bluuebunny/crossref_metadata_2025_split huggingface dataset:
The tree peony nuclear factor Y transcription factor PrNF‐YC2 promotes seed oil accumulation
Authors: Yang Weizong , Xin Ziwei , Hu Jiayuan , Zhang Yanlong , Zhang Qingyu , Niu Lixin 
Published: April 2023

SUMMARYSeed oil not only provides energy for seed postgermination development but also provides essential nutrients and raw materials for human products. However, the transcriptional regulatory mechanism controlling seed oil accumulation remains largely unknown. Tree peony (Paeonia rockii) is an emerging woody oilseed crop in China that is known for its high‐quality seed oil. Here, we revealed that a tree peony nuclear factor Y transcription factor, PrNF‐YC2, is expressed predominantly in developing seeds and functions as an essential positive regulator of seed oil accumulation. PrNF‐YC2 promoted oil accumulation in both transient ectopic overexpression Nicotiana benthamiana leaves and stable transgenic Arabidopsis thaliana seeds, globally upregulating the expression of genes involved in oil accumulation. In contrast, PrNF‐YC2‐silenced tree peony leaves using a virus‐induced gene silencing system showed reduced oil content and expression of oil synthesis‐related genes, including four master positive regulators contributing to oil accumulation, namely, LEAFY COTYLEDON1 (LEC1), ABSCISIC ACID INSENSITIVE3 (ABI3), FUSCA3 (FUS3), and WRINKLED1 (WRI1). We demonstrated that PrNF‐YC2 directly activates PrLEC1 and PrABI3 alone and indirectly activates PrFUS3 and PrWRI1 by interacting with PrLEC1. Moreover, interaction with PrLEC1 also enhances the activation capacity of PrNF‐YC2. The activation of these four master positive regulators by PrNF‐YC2 triggered the upregulation of numerous oil synthesis‐related genes, thus promoting oil accumulation. These findings provide new insights into the regulatory mechanism of seed oil accumulation and manipulation of PrNF‐YC2 may be beneficial for enhancing oil yield in tree peony and other oilseed crops.
The Kℵ0$K^{\aleph _0}$ game: Vertex colouring
Authors: Bowler Nathan , Emde Marit , Gut Florian 
Published: April 2023

AbstractWe investigate games played between Maker and Breaker on an infinite complete graph whose vertices are coloured with colours from a given set, each colour appearing infinitely often. The players alternately claim edges, Maker's aim being to claim all edges of a sufficiently colourful infinite complete subgraph and Breaker's aim being to prevent this. We show that if there are only finitely many colours, then Maker can obtain a complete subgraph in which all colours appear infinitely often, but that Breaker can prevent this if there are infinitely many colours. Even when there are infinitely many colours, we show that Maker can obtain a complete subgraph in which infinitely many of the colours each appear infinitely often.
Association Between Moderate Physical Activity Level and Subsequent Frailty Incidence Among Community-Dwelling Older Adults: A Population-Based Cohort Study
Authors: Zhao Wenjing , Ukawa Shigekazu , Sasaki Sachiko , Okada Emiko , Kishi Tomoko , Kondo Kastunori , Tamakoshi Akiko 
Published: April 2023

Our study aimed to demonstrate the association between physical activity (PA) and frailty incidence among Japanese community-dwelling older adults with a narrow age range of 70–74 years. This study included 485 participants from the Japan Gerontological Evaluation Study. Frailty was assessed at baseline and 3 years later by using the Kaigo-Yobo Checklist. PA was assessed using the short-term International PA Questionnaire at baseline. Logistic regression was performed to calculate the odds ratio with 95% confidence intervals after adjusting for potential confounders. The associations of frailty scores with both PA volume and daily walking time presented a U-shaped curve, albeit only the latter was statistically significant. After adjusting for potential confounders, walking for 0.5–1 hr/day displayed a greater association with decreased frailty risk than higher levels of daily walking time. Further study is needed to cumulate the evidence that moderate PA levels may delay frailty incidence and improve the aging process.
Abstract CT240: On-going phase 1A clinical trial for AG01 an first-in-class anti-progranulin (GP88) monoclonal antibody in patients with advanced malignancies
Authors: Tkaczuk Katherine R. , Rosenblatt Paula , Mehra Ranee , Scilla Katherine A. , Tait Nancy , Caple Katerra , Yue Binbin , Serrero Ginette 
Published: April 2023

