bluuebunny/crossref_metadata_2025 huggingface dataset:
Flexible Polycarbonate and Copoly(Imide‐Carbonate)s‐Based Frequency Selective Surface for Electromagnetic Shielding Application
Authors: Murugesan A. , Ramprabhu S. , Kumar P. Senthil
Published: April 2024

Optically transparent polycarbonates (PCs) and Copoly(Imide‐Carbonate)s (Co‐PICs) were synthesized by the melt polycondenzation method. Rigid (imide) and flexible (‐O‐ and –C(CH3)2−) moieties were incorporated in the structure of bisimide diol comonomer using 4‐aminophenol and 4,4′‐(4,4′‐isopropylidenediphenoxy) bis(phthalic anhydride). The structural properties of synthesized comonomers and polymers were confirmed by 1H, 13C‐NMR and FT‐IR spectra. Thermal properties of polycarbonates and copolycarbonates were examined using DSC and TG analysis. Thermal properties (glass transition (Tg) and thermal decomposition (Td) temperature) of copolymers were enhanced without sacrificing properties of BPA‐based PC (high transparency, ductility, and processability) by the incorporation of active functional bisimide diol comonomer (5–10 mole %) in the polycarbonate backbone. Different sets of PCs and Co‐PICs thin film substrates were prepared by the solvent casting method and used to design frequency selective surface. The proposed flexible FSS offers shielding of 20 dB at 8.8 GHz. In addition, the FSS offers polarization independent operation with its symmetrical unit cell geometry.
Effects of Sheep Bone Peptide-Chelated Calcium on Calcium Absorption and Bone Deposition in Rats Fed a Low-Calcium Diet
Authors: Hu Guanhua , Li Xiaotong , Su Rina , Corazzin Mirco , Dou Lu , Sun Lina , Hou Puxin , Su Lin , Jin Ye , Zhao Lihua
Published: April 2024

Sheep bones, as the main byproduct after sheep slaughter, are rich in proteins, but their utilization in deep processing is relatively low. Currently, calcium deficiency is a common health issue that can lead to metabolic bone diseases. Peptide calcium chelate is considered a superior substance, having a significant effect on improving the absorption and utilization efficiency of calcium in the human body. This study used sheep bone byproducts as the raw material to prepare sheep bone peptide-chelated calcium (SBP-Ca) and its structure was characterized and analyzed in depth. SBP-Ca was supplemented in a low-calcium diet to assess its effects on calcium absorption and bone formation in a rat model experiencing calcium deficiency. The results showed that under optimal preparation conditions for SBP-Ca (peptide-calcium ratio set at 1 : 1, pH maintained at 7, temperature set to 45°C, and duration of 60 min), calcium could chelate with sheep bone peptide (SBP) at the sites C=O, -NH2, and -COOH sites, forming a structurally dense SBP-Ca with a chelation rate of up to 89.24%. In rats fed a low-calcium diet, SBP-Ca significantly improved the rat femoral diameter, dry weight, trabecular bone structure, bone density, and bone volume fraction (P<0.05). A decline in serum alkaline phosphatase levels (P<0.05), elevation in bone calcium content, and a rise in serum osteocalcin levels (P<0.05) were observed. Furthermore, morphological studies on bone tissue suggest that SBP-Ca has the ability to restore trabecular bone structure. In conclusion, SBP-Ca has been successfully prepared as a novel calcium absorption promoter. By improving the bioavailability of calcium, bone formation was facilitated, demonstrating a significant application value in the prevention of calcium deficiency disorders.
Edge AI‐Based Smart Intersection and Its Application for Traffic Signal Coordination: A Case Study in Pyeongtaek City, South Korea
Authors: Lee Seongjin , Baek Seungeon , Woo Wang-Hee , Ahn Chiwon , Yoon Jinwon
Published: April 2024

Recently, smart intersections have emerged as a novel intelligent transportation system (ITS) solution that integrates traffic monitoring, optimal signal control, and even traffic safety. Although smart intersections have been prevalent in many cities, there are a few drawbacks in their practical operations. First, there are inevitable delays in transmitting and processing the video data. Second, there is still a need to develop a real‐time signal control method leveraging the acquired data from smart intersections. Thus, this study aims to construct edge AI‐based smart intersections and to provide their application for traffic signal coordination. To this end, we install smart intersections on three consecutive intersections of Route 45 in Pyeongtaek city, South Korea. The real‐time traffic data are collected by an edge AI video analysis model which is compressed and optimized for its operation in on‐site edge devices. The optimized model maintains a similar level of accuracy (93.64%), even if the size is reduced by 97.8% compared to the original. Next, we utilize the LT2 model to treat the coordination failure problem in nonpeak hours occurring unnecessary delays of the side‐streets with relatively high demands. We complement some constraint conditions in order to consider the compatibility with the current legacy system. The experiment is conducted on a virtual environment of which geometry and traffic demand are configured based on the features of the study site. The numerical results conclude that the optimal offsets calculated by the LT2 model effectively manage bandwidths for multidirectional flows based on the real‐time traffic demands collected from the edge AI‐based smart intersections. This study contributes to serve high‐resolution real‐time traffic data using edge AI on smart intersections and to provide a case study for signal coordination.
Length-Based Spawning Potential Ratio (LB-SPR) for Red Grouper (Epinephelus morio) and Associated Species in the Commercial Fishery of the Yucatan Peninsula, Mexico
Authors: Rincón‒Sandoval Luis Alberto , López‒Rocha Jorge Alberto
Published: April 2024

The study calculated the Length-Based Spawning Potential Ratio (LB-SPR) for several species, including red grouper (Epinephelus morio), black grouper (Mycteroperca bonaci), gag grouper (M. microlepis), yellowtail snapper (Ocyurus chrysurus), lane snapper (Lutjanus synagris), hogfish (Lachnolaimus maximus), and white grunt (Haemulon plumierii). Data were obtained from the small-scale commercial fleet operating in the red grouper fishery on the Campeche Bank within the Yucatan Peninsula. Monthly records of total length (cm) from April 2017 to May 2018, totaling 10,182 fish, were collected from five fishing ports along the Yucatan Peninsula coast. Biological data, such as growth and reproductive patterns and exploitation parameters were gathered from scientific literature. The LB-SPR package on the R Core Team platform was utilized for analysis. Despite being the largest, groupers exhibited immaturity (SL50<L50) and low Spawning Potential Ratio (SPR). Red and black groupers showed particularly low SPR values (0.10 and 0.05, respectively), indicating a looming risk of local extinction. The gag grouper achieved the highest SPR value (0.26) among groupers, although it was very close to the minimum critical value (i.e., 0.20). Snappers, hogfish, and white grunt were generally captured in the adult state (SL50>L50). Yellowtail, hogfish, and white grunt displayed high SPR values (0.44, 0.72, and 0.98, respectively). Lane snapper had a low SPR (0.28) but fell within the range for maintaining satisfactory stock productivity, albeit with reduced yields. The findings emphasize the urgent need to adjust the current management framework for the red grouper fishery, focusing on improving fishing gear selectivity to address heightened pressure on both juvenile groupers and adult lane snapper. Implementing these measures is crucial to mitigate the risks of local extinction and population decline for each species.
Abstract CT094: Targeting CSF1R with BLZ945 results in effective peripheral and tumor immune microenvironment modulation in advanced solid tumors and may be associated with limited efficacy in recurrent non-mesenchymal glioblastoma
Authors: Alcazar Carlos Rodrigo Gil Del , Xu Virginia , Lin Chia-chi , Gil-Martin Marta , Naing Aung , Fan Liqiong , Yang Fang , Quinn David , Wu Jincheng , Quadt Cornelia , Mataraza Jennifer
Published: April 2024

Colony-stimulating factor 1 receptor (CSF-1R) signaling is involved in regulating monocyte differentiation, and the recruitment and survival of tumor-associated macrophages (TAMs). BLZ945 is a small molecule, highly selective, orally bioavailable, potent kinase inhibitor of CSF-1R that has shown the ability to reduce the recruitment of TAMs in animal models and promote infiltration of effector T cells into the tumor in preclinical models. Given the potential effects of BLZ945 on effector T-cell activity, a combination of BLZ945 with the programmed death 1 (PD-1) inhibitor spartalizumab was investigated in 1) a dose escalation phase I clinical trial with advanced solid tumor patients; and 2) an expansion phase II clinical trial in adult patients with relapsed/refractory glioblastoma (GBM) after standard of care and other lines of therapy (NCT02829723). The percentages of non-classical and intermediate monocytes in the PBMC fraction were decreased after treatment at multiple doses and schedules of treatment tested in the escalation phase. Screening and on-treatment paired tumor biopsy samples from the escalation phase were analyzed by RNA sequencing. Downregulated genes have been noted as macrophage-specific genes, suggesting that treatment with BLZ945 is downregulating macrophages in the tumor microenvironment. There appeared to be a trend for a reduction in TAM gene signatures and increase in T-cell inflammation signatures upon treatment with single-agent BLZ945 or BLZ945 + spartalizumab. RNA-sequencing analysis from archival surgical resection GBM samples from the expansion phase, revealed a potential correlation between PDGFRA gene expression and best percent change in tumor size. This suggests that non-mesenchymal GBM, for which PDGFRA is part of the defining signature, are more sensitive to the treatment. DNA-sequencing of these archival samples also revealed mutations in p53 in the tumors with partial responses but no mutations in EGFR or TERT.

