bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6375: Augmented intelligence to define drug targets associated with triple negative breast cancer (TNBC) metabolic reprogramming
Authors: Jenna Sarah , Boucher Benjamin , Dudragne Liebaut , Diallo Abdoulaye Baniré 
Published: June 2022

Abstract
Introduction: Basal-like breast cancer (BLBC; TNBC) cells use aerobic glycolysis at a higher rate than Luminal A (LumA) cells. Metabolic reprogramming using aerobic glycolysis (Warburg effect), is correlated with increased aggressiveness of cancer cells and poor outcome in patients. Therefore, genes involved in this pathway are promising targets for developing cancer therapeutics.
Method: MIMs has developed a unique platform of augmented intelligence that combines bioinformatics, systems biology and artificial intelligence. It integrates multi-layered omics data with a knowledge-base that aggregates structured data from more than 140 databases as well as unstructured data from the scientific literature. Using this approach a genetic interaction graph (GI-Graph) is inferred per patient, capturing functional relationships between genes in the specific context of the tumor. The GI-Graphs are subsequently used to train supervised machine learning algorithms for predicting gene functionality and potential as a target. Preliminary analysis was performed on transcriptomic data from 321 LumA and 162 TNBC samples, from the TCGA Data Portal and a predictive model was developed using two GI-Graphs from the two subgroups. Briefly, subgraphs, containing genes with functional interactions with the known genes in OXPHOS and glycolysis pathways, were used to extract gene attributes, and to build an algorithm that predicts involvement of a gene in the Warburg effect. Using a testing gene set extracted from the literature the performance of the model was assessed, which showed a true positive rate of 18% and a false positive rate of 0.36%, and outperformed 5-times the classical bioinformatics tools.
Results: This model predicted 108 genes as the top 1% genes being involved in the metabolic reprogramming of TNBC. Additional information from MIMs’ platform, including differential gene expression between LumA and TNBC, gene pleiotropy and essentiality and the topological metrics, enabled the life scientists to further refine the gene lists, based on the expected characteristics of a good target in oncology. Following this process, 30 genes were selected as potential targets controlling the metabolic reprogramming of TNBC, among which 4 genes were already evaluated in TNBC clinical trials.
Conclusion: Our preliminary data strongly supports that the predictive model based on the GI-Graphs has the potential to identify promising therapeutic targets for TNBC.
Citation Format: Sarah Jenna, Benjamin Boucher, Liebaut Dudragne, Abdoulaye Baniré Diallo. Augmented intelligence to define drug targets associated with triple negative breast cancer (TNBC) metabolic reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6375.
Abstract 6392: Predicting malignancy in indeterminate pulmonary nodules using quantitative CT imaging
Authors: Bloch Kate M. , Shi Xingyi , Duan Fenghai , Washko George R. , Spira Avrum , Aberle Denise R. , Estepar Raul S. , Billatos Ehab , Lenburg Marc E. ,   on behalf of the DECAMP Investigators
Published: June 2022

Abstract
With an increasing number of positive lung cancer screening trials and the growing utilization of low dose CT screening, the detection of indeterminate pulmonary nodules is an important clinical problem. A biomarker that will be able to differentiate between benign andmalignant nodules would help to accelerate diagnosis and reduce unnecessary and invasive procedures. Here, we investigated the utility of quantitative radiomics to predict malignancy of small pulmonary nodules. Data including cancer status, age, gender, smokingstatus and CT radiomics data, from 242 patients accrued from the Detection of Early Lung Cancer Among Military Personnel (DECAMP1) consortium was used. DECAMP1 is a prospective study of 500 current or former smokers with indeterminate pulmonary nodules (0.7-3.0 cm). A total of 446 quantitative radiomic features were extracted from CT images of each patient. For the prediction models, various feature selection methods and machine learning algorithms including Random Forest, Gradient Boosting Machine and Support Vector Machine were used. Data was split into train and test set with tenfold cross-validation.Models were evaluated using; Accuracy, Sensitivity, Specificity and Area under the curve - a receiver operating characteristic curve (AUC-ROC). In terms of predictive performance, the AUC value was 0.64 (95% CI: 0.50-0.78) for the clinical model and 0.77 (95% CI: 0.64-0.90) for the radiomics model. Adding clinical features to the radiomics model (gender, age, smoking status) did not improve the model. We have also investigated the slice thickness and scanner (PET vs PET-CT) variables on the models’ performance and saw a modest improvement of the AUC values when using more homogenous data. In this study, we showed the potential of radiomics for lung cancer prediction in DECAMP1.For future work, we are planning to test whether incorporating bronchial gene expression data improves lung cancer detection and to validate these findings in separate, independent cohorts.
Citation Format: Kate M. Bloch, Xingyi Shi, Fenghai Duan, George R. Washko, Avrum Spira, Denise R. Aberle, Raul S. Estepar, Ehab Billatos, Marc E. Lenburg, on behalf of the DECAMP Investigators. Predicting malignancy in indeterminate pulmonary nodules using quantitative CT imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6392.
Abstract 674: Tracking the transcriptome of lung cancer-associated fibroblasts within the TRACERx lung study from patient to culture models reveals phenotypic plasticity and instructive cues from cancer cells
Authors: Naito Yutaka , Hynds Robert , Novo David , Chakravarty Probir , Kelly Gavin , Swanton Charles , Honda Kazufumi , Sahai Erik ,   TRACERx Consortium
Published: June 2022

