZMYND8 was a master transcriptional regulator of 27-HC metabolism. It increased cholesterol biosynthesis and oxidation but blocked cholesterol efflux and 27-HC catabolism leading to accumulation of 27-HC in BCSCs. Consequently, 27-HC promoted EMT, oncogenic transformation, and tumor initiation through activation of liver X receptor. These findings reveal that ZMYND8 is an epigenetic booster that drives breast tumor initiation through metabolic reprogramming.

Citation Format: Weibo Luo, Maowu Luo. ZMYND8 is an epigenetic regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A009.
Abstract A012: Transcription factor expression repertoire basis for epigenetic and transcriptional subtypes of colorectal cancers
Authors: Bhandari Yuba R. , Krishna Vinod , Powers Rachael , Parmar Sehej , Thursby Sara-Jayne , Gupta Ekta , Kulak Ozlem , Gokare Prashanth , Reumers Joke , Van Wesenbeeck Liesbeth , Bachman Kurtis E. , Baylin Stephen B. , Easwaran Hariharan
Published: December 2022

Colorectal cancers (CRCs) form a heterogenous group classified into epigenetic and transcriptional subtypes. The basis for the epigenetic subtypes, exemplified by varying degrees of promoter DNA hypermethylation, and its relation to the transcriptional subtypes is not well understood. We now link cancer-specific transcription factor (TF) expression dysregulation to methylation alterations near TF-binding sites at promoter and enhancer regions in CRCs and their pre-malignant precursor lesions to provide mechanistic insights into the origins and evolution of the CRC molecular subtypes. A gradient of TF-expression changes forms a basis for the subtypes of abnormal DNA methylation, termed CpG-island promoter DNA methylation phenotypes (CIMP), in CRCs and other cancers. CIMP is tightly correlated with cancer-specific hypermethylation at enhancers, which we term CpG-enhancer methylation phenotype (CEMP). CIMP/CEMP coordination appears to be driven by augmented downregulation of TFs with common binding sites at the hypermethylated enhancers and promoters. The dysregulated expression of TFs related to CIMP/CEMP subtypes occurs early during CRC development, detectable in pre-malignant adenomas. TF-based profiling further identifies patients with worse overall survival. Importantly, altered expression of these TFs discriminates the transcriptome-based consensus molecular subtypes (CMS), thus providing a common basis for CIMP and CMS subtypes.

Citation Format: Yuba R. Bhandari, Vinod Krishna, Rachael Powers, Sehej Parmar, Sara-Jayne Thursby, Ekta Gupta, Ozlem Kulak, Prashanth Gokare, Joke Reumers, Liesbeth Van Wesenbeeck, Kurtis E. Bachman, Stephen B. Baylin, Hariharan Easwaran. Transcription factor expression repertoire basis for epigenetic and transcriptional subtypes of colorectal cancers. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A012.
Abstract A023: Sensitivity/resistance mechanisms to KDM5 inhibition in basal breast cancer
Authors: DiCiaccio Benedetto , Papachristou Evangelia , Papanastasiou Malvina , Reiter Andrew , Carroll Jason , Polyak Kornelia
Published: December 2022

We previously described that the KDM5B histone H3 lysine 4 demethylase is amplified and overexpressed in luminal estrogen receptor positive breast cancer, and its activity is associated with resistance to endocrine therapies. We have found that the KDM5A paralog is specifically amplified and overexpressed in basal breast cancer, providing a novel therapeutic opportunity for an aggressive breast cancer subtype. To identify modulators of KDM5 inhibitor sensitivity in KDM5A-amplified basal breast cancer, we performed a genome wide CRISPR viability screen in a KDM5A-amplified basal breast cancer cell line. Our CRISPR screen results and follow up studies implicate Rho-GTPase signaling and the transcriptional repressor ZBTB7A as modulators of cellular response to KDM5 inhibition. We are currently investigating the underlying mechanisms for how these components alter sensitivity/resistance to KDM5 inhibition. Our results suggest potential therapeutic opportunities of inhibiting the KDM5 family of H3K4 demethylases in basal breast cancer.