Abstract
Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats which is the largest member of the granulin-epithelin protein family. PGRN/GP88 has been demonstrated as a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC), lung prostate, ovarian and digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence in breast, lung cancers while elevated serum PGRN/GP88 level in metastatic breast, lung, ovarian and prostate cancer patients. Elevated PGRN/GP88 levels are associated with poor outcomes such as progression and shortened survival. An anti-human PGRN/GP88 monoclonal antibody able to inhibit PGRN/GP88 action in vitro and in vivo has been developed, chimerized and expressed in CHO cells. All IND enabling activities including pharmacology, GMP manufacturing, formulation and GLP toxicology studies have been conducted. The IND application has been filed and cleared by the Food and Drug Administration. A first-in-human, first-in-class phase 1 safety and efficacy clinical study of AG01 in patients with solid tumors and advanced disease with special focus on patients with breast, lung and ovarian cancers has been initiated and is on-going at the University of Maryland Greenebaum Cancer Center. The trial is registered as NCT05627960 to clinicaltrials.gov site. Supported by grants R44CA162629 and R44CA224718 from the National Cancer Institute to GS.
Citation Format: Katherine R. Tkaczuk, Paula Rosenblatt, Ranee Mehra, Katherine A. Scilla, Nancy Tait, Katerra Caple, Binbin Yue, Ginette Serrero. On-going phase 1A clinical trial for AG01 an first-in-class anti-progranulin (GP88) monoclonal antibody in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT240.
Abstract CT249: A study to evaluate the safety and tolerability of the covalent phosphoinositide-3-kinase (PI3K)-alpha Inhibitor, TOS-358, in adult subjects with select solid tumors
Authors: Fakih Marwan , Sohal Davendra P. , Hafez Navid , Berlin Jordan D. , Hari Kimberly , Trifan Ovid C. 
Published: April 2023

Abstract
Background: TOS-358 is an orally available, highly selective covalent inhibitor of PI3Kα capable of achieving a deep and durable inhibition of PI3K-AKT signaling with virtually no off-target effects. In patient-derived xenograft models, TOS-358 has shown anti-cancer activity in several different tumor types including breast, colorectal, gastric, head and neck, bladder, and esophageal cancer, and its’ activity was superior to non-covalent compounds targeting PI3Kα. Administered at the equivalent dose, TOS-358 has shown a good safety profile in 28-day repeat dose toxicity studies in rats and dogs.
Methods: The TOS-358-001 study is a multicenter dose escalation (phase 1) and dose expansion (phase 1b) clinical study evaluating the safety, tolerability, and preliminary efficacy of TOS-358. Eligible subjects are adults with one of protocol-defined tumor types, known PIK3CA mutation or amplification, adequate organ function, ECOG performance status 0 or 1, available archived or fresh tumor tissue for PIK3CA mutation detection and no prior treatment with PI3K, AKT or mTOR inhibitors (except subjects with breast cancer). The phase 1 portion of the study follows a 3+3 dose escalation design and is intended to determine the minimum effective dose (MED) and the maximum tolerated dose (MTD) of TOS-358 when administered orally on a once daily (QD) or a twice daily (BID) schedule, and the recommended phase 2 dose (RP2D). Cohort expansions at the MTD and MED to support the RP2D selection are planned. The phase 1b portion of the study will enroll subjects with tumor PIK3CA mutations or amplifications in several tumor-specific cohorts (colorectal, gastric, non-small cell lung, breast, squamous cell carcinoma of the head and neck, urothelial and select gynecological cancers) to further assess the safety and tolerability of TOS-358 and to evaluate the initial efficacy of the investigational agent. Enrolment to the study commences in US with European sites planned to open later in 2023. Clinical trial information: NCT05683418.
Citation Format: Marwan Fakih, Davendra P. Sohal, Navid Hafez, Jordan D. Berlin, Kimberly Hari, Ovid C. Trifan. A study to evaluate the safety and tolerability of the covalent phosphoinositide-3-kinase (PI3K)-alpha Inhibitor, TOS-358, in adult subjects with select solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT249.
Abstract CT267: ENB-003, an ETBR antagonist, in combination with pembrolizumab for advanced solid tumor: The ENBolden trial
Authors: Jamal Sumayah , Nagrial Adnan , Carlino Matteo , Cosman Rasha , Joshua Anthony , Eek Richard , Piha-Paul Sarina , Hamid Omid , Liu Jenny 
Published: April 2023