Abstract
Cancer-associated fibroblasts (CAFs) play a pivotal role in cancer progression by enhancing extracellular matrix remodeling, cancer cell invasion, and mediating inflammatory environment. Therefore, CAFs have become targets for cancer therapies. However, a major hurdle to developing such therapies are the challenges of studying CAFs in culture - specifically it remains unclear which CAF functions and phenotypes are sustained during in vitro culture and the signaling pathways driving distinct CAF phenotypes.
We investigated whether CAF phenotypes and functions are sustained or changed during 2D CAF culture under in vitro systems, our analysis included early passage, late passage, and immortalized cultures, as well as CAFs in coculture with cancer cell lines. Transcriptomic analysis revealed that inflammatory-related gene expression programs were suppressed in late passage and immortalized CAFs compared with early passage equivalents. Direct co-culture with lung cancer cells can revert the inflammatory gene expressions in immortalized CAFs such that they partially resemble early passage CAFs. In contrast, indirect coculture with lung cancer cells - in which CAFs could not form cell-cell contacts with cancer cells - had a less significant effect on immortalized CAF inflammatory gene expression but could induce TGFβ regulated genes. Interestingly, inhibition of the TGFβ signaling pathway potentiated the inflammatory gene expression network induced by direct co-culture, suggesting that the signaling mediated by direct cellular interaction is antagonistic to the TGFβ signaling pathway.
These data further our understanding of cancer cell – CAF crosstalk and will help to develop in vitro assays that more closely maintain the state of CAFs observed in tissue.
Citation Format: Yutaka Naito, Robert Hynds, David Novo, Probir Chakravarty, Gavin Kelly, Charles Swanton, Kazufumi Honda, Erik Sahai, TRACERx Consortium. Tracking the transcriptome of lung cancer-associated fibroblasts within the TRACERx lung study from patient to culture models reveals phenotypic plasticity and instructive cues from cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 674.
Abstract 759: Analytical performance of a novel next generation sequencing assay for myeloid MRD
Authors: Zhang Hua , Peng Xinzhan , Luo Guobin , Kraltcheva Annie , Mandelman David , Swimley Michelle , Pazol Eli , Espinoza Jose , Mitchell Scott , Ding Bo , Singh Ratnesh , Fenger Doug , Li Na , Hatch Andrew , Mozhayskiy Vadim , Roman Steven , Rozenzhak Sophie 
Published: June 2022

Abstract
The detection of molecular measurable residual disease (MRD) for acute myeloid leukemia (AML) has shown promise as a prognostic for AML. To support clinical and translational research into potential strategies for MRD monitoring applications in the future, a next-generation sequencing (NGS) assay, the Oncomine Myeloid MRD Assay (RUO), was developed. This assay utilizes Unique Molecular Tags (UMT) and Ion AmpliSeq HD™ technology to detect ultra-low frequency genetic alterations from blood or bone marrow samples. The workflow includes manual AmpliSeq HD library construction, templating on Ion Chef™, and sequencing on Ion GeneStudio™ sequencers. The assay contains both DNA and RNA targeted panels to detect SNVs, indels, fusion markers, and microhaplotype. The DNA panel covers 1256 hotspots in 33 genes, including key mutations in NPM1, FLT3, DNMT3A and full gene coverage for CEBPA and TP53. The panel achieved a limit of detection (LOD) of 0.1% when tested on 27 reference genomic DNA samples and over 40 clinical research samples. The RNA panel detects 1003 fusion isoforms for 27 fusion driver genes, including BCR-ABL1, RUNX1, CBFB-MYH11, and KTM2A (MLL) partial tandem duplications (PTDs) and fusions. The assay also includes a Microhaplotyping panel to monitor chimerism. The workflow is analytically verified and includes an optimized analysis pipeline for sensitive and accurate MRD detection. Overall, this comprehensive Myeloid MRD (RUO) assay reliably identifies DNA mutations and fusions with high sensitivity and provides a new tool for myeloid MRD research. RUO: For Research Use Only. Not for use in diagnostic procedures.
Citation Format: Hua Zhang, Xinzhan Peng, Guobin Luo, Annie Kraltcheva, David Mandelman, Michelle Swimley, Eli Pazol, Jose Espinoza, Scott Mitchell, Bo Ding, Ratnesh Singh, Doug Fenger, Na Li, Andrew Hatch, Vadim Mozhayskiy, Steven Roman, Sophie Rozenzhak. Analytical performance of a novel next generation sequencing assay for myeloid MRD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 759.
Abstract 774: Microdissected gene expression profiling of recurrent nasopharyngeal carcinoma
Authors: Tay Joshua , Teo Wei Keat , Goh Chuan Keng , Wu Bing Cheng , Loh Kwok Seng 
Published: June 2022

Abstract
Nasopharyngeal cancer (NPC) is an EBV-driven epithelial carcinoma with a recurrence rate of 30%. Biological pathways and predictive markers for recurrence remain understudied. Further, NPC tumors are associated with an intense inflammatory infiltrate, masking gene expression signals from the tumor epithelial compartment. We perform laser-capture microdissection on a preliminary cohort of 12 tumors, including primary tumors from recurrent and non-recurrent cases matched for stage of disease. Smart-3SEQ, a novel 3’ end RNA-Seq technique which allows for the accurate quantification of transcript abundance in FFPE samples, was performed to obtain gene expression libraries. Tumor epithelial and microenvironment regions from were separately microdissected, giving a total of 42 histologically-pure gene expression libraries. Raw reads were mapped to the human hg19 and EBV genomes and gene expression counts were obtained with Subread. Differential gene expression and gene set enrichment was performed in R with DESeq2 and fgsea respectively. We observed that primary NPC tumors that did not recur were significantly enriched for immune processes, including leukocyte mediated immunity, innate immune response and lymphocyte activation (padj &lt; 1E-9 for all). The top differentially expressed genes in this group included mediators of inflammation such as STAT1 (padj = 0.0204). Critically, these gene expression changes were observed within the tumor epithelial compartment. In contrast, primary NPC tumors that eventually recurred were enriched for known oncogenes including BCL2 (padj = 0.000420). These findings suggest that heterogeneity in gene expression between NPC tumors play an important role in treatment response. Further work to define gene expression subtypes of NPC tumors will be helpful for patient stratification and personalized care.
Citation Format: Joshua Tay, Wei Keat Teo, Chuan Keng Goh, Bing Cheng Wu, Kwok Seng Loh. Microdissected gene expression profiling of recurrent nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 774.
Abstract 775: Evaluation of Erb-B2 expression from archival tumor tissue in early stage epithelial ovarian carcinoma patient prognosis
Authors: Rao Kavitha Advikolanu , Magliocco Anthony , Maksymiuk Andrew 
Published: June 2022

