bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-295: Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma
Authors: Han Mingzhi , Wang Shuai , Li Xingang , Wang Jian , Bjerkvig Rolf 
Published: August 2019

Abstract
BACKGROUND
Tumor cells display higher cholesterol levels compared to normal cells and emerging evidence indicates a pivotal role of cholesterol content in tumor cell proliferation and growth mediated by a dysregulation of key regulators involved in cholesterol homeostasis has been implicated in various cancers. In this study, we assessed the dependency of glioblastoma (GBM) cells to extracellular cholesterol levels for growth. Through analysis of whole-transcriptome databases, we identified the cholesterol homeostasis-related genes whose expression are dysregulated in gliomas. One of the most dramatically down-regulated genes identified encodes cholesterol 24-hydroxylase (CYP46A1), a brain-specific enzyme responsible for elimination of cholesterol via conversion of cholesterol to 24(S)-hydroxycholesterol (24OHC).
METHODS
Molecular and clinical data was obtained from publicly genomic databases. Immunohistochemistry was applied to assess the protein level of CYP46A1 in tissue microarrays. Functionally, CYP46A1 overexpression was determined using lentiviral constructs in LN229 and a primary glioblastoma cell line (GBM#P3). Cells were characterized in vitro and implanted in vivo to generate orthotopic xenografts in order to assess their molecular status, cell survival, and self-renewal by western blotting, flow cytometry, and extreme limiting dilution assay (ELDA), respectively.
RESULTS
Down-regulation of CYP46A1 was found in malignant glioma samples compared to normal brain tissue. Importantly, reduced CYP46A1 expression was associated with aggressive clinicopathological features and poor prognosis of GBM patients. In functional assays, restoration of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. Consistent, treatment of GBM cells with 24OHC inhibited tumour growth and induced apoptosis in a concentration dependent manner. RNA-seq data showed that 24OHC regulated LXR and sterol regulatory-element binding protein 1 (SREBP1) signalling activity.
Intriguingly, efavirenz (EFV), a widespread used anti-HIV medication that effectively penetrates the blood–brain barrier, has recently been reported as a potent activator of the CYP46A1 enzyme. The therapeutic potential of EFV is currently being assessed in vivo and the data will be presented.
CONCLUSIONS
Collectively, our findings demonstrate that CYP46A1 is a critical cellular cholesterol regulator in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target in GBM.
Citation Format: Mingzhi Han, Shuai Wang, Xingang Li, Jian Wang, Rolf Bjerkvig. Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-295.
Abstract LB-299: A comprehensive platform of patient-derived xenografts and matched cell lines mirrors the genomic landscape of colorectal cancer
Authors: Lazzari Luca , Corti Giorgio , Isella Claudio , Montone Monica , Arcella Pamela , Zanella Eugenia , Novara Luca , Barbosa Fabiane , Cassingena Andrea , Cancelliere Carlotta , Medico Enzo , Sartore-Bianchi Andrea , Siena Salvatore , Bertotti Andrea , Trusolino Livio , Nicolantonio Federica Di , Linnebacher Michael , Bardelli Alberto , Arena Sabrina 
Published: August 2019

Abstract
Preclinical models that accurately reflect patients’ tumor with regards to histopathology, genomics, and therapeutic response represent a compelling need to fuel the progress of effective cancer treatments. Patient-derived tumor xenografts (PDXs) have significantly accelerated this process, but, although they closely mirror structural and molecular features of the tumor of origin, they still retain important restrictions related to maintenance costs and large-scale screening. To overcome this issue, we have established a novel platform of 2D-cell lines (xeno-cell lines, XL) derived from PDXs of colorectal cancer (CRC) from which patient’s germline gDNA was available. We have characterized XL-cells at multiple levels to confirm their proximity to the PDXs of origin and to assess their suitability as patient avatars in vitro to interrogate functional networks in colorectal cancer. All XL-cells showed an epithelial-like morphology and phenotype, as also confirmed by EMT biomarker transcriptomic analysis. Whole exome and RNA-seq analyses showed that genomic features were consistently preserved between PDXs and matched cell models. Expression analysis revealed the XL-line collection as a significant representative of all CRC subtypes (CMS and CRIS subgroups). Furthermore, genomic analysis allowed the identification of molecular biomarkers of response and resistance to targeted therapies, including EGFR and HER2 blockade. In particular, molecular determinants of resistance to dual-HER2 blockade previously reported in the Heracles-A trial were validated in XL-cells. In conclusion, the XL-cell line and PDX platform represents a unique and comprehensive preclinical tool to validate gene function e to identify novel pharmacological vulnerabilities in colorectal cancer.
Citation Format: Luca Lazzari, Giorgio Corti, Claudio Isella, Monica Montone, Pamela Arcella, Eugenia Zanella, Luca Novara, Fabiane Barbosa, Andrea Cassingena, Carlotta Cancelliere, Enzo Medico, Andrea Sartore-Bianchi, Salvatore Siena, Andrea Bertotti, Livio Trusolino, Federica Di Nicolantonio, Michael Linnebacher, Alberto Bardelli, Sabrina Arena. A comprehensive platform of patient-derived xenografts and matched cell lines mirrors the genomic landscape of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-299.
Abstract SY15-03: Coding and noncoding genome for blood biopsy
Authors: Hayes Daniel F. , Alix-Panabières Catherine , Calin George A. 
Published: August 2019

Abstract
The development of effective diagnostic and prognostic biomarkers is crucial for early detection of cancer, prediction of clinical outcome, detection and monitoring minimal residual disease, and identification of patients who can benefit from therapy. Furthermore, they can provide important information of biological characteristics of tumor. Liquid biopsy, an alternative and non-invasive technique to surgical biopsy, enables the investigation of tumor markers in biological fluids, such as serum/plasma, urine, saliva, and pleural effusion. Increasing interest on liquid biopsy has grown over the past decade with particular focus on circulating non-coding RNAs (ncRNAs) and tumor-derived cell-free DNA (cfDNA) as cancer biomarkers. Owing to their high abundance and stability in biological fluids, circulating ncRNAs and tumor-derived cell-free DNA have potential utility to provide information on tumor biology (e.g.: EGFR and PIK3CA mutational status) which can help both diagnosis and prediction of effects of treatments, including standard treatment, targeted therapies, and immunotherapies. Recent advances in the field have highlighted the role of circulating ncRNAs in cell-to-cell communication. Particularly, ncRNAs can be transported through extracellular vesicle-mediated transfer to recipient cells, where they exert their functions of gene expression regulation, with implications for cancer progression and therapy resistance. This characteristic of circulating ncRNAs introduces an additional step in the information on tumor biology that can be obtained from liquid biopsy. Besides cancer, ncRNAs can also serve as biomarkers for microbial infection. Indeed, miRNAs originated from non-human genomes (xeno-miRNAs), such as viral miRNAs (Epstein-Barr virus, Kaposi sarcoma-associated herpesvirus), have been shown to be present in human body fluids. They can be used as biomarkers for diagnosis, prediction of clinical outcome, and the can also mediate cell-to-cell communication. Liquid biopsy has the potential to serve as additional tool to improve diagnosis, prognosis, prediction of treatment responses, and can provide information of biological characteristics of tumor.
Citation Format: Daniel F. Hayes, Catherine Alix-Panabières, George A. Calin. Coding and noncoding genome for blood biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY15-03.
Abstract SY19-02: Metabolic tumor suppressors and disease progression
Authors: Simon M Celeste 
Published: August 2019

Abstract
Altered tumor cell metabolism is now firmly established as a hallmark of human cancer. Downstream of oncogenic events, metabolism is re-wired to support cellular energetics and supply the building blocks for biomass expansion and cell motility. Rapid, uncontrolled proliferation results in tumor growth beyond the reach of existing vasculature and triggers cellular adaptations to overcome limiting nutrient and oxygen delivery. However, oncogenic activation and metabolic re-programming also elicit cell intrinsic stresses, independent of the tumor microenvironment. To ensure metabolic robustness and stress resistance, pro-growth signals downstream of oncogene activation or tumor suppressor loss simultaneously activate homeostatic processes. Here, I will summarize adaptive mechanisms based on loss of fructose-1,6-bisphosphatases FBP1 and FBP2 in the settings of renal carcinoma, liver cancer, and soft tissue sarcoma. Both FBPs function in the cytoplasm and the nucleus to carry out enzymatic activity-dependent and -independent processes that suppress tumor growth. FBP1 and FBP2 impact both malignant and stromal cells in the tumor microenvironment, including inflammayory cells. Ultimately, an understanding of the adaptations required downstream of specific metabolic tumor suppressors could reveal targetable metabolic vulnerabilities.
Citation Format: M Celeste Simon. Metabolic tumor suppressors and disease progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY19-02.
Abstract SY21-02: Oncometabolites suppress homologous recombination DNA repair by inhibition of chromatin remodeling at the DNA double-strand break
Authors: Sulkowski Parker S. , Oeck Sebstian , Li Jing , Shuch Brian , King Megan C. , Bindra Ranjit S. , Glazer Peter M. 
Published: August 2019

Abstract
Elevated levels of the metabolites, 2-hydroxyglutarate (2HG), fumarate, and succinate, can occur in human malignancies due to somatic mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) genes or germline mutations in fumarate hydratase (FH) and succinate dehydrogenase (SDH) genes, respectively. Mutations in IDH1 and IDH2 are found in a large number of human malignancies, most notably gliomas and acute myelogenous leukemias, along with cholangiocarcinomas, chondrosarcomas, and melanomas. Inherited mutations in FH and SDH, are linked to the familial cancer predisposition syndromes, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and Hereditary Paraganglioma and Pheochromocytoma (SDH PGL/PCC), respectively. These structurally related metabolites inhibit α-ketoglutarate-dependent enzymes, including dioxygenases that modify chromatin. We have shown that they consequently suppress the pathway of homology-dependent DNA repair (HDR), conferring an exquisite sensitivity to PARP inhibitors that is currently being tested in clinical trials. In this presentation, we will discuss our recent work elucidating the mechanistic basis for this suppression of DNA repair. Rather than acting indirectly through epigenetic regulation of gene expression, we find that these metabolites act directly by inhibiting HDR factor recruitment to DNA double-strand breaks (DSBs). The metabolites inhibit the lysine demethylases, KDM4A/B, causing aberrant hypermethylation of H3K9 and disrupting signaling at the break, thereby delaying the stepwise recruitment of key HDR factors. These results define a novel mechanism of decreased DNA repair in oncometabolite producing human tumors and may provide the basis for the rational design of novel therapeutic strategies for these malignancies.
Citation Format: Parker S. Sulkowski, Sebstian Oeck, Jing Li, Brian Shuch, Megan C. King, Ranjit S. Bindra, Peter M. Glazer. Oncometabolites suppress homologous recombination DNA repair by inhibition of chromatin remodeling at the DNA double-strand break [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY21-02.
Abstract SY25-02: Widespread germline-somatic regulatory differences in renal cell carcinoma prioritize risk mechanisms
Authors: Gusev Alexander , Spisak Sandor , Abbasi Forough , Fay Andre , Carol Hallie , Seo Ji-Heui , Choueiri Toni , Lawrenson Kate , Freedman Matthew 
Published: August 2019

Abstract
Determining the function of non-coding regulatory variants in cancer remains a key challenge. We investigated genetic (germline and somatic) determinants of regulatory mechanisms in renal cell carcinoma (RCC) using H3K27ac ChIP-seq data in 10 matched tumor/normal samples and RNA-seq data from 496/66 tumor/normal samples from The Cancer Genome Atlas (TCGA). Unsupervised clustering of H3K27ac activity cleanly separated tumor from normal individuals, highlighting extensive epigenetic reprogramming during transformation. We developed a novel method to test each chromatin feature for allele-specific activity (asQTL) and evaluate tumor/normal differences in allele-specificity (d-asQTLs) while modelling local structural variation and read overdispersion. At an FDR of 5%, we identified 1,356 unique asQTL chromatin peaks in normal tissues; 2,868 in tumors; and 1,054 d-asQTLs (primarily imbalanced in tumor). The d-asQTL peaks were significantly enriched for RCC GWAS heritability (32x, P=1.8x10-3), more so than any other functional feature including all H3K27ac peaks (12x), super-enhancers (5x), and regions near asQTL genes (4x). Intersection of asQTLs with RCC genome-wide association study (GWAS) data identified putative functional features for 6/17 known loci including tumor-specific activity at SCARB1, which has recently been implicated as a prognostic biomarker in RCC. d-asQTLs were significantly enriched for tumor-specific binding of transcription factors in the hypoxia pathway, implicating a general mechanism for polygenic germline-somatic interaction.
Citation Format: Alexander Gusev, Sandor Spisak, Forough Abbasi, Andre Fay, Hallie Carol, Ji-Heui Seo, Toni Choueiri, Kate Lawrenson, Matthew Freedman. Widespread germline-somatic regulatory differences in renal cell carcinoma prioritize risk mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY25-02.
Abstract SY31-01: Development and validation of a clinical-grade cell-free DNA profiling assay: MSK-ACCESS
Authors: Tsui Dana Wai Yi 
Published: August 2019

Abstract
Cell-free DNA profiling noninvasively reveals the underlying tumor genomic profiles to guide treatment decisions, especially important when the tumor is in a site that is difficult or risky to access. It has the potential to guide treatment stratification, monitor disease responses, identify resistance mechanisms and detection of minimal residual disease or relapse.Clinical implementation of molecular profiling assay requires the establishment of robust quality controls throughout the process including pre-analytical procedures, such as sample collection and processing, analytical steps such as molecular assay specification and bioinformatics algorithm, as well as data reporting.
This talk will describe an academic institutional effort to develop and validate a clinical-grade cell-free DNA profiling assay for patient care. We will discuss considerations behind the development, including factors such as analytical sensitivity required for individual clinical applications, operational and logistical efficiency, regulatory requirement and clinical annotation to guide decisions. We will also present the validation studies required by the New York State Department of Health to demonstrate robustness of the assay before clinical deployment.
The assay we have developed, called MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), is a custom next-generation sequencing assay covering selected exons from 129 cancer-related genes for ultra-sensitivity detection of somatic mutations from plasma. Using ultra-high depth (&gt;15,000x) sequencing, with duplex unique molecular indexing (UMI), unique dual sample barcodes, and background error suppression, MSK-ACCESS is able to detect low-frequency (0.1%) variants with high confidence. We validated MSK-ACCESS using plasma samples collected from healthy non-cancer individuals and cancer patients with known mutations in selected genes of interest. We evaluated the analytical performance of the assays such as accuracy, intra- and inter-assay reproducibility using control samples and samples with known mutation data established by orthogonal assays. With the growing interest on cell-free DNA profiling for molecular diagnostics, it is crucial to ensure robustness of each assay to deliver high-quality data to guide decisions. Establishing analytical performance is the first step precedes large-scale prospective trials to further demonstrate clinical utility of cell-free DNA as a biomarker.
Citation Format: Dana Wai Yi Tsui. Development and validation of a clinical-grade cell-free DNA profiling assay: MSK-ACCESS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY31-01.
Abstract SY37-03: Clock-HIF signaling in the epigenetic control of glucose metabolism
Authors: Peek Clara Bien 
Published: August 2019

Abstract
Circadian systems play a central role in energy harvesting and storage across daily cycles of fuel availability. In vertebrates, clock genes promote metabolic constancy by coordinating the phase and expression of genes involved in glycolytic and oxidative metabolism. Our previous studies, as well as those from others, revealed that circadian transcription factors (TFs) display functional interactions with the hypoxia-inducible factor (HIF) pathway. Our previous studies demonstrated impaired hypoxic expression of known canonical HIF target genes in Bmal1-/- myotubes and fibroblasts, including those involved in anaerobic glycolysis, angiogenesis, and the HIF pathway. We also observed time-of-day-dependent activation of HIF targets in muscle tissue, raising the possibility that the clock acts to ‘gate’ the induction of HIF targets at different circadian phases. Moreover, we found that hypoxia and HIF can reciprocally regulate direct BMAL1 targets, suggesting a close association between hypoxic and circadian transcriptional networks. Finally, transcriptome profiling studies reveal strikingly little overlap in the subset of BMAL1-dependent genes in normoxia versus hypoxia, suggesting either global remodeling of ‘accessible’ chromatin at sites of promoters and enhancers allowing for altered BMAL1-dependent transcription. Collectively, our data reveal coupling of the HIF and circadian TF pathways producing rhythmic adaptation to hypoxic stress.
Citation Format: Clara Bien Peek. Clock-HIF signaling in the epigenetic control of glucose metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY37-03.
Abstract SY42-03: Systematic interrogation of cancer dependencies and synthetic lethal interactions
Authors: Hahn William C. 
Published: August 2019

Abstract
Although molecular profiling of human tumors is becoming increasingly routine, the use of this data to guide remains limited to a subset of patients. To complement genome characterization studies, we have used genome scale gain and loss of function approaches to identify genes required for cell survival and transformation. Specifically, we have performed systematic studies to interrogate rare alleles found altered in cancer genomes and used advances in synthetic gene synthesis to prospectively interrogate all possible alleles of known cancer genes. In parallel, we have performed both genome scale RNAi and CRISRP-Cas9 screens in hundreds of cancer cell lines to identify differentially essential genes and the context that specifies gene dependency. Integrating these studies with genome characterization of human tumors and protein-protein interaction databases facilitates the identification of genes and pathways required for the survival of specific cancer subtypes. These studies allow us to define a global cancer dependencies map, which will help further operationalize precision cancer medicine.
Citation Format: William C. Hahn. Systematic interrogation of cancer dependencies and synthetic lethal interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY42-03.
Vitamin D in Term Newborns: Relation with Maternal Concentrations and Birth Weight
Authors: Esmeraldo Carmem U.P. , Martins Maria Eliana P. , Maia Evanira R. , Leite Jéssica Lissandra A. , Ramos José Lucas S. , Gonçalves Jr Jucier , Neta Cicera M. , Suano-Souza Fabíola Isabel , Sarni Roseli O.S. 
Published: August 2019

<b><i>Objective:</i></b> To evaluate vitamin D serum levels of term newborns and relate them to maternal concentrations and birth weight. <b><i>Methods:</i></b> Cross-sectional study carried out with 225 mothers and their term newborns. Data collected were maternal health, prenatal care, gestational, and anthropometric data of the newborns. The following laboratory tests were performed: serum levels of 25(OH)D, calcium, phosphorus, magnesium, and alkaline phosphatase. <b><i>Results:</i></b> Of the 225 newborns included in the study, 119 (52.9%) were males, the mean birth weight was 3,198 ± 421.4 g, and the gestational age was 39.1 ± 1.1 weeks. Of these, 20 (8.9%) were small and 12 (5.3%) were large for gestational age. A 25(OH)D sufficiency was found in 25.8% of mothers and 92% of newborns. The mean 25(OH)D concentrations of newborns was higher than that of the mothers 48.7 ± 15.2 ng/mL vs. 26.0 ± 6.7 ng/dL (<i>p</i> &#x3c; 0.001), correlating inversely with birth weight (<i>r</i> = –0.249; <i>p</i> &#x3c; 0.001). Small for gestational age (SGA) newborns had higher concentrations of 25(OH)D compared to adequate and large for age (<i>p</i> &#x3c; 0.001). <b><i>Conclusion:</i></b> In conclusion, this study showed strong positive correlation between maternal and neonatal 25(OH)D concentrations, with higher values in newborns. The highest 25(OH)D concentrations were found in SGA term infants. We speculated these findings could be influenced by newborn body composition.