bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB270: VRTX531, a potent and selective inhibitor of USP1 for treatment of BRAC1/2mut and HRD+ cancers
Authors: Surampudi Uday Kumar , Bhavar Prashant Kashinath 
Published: April 2024

Abstract
Tumors characterized by deficiencies in DNA double-strand break (DSB) repair mechanisms, such as those harboring mutations in BRCA1/2, are commonly addressed through the administration of poly (ADP-ribose) polymerase-1 (PARP1) inhibitors or platinum-based chemotherapy. While these treatments offer clinical advantages, a significant number of patients eventually develop resistance, underscoring the necessity for innovative therapeutic strategies. USP1 belongs to the ubiquitin-specific processing (UBP) family of proteases, playing a pivotal role in modulating DNA damage response (DDR) pathways. VRTX531 is a novel potent, selective and allosteric inhibitor of USP1 with an IC50 of &lt;50 nm in tested across a broad range of tumor lineages including MDAMB-436 and cell lines and UWB1.289. VRTX531, compound induces cell death through a pathway that is distinct from PARP inhibitors and compound demonstrates robust synergy when combined with first- or second-generation PARP inhibitors. Moreover, the compound exhibited profound activity alone and in combination with PARP inhibitor in BRCA1/2 mut and HRD+ tumors. VRTX531 exhibited exemplary pharmacokinetics and safety in preclinical studies and is expected to enter preclinical testing in H1, 2024. VRTX531 is being evaluated as a single agent and in combination with PARP1 inhibitor in patients with BRCA1/2 mut or HRD+ tumors that are naïve to PARP inhibitors and with prior PARP inhibitor history.
Citation Format: Uday Kumar Surampudi, Prashant Kashinath Bhavar. VRTX531, a potent and selective inhibitor of USP1 for treatment of BRAC1/2mut and HRD+ cancers [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 LB270.
Abstract LB387: Microphysiological modeling of gastric cancer vasculature using iPSC-derived endothelial cells
Authors: Ko Jihoon , Jeon Noo Li , Oh Young Sun 
Published: April 2024

Abstract
Generated induced pluripotent stem cells (iPSCs) from the blood of patients with advanced gastric cancer, differentiating them into endothelial cells and fibroblasts. Utilizing microfluidic 3D cell culture, we intricately reconstructed the observed abnormal blood vessels in gastric cancer patients in a three-dimensional format, capturing real-time neovasculature. Applying deep learning techniques, we virtually labeled the growing blood vessels with fluorescence, unveiling thin and tortuous morphological characteristics specific to patient iPSCs, distinct from those derived from human umbilical cord endothelial cells. The development of a tumor model, vascularized with cancer cells from the same donor, establishes a versatile testbed for evaluating personalized cancer vascular models. Through comprehensive morphological and functional assessments, this platform facilitates screening for patient-specific combination therapies and holds promise as a model for immune response testing.
Citation Format: Jihoon Ko, Noo Li Jeon, Young Sun Oh. Microphysiological modeling of gastric cancer vasculature using iPSC-derived endothelial cells [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 LB387.
Abstract LB390: Enhancing prostate cancer diagnosis: A deep learning approach for DNA ploidy prediction from whole slide images
Authors: Cobos Josselyn Sofia Vergara , Carrillo-Perez Francisco , Pizurica Marija , Andor Noemi , Gevaert Olivier 
Published: April 2024

Abstract
Prostate cancer is distinguished by unique histological alterations in glandular architecture, observable in Whole Slide Images (WSIs). The disease is further characterized by pronounced genomic instability, exemplified by biomarkers such as DNA ploidy. While the Gleason Score effectively assesses the histological changes, the manual evaluation of DNA ploidy is subjective and time-consuming. Addressing the need for an objective diagnostic tool, our study developed a deep learning model aimed at accurately predicting DNA ploidy using publicly available WSI from the Cancer Genome Atlas (TCGA).
Utilizing a ResNet-18 convolutional neural network, we trained the model on WSIs from 200 TCGA patients to extract features and predict total mRNA expression. The model was further refined using data from 19 TCGA patients, focusing on ploidy number prediction. Comparative analysis against a random reference model revealed significant improvements of ploidy prediction in Mean Absolute Error (MAE) by 43.52%, Mean Absolute Percentage Error (MAPE) by 43.59%, and Mean Squared Error (MSE) by 67.86%. These enhancements were statistically validated (p-values: MAE - 7.07E-06, MAPE - 7.69E-06, MSE - 3.14E-05) and substantiated by large Cohen's d values (MAE - 2.88, MAPE - 2.86, MSE - 2.42), confirming the model's advanced predictive accuracy and practical utility.
This approach, validated further on a separate TCGA hold-out test set, signifies a major leap in prostate cancer diagnostics. By integrating mRNA prediction checkpoints, our model not only refines ploidy assessment but also sets the stage for correlating these predictions with patient clinical outcomes. These developments promise to enhance existing diagnostic methods, offering a more objective and efficient tool for DNA ploidy assessment in prostate cancer prognosis and treatment planning.
Citation Format: Josselyn Sofia Vergara Cobos, Francisco Carrillo-Perez, Marija Pizurica, Noemi Andor, Olivier Gevaert. Enhancing prostate cancer diagnosis: A deep learning approach for DNA ploidy prediction from whole slide images [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 LB390.
Abstract LB427: UBA1 blockade induces homologous recombination deficiency and is synthetic lethal with PARP inhibition
Authors: Awasthi Sharad , McGrail Daniel J. , Yi S. Stephen , Sahni Nidhi 
Published: April 2024