Citation Format: Carlos Rodrigo Gil Del Alcazar, Virginia Xu, Chia-chi Lin, Marta Gil-Martin, Aung Naing, Liqiong Fan, Fang Yang, David Quinn, Jincheng Wu, Cornelia Quadt, Jennifer Mataraza. Targeting CSF1R with BLZ945 results in effective peripheral and tumor immune microenvironment modulation in advanced solid tumors and may be associated with limited efficacy in recurrent non-mesenchymal glioblastoma [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 CT094.
Abstract LB002: Deactivation of ligand-receptor interactions enhancing lymphocyte infiltration drives melanoma resistance to immune checkpoint blockade
Authors: Sahni Sahil , Wang Binbin , Wu Di , Dhruba Saugato Rahman , Nagy Matthew , Patkar Sushant , Ferreira Ingrid , Wang Kun , Ruppin Eytan
Published: April 2024

Immune checkpoint blockade (ICB) is a promising cancer therapy; however, resistance often develops. To learn more about ICB resistance mechanisms, we developed IRIS (Immunotherapy Resistance cell-cell Interaction Scanner), a machine learning model aimed at identifying candidate ligand-receptor interactions (LRI) that are likely to mediate ICB resistance in the tumor microenvironment (TME). We developed and applied IRIS to identify resistance-mediating cell-type-specific ligand-receptor interactions by analyzing deconvolved transcriptomics data of the five largest melanoma ICB therapy cohorts. This analysis identifies a set of specific ligand-receptor pairs that are deactivated as tumors develop resistance, which we refer to as resistance deactivated interactions (RDI). Quite strikingly, the activity of these RDIs in pre-treatment samples offers a markedly stronger predictive signal for ICB therapy response compared to those that are activated as tumors develop resistance. Their predictive accuracy surpasses the state-of-the-art published transcriptomics biomarker signatures across an array of melanoma ICB datasets. Many of these RDIs are involved in chemokine signaling. Indeed, we further validate on an independent large melanoma patient cohort that their activity is associated with CD8+ T cell infiltration and enriched in hot/brisk tumors. Taken together, this study presents a new strongly predictive ICB response biomarker signature, showing that following ICB treatment resistant tumors turn inhibit lymphocyte infiltration by deactivating specific key ligand-receptor interactions.

Citation Format: Sahil Sahni, Binbin Wang, Di Wu, Saugato Rahman Dhruba, Matthew Nagy, Sushant Patkar, Ingrid Ferreira, Kun Wang, Eytan Ruppin. Deactivation of ligand-receptor interactions enhancing lymphocyte infiltration drives melanoma resistance to immune checkpoint blockade [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 LB002.
Abstract LB053: A novel BRAF-specific allosteric inhibitor that effectively targets acquired RAFi-resistant BRAF(V600E) cancers and RAS-mutated cancers in vitro and in vivo
Authors: Hu Jiancheng
Published: April 2024

Targeting hyperactive RAS-RAF-MEK-ERK signaling for treating cancers has achieved a promising outcomes, and a number of RAS/RAF inhibitors have been applied to clinical cancer treatment. However, these inhibitors have only a short-term efficacy and their effectiveness is abrogated by acquired drug resistance in less than one year. For those resistant/refractory RAS/RAF-mutated cancers, there’s no effective therapeutics available in clinic. In this study, we developed a novel BRAF-specific inhibitor that docks on an allosteric site on BRAF kinase domain. This inhibitor effectively killed both primary and drug-resistant cancer cell lines with RAS mutation or BRAF(V600E) mutation in vitro and inhibited the growth of xenografted cancers derived from these cell lines in vivo without apparent toxicity. Mechanistically, we found that although this inhibitor blocked the catalytic activity of BRAF in vitro kinase assay, it triggered a super high ERK signaling through improving BRAF/CRAF heterodimerization and hence induced cellular apoptosis of cancer cells with RAS mutation or BRAF(V600E) mutation. Surprisingly, there’s no drug resistance occurring when treating cancer cells with RAS mutation or BRAF(V600E) mutation at a low concentration. To further evaluate the efficacy of this BRAF against RAS/RAF-mutated cancers in vivo, we constructed a series of pancreatic patient-derived xenograft cancer models with Kras G12D or G12V mutations, and found that our BRAF inhibitor exhibited a comparable or much better efficacy than Kras G12D-specific inhibitor on theses PDX models. Altogether, our data indicated that our BRAF-specific allosteric inhibitor may serve as a good therapeutic drug for treating BRAF(V600E)/RAS- cancers, particularly those resistant/refractory cancers, though it still need further evaluations via clinical trials.

Citation Format: Jiancheng Hu. A novel BRAF-specific allosteric inhibitor that effectively targets acquired RAFi-resistant BRAF(V600E) cancers and RAS-mutated cancers in vitro and in vivo [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 LB053.
Abstract LB097: Sensitive detection of central nervous system tumors using a sequencing based cerebrospinal fluid test
Authors: Douville Christopher B. , Bettegowda Chetan
Published: April 2024

The current approach to diagnosing and monitoring tumors of the central nervous system relies almost exclusively on radiographic imaging and neurosurgical procedures. Cerebrospinal fluid (CSF) is appealing for diagnosis because it is already part of the standard of care for the diagnosis or management of several types of CNS disease, including cancer, and the tumor DNA is more highly concentrated inside the blood brain barrier than in plasma or other bodily fluids. Even though cytology is widely used, sensitivity remains low ranging from 2% to 50%, depending on cancer type. We report an analytic technique that efficiently introduces identical molecular barcodes to both strands of CSF template DNA molecules for the identification of cancer specific somatic mutations and copy number alterations. We apply this approach to 126 CSF samples obtained from individuals with known primary or metastatic tumors involving the brain and 36 CSF samples obtained from individuals with non-neoplastic neurological conditions such as multiple sclerosis and another neurologic conditions. We correctly detect 91% of cancers at a specificity of 94.5%. In cases (n=20) where standard of care cytology was available, cytology detected 25% of cancers while our molecular assay detected 90%. Our approach has the capacity to be used in combination with other clinical, radiologic, and laboratory-based data to inform the diagnosis and management of patients with suspected cancers of the brain.

Positives n= Sensitivity GBM 42 46 91.3% Lymphoma 22 24 91.7% Medulloblastoma 14 16 87.5% Metastases 37 40 92.5%

Citation Format: Christopher B. Douville, Chetan Bettegowda. Sensitive detection of central nervous system tumors using a sequencing based cerebrospinal fluid test [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 LB097.
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

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 <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

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

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

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

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

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

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

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.
Trade-Offs in the Sensory Brain between Diurnal and Nocturnal Rodents
Authors: Morrow Andrea , Smale Laura , Meek Paul Douglas , Lundrigan Barbara
Published: April 2024

Introduction: Transitions in temporal niche have occurred many times over the course of mammalian evolution. These are associated with changes in sensory stimuli available to animals, particularly with visual cues, because levels of light are so much higher during the day than at night. This relationship between temporal niche and available sensory stimuli elicits the expectation that evolutionary transitions between diurnal and nocturnal lifestyles will be accompanied by modifications of sensory systems that optimize the ability of animals to receive, process, and react to important stimuli in the environment. Methods: This study examines the influence of temporal niche on investment in sensory brain tissue of 13 rodent species (five diurnal; eight nocturnal). Animals were euthanized and the brains immediately frozen on dry ice; olfactory bulbs were subsequently dissected and weighed, and the remaining brain was weighed, sectioned, and stained. Stereo Investigator was used to calculate volumes of four sensory regions that function in processing visual (lateral geniculate nucleus, superior colliculus) and auditory (medial geniculate nucleus, inferior colliculus) information. A phylogenetic framework was used to assess the influence of temporal niche on the relative sizes of these brain structures and of olfactory bulb weights. Results: Compared to nocturnal species, diurnal species had larger visual regions, whereas nocturnal species had larger olfactory bulbs than their diurnal counterparts. Of the two auditory structures examined, one (medial geniculate nucleus) was larger in diurnal species, while the other (inferior colliculus) did not differ significantly with temporal niche. Conclusion: Our results indicate a possible indirect association between temporal niche and auditory investment and suggest probable trade-offs of investment between olfactory and visual areas of the brain, with diurnal species investing more in processing visual information and nocturnal species investing more in processing olfactory information.
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

