bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 437: Hydrogen sulfide switches the glucose metabolism through sulfhydration on pyruvate kinase M2
Authors: Chien Po-Chen , Wang Rong-Hsuan , Chen Pin-Ru , Chen Yue-Ting , Chen Yi-Chang , Chu Yu-Hsin , Chien Chia-Chen , Lo Shao-Yun , Wang Zhong-Liang , Tsou Min-Chen , Chen Ssu-Yu , Chiu Guang-Shen , Chen Wen-Ling , Wu Yi-Hsuan , Wang Hui-Ching , Lin Shu-Yi , Wang Wen-Ching , Kung Hsing-Jien , Wang Lu-Hai , Cheng Hui-Chun , Lin Kai-Ti 
Published: March 2024

Abstract
Cancer cells reprogram their glucose metabolism from oxidative phosphorylation to aerobic glycolysis. This metabolic transformation is partly based on the activity alterations of a rate limiting enzyme known as the pyruvate kinase M2 (PKM2), which is responsible for the conversion of phosphoenolpyruvate (PEP) into pyruvate. Attributed to its critical regulatory role. PKM2 is recognized as the pivotal enzyme in cancer glucose metabolism By reducing the enzyme activity of PKM2, cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Hydrogen sulfide (H2S), an endogenously produced gasotransmitter that acts as a critical mediator in multiple physiological processes, modifies proteins mainly through the persulfide (-SSH) bond formation, which is called sulfhydration. Our preliminary study demonstrates that H2S stimulates PKM2 sulfhydration at multiple cysteine residues, including cysteine 326, leading to the destabilization of active tetrameric PKM2 form into dimers or monomers. The PKM2 dimer/monomer further translocates into the nucleus to simulate the activation of glycolytic related genes. Blocking PKM2 sulfhydration at cysteine 326 through amino acid mutation stabilizes PKM2 tetramer and crystal structure further indicates that the tetramer organization of PKM2C326S is different from the currently known T or R states, revealing PKM2C326S as a newly identified intermediate form. Blocking PKM2 sulfhydration at cysteine 326 inhibited cell proliferation and tumor growth in xenograft mouse model. In summary, our current study illustrates that H2S-mediated sulfhydration induces the dissociation of the PKM2 tetramer, resulting in the reduced PKM2 activity and subsequently inhibits breast cancer cell proliferation and tumor growth. Targeting the sulfhydration site of PKM2 emerges as a promising therapeutic target specific for cancer metabolism.
Citation Format: Po-Chen Chien, Rong-Hsuan Wang, Pin-Ru Chen, Yue-Ting Chen, Yi-Chang Chen, Yu-Hsin Chu, Chia-Chen Chien, Shao-Yun Lo, Zhong-Liang Wang, Min-Chen Tsou, Ssu-Yu Chen, Guang-Shen Chiu, Wen-Ling Chen, Yi-Hsuan Wu, Hui-Ching Wang, Shu-Yi Lin, Wen-Ching Wang, Hsing-Jien Kung, Lu-Hai Wang, Hui-Chun Cheng, Kai-Ti Lin. Hydrogen sulfide switches the glucose metabolism through sulfhydration on pyruvate kinase M2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 437.
Abstract 4382: PKC-ι/ζ signaling is crucial for apoptosis/pyroptosis inhibition and invasiveness of glioblastoma cells through upregulation of β-catenin, PDK1/Akt1 and Smad cascades via 14-3-3
Authors: Lajmi Luke , Ratnayake Wishrawana S. , Khalid Khandker M. , Breedy Sloan , Todman Aaron , Smalley Tracess , Apostolatos Christopher A. , Hill Robert , Acevedo-Duncan Mildred 
Published: March 2024

Abstract
Glioblastoma (GB) is an aggressive form of brain cancer derived from astrocytes. Poor predictability of patient outcomes has limited the development of current therapeutic treatments of GB mainly due to the development of drug resistance. Comparative over-expression of atypical protein kinase C-iota and zeta (aPKC-ι/ζ) in GB cells and tissue samples were previously reported. This study establishes the downstream effects of PKC-ι/ζ attenuation on key cellular signaling which governs apoptosis, pyroptosis, survival, proliferation and epithelial-mesenchymal transition (EMT). Our data suggested that aPKC knockdown of expression induces apoptosis and works as an antecedent of pyroptosis. Data also suggested that involvement of Akt1 and PDK1 in aPKC maturation process weakened due to aPKC attenuation. aPKC attenuation downregulated Ras/Erk1 and canonical β-catenin pathways which resulted in reduced transcriptional activities of Stat3, c-Myc, c-Jun and β-catenin. In addition SNAIL1, SLUG, and PRRX1 were diminished that have been known to stimulate EMT. Proteins 14-3-3 and Smad2/3 acted as molecular adaptors between these pathways. A PKC-ι specific inhibitor 5-amino-1-(2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and a PKC-ζ specific inhibitor 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat) were used to conduct in-vivo experiments using mouse models. Intravenous and oral administration of ICA-1S resulted in the reduction of tumor growth by approximately 30% in athymic nude mice for U-87 xenografts. Taken together, these results suggest that not only do aPKCs play a central role in GB progression, invasiveness, and cell survival, but that effective therapeutics can be developed to specifically target oncogenic aPKCs.
Citation Format: Luke Lajmi, Wishrawana S. Ratnayake, Khandker M. Khalid, Sloan Breedy, Aaron Todman, Tracess Smalley, Christopher A. Apostolatos, Robert Hill, Mildred Acevedo-Duncan. PKC-ι/ζ signaling is crucial for apoptosis/pyroptosis inhibition and invasiveness of glioblastoma cells through upregulation of β-catenin, PDK1/Akt1 and Smad cascades via 14-3-3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4382.
Abstract 4411: Enhancing scalability and consistency in clinical multiomics via an optimized fixed cell ATAC-seq method​
Authors: Winders Dafne Alves , Graham Riley , Mao Xiangying , De Vito Ilaria , O'Hara Andrea , Turner Laure , Latif Haythem 
Published: March 2024

Abstract
ATAC-seq has an emerging role in decoding mechanisms of gene regulation, offering valuable insights into pathology and treatment response in disease models. However, clinical adoption of ATAC-seq methods has been limited by logistical hurdles, including time-sensitive processing of fresh samples and compromised viability of cryopreserved cells. These constraints, compounded by changes in open chromatin regions (OCRs) following cryopreservation, introduce unintended bias and pose significant obstacles for the translational impact of ATAC-seq experiments. ​
Here, we introduce an optimized fixed-cell ATAC-seq approach to overcome these limitations and unlock new sample types for ATAC-seq analyses. Our solution improves and simplifies the workflow from sample collection to clinical deliverable. This method enables ATAC-seq investigation of a diverse range of samples and facilitates the execution of complex experimental designs, including time course studies and high throughput screening.​To demonstrate the effectiveness of this method, we compared our optimized fixed-cell method with traditional ATAC-seq preparations in both fresh and cryopreserved GM12878 cells in parallel. Human GM12878 cell line was obtained from Coriell Institute for Medical Research5. Remarkably, we observed consistent genome-wide patterns of OCR enrichment at key regulatory elements across the three sample preparation methods. We observed consistent OCR enrichment across the promoter region of known highly-expressed B-cell genes including CD48 and LCP1, underscoring this assay’s ability to detect chromatin changes at key genes in human disease models. ​
To investigate the potential for multiomic analysis using this method, we prepared RNA-seq libraries from fixed-cell samples in parallel to ATAC-seq. We observed significantly elevated gene expression related to B-cell function and B-cell diseases, demonstrating our method’s compatibility with RNA-seq data collection and integration. This optimized fixed-cell ATAC-seq approach offers enhanced scalability and consistency over conventional methods and presents new opportunities for the multiomic analysis of chromatin and transcriptional activity genome-wide from a single sample in both clinical and research settings.
Citation Format: Dafne Alves Winders, Riley Graham, Xiangying Mao, Ilaria De Vito, Andrea O'Hara, Laure Turner, Haythem Latif. Enhancing scalability and consistency in clinical multiomics via an optimized fixed cell ATAC-seq method​ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4411.
Abstract 4415: Utilization of MBD-seq to elucidate differentially methylated regions in cfDNA across healthy and cancer patients
Authors: Michelon Camille , Egan Brian , Delatte Benjamin 
Published: March 2024

Abstract
5-Methylcytosine (5-mC) is the most abundant epigenetic DNA modification in eukaryotes. The presence of 5-mC alters gene expression and genome metabolism, and its deregulation is associated with many human diseases. Cell-free DNA (cfDNA) released from apoptotic cells has recently gained attention, as mutations or epimutations (e.g. 5-mC variations) detected in cfDNA were shown to have high diagnostic potential to assess the presence, stage and outcome of several cancers. However, 5-mC detection in cfDNA remains a challenge as input material is often very scarce. MBD-Seq is a method that leverages the ability of Methyl-CpG-binding domain protein 2 (MBD2) to capture and detect highly methylated regions of DNA genome-wide. We evaluated MBD-Seq for the detection of aberrant methylation patterns in cfDNA from healthy and diseased patients. We found MBD-seq on cfDNA to be specific (over 100-fold mC:C detection ratio) and sensitive (5 ng of input cfDNA). Applying MBD-seq to samples from healthy vs colorectal and breast cancer patients showed striking differences in methylation of key tumor-associated genes. Hence, MBD-Seq can elucidate aberrant methylation patterns from cfDNA, highlighting its potential as a diagnostics tool for the detection of cancer.
Citation Format: Camille Michelon, Brian Egan, Benjamin Delatte. Utilization of MBD-seq to elucidate differentially methylated regions in cfDNA across healthy and cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4415.
Abstract 4435: Taurine metabolism as a marker for pancreatic cancer
Authors: Nam Hoonsik , Lee Woohyung , Nguyen Ha T. , Mai Linh X. , Kim Song Cheol , Park Sunghyouk 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC), known for its aggressive nature and poor prognosis, presents a significantly altered metabolic landscape compared to normal pancreatic tissue, a feature that has been the focus of recent research but remains underexplored in actual pancreatic tissues. In this study, we undertook an untargeted metabolomics analysis to compare the metabolic profiles of PDAC with matched normal tissues, revealing a notable elevation in taurine levels in PDAC. This increase was further validated through immunohistochemistry in separate PDAC and normal tissue samples. To delve deeper, we conducted a comprehensive bioinformatics analysis, integrating transcriptomic and proteomic data, which identified the taurine metabolism pathway as significantly altered, with ADO emerging as a pivotal gene in this process. Further investigations, including gene modulation and xenograft models, demonstrated that ADO knockdown curtails cancer cell proliferation and tumor growth, potentially impacting the Raf-MEK-ERK signaling pathway. Clinically, the ADO-Taurine axis was found to have substantial prognostic significance, correlating with recurrence rates and survival in PDAC patients. These insights collectively suggest that the ADO-Taurine axis, through its modulation of taurine metabolism, presents as a promising biomarker for PDAC prognosis and a potential avenue for therapeutic development.
Citation Format: Hoonsik Nam, Woohyung Lee, Ha T. Nguyen, Linh X. Mai, Song Cheol Kim, Sunghyouk Park. Taurine metabolism as a marker for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4435.
Abstract 4463: Metabolic reprogramming through Notch1 signaling promotes a survival advantage in pancreatic neuroendocrine tumor cells
Authors: Guenter Rachael , Chen Weisheng , Herring Brendon , Golivi Yuvasri , Sammy Melissa , Whitt Jason , Jaskula-Sztul Renata , Chen Herbert , Rose J. Bart 
Published: March 2024

Abstract
Background: Cancer cells utilize both oxidative phosphorylation (OXPHOS) and glycolysis to generate energy. Switching between OXPHOS and glycolysis can promote tumor progression. The mechanisms governing oncogenic metabolic reprogramming are largely unknown, but recent data has suggested that Notch1 dysregulation in cancer cells can contribute to altered metabolic phenotypes. We hypothesized that Notch1 signaling supports metabolic reprogramming in pancreatic neuroendocrine tumor (pNET) cells.
Methods: We established a Notch1-knockout pNET cell line (BON-N1-KO) by deleting Notch1 at exon 3 in a pNET cell line (BON) using CRISPR/Cas9. Proliferation over time was measured using a trypan blue exclusion test. Seahorse Glycolytic Rate Assay and Mitochondria Stress Test were used to measure the glycolytic and mitochondrial activities of cells. A glycolysis deprivation assay was employed to determine cell viability at varying glucose concentrations. Single end RNAseq was performed using the Illumina NGS platform, to a read depth of 50M.