Abstract
Therapeutic strategies targeting DNA damage have revolutionized cancer treatment, yet their efficacy often comes at the cost of substantial adverse effects. The emergence of poly-ADP-ribose polymerase (PARP) inhibition as a targeted approach to disrupt DNA repair in tumors deficient in homologous recombination (HR) has shown promise. However, the limited response of most cancers to PARP inhibitors has posed a significant challenge. This study employs a genome-wide CRISPR knockout functional genomics screen, revealing that depletion of ubiquitin-activating enzyme E1 (UBA1) enhances sensitivity to PARP inhibition in HR-proficient ovarian cancer cells. Validation across different ovarian and breast cancer cell lineages, utilizing cell line and organoid models, establishes that pharmacological inhibition of UBA1, a pivotal player in ubiquitination, sensitizes cells to PARP inhibition and other DNA damaging therapies. In vivo experiments combining PARP and UBA1 inhibition demonstrate not only tolerability but also significant extension of survival in patient-derived xenografts compared to individual therapies. Mechanistic studies uncover that UBA1 inhibition not only impedes HR repair, sensitizing cells to PARP inhibition, but also induces widespread increases in PARylation, subsequently targeted by PARP inhibition. These findings underscore the multifaceted pathways through which UBA1 inhibition potentiates the efficacy of PARP inhibition. The demonstrated tolerability and substantial therapeutic gains establish the combined approach as a promising strategy to maximize the benefits of PARP inhibition in cancer therapy.
Citation Format: Sharad Awasthi, Daniel J. McGrail, S. Stephen Yi, Nidhi Sahni. UBA1 blockade induces homologous recombination deficiency and is synthetic lethal with PARP inhibition [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 LB427.
Abstract LB453: Distinct mechanism of CXCR7 activation in EGFR-mutated NSCLC by chemokines
Authors: Gunder Laura C. , Pulido Ines , Becker Jeffrey H. , Massad Malek G. , Shimamura Takeshi 
Published: April 2024

Abstract
Erlotinib and gefitinib, EGFR TKIs, have markedly improved outcomes for NSCLC patients with EGFR mutations. However, resistance eventually develops, with the T790M mutation evident in over 50% of resistant tumors. Other resistance pathways include MET amplification, SCLC transformation, and EMT. Osimertinib, a third-generation EGFR TKI, targets the T790M mutation and is approved as a first-line treatment, reducing the incidence of T790M-related resistance. Nonetheless, non-T790M resistance mechanisms such as mesenchymal transformation are on the rise. The molecular targets or exact mechanisms of EGFR TKI resistance with mesenchymal phenotypes remain elusive. We have discovered that ERK reactivation, commonly found in EGFR TKI-resistant cells with a mesenchymal phenotype, is due to activation of an atypical GPCR, CXC chemokine receptor type 7 (CXCR7). CXCR7 is overexpressed in a cell line, an EGFR TKI-resistant tumor model, and in samples from patients that progressed on EGFR TKIs. Currently, there are no effective CXCR7 inhibitors to evaluate in NSCLC; the mechanisms and ligands for CXCR7 are not fully understood. To evaluate ligand-dependent activation of CXCR7, we generated HEK293 cells and EGFR-mutant NSCLC cells ectopically-expressing CXCR7 and stimulated the cells with CXCL12, a well-documented ligand for CXCR7. Exposures of HEK293 cells with CXCR7 to CXCL12 resulted in the internalization of CXCR7 followed by the activation of the MAPK pathway within 30 minutes of EGFR TKI treatment whereas MAPK activation in EGFR mutant NSCLC cells took 8 hours. MIF activation was also delayed in NSCLC compared to the HEK293 model, requiring the presence of an EGFR TKI. We discovered that CXCR7 co-immunoprecipitated with mutant EGFR in NSCLC cells while CXCR7 did not co-immunoprecipitate when EGFR was inhibited. Furthermore, we discovered additional chemokines including GDF15 that activate the CXCR7-MAPK axis and promote cell migration, a key characteristic of the mesenchymal phenotype in EGFR mutant cells. Taken together, we elucidated a unique mechanism of ligand-induced activation of CXCR7 and downstream MAPK pathway by canonical and putative ligands. This complex mechanism of CXCR7 activation in EGFR mutant NSCLC suggests that preventing the receptor-ligand binding may not be feasible in the context of overcoming EGFR TKI resistance.
Citation Format: Laura C. Gunder, Ines Pulido, Jeffrey H. Becker, Malek G. Massad, Takeshi Shimamura. Distinct mechanism of CXCR7 activation in EGFR-mutated NSCLC by chemokines [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 LB453.
Abstract ND12: Discovery of PF-07220060, a potent and selective CDK4 inhibitor
Authors: Anders Lars , Gallego Gary 
Published: April 2024