Abstract
In this retrospective study, Erb-B2 expression was assessed in 106 patients using Paraffin-Embedded Tissue (PET) to determine the prognostic value in Epithelial Ovarian Carcinoma (EOC) patients diagnosed at Saskatoon Cancer Center between the years 1983-1995. Relationship between Erb-B2 positivity and patient tumor characteristics was assessed for Overall Survival (OS) and Relapse-Free Survival (RFS) by Kaplan-Meier method. Based on the intensity of stain with a polyclonal antibody (A485, 1/400 dilution), cases with markedly intense cytoplasmic and membranous immunoreactivity were classified as Erb-B2 over-expressors. Erb-B2 was overexpressed in 13 (12%) cases. The mean age of the patients was 56 years (range 18-84 years). The patient population consisted of 64 Stage I and II, Early Stage (ES) and 36 cases with Stage III and IV Advanced Stage (AS). Data on histologic grade was available in 81 cases. 58 patients received platinum-containing regimen, 13 melphalan, and in 9 cases combination chemotherapy. Erb-B2 expression did not influence OS and RFS in these patients. Similarly, there was no significant relation to OS and RFS between Erb-B2 and age, grade, and patients with No Evidence of Disease (NED). Of the 64 cases with ES disease, 16 cases had Grade 2 tumor with Erb-B2 over-expression in 4 cases. Grade 2 tumors with Erb-B2 overexpression indicated significant relationship to OS and RFS, p=0.01, (median = 30 months, CI: 26 - 68) and p=0.05, (median = 15 months, CI: 13 - 68). Furthermore, in 21 cases with ES, Endometrioid histology and Erb-B2 expressors 6/21 (28%) experienced significantly shorter OS compared to non-expressors p=0.005, (median = 48 months, CI: 22 - 74) (mean = 134 months, CI: 124 - 144). In conclusion, Erb-B2 overexpression could be detected in only limited EOC cases in PET and appears to have no prognostic influence. Additionally, endometrioid carcinoma and grade 2, ES certainly reflect the importance of sub-group analysis. In ovarian carcinoma distribution of stage, histology, and grading of tumor cells are conventional markers for prognosis. Finally, Erb-B2 status detected by immunohistochemistry, in a subgroup of patients with high-degree of HER2 positivity/focal amplification may likely have better clinical outcome with anti-HER2 agents.
Citation Format: Kavitha Advikolanu Rao, Anthony Magliocco, Andrew Maksymiuk. Evaluation of Erb-B2 expression from archival tumor tissue in early stage epithelial ovarian carcinoma patient prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 775.
Abstract 799: HLTF and SHPRH in mismatch repair and cancer
Authors: Miller Anna Kristin , Mao Guogen , Rahal Christine , Putnam Christopher , Goellner Eva 
Published: June 2022

Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer deaths, with an increasing rate of CRC diagnosis in younger individuals. MMR is the DNA repair mechanism that repairs DNA mispairs and small insertions or deletions remaining after replication. MMR is also required for apoptosis after certain types of exogenous DNA damage that result in damage-associated mispairs. MMR defects are the underlying cause of Lynch syndrome, a familial cancer predisposition syndrome that increases susceptibility to multiple cancers, specifically colorectal cancer. MMR defects are also commonly found in sporadic colorectal cancers. Model systems such as Saccharomyces cerevisiae, Escherichia coli, and human cell lines have been used to study the MMR proteins and pathways. The basics of the MMR mechanism are fairly well understood; however, proteins associated with MMR are still being identified, and the roles of these proteins are largely unknown. We have identified the yeast protein Rad5 as an interactor with the yeast MMR proteins Msh2 and Mlh1. Rad5 is a helicase and an E3 ubiquitin ligase which is involved in post-replicative repair and damage tolerance. However, to date, Rad5 has no known role in MMR. We have determined that these interactions are conserved through evolution to human Rad5 homologs, HLTF and SHPRH. The Rad5 interactions with Mlh1 and Msh2 appear to be split between the human homologs with human Msh2 interacting with HLTF and human Mlh1 interacting with SHPRH. We have found that loss of SHPRH induces resistance to MMR-mediated apoptosis. Current experiments are in progress to determine the binding sites between these proteins. We are also investigating what functional impact the Rad5 homologs have on mutation rate and MMR-induced apoptosis and how the interactions affect the roles of MMR. Together this will allow for a deeper understanding of how accessory proteins may influence canonical and non-canonical MMR. Since MMR status is currently used to determine patient treatment, understanding how commonly mutated accessory factors interact is critical.
Citation Format: Anna Kristin Miller, Guogen Mao, Christine Rahal, Christopher Putnam, Eva Goellner. HLTF and SHPRH in mismatch repair and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 799.
Abstract 854: The role of protocadherin, FAT2 in breast cancer
Authors: Roache Thomas , Sumera Megan , Laird Zalaila , Datta Amrita 
Published: June 2022