Results: Over time, pNET cells lacking Notch1 (BON-N1-KO) proliferated slower than wildtype (WT) cells (p=0.034). Compared to WT BON, the BON-N1-KO cells had reduced basal oxygen consumption rate (28.2 ± 1.3 vs. 40.7 ± 1.4; p=0.02, ATP production (21.9 ± 1.0 vs. 29.6 ± 0.98; p=0.04), and maximal respiration (39.4 ± 1.7 vs. 63.7 ± 2.1; p=0.004). BON-N1-KO cells also had a reduction in basal glycolysis, as measured by proton efflux rate, compared to WT (48.7 ± 2.6 vs. 57.7 ± 6.2; p=0.2). To further test metabolic reprogramming, WT and BON-N1-KO cells were starved of glucose (0mM), compared to normal glucose (17.5mM) and viability was measured over time. By day 5, the BON-N1-KO group had a viability of 0%, whereas 12.8% of WT cells were alive (p=0.038). To determine if Notch1 loss was associated with altered expression of established metabolic genes, we performed RNAseq. Differential gene expression analysis found that OXPHOS-related genes (UQCC2, COX15, COX20) and glycolysis-related genes (Slc1a1, Slc2a4, Hk1, Hk2) were significantly down-regulated in BON-N1-KO cells.
Conclusions: Our study shows that Notch1 signaling facilitates metabolic reprogramming as a survival advantage in pNET cells. Targeting Notch1 signaling to mediate cellular metabolism may be a novel therapeutic strategy in pNETs.
Citation Format: Rachael Guenter, Weisheng Chen, Brendon Herring, Yuvasri Golivi, Melissa Sammy, Jason Whitt, Renata Jaskula-Sztul, Herbert Chen, J. Bart Rose. Metabolic reprogramming through Notch1 signaling promotes a survival advantage in pancreatic neuroendocrine tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4463.
Abstract 4473: Targeting matrix metalloproteinase-3 (MMP-3) in high-grade serous ovarian cancer
Authors: Reyes-Burgos Víctor G. , Hernández-O'Farrill Eliud , Quiñones Luis E. Vazquez , Flores-Colón Marienid , Valiyeva Fatima , Vivas-Mejía Pablo E. 
Published: March 2024

Abstract
High-Grade Serous Ovarian Cancer (HGSOC) is the most aggressive and lethal gynecological malignancy. Surgery and chemotherapy (with platinum compounds) are the main treatments. Many patients relapse and develop chemotherapy resistance, limiting the therapeutic utility of these therapies. This persistent resistance makes HGSOC treatment difficult. Cisplatin-resistant ovarian cancer cells upregulate Matrix Metalloproteinase-3. MMP3 is an enzyme involved in active tissue remodeling and extracellular matrix protein breakdown during dynamic physiological processes. The structure of MMP3 includes the prodomain, the catalytic domain and the hemopexin domain. We showed that MMP3 protein levels are higher in cisplatin resistant as compared with cisplatin sensitive HGSOC cells. Our research team showed that small interference RNA (siRNA)-mediated MMP3 knockdown reduced cisplatin-resistant ovarian cancer cell growth and invasion. This data indicates that MMP3 may be a promising HGSOC treatment target. Targeting MMP3 with small chemical inhibitors (SCI) could represent a better option than siRNA because SCI are more stable and easier to deliver. The purpose of this project is to design SCI of MMP3 in the propeptide, catalytic, and hemopexin domains of MMP3. We used in silico methods to identify MMP3 inhibitors in these domains. The ZINC20 database of commercially compounds was used for virtual screening using Python Prescription (PyRx) software. We identified 25 ligands out of 370,000 with the greatest affinity for each MMP3 functional domains. SwissADME was then used to evaluate in silico absorption, distribution, metabolism, pharmacokinetics, drug-likeliness, and medicinal chemistry. This research lays the groundwork for HGSOC therapeutic strategies to improve treatment efficacy, especially for chemotherapy-resistant patients.
Citation Format: Víctor G. Reyes-Burgos, Eliud Hernández-O'Farrill, Luis E. Vazquez Quiñones, Marienid Flores-Colón, Fatima Valiyeva, Pablo E. Vivas-Mejía. Targeting matrix metalloproteinase-3 (MMP-3) in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4473.