Abstract
Programmed cell death 1 (PD-1) inhibitors have minimal effect in ovarian cancer (OC) and pancreatic ductal adenocarcinoma (PDAC). Selective endothelin B receptor (ETBR) blockade stimulates T cell tumor infiltration and synergizes with anti-PD-1 therapy in OC and PDAC mouse models. We are conducting an ongoing Phase Ib, open-label dose escalation study to assess the safety and tolerability of the selective ETBR antagonist ENB-003 (vodudeutentan) in combination with pembrolizumab in metastatic PDAC, OC and other advanced solid tumors (NCT04205227). The primary objectives are safety and tolerability. Secondary objectives include overall survival (OS), progression free survival (PFS), and disease control rate (DCR). Chemotherapy-resistant PDAC and platinum refractory/platinum resistant OC patients were microsatellite stable (MSS). The ENB-003 plus pembrolizumab combination was well tolerated across 6 dosing cohorts with no increase in toxicity above what is typically observed with pembrolizumab as a single agent. Encouraging preliminary efficacy signals have been observed. The DCR across 21 patients is 43% including 8 patients with stable disease (38%) and 1 (5%) with partial response (PR). The DCR for OC is 100% including 3 patients with stable disease (75%) and one MSS, PDL1 negative platinum refractory patient with a 95% PR (25%) of 12-month duration. In the current and final cohort, 3 PAC patients have been treated. One 4th line PDAC patient has exceeded 6-month survival (33%). We also observed a 7-month arrest of disease progression in a tonsillar SCC patient with innate resistance to anti-PD1. These data suggest that ETBR blockade is well tolerated, may expand the benefit of anti-PD1 in drug resistant solid tumors and warrants further study in subsequent trials.
Citation Format: Sumayah Jamal, Adnan Nagrial, Matteo Carlino, Rasha Cosman, Anthony Joshua, Richard Eek, Sarina Piha-Paul, Omid Hamid, Jenny Liu. ENB-003, an ETBR antagonist, in combination with pembrolizumab for advanced solid tumor: The ENBolden trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT267.
Abstract LB003: BI 907828: A highly potent MDM2-p53 antagonist suitable for intermittent dose schedules
Authors: Gollner Andreas , Sini Patrizia , Rudolph Dorothea , Weinstabl Harald , Ramharter Juergen , Weyer-Czernilofsky Ulrike , Golubovic Bojana , Grempler Rolf , Pitarch Alejandro Pérez , Sailer Reinhard , McConnell Darryl B. , Kraut Norbert 
Published: April 2023

Abstract
The E3 ligase MDM2 controls the tumor suppressor function of p53, which is encoded by the TP53gene. Compounds designed to bind to MDM2 preventing its interaction with p53 restore the ability of p53 to combat the pathogenic processes that underly cancer development. It has become clear from early clinical experience that thrombocytopenia represents an on-target, dose-limiting toxicity that may restrict the therapeutic utility of first-generation MDM2 inhibitors. Dosing less frequently, while maintaining efficacious exposure levels, has been proposed as an approach to mitigate side effects and improve the therapeutic window. In this -Late Breaking- session we present the discovery and preclinical evaluation of BI 907828, a highly potent, orally bioavailable and selective molecule binding to MDM2 and preventing its interaction with p53. The compound was designed to have a long half-life to enable intermittent dosing schedules in the clinic where it showed a manageable safety profile in a Phase Ia/Ib, dose-escalation/expansion study and encouraging signs of antitumor activity in patients with advanced DDLPS and WDLPS. BI 907828 is actively investigated in several clinical trials including the Phase II/III Brightline-1 study that aims to evaluate whether it is superior to doxorubicin in the first-line treatment of advanced/metastatic DDLPS. BI 907828 belongs to the class of spiro-oxindole MDM2-p53 antagonists and was discovered starting from an optimized core structure with improved chemical stability. Structure-based medicinal chemistry optimization including rigidification of the scaffold were key to accomplish the desired profile which was tested preclinically in several in vivo MDM2-amplified xenograft models where treatment with BI 907828 showed efficient tumor growth inhibition and regression.
Citation Format: Andreas Gollner, Patrizia Sini, Dorothea Rudolph, Harald Weinstabl, Juergen Ramharter, Ulrike Weyer-Czernilofsky, Bojana Golubovic, Rolf Grempler, Alejandro Pérez Pitarch, Reinhard Sailer, Darryl B. McConnell, Norbert Kraut. BI 907828: A highly potent MDM2-p53 antagonist suitable for intermittent dose schedules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB003.
Abstract LB006: Interactome analysis identifies signaling pathways activated by ETV6-NTRK3 oncogenic gene fusions
Authors: Kinnunen Matias , Liu Xiaonan , Salokas Kari , Keskitalo Salla , Varjosalo Markku 
Published: April 2023