Abstract
PF-07220060 was developed based on the clinical need to improve efficacy and safety outcomes in patients treated with currently approved dual CDK4/6 inhibitors, including Palbociclib. Although all dual CDK4/6 inhibitors increase response rates and prolong disease control, they show common dose-limiting hematologic toxicities, foremost neutropenia. This poses challenges to provide these agents at doses necessary to extinguish cell cycling in tumors. Human ER+ breast cancer cells are highly dependent on CDK4 but not CDK6. By contrast, CDK4 is dispensable for human bone marrow derived cells, or cells enriched for neutrophil precursors or hematopoietic stem cells. This is primarily due to the compensatory role of CDK6 in these compartments. These observations prompted us to develop PF-07220060, an aminopyrimidine-based inhibitor, endowed with 20-fold and 4-fold increased selectivity for CDK4 over CDK6 when compared to Palbociclib and Abemaciclib/Ribociclib, respectively. CDK4-over-CDK6 selectivity is explained by G-loop conformational differences between the two kinases, with the G-loop of CDK4 being more flexible, assuming a more open conformation when bound to CDK4 selective versus non-selective inhibitors. PF-07220060 reduces dose-limiting neutropenia in beagle dogs by 15-fold when compared with Palbociclib, consistent with early clinical data obtained with PF-07220060. Higher tolerated plasma concentrations of PF-07220060 versus dual CDK4/6 inhibitors enable increased inhibition of CDK4 kinase activity in tumors. This translates to improved tumor growth inhibition across CDK4-driven models of human breast and prostate cancer at clinically relevant doses. Our work establishes proof-of-concept for CDK4 selective inhibition and introduces a best-in-class CDK4 inhibitor for treatment of HR+ HER2- breast cancer and other CDK4 dependent tumor types.
Citation Format: Lars Anders, Gary Gallego. Discovery of PF-07220060, a potent and selective CDK4 inhibitor [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 ND12.
Abstract SY05-01: Targeting chromatin adaptor proteins in cancer
Authors: Soto-Feliciano Yadira 
Published: April 2024

Abstract
Menin interacts with oncogenic fusion proteins produced by MLL1 rearrangements, and small molecules capable of disrupting these interactions are currently under investigation in clinical trials for the treatment of leukemia. Our research, which combines chromatin-focused and genome-wide CRISPR screenings with a range of genetic, pharmacological, and biochemical strategies in both mouse and human models, has led to the discovery of a molecular mechanism that acts as a switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes, influencing the efficacy of Menin-MLL inhibitors. We demonstrate that the MLL1-Menin complex plays a critical role in maintaining leukemia cell survival by preventing the MLL3/4-UTX complex from binding to certain gene promoters. Interruption of the Menin-MLL1 interaction results in the UTX-dependent transcriptional activation of a tumor suppressor gene program, which significantly influences therapeutic outcomes in both murine and human leukemia models. Notably, the therapeutic activation of this gene program through CDK4/6 inhibitors can overcome resistance in leukemia cells that do not respond to Menin inhibitors. The identification of this molecular switch between MLL1-Menin and MLL3/4-UTX complexes on chromatin highlights the complex roles of these evolutionarily conserved epigenetic regulators and underscores their importance in understanding and addressing the molecular mechanisms underlying response and resistance in leukemia treatment trials.
Citation Format: Yadira Soto-Feliciano. Targeting chromatin adaptor proteins in 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 SY05-01.
Abstract SY19-03: Mechanisms of sensitivity and resistance to CDK2 inhibitors
Authors: Spencer Sabrina L. 
Published: April 2024