Abstract 4474: Novel analogs of 4-substituted pyrrolo[2,3-d]pyrimidines as dual-targeted mEGFR/AURKA inhibitors for lung cancer
Authors: Kurup Sonali , Carpenter Gabe , Satawa Samantha , Amissah Felix , Lisabeth Erika , Giletto Matthew , Ellsworth Edmund 
Published: March 2024

Abstract
Small molecule, mutant epidermal growth factor receptor kinase (mEGFR) inhibitors such as osimertinib and erlotinib constitute the recommended therapy for mEGFR-positive non-small cell lung cancer (NSCLC). However, mEGFR inhibitors are ineffective in NSCLC over time due to mutations within mEGFR and redundant signaling pathways such as mutant KRAS (mKRAS) that bypass mEGFR inhibition. Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on tumor growth inhibition and tumor resistance. Studies have shown that resistance to mEGFR inhibitors was overcome when mEGFR inhibitors were combined with aurora kinase (AURK) inhibitors. Additionally, mEGFR inhibitors were found to retain their anticancer effects in mKRAS-positive NSCLC cells if given concurrently with AURK inhibitors. Kurup et al. previously reported a series of 4-substituted pyrrolo[2,3-d]pyrimidines as dual mEGFR/AURKB inhibitors. Novel analogs of 1-5 have been designed to incorporate AURKA inhibition while maintaining mEGFR inhibition. Molecular modeling was utilized to guide selectivity for AURKA over AURKB. This study led to the identification of novel dual-targeted mEGFR/AURKA inhibitors with demonstrated inhibition of mKRAS+ NSCLC and mEGFR+ NSCLC. The design, synthesis, kinase inhibitory activities, and anticancer effects for these novel analogs will be presented. Structure-activity relationships for dual mEGFR/AURKA inhibition will be defined.
Citation Format: Sonali Kurup, Gabe Carpenter, Samantha Satawa, Felix Amissah, Erika Lisabeth, Matthew Giletto, Edmund Ellsworth. Novel analogs of 4-substituted pyrrolo[2,3-d]pyrimidines as dual-targeted mEGFR/AURKA inhibitors for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4474.
Abstract 4532: Discovery of DAT-1000A, a potent Polθ inhibitor that significantly enhances anti-tumor efficacy in combination with PARP inhibitor in homologous-recombination-deficient tumors
Authors: Yan Dan , Zhang Yao , Zhang Yan , Zhang Jingxi , Wang Bin , Chen Huixian , Shi Jingxue , Lin Xiaoling , Zhuo Jincong , Zhou Kevin 
Published: March 2024

Abstract
Cancers exhibiting homologous recombination (HR) repair deficiencies due to mutations in genes like BRCA1 or BRCA2 rely on alternative DNA damage response (DDR) pathways to uphold genomic integrity. This vulnerability allows for the targeted disruption of these pathways through synthetic lethality approaches. DNA polymerase theta (Polθ, encoded by POLQ) assumes a crucial role in mending DNA double-strand breaks (DSB) via microhomology-mediated end-joining (MMEJ), one of the principal pathways for repairing DNA DSB. Notably, Polθ expression is minimal in normal tissues but becomes upregulated in HR-deficient cancer cells, positioning Polθ as a prime target for synthetic lethality in HRD cancers. Reversion mutations in HR-related genes frequently employ micro-homology deletion mechanisms. Consequently, the inhibition of Polθ holds the potential to thwart the emergence of PARPi resistance, primarily driven by BRCA reversion mutations. In this context, we introduce DAT-1000A, a novel small-molecule Polθ inhibitor exhibiting potent activity with a single-digital nanomolar IC50 value. Its efficacy in MMEJ functional assays validates its on-target cellular activity. Assessments of cell viability in HR-deficient BRCA2-KO DLD-1 cells, compared to their parental counterparts, reveal a striking synthetic lethality window exceeding 500-fold. Additionally, DAT-1000A displays synergistic anti-proliferative effects when combined with PARP inhibitors in BRCA1/2-mutated cells. In BRCA1/2-mutated xenograft models, DAT-1000A demonstrates robust and sustained tumor regression, as evidenced by the level of γH2AX, a common marker for double-strand breaks, which closely correlates with anti-tumor efficacy. Importantly, high-dose DAT-1000A treatment in mice elicits no significant abnormalities, underscoring its excellent tolerability. Collectively, DAT-1000A emerges as a novel Polθ inhibitor, offering both potent activity and a favorable safety profile, and holds promise for advancing therapeutic options in the realm of HRD cancer treatment.
Citation Format: Dan Yan, Yao Zhang, Yan Zhang, Jingxi Zhang, Bin Wang, Huixian Chen, Jingxue Shi, Xiaoling Lin, Jincong Zhuo, Kevin Zhou. Discovery of DAT-1000A, a potent Polθ inhibitor that significantly enhances anti-tumor efficacy in combination with PARP inhibitor in homologous-recombination-deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4532.