Abstract
Protocadherins are cell adhesion molecules that belong to the cadherin superfamily. They are novel cadherin like proteins predominantly associated with early development and morphogenesis, cell growth and patterning, cell-cell adhesion, cell motility (including cell invasion and migration). The Fat-protocadherins are derived from an ancestral Drosophila FAT like cadherin and are evolutionarily conserved. They have been primarily implicated in neuronal cell development and cancer. Several studies have implicated protocadherin dysfunction in cancer. Loss of protocadherin expression, chromosome deletion and epigenetic silencing have been implicated in kidney, prostate, colorectal and breast cancer. More recently they have been implicated in gastric tumors and gliomas. Based on these findings, protocadherins are thought to be tumor suppressors and in general seem to regulate cancer cell proliferation, migration and/or apoptosis. However, multiple exceptions have also been observed and individual protocadherin functions seem to be context-dependent, as some can be considered either tumor suppressors or proto-oncogenes according to the type of cancer being examined. The mechanistics of the roles of the protocadherins in neuronal development have been well dissected but most oncological studies have focused on their characterization as potential biomarkers while the molecular signaling pathways through which the protocadherins regulate growth, invasion and metastasis are still poorly understood. For example recent research has shown that FAT1 is repressed in oral cancer owing to homozygous deletion or epigenetic silencing and is preferentially downregulated in invasive breast cancer. On the other hand, FAT1 is upregulated in leukemia and prognosis of preB-ALL patients with FAT1 upregulation is poor. Therefore FAT1 is tumor suppressive or oncogenic in a context-dependent manner, while FAT4 is tumor suppressive. FAT2 is highly expressed in breast cancer and lung squamous cell carcinoma and the elevated expression of FAT2 is correlated with poor patient outcome.Our preliminary research analysis of the TCGA data from the Genomic Data Commons Portal shows that protocadherins FAT4 and FAT1 are among the top dysregulated genes in cancer. We have also determined that FAT2 has higher Copy Number Variation (CNV) gain events than loss events. Given that there is a well-known concordance between CNV and differential gene expression we believe that FAT2 has a paradoxical oncogenic role in breast cancer.
Citation Format: Thomas Roache, Megan Sumera, Zalaila Laird, Amrita Datta. The role of protocadherin, FAT2 in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 854.
Abstract 88: ATAD3A enhances head and neck cancer malignancy via mitochondrial ERK1/2 signaling
Authors: Lang Liwei , Loveless Reid , Qin Zhaohui , Qiu Peng , Shay Chloe , Teng Yong 
Published: June 2022

Abstract
Targeting mitochondria as a cancer therapeutic strategy has attracted more and more attention in the recent years. ATAD3A is identified as a nuclear-encoded mitochondrial enzyme that regulates mitochondrial dynamics, cholesterol metabolism, and signal transduction. However, its impact and underlying regulatory mechanisms in cancers remain to be determined. We report here that ATAD3A is highly expressed in head and neck squamous cell carcinoma (HNSCC), where it plays a critical role in favoring tumor progression. Loss of ATAD3A expression dramatically incudes tumor regression in orthotopic tongue tumor-bearing mice, whereas gain of ATAD3A expression produces the opposite effects. Mechanistically, ATAD3A binds to ERK1/2 at HNSCC cell mitochondria in the presence of VDAC1, and this interaction is essential for the activation of mitochondrial ERK1/2 signaling. Most importantly, the ATAD3A-ERK1/2 signaling axis enhances HNSCC development in a Ras-independent manner and, thus, tumor suppression is more effectively achieved when ATAD3A and Ras signaling pathways are co-inhibited. These novel findings highlight the importance of activation of ATAD3A-ERK1/2 axis in cancer progression and suggest that combined targeting of ATAD3A and Ras signaling could potentiate anticancer activity for HNSCC treatment.
Citation Format: Liwei Lang, Reid Loveless, Zhaohui Qin, Peng Qiu, Chloe Shay, Yong Teng. ATAD3A enhances head and neck cancer malignancy via mitochondrial ERK1/2 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 88.