Abstract
CDK2 is a core cell-cycle kinase that phosphorylates many substrates to drive progression through the cell cycle. We used several CDK2 inhibitors in clinical development to interrogate CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models. In normal mammary cells and estrogen receptor-positive breast cancer cells, CDK2 inhibition causes a rapid loss of substrate phosphorylation that is rapidly restored by a hard-wired cell-cycle buffering mechanism. In this mechanism, CDK4/6 backstops Rb1 hyper-phosphorylation to maintain Cyclin A2 expression, enabling re-activation of CDK2 in the presence of CDK2 inhibitor. By contrast, CCNE1-amplified ovarian cancers do not exhibit this rapid rebound. Our results augment our understanding of CDK plasticity and CDK dependencies, delineate the genetic backgrounds in which this adaptive rebound upon CDK2 inhibition can occur, and suggest contexts in which CDK2 inhibition will be most effective as a cancer therapy.
Citation Format: Sabrina L. Spencer. Mechanisms of sensitivity and resistance to CDK2 inhibitors [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 SY19-03.
Hybrid approach for vegetable price forecasting in electronic commerce platform
Authors: Choong Kar Yan , Sudin Suhizaz , A. Raof Rafikha Aliana , Ong Rhui Jaan 
Published: April 2024

<span lang="EN-US">The significance of the agriculture sector in Malaysia is often overlooked, and there is a notable deficiency in the advancement of digitalization within the country's agricultural domain. The integration of a price forecasting model in the platform enables the relevant parties, including farmers, to make informed decisions and plan their crop selection based on projected future prices. In this research, the authors proposed the hybrid approach with the combination of linear model and non-linear model in doing the vegetable price forecasting model. The hybrid SARIMA-DWT-GANN model is utilized to forecast the monthly vegetable prices in Malaysia. The historical vegetable price data is collected from the FAMA Malaysia and split into training/test set for modelling. The performance of the models is evaluated on the accuracy metrics including MAE, MAPE, and RMSE. The forecasted results using the proposed hybrid model are compared to that using the single SARIMA model. In conclusion, the hybrid SARIMA-DWT-GANN model is superior to the individual model, which obtained the smaller MAE, RMSE, and got the forecast accuracy of at least 95%. </span>
Image translation between human face and wayang orang using U-GAT-IT
Authors: Nurdenara Ciara , Fawwaz Al Maki Wikky 
Published: April 2024

<span lang="EN-US">Wayang orang performance is one of the Indonesian traditional cultures. The wayang orang players took about an hour to become a proper wayang orang since it takes time to have makeup and to find the appropriate costume before the performance is held. This problem can be solved by developing a computer-based simulation on applying makeup and traditional costume to the face and head of the wayang orang player, respectively. This task can be completed by using image translation. Therefore, people's images can be transformed into wayang orang images. This study aims to translate human faces into wayang orang by adding makeup and accessories using the U-GAT-IT with an unpaired dataset consisting of 1216 data trains and 240 data tests. The challenge of this research is to maintain the image background and the facial identity component in the input image. This research employs quantitative testing employ Kernel Inception Distance (KID), <em>Frèchet</em> Inception Distance (FID), and Inception Score (IS) to evaluate the quality of the output image obtained from the generator. The experimental results show that U-GAT-IT produces a better result than DCLGAN does according to the value of IS, FID, and KID. The IS, FID, and KID obtained by implementing U-GAT-IT are 2.414, 0.924, and 4.357, respectively.</span>
Reference Values for Indexed Echocardiographic Chamber Sizes in Older Adults: The Multi‐Ethnic Study of Atherosclerosis
Authors: Strom Jordan B. , Mukherjee Monica , Beussink‐Nelson Lauren , Gardin Julius M. , Freed Benjamin H. , Shah Sanjiv J. , Afilalo Jonathan 
Published: April 2024

Background
Normalization of echocardiographic chamber measurements for body surface area may result in misclassification of individuals with obesity or sarcopenia. Normalization for alternative measures of body size may be preferable, but there remains a dearth of information on their normative values and association with cardiovascular function metrics.

Methods and Results

A total of 3032 individuals underwent comprehensive 2‐dimensional echocardiography at Exam 6 in MESA (Multi‐Ethnic Study of Atherosclerosis). In the subgroup of 608 individuals free of cardiopulmonary disease (69.5±7.0 years, 46% male, 48% White, 17% Chinese, 15% Black, 21% Hispanic), normative values were derived for left and right cardiac chamber measurements across a variety of ratiometric (body surface area, body mass index, height) and allometric (height
1.6
, height
2.7
) scaling parameters. Normative upper and lower reference values were provided for each scaling parameter stratified across age groups, sex, and race or ethnicity. Among scaling parameters, body surface area and height were associated with the least variability across race and ethnicity categories and height
2.7
was associated with the least variability across sex categories.

Conclusions
In this diverse cohort of community‐dwelling older adults, we provide normative values for common echocardiographic parameters across a variety of indexation methods.