Abstract
Chromosomal translocations creating fusion genes are among the most common mutation class of known cancer genes, and they have long been identified as driver mutations in certain types of cancer. Recently, oncogenic fusion genes (oncofusions, OFs) have been found in many hematological and solid tumors, demonstrating that translocations are a common cause of malignancy. The frequency of recurrent gene fusions varies depending of the specific type of cancer, but currently identified translocations are estimated to drive up-to 20% of cancer morbidity. In many occasions the oncofusion is the sole driver of oncogenesis when present and certain oncofusion pairs are typically found in one or few specific cancers.
ETV6-NTRK3 (EN) oncofusion, is a product of the chromosomal t(12; 15)(p13; q25) translocation, which fuses the N-terminal SAM (sterile alpha motif) domain of ETV6 to the C-terminal protein tyrosine kinase domain of NTRK3 (also known as TrkC). EN is expressed from the ETV6 promoter in the fused chromosome 15. The ETV6 promoter is generally more active, than NTRK3 promoter, and causes EN fusions to be expressed more highly in several tissues and especially in bone marrow and salivary glands. ETV6 forms fusions with many kinases, which are found in hematological malignancies and solid tumors. Except for ETV6-NTRK3, other ETV6-kinase fusions are reported in either hematological or solid malignancies and ETV6-NTRK3 further distinguishes itself by being also reported in several subtypes in both cases. Four EN variants with alternating break points have since been detected in a wide range of human cancers. To provide insight into EN oncogenesis, we employed a proximity labeling mass spectrometry approach to define the molecular context of the EN fusions. We identify 237 high-confidence interactors, which link EN fusions to several key signaling pathways, including ERBB, Insulin and JAK/STAT. We then assess the effects of EN variants on these pathways, and show that the pan NTRK inhibitor selitrectinib (LOXO-195) inhibits the oncogenic activity of EN2, the most common variant. This systems-level analysis of defines the molecular framework in which EN oncofusions operate to promote cancer.
Citation Format: Matias Kinnunen, Xiaonan Liu, Kari Salokas, Salla Keskitalo, Markku Varjosalo. Interactome analysis identifies signaling pathways activated by ETV6-NTRK3 oncogenic gene fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB006.
Abstract LB021: KN-052, a novel PDL1/OX40 bispecific antibody, exhibits potent antitumor efficacy
Authors: Xu Ting , Wang Pilin , Fu Yang-Xin , Guo Kangping , Peng Jianjian 
Published: April 2023

Abstract
KN052 is a recombinant PDL1/OX40 bispecific antibody which can block PDL1 and PD1/CD80 pathway and active the OX40 signal pathway at the same time. Inhibited PDL1 can block cancer cells to evade T-cell-mediated immune responses and restores T-cell activation and antitumor responses. On the other hand, biding to OX40 which normally expressed on Treg cells can induce ADCC effect and kill the Treg cells. There is a synergistic effect between the blocking of PDL1 pathway and the activation of OX40 signal pathway in cell base assay. PBMCs from four healthy donors showed significant T cell activation effect under the stimulation of superantigen SEB, and the activity of PBMCs from three healthy donors was significantly stronger than that of two single target control antibodies alone and in combination. The anti-tumor activity of KN052 was evaluated by using hPD-L1/hOX40 humanized mouse with MC38 MCA205 syngeneic model. Significant anti-tumor effects were observed in both models in a dose-dependent manner. The HNSTD (highest non-severely toxic dose) of KN052 was determined as 30mg/kg in cynomolgus monkeys. These preclinical data demonstrated acceptable PK and safety profile of KN052 and indicated its potential in a variety of tumors.
Citation Format: Ting Xu, Pilin Wang, Yang-Xin Fu, Kangping Guo, Jianjian Peng. KN-052, a novel PDL1/OX40 bispecific antibody, exhibits potent antitumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB021.
Abstract LB066: Machine learning algorithm for drug discovery targeting new co-transcription factors of HIF1A
Authors: Zhang Yuxiang , Wang Saidi , Hu Haiyan , Li Xiaoman 
Published: April 2023