Citation Format: Benedetto DiCiaccio, Evangelia Papachristou, Malvina Papanastasiou, Andrew Reiter, Jason Carroll, Kornelia Polyak. Sensitivity/resistance mechanisms to KDM5 inhibition in basal breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A023.
Abstract A026: Epigenetic factor competition reshapes the EMT landscape
Authors: Al-Radhawi M. Ali , Tripath Shubham , Zhang Yun , Sontag Eduardo , Levine Herbert
Published: December 2022

The emergence of and transitions between distinct phenotypes in isogenic cells can be attributed to the intricate interplay of epigenetic marks, external signals, and gene regulatory elements. These elements include chromatin remodelers, histone modifiers, transcription factors, and regulatory RNAs. Mathematical models known as Gene Regulatory Networks (GRNs) are an increasingly important tool to unravel the workings of such complex networks. In such models, epigenetic factors are usually proposed to act on the chromatin regions directly involved in the expression of relevant genes. However, it has been well-established that these factors operate globally and compete with each other for targets genome-wide. Therefore, a perturbation of the activity of a regulator can redistribute epigenetic marks across the genome and modulate the levels of competing regulators. These interactions have been brought to the fore by recent experiments (Zhang, Donaher et al, 2022) reporting that the knockouts of different histone methyltransferases can induce two distinct trajectories of EMT, characterized by distinct and unexpected changes in gene expression profiles. In this work, we propose a new modeling framework that combines local transcriptional regulation with global epigenetic control, and show that complex interplay between transcriptional and epigenetic control can lead to rich gene expression dynamics. We use our modeling framework to understand the effects of various epigenetic perturbations on the epithelial-mesenchymal transition, a crucial cellular process involved in both health and disease. We note that the interplay between epigenetic competition, the EMT transcriptional network, and the baseline transcriptional context can result in counter-intuitive experimental observations, and generate unique paths for cells to transition between epithelial and mesenchymal states. We apply our modeling framework to explain the aforementioned recent experimental findings (Zhang, Donaher et al, 2022), and we use it to offer verifiable predictions. One crucial takeaway from our modeling is that experiments involving epigenetic perturbations must be analyzed with care due to the possibility of widespread cross-talk between the genomic targets of different epigenetic factors. This means that the biological consequence of perturbation to an epigenetic modifier could be an outcome of changes in the expression levels of its direct genomic targets or simply a side-effect from the dilution and distribution of an entirely different epigenetic modifier.

Citation Format: M. Ali Al-Radhawi, Shubham Tripath, Yun Zhang, Eduardo Sontag, Herbert Levine. Epigenetic factor competition reshapes the EMT landscape. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A026.
Abstract A028: Investigating the epigenetic landscape of chemotherapy-induced polyaneuploid prostate cancer cells
Authors: Gonye Anna , Kim Chi-Ju , Pienta Ken , Amend Sarah
Published: December 2022

While localized prostate cancer (PCa) has a high treatment success rate, over 30,000 individuals in the United States and 350,000 men globally die each year from therapy resistant, metastatic PCa. A thorough understanding of the factors contributing to PCa recurrence following development of therapy resistance is acutely needed in order to develop efficacious treatments and disease-management strategies. Our group and others have identified a unique minority population of physically enlarged cancer cells with polyaneuploid genomes, termed polyaneuploid cancer cells (PACCs), in the tumors of patients with metastatic prostate cancer and in other tumor types. PACCs are the result of a polyaneuploid transition that occurs when aneuploid cancer cells experience environmental or therapeutic stress. These aneuploid cancer cells then pause their cell cycle after whole genome doubling to survive the environmental insult. Cancer cells in the PACC state appear to be quiescent and have an increased capacity for invasion/motility, an ability to endure in stressful or novel environments, and a propensity to undergo depolyploidization to re-establish the cancer cell population. We hypothesize that PACCs are critical players in prostate cancer therapy resistance and recurrence. We seek to better understand the life cycle of the PACC state in PCa in order to inform the design of new therapeutic strategies that prevent disease recurrence. Our data suggests that PCa cells in the PACC state tend to have a large polyploid single nucleus more frequently than multiple smaller, single nuclei, though both are observed at all timepoints in PACC recovery. Nuclear morphology and size certainly will impact the way that a cell organizes and utilizes its genome. Additionally, genome organization and stability have been demonstrated to be important factors/drivers of cancer development, progression, and recurrence. Importantly, epigenetic changes such as histone modifications can drastically affect chromatin condensation, which subsequently can alter the gene accessibility and transcription profile of a cell. We hypothesize that cancer cells in the PACC state have different histone modifications and different regions of accessible chromatin compared to parental cancer cells, and that these differences will also impact the gene expression of PACCs.