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%. 
Semi-supervised spectral clustering using shared nearest neighbour for data with different shape and density
Authors: YouSheng Gao , Aminuddin Raihah , Hamzah Raseeda , Ang Li , Abdul Rahim Siti Khatijah Nor
Published: April 2024

In the absence of supervisory information in spectral clustering algorithms, it is difficult to construct suitable similarity graphs for data with complex shapes and varying densities. To address this issue, this paper proposes a Semi-supervised Spectral Clustering algorithm based on shared nearest neighbor. The proposed algorithm combines the idea of semi-supervised clustering, adding Shared Nearest Neighbor information to the calculation of the distance matrix, and using pairwise constraint information to find the relationship between two data points, while providing a portion of supervised information. Comparative experiments were conducted on artificial data sets and University of California Irvine machine learning repository datasets. The experimental results show that the proposed algorithm achieves better clustering results compared to traditional K-means and spectral clustering algorithms.
Towards a disease prediction system: BioBERT-based medical profile representation
Authors: Hatoum Rima , Alkhazraji Ali , Ibrahim Zein Al Abidin , Dhayni Houssein , Sbeity Ihab
Published: April 2024

Healthcare professionals are increasingly interested in predicting diseases before they manifest, as this can prevent more serious health conditions and even save lives. Machine learning techniques are now playing an important role in healthcare, including in the early prediction of diseases based on prior medical knowledge. However, one of the biggest challenges is how to represent medical information in a way that can be processed by machine learning algorithms. Medical histories are often in a format that computers cannot read, so filtering and converting this information into numerical representations is a crucial step. This process has become easier with the advancement of natural language processing techniques. In this paper, we propose three representations of medical information, two of which are based on BioBERT, the latest text representation techniques for the biomedical sector. The efficiency of these representations is tested on the MIMIC-III database, which contains information on 46,520 patients. The focus of the study is on predicting Coronary Artery Disease, and the results demonstrate the effectiveness of the proposed approach. The study highlights the importance of medical history in disease prediction and demonstrates the potential of machine learning techniques to advance healthcare.
Image translation between human face and wayang orang using U-GAT-IT
Authors: Nurdenara Ciara , Fawwaz Al Maki Wikky
Published: April 2024

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), Frèchet 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.
mTOR Inhibition Prolongs Survival and Has Beneficial Effects on Heart Function After Onset of Lamin A/C Gene Mutation Cardiomyopathy in Mice
Authors: Wu Wei , Jin Qi , Östlund Cecilia , Tanji Kurenai , Shin Ji-Yeon , Han Jiying , Leu Cheng-Shiun , Kushner Jared , Worman Howard J.
Published: April 2024

BACKGROUND:

Mutations in
LMNA
encoding nuclear envelope proteins lamin A/C cause dilated cardiomyopathy. Activation of the AKT/mTOR (RAC-α serine/threonine-protein kinase/mammalian target of rapamycin) pathway is implicated as a potential pathophysiologic mechanism. The aim of this study was to assess whether pharmacological inhibition of mTOR signaling has beneficial effects on heart function and prolongs survival in a mouse model of the disease, after onset of heart failure.

METHODS:

We treated male
Lmna
H222P/H222P
mice, after the onset of heart failure, with placebo or either of 2 orally bioavailable mTOR inhibitors: everolimus or NV-20494, a rapamycin analog highly selective against mTORC1. We examined left ventricular remodeling, and the cell biological, biochemical, and histopathologic features of cardiomyopathy, potential drug toxicity, and survival.

RESULTS:

Everolimus treatment (n=17) significantly reduced left ventricular dilatation and increased contractility on echocardiography, with a 7% (
P
=0.018) reduction in left ventricular end-diastolic diameter and a 39% (
P
=0.0159) increase fractional shortening compared with placebo (n=17) after 6 weeks of treatment. NV-20494 treatment (n=15) yielded similar but more modest and nonsignificant changes. Neither drug prevented the development of cardiac fibrosis. Drug treatment reactivated suppressed autophagy and inhibited mTORC1 signaling in the heart, although everolimus was more potent. With regards to drug toxicity, everolimus alone led to a modest degree of glucose intolerance during glucose challenge. Everolimus (n=20) and NV-20494 (n=20) significantly prolonged median survival in
Lmna
H222P/H222P
mice, by 9% (
P
=0.0348) and 11% (
P
=0.0206), respectively, compared with placebo (n=20).

CONCLUSIONS:

These results suggest that mTOR inhibitors may be beneficial in patients with cardiomyopathy caused by
LMNA
mutations and that further study is warranted.
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.