Abstract
Hypoxia-inducible factor 1 alpha (HIF1A) activation drives cellular adaption to low oxygen stress in malignant and non-malignant cells. HIF1A transcriptionally regulates many genes in key processes like angiogenesis and metastasis, facilitating the cell’s survival. Interestingly, HIF1A is able to carry out its regulatory functions by forming protein-protein interactions with its co-transcription factors. Since low oxygen conditions are frequently present in cancerous cells, we predict that these co-transcription factors could serve as new cancer therapeutic targets. Our recent work has thus focused on identifying motifs in HIF1A ChIP-Seq sequences and discovering novel HIF1A co-transcription factors. In this study, we leveraged cutting-edge deep learning methods, including a hybrid convolutional neural network (CNN) and recurrent neural network (RNN) based motif-discovery model, and discovered several novel motifs. We also look to predict potential therapeutic drugs against the identified co-transcription factors using a machine-learning drug discovery model that evaluates therapies based on their half-maximal inhibitory concentration (IC50). We have so far found several small molecules that could adequately modulate the activity of the identified co-transcription factors. Our results could lead to new therapeutic approaches against HIF1A-dependent cancers such as colon, breast, gastric, lung, brain, and prostate.
Citation Format: Yuxiang Zhang, Saidi Wang, Haiyan Hu, Xiaoman Li. Machine learning algorithm for drug discovery targeting new co-transcription factors of HIF1A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB066.
Abstract LB069: Predictive modeling of drug sensitivity based on the genetic dependency
Authors: Song Bicna , Chao Lumen , Cheng Xiaolong , Gao Yuan , Shan Ruocheng , Li Wei 
Published: April 2023

Abstract
Functional genetic screens have been frequently used to repurpose existing drugs or to identify new drug targets. However, the associations between hits on screens and candidate drugs have been unclear, and a manual approach to directly infer drug candidates from “druggable” candidates suffers from its laborious, ad hoc investigation and low accuracy. Here, we describe a systematic approach to explore the associations between genetic dependencies and drug sensitivity of cancer cell lines and to identify potential drug repositioning opportunities. We first developed drug sensitivity predictive models trained on genome-wide CRISPR-Cas9 knockout viability profiles and large-scale drug response screens of 4,518 drugs from DepMap. We obtained the highest predictive power from the decision-tree-based models and observed previously reported associations between gene perturbation and drug response. For example, cancer cells that are more sensitive to TP53 or MDM2 perturbation were more sensitive to MDM inhibitors, and EGFR or ERBB2 dependency strongly predicted the sensitivity of cells to EGFR inhibitors. Interestingly, for 3,260 drugs with known targets, only 1.5% of these genes were selected as top features to predict drug sensitivity, indicating that genes that are not the direct targets of drugs should be considered. In addition, we applied our models to the CRISPR-Cas9 knockout screens that target 1,805 “druggable” genes and predicted the sensitivity of cancer cells to known and novel drugs. Furthermore, we were able to validate the candidate drugs using cell viability assays. Finally, a multi-class classification deep learning model, based on the TorchDrug framework, reaches higher recall values than a decision-tree-based method but with much lower precision values. Our study provided the first systematic evaluation between large-scale gene dependency and drug responses. The machine learning predictive model provides an in-silico approach to perform drug screens from functional genetic screens.
Citation Format: Bicna Song, Lumen Chao, Xiaolong Cheng, Yuan Gao, Ruocheng Shan, Wei Li. Predictive modeling of drug sensitivity based on the genetic dependency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB069.