Citation Format: Anna Gonye, Chi-Ju Kim, Ken Pienta, Sarah Amend. Investigating the epigenetic landscape of chemotherapy-induced polyaneuploid prostate cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A028.
Abstract B001: Chromatin engineering using a dCas9-based inducible dimerization system
Authors: Bergwell Mary , Park JinYoung , Pistoni Laura , Kirkland Jacob G.
Published: December 2022

Epigenetic cancers lead to tumor progression via oncogene activation, tumor suppressor silencing, cell fate transitions, and genomic instability. Approximately 50% of tumors have alterations in Chromatin regulators. One group of Chromatin regulators, the mSWI/SNF complexes, are mutated in 20% of tumors making them one of the most mutated chromatin regulator complexes in cancer. In the past, the mechanism of action of ATP-dependent chromatin regulators, such as mSWI/SNF was largely explored using in vitro methods based on measurements of nucleosome mobility. These studies were limited by the fact that these assays were not sensitive to tissue-specific chromatin modifications, topology, long-range interactions, and complex patterns of histone modifications as well as patterns of DNA methylation and human disease mutational backgrounds. To circumvent these problems, we developed the FIRE-Cas9 system that allows one to recruit a specific chromatin regulator and follow the consequences with minute-by-minute kinetics on physiologic chromatin. I can examine any locus of biological or medical importance in virtually any cell type using this technique. We can recruit endogenous proteins or protein complexes such as different mSWI/SNF complexes, histone methyltransferases, or histone demethylases and assay changes in chromatin state and transcriptional state. Because chromatin regulator complexes have alterations in many human cancers, it is imperative to understand the mechanism of action of these complexes with unparalleled precision as a basis for therapeutic development. The FIRE-Cas9 system allows one to do this for the first time.

Citation Format: Mary Bergwell, JinYoung Park, Laura Pistoni, Jacob G. Kirkland. Chromatin engineering using a dCas9-based inducible dimerization system. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B001.
Abstract B004: Analysis of epigenetic marks and mechanisms in disease: Your guide to a successful assay
Authors: Comeau Christopher C. , Guo Angela H. , Chen Fang , Fry Christopher J.
Published: December 2022

Like the chromatin immunoprecipitation (ChIP) assay, Cleavage Under Targets & Release Using Nuclease is a powerful and versatile technique used for probing protein-DNA interactions within the natural chromatin context of the cell. The assay can be combined with downstream qPCR or NG-seq to analyze histone modifications and binding of transcription factors, DNA replication factors, or DNA repair proteins at specific target genes or across the entire genome. It provides a rapid, robust, and true low cell number assay for detection of protein-DNA interactions in the cell. Unlike the ChIP assay, it is free from formaldehyde cross-linking, chromatin fragmentation, and immunoprecipitation. Previously, we have shown that, compared to ChIP, it requires fewer starting cells (100K), has a much faster protocol (one day from cells to DNA), generates lower background signal (requires less sequencing depth), and offers spike-in control DNA for effective normalization of signal between samples and between experiments. We recently updated the CST Assay Kit for use with 5,000-20,000 cells and added protocols for fixed cells and tissue. I will discuss the basics of the assay and important factors to consider when setting up your experiment. In addition, I will provide data showing the versatility of this assay for mapping various histone modifications, transcription factor, and transcription cofactor binding across multiple sample types. Finally, I will discuss how the general protocol is optimized for greater signal to noise ratio, reduced number of starting cells, and provide an alternative digestion method to prepare the input DNA as a critical control of the experiment.

Citation Format: Christopher C. Comeau, Angela H. Guo, Fang Chen, Christopher J. Fry. Analysis of epigenetic marks and mechanisms in disease: Your guide to a successful assay. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B004.
Abstract B016: A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons
Authors: Starble Rebecca M. , Sun Eric G. , Jensen Tyler B. , Gbyli Rana , Sun Ning , Xiao Andrew Z.
Published: December 2022

Lung cancer is the leading cause of cancer-related death worldwide and affects over 2 million people each year. In lung adenocarcinoma (LUAD), somatic activating mutations of epidermal growth factor receptor (EGFR) occur in approximately 15% of patients. The first-line therapy for patients with EGFR-mutant LUAD is administration of osimertinib, an EGFR tyrosine kinase inhibitor (TKI). While many patients’ tumors initially respond to osimertinib treatment, resistance inevitably develops in most cases, which is a major challenge that hinders treatment efficacy. One common mechanism of resistance to osimertinib is the amplification of oncogenes, such as MET, HER2, and RET. Despite the high prevalence of oncogene amplifications in resistant tumors, the mechanisms that control oncogene amplification and transcription are poorly understood. Recent work has shown that oncogenes are frequently amplified on extrachromosomal DNA (ecDNA), which are circularized and highly amplified DNA sequences that are present in at least 14% of human cancers. Additional studies have implicated ecDNA amplification in the acquisition of resistance to TKIs, yet the mechanisms through which ecDNA is regulated are largely unknown. In the present study, we have identified a novel epigenetic factor that promotes the acquisition of TKI resistance through the organization and transcription of oncogene amplicons, some of which occur on ecDNA. To determine whether this factor binds to DNA, we used and found that it is enriched at the promoters of amplified oncogenes. Further, we performed protein immunoprecipitation followed by mass spectrometry and identified multiple candidate interacting factors, such as histone readers and components of the cohesin machinery. Depletion of this epigenetic factor prevents the acquisition of TKI resistance and leads to reduced transcription of oncogene amplicons. Thus, we propose a novel mechanism that promotes the acquisition of TKI resistance via the spatial organization and transcription of oncogene amplicons.

Citation Format: Rebecca M. Starble, Eric G. Sun, Tyler B. Jensen, Rana Gbyli, Ning Sun, Andrew Z. Xiao. A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B016.
Abstract B017: Dysregulation of ultra long-range DNA methylation canyon interactions in human acute myeloid leukemia
Authors: Wang Xue Qing D. , Feng Fan , Dou Yali , Liu Jie , Zhang Xiaotian
Published: December 2022

DNA methylation Canyons (DMCs) are genomic regions devoid of DNA methylation over 3.5kb in hematopoietic stem cells (HSCs). DMCs form ultra long-range interactions spanning decades of megabases specifically in HSCs. These ultra-long DMC interactions between DMCs relies on the strong Polycomb binding inside DMC regions. DMCs are hypermethylated and partially activated in cancer. However, its 3D genomic alterations have not been examined extensively. Here we profiled the high-resolution 3D genomic interactions in 7 primary human acute myeloid leukemia (AMLs). Focusing on DMCs' epigenome state, we found that DMCs in all AMLs are hypermethylated and lose the strong Polycomb enrichment within DMCs in comparison with HSC. Based on the DMC interactions, we discovered two subtypes of AMLs with distinct 3D genomic dysregulation of DMCs’ long-range interactions. In the first AML subtype, DMCs’ interactions are still strong as HSPC but gained leukemia-specific long-range interactions. This subtype is enriched for WT1 mutations and is characterized by the expression of CD34 on blast cells. This particular subtype displayed a global basal level increase in the H3K27me3 mark in the genome. This particular subtype of AML is also sensitive to the EZH2 inhibitor treatment. The EZH2 inhibitor treatment leads to the differentiation of blasts and reduces the colony-forming ability of this subtype of AML. Further dissection shows the EZH2 inhibitors could eradicate the leukemia-specific ultra-long range interactions. In the second subtype of AML, 3D genomic interactions between DMCs significantly lost in AMLs with high HOX cluster gene expression (MLL-r and NPM1c+ AMLs). We further found repressive DMC genes, which are developmental transcriptional factors(TFs) in organ formation are activated in these AMLs. Interestingly, these developmental TFs are involved in forming leukemia-specific long-range interactions independent of CTCF-mediated TADs and chromosomal loops. Among those TFs, IRX3 and IRX5 are frequently activated in MLL-r, NPM1c+ AML and MPAL. These two genes have also been shown before to immortalize bone marrow progenitor cells and block differentiation of these progenitor cells. The loci of these two genes form strong long-range connections to an upstream FTO enhancer mimicking the 3D genomic structure observed in developing muscle and brains.

Citation Format: Xue Qing D. Wang, Fan Feng, Yali Dou, Jie Liu, Xiaotian Zhang. Dysregulation of ultra long-range DNA methylation canyon interactions in human acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B017.
Abstract B026: Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets
Authors: Tang Fanying , Xu Duo , Wang Shangqian , Wong Chen Khuan , Martinez-Fundichely Alexander , Lee Cindy , Cohen Sandra , Park Jane , Hill Corinne , Eng Kenneth , Bareja Rohan , Han Teng , Liu Eric Minwei , Palladino Ann , Di Wei , Gao Dong , Abida Wassim , Beg Shaham , Puca Loredana , Meneses Maximiliano , De Stanchina Elisa , Berger Michael , Gopalan Anuradha , Dow Lukas , Mosquera Juan Miguel , Beltran Himisha , Sternberg Cora , Chi Ping , Scher Howard , Sboner Andrea , Chen Yu , Khurana Ekta
Published: December 2022

In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR) dependence leads to clinically aggressive tumors with few therapeutic options. We used ATAC-seq (assay for transposase-accessible chromatin sequencing), RNA-seq, and DNA sequencing to investigate 22 organoids, six patient-derived xenografts, and 12 cell lines. We identified the well-characterized AR-dependent and neuroendocrine subtypes, as well as two AR-negative/low groups: a Wnt-dependent subtype, and a stem cell–like (SCL) subtype driven by activator protein–1 (AP-1) transcription factors. We used transcriptomic signatures to classify 366 patients, which showed that SCL is the second most common subtype of CRPC after AR-dependent. Our data suggest that AP-1 interacts with the YAP/TAZ and TEAD proteins to maintain subtype-specific chromatin accessibility and transcriptomic landscapes in this group. Together, this molecular classification reveals drug targets and can potentially guide therapeutic decisions.

Citation Format: Fanying Tang, Duo Xu, Shangqian Wang, Chen Khuan Wong, Alexander Martinez-Fundichely, Cindy Lee, Sandra Cohen, Jane Park, Corinne Hill, Kenneth Eng, Rohan Bareja, Teng Han, Eric Minwei Liu, Ann Palladino, Wei Di, Dong Gao, Wassim Abida, Shaham Beg, Loredana Puca, Maximiliano Meneses, Elisa De Stanchina, Michael Berger, Anuradha Gopalan, Lukas Dow, Juan Miguel Mosquera, Himisha Beltran, Cora Sternberg, Ping Chi, Howard Scher, Andrea Sboner, Yu Chen, Ekta Khurana. Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B026.
Abstract B031: PRC2 inhibitor suppresses angiogenesis in Hepatocellular carcinoma (HCC) by up-regulation of anti-angiogenic factors vasohibin1 (VASH1) and tissue inhibitor of metalloproteinases 3 (TIMP-3)
Authors: Zhang Hailong
Published: December 2022

Tumor-associated angiogenesis plays a crucial role in the progression of tumor, especially in highly vascularized cancer, such as Liver hepatocellular carcinoma (LIHC), ovarian cancer, lung cancer, human head and neck cancers. Clinical research has shown that LIHC cells upregulate expression of vascular endothelial growth factor A (VEGFA), and induce proliferation and migration of epithelial cells under hypoxia condition, however, the mechanism of angiogenesis has not been completely elucidated in LIHC, especially in epigenetic regulation level. Polycomb repressive complex 2 (PRC2) is a multi-subunit protein complex that catalyzes the methylation of histone H3 at lysine 27, Enhancer of Zeste homolog 2 (EZH2) is the catalytic subunit, while embryonic ectoderm development (EED) recognizes H3K27me3 and enhance the catalytic activity of EZH2. A recent study suggests PRC2 promote angiogenesis in human ovarian carcinoma, while the detailed mechanism this process has not been illustrated. In this paper, we show BR1763, a potent, selective and orally bioavailable small-molecule inhibitor of EED, inhibits PRC2 activity, promote expression of vasohibin1 (VASH1) and tissue inhibitor of metalloproteinases 3 (TIMP3) in certain Hepatocellular Carcinoma (HCC) cells, and induces tumor growth inhibition by suppression of tumor-associated angiogenesis in vivo.

Citation Format: Hailong Zhang. PRC2 inhibitor suppresses angiogenesis in Hepatocellular carcinoma (HCC) by up-regulation of anti-angiogenic factors vasohibin1 (VASH1) and tissue inhibitor of metalloproteinases 3 (TIMP-3). [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B031.
Abstract IA010: The lncRNA Firre functions as a transcriptional activator from a distance
Authors: Rinn John L. , Much Christian , Lasda Erika , Lewandowski Jordan , Smallegan Michael
Published: December 2022

There are currently over 16,000 long-noncoding RNAs (lncRNAs) annotated in mammalian genomes, a number on par with protein-coding genes. Numerous studies have demonstrated that lncRNAs can influence gene expression programs, but lack the temporal resolution to identify the immediate regulatory events. Thus, even for the most well studied the early and primary targets of lncRNAs remains elusive. Here we describe a multifaceted effort to determine the primary targets of a lncRNA and the underlying temporal dynamics. Our approach combines several genetically defined loss-of and gain-of-function, rescue, and inducible lncRNA models. We further resolved gene regulatory events temporally (30 min to four days). Applying this approach, we find that the lncRNA Firre is an RNA-based transcriptional activator. These transcriptional activation events are not mediated by the epigenetic regulators PRC2, WDR5, or G9A, nor are they due to the proximal binding of the Firre lncRNA. Instead, Firre activates transcription by increasing chromatin accessibility (approximately 30 min after induction) and activating primary target genes (about two hours later). Overall, this study suggests Firre functions as an RNA-based transcriptional activator.

Citation Format: John L. Rinn, Christian Much, Erika Lasda, Jordan Lewandowski, Michael Smallegan. The lncRNA Firre functions as a transcriptional activator from a distance. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA010.
Abstract IA022: Aberrant transcriptional condensates in cancer: Mechanisms and implications
Authors: Wan Liling
Published: December 2022

While growing evidence suggests the prevalence of nanoscale protein condensates on chromatin, their mechanisms of formation and functional significance in normal and disease states remain largely unclear. I will present our ongoing work linking aberrant condensates and cancer. In Wilms tumor and leukemia, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation activity. We discover that these mutations, clustered in ENL’s structured acetyl-binding YEATS domain, trigger aberrant condensates at endogenous genomic targets through a network of multivalent homotypic and heterotypic interactions. Crystal structures of four different ENL mutant YEATS domains reveal structural changes critical for condensate formation. In addition, two oppositely charged disordered regions in ENL mutants play distinct yet complementary roles in regulating the initiation and growth of condensates. ENL mutant condensates enrich for an aberrantly high amount of transcription elongation factors which, in turn, also contribute to condensate formation. Importantly, perturbing these condensates in situ via extensive mutagenesis establish their causal role in oncogenic gene activation. Interestingly, expression of ENL mutants beyond endogenous levels results in larger droplet-like condensates that suppress oncogenic gene activation, indicating a dosage-sensitive function of oncogenic proteins prone to condensation. Together, by elucidating how cancer-associated transcriptional condensates occur and function, our work reveals a poorly recognized role of structured domains in the formation of biomolecular condensates and lends crucial experimental support to establish condensate dysregulation as an under-appreciated oncogenic mechanism. These insights would open new areas of investigation and nominate novel therapeutic approaches.

Citation Format: Liling Wan. Aberrant transcriptional condensates in cancer: Mechanisms and implications. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA022.