bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 430: Prostate specific antigen (PSA) as a diagnostic and prognostic marker of prostate cancer
Authors: Simon Ronald , Kluth Martina , Fischer Kristine , Bonk Sarah , Hube-Magg Claudia , Höflmayer Doris , Lennartz Maximilian , Lutz Florian , Sauter Guido , Büscheck Franziska , Uhlig Ria , Dum David , Luebke Andreas M. , Wittmer Corinna , Jacobsen Frank , Burandt Eike , Steurer Stefan , Wilczak Waldemar , Minner Sarah 
Published: August 2019

Abstract
Since several decades, prostate specific antigen (PSA) is regarded as a specific marker for healthy and neoplastic prostate tissues, and PSA level changes in blood and tissue are discussed as prognostic markers of prostate cancer. Using a custom-made mouse monoclonal anti-PSA antibody, we studied expression of PSA in a tissue microarray (TMAs) comprising 17,456 prostate cancers with long-term follow-up data. PSA staining was typically present in the cytoplasm and pronounced at the apical cell pole. PSA expression was often reduced (15%) or even completely lost (1%). Reduction of PSA expression was significantly linked to adverse features of prostate cancer, including advanced stage, high classical and quantitative Gleason grade, presence of lymph node metastasis, a positive surgical margin, increased cell proliferation, and reduced time to recurrence (p&lt;0.0001 each). Complete lack identified a small subset of patients with the worst prognosis. There was also in impact of the subcellular localization of PSA expression: Loss of the apical staining pattern worsened the prognosis in cancers with otherwise identical levels of cytoplasmic staining. In a multivariable analysis including pT stage, Gleason grade, nodal stage, and resection margin status, loss of PSA expression proved to predict outcome independently from these parameters. Of note, PSA even stratified the prognosis of 971 cancers harboring PTEN deletions in our cancer set. In conclusion, gradual reduction of PSA staining, including a loss of the apical staining pattern, is a strong and independent prognostic marker in prostate cancer.
Citation Format: Ronald Simon, Martina Kluth, Kristine Fischer, Sarah Bonk, Claudia Hube-Magg, Doris Höflmayer, Maximilian Lennartz, Florian Lutz, Guido Sauter, Franziska Büscheck, Ria Uhlig, David Dum, Andreas M. Luebke, Corinna Wittmer, Frank Jacobsen, Eike Burandt, Stefan Steurer, Waldemar Wilczak, Sarah Minner. Prostate specific antigen (PSA) as a diagnostic and prognostic marker of prostate 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 430.
Abstract 4313: Identifying and characterizing epigenetic «driver» genes («epidrivers») in regulatory pathways involved in tumorigenesis and tumour cell plasticity
Authors: Halaburkova Andrea , Cahais Vincent , Cuenin Cyrille , Khoueiry Rita , Ouzounova Maria , Ghantous Akram , Herceg Zdenko 
Published: August 2019

Abstract
One of the ground-breaking discoveries of the international cancer genome sequencing endeavours is the high frequency of mutational and non-mutational changes in epigenetic regulator genes (ERGs), which constitute a “genetic smoking gun” that epigenetic mechanisms lie in the very heart of cancer biology. However, functional importance of disruption of ERGs in tumorigenesis and cancer phenotype is poorly understood. We hypothesise that these genes are candidates to be drivers («epidrivers») of cancer onset and progression, thus regulating mechanisms underpinning cancer development. Moreover, deregulation of epidrivers may play a role in epithelial-to-mesenchymal transition (EMT) and emergence of cancer resilience. The overarching aim of this study was to identify and functionally characterize “Epidrivers” in tumorigenesis and cancer cell plasticity. To this end, we have set up novel epigenome-wide functional screens in human cultured cells (and organoids) combined with state-of-the-art genome-editing approach (based on CRISPR/Cas9 screen) and multiparametric phenotyping. We designed a custom-made lentiviral CRISPR library that consists of 1,649 gRNAs targeting all known ERGs (426 genes). Lentiviral CRISPR library was used to deliver the ERG gRNAs to target cells expressing the RNA-guided DNA endonuclease Cas9. Independent clones (derived from transduced breast and lung cancer cell lines constitutively expressing Cas9) are screened for acquisition of distinct features of transformed cells. The results of the identification of Epidriver genes based on the analysis of deregulation of core cellular processes, epigenome (ChIP-seq) as well as EMT and multiparametric phenotyping, will be presented.
Citation Format: Andrea Halaburkova, Vincent Cahais, Cyrille Cuenin, Rita Khoueiry, Maria Ouzounova, Akram Ghantous, Zdenko Herceg. Identifying and characterizing epigenetic «driver» genes («epidrivers») in regulatory pathways involved in tumorigenesis and tumour cell plasticity [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 4313.
Abstract 4315: UNC0642 inhibits G9a and induces apoptosis of human bladder cancer cells
Authors: Huang Ruimin , Sun Jingya , Li Meiqian , Dong Yu , Zhang Yuanheng , Yan Jun 
Published: August 2019

Abstract
Urinary bladder cancer (UBC) is one of the most common malignancies in the world, with the characteristics of frequent recurrence and metastasis despite the standard chemotherapy with gemcitabine and cisplatin combination. Hence, it is needed to develop new drugs to tackle down UBC. Histone modifiers, which are frequently dysregulated in cancer development, are excellent drug targets for cancer treatment. Here, we found that G9a, one of the histone H3 methyltransferases, was overexpressed significantly in human UBC patients, using the expression data from public databases. In the TCGA Provisional dataset, the average expression level of G9a in primary UBC samples (n=408) was 1.6-fold as much as that in normal bladder samples (n=19; P &lt; 0.001). Knockdown G9a by small interfering RNA decreased cell viability and induced apoptosis in human UBC cell lines. Thus, UNC0642, a small molecule inhibitor targeting G9a with high selectivity, low cytotoxicity, and excellent in vivo pharmacokinetic properties, was chosen to test the inhibitory effect on UBC cells. UNC0642 decreased the level of histone H3K9me2, the downstream target of G9a, and increase apoptosis of UBC cells in vitro in a dose-dependent manner. UNC0642 exhibited similar inhibitory effects on the J82 xenografts, without the loss of body weight of mice. Targeting G9a in vivo reduced Ki67 expression and increase the level of cleaved Caspase 3 and BIM protein by immunohistochemistry and Western blot analysis, respectively. Taken together, our data indicate that G9a may be a promising therapeutic target for UBC, and an epigenetics-based therapy by UNC0642 is suggested.
Citation Format: Ruimin Huang, Jingya Sun, Meiqian Li, Yu Dong, Yuanheng Zhang, Jun Yan. UNC0642 inhibits G9a and induces apoptosis of human bladder cancer cells [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 4315.
Abstract 4326: Epigenetic control of chromosome instability by STAT3 in gastric cancer
Authors: Chuang Yu Ming , Hung Sheng-Jou , Chou Jiang Liang , Huang Wan-Hong , Yan Pearlly S. , Liu Tsunglin , Chan Michael W.Y. 
Published: August 2019

Abstract
Gastric cancer is one of the most common causes of cancer death worldwide. Aberrant activation of JAK/STAT3 signaling is frequently observed in gastric cancer and associated with cancer progression. Our previous studies demonstrated that several STAT3 targets and tumor suppressors such as NR4A3 and GATA6 are found to be epigenetically silenced by DNA methylation in gastric cancer. However, the role of aberrant JAK/STAT3 signaling in the epigenetic changes of downstream targets is not fully understood. In this study, by using Methylation EPIC array, we compared the global methylation changes in gastric cancer patient samples with different STAT3 activation level. In silico analysis was also performed to identify STAT3 binding sites in those differentially methylated loci. Hypermethylated loci which are functionally relate carcinogenesis and mediated by STAT3 expression were examined. Interestingly, SMARCAL1, which was involved in chromosome stability and alternative lengthening of telomeres was identified. Unexpectedly, differentially methylated region (DMR) was not occurred in the promoter, but enhancer region located in the CpG island shore. Additionally, we also found a transcription factor binding site, YY1, which was a methylation-sensitive enhancer-promoter regulator, in this DMR region. By using a statistic shuffling model, we found that STAT3 related methylation changes were significantly associated with H3K4me1 and H3K27me3 at that region. TCGA dataset also indicated that this DMR with dramatic changes was occurred in chromosome instability (CIN) subtype of gastric cancer, whereas the expression of SMARCAL1 was decreased in precancerous lesion in previous published data. Taken together, STAT3-related methylation changes may regulate the activity of enhancer and affect the expression of SMARCAL1, during gastric cancer progression.
Citation Format: Yu Ming Chuang, Sheng-Jou Hung, Jiang Liang Chou, Wan-Hong Huang, Pearlly S. Yan, Tsunglin Liu, Michael W.Y. Chan. Epigenetic control of chromosome instability by STAT3 in gastric 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 4326.
Abstract 4356: Menin and ATF4 cooperate to drive serine biosynthesis in Ewing sarcoma
Authors: Jimenez Jennifer , Svoboda Laurie K. , Sud Sudha , Kerk Samuel , Grembecka Jolanta , Lyssiotis Costas A. , Lawlor Elizabeth R. 
Published: August 2019

Abstract
Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor. We previously reported that the scaffolding protein menin is overexpressed by ES, and that menin inhibition results in impaired ES cell proliferation, survival, and tumorgenicity. Additionally, our recent studies revealed a previously undescribed role for menin in the activation of the serine biosynthetic pathway (SSP), a critical metabolic pathway that is aberrantly activated in many human cancers. The biologic functions of menin are largely determined by its protein-binding partners, the best characterized of which is the histone methyltransferase MLL. In the current study, we are investigating the mechanistic link between menin and the SSP to determine whether menin activates the SSP via epigenetic trithorax complexes.
Our data show that the core SSP enzymes, PHGDH, PSAT1, and PSPH are highly expressed by ES. Moreover, expression of all three genes is highly correlated in primary tumors, suggesting that they may be coordinately regulated by an upstream factor. In other cancer types, activation of the SSP has been shown to result from amplification of the PHGDH locus or activation of the master transcriptional regulator, ATF4. We have found that PHGDH is not amplified in ES but ATF4 is overexpressed, and ATF4 loss of function leads to growth inhibition. Q-RT-PCR and western blot of ES cells following ATF4 knockdown reveals down-regulation of PHGDH, PSAT1, and PSPH. In addition, ChIP-qPCR shows enrichment of ATF4 binding at SSP gene promoters, which is diminished by treatment with MI-503, a menin:MLL interaction inhibitor. Menin inhibition with MI-503 also leads to loss of ATF4 expression, coincident with loss of SSP expression. Additionally, ChIP-qPCR shows enrichment of menin binding at the ATF4 gene promoter, which is associated with H3K4me3 enrichment. Preliminary studies show that ATF4 over-expression via lentiviral transduction may rescue the loss of SSP gene expression induced by MI-503. Together these findings support the hypothesis that ATF4 acts downstream of menin to drive SSP activation in ES. Ongoing studies are assessing whether this is mediated by trithorax-dependent or –independent functions of menin.
Citation Format: Jennifer Jimenez, Laurie K. Svoboda, Sudha Sud, Samuel Kerk, Jolanta Grembecka, Costas A. Lyssiotis, Elizabeth R. Lawlor. Menin and ATF4 cooperate to drive serine biosynthesis in Ewing sarcoma [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 4356.
Abstract 4366: Characterization of diacetylspermine as a metabolic urinary biomarker in breast cancer using patient-derived xenografts
Authors: Velenosi Thomas J. , Krausz Kristopher W. , Gonzalez Frank J. 
Published: August 2019

Abstract
Breast cancer is a heterogeneous disease and is currently diagnosed using clinical biomarkers to classify tumors and guide therapy. However, drug resistance is a major cause of treatment failure and current methods can only detect resistance after several months following drug therapy. Thus, there is a need for novel biomarkers to track breast cancer prognosis, diagnosis, and to monitor therapeutic efficacy. Polyamines are polycations that support the production of nucleic acids and are necessary for transcription, DNA replication and cell cycle progression. The rate-liming step in polyamine catabolism is the acetylation of spermine and spermidine by spermine/spermidine acetyl-transferase (SAT1). Indeed, diacetylspermine has been identified as a clinical urinary biomarker of early and late stage breast cancer. Despite multiple clinical studies citing the potential for diacetylspermine as a cancer biomarker, the oncogenic events contributing to increased diacetylspermine production are largely unknown. To identify metabolic biomarkers of breast cancer progression and therapeutic efficacy, an untargeted metabolomics study was performed using urine samples from mice implanted with breast cancer patient derived xenografts (PDXs). NSG mice were engrafted with a doxorubicin sensitive (Dox-Sens) or a doxorubicin resistant (Dox-Res) PDX. When tumors reached 100-200 mm3, mice were administered intravenous doxorubicin (2 mg/kg) or vehicle control once weekly for three weeks. Mice were placed in metabolic cages for 24 hours after each treatment to collect urine. At 28 days, a final 24-hour urine collection was performed in the absence of drug treatment followed by euthanization (n = 9). Untargeted metabolomics revealed diacetylspermine as the most significantly altered metabolite in urine samples by two-way repeated measures ANOVA (p = 1.26x10-11, q = 4.82 x 10-8). Urinary diacetylspermine was correlated with growth of the Dox-Sens tumors and undetectable in urine from mice with Dox-Res tumors. Remarkably, when Dox-Sens mice were treated with doxorubicin, there was a further increase in diacetylspermine despite the decrease in tumor size. These results demonstrate the potential utility of urinary diacetylspermine as a biomarker for monitoring tumor growth and doxorubicin treatment efficacy. Furthermore, these breast cancer PDX models have provided an opportunity to characterize the mechanism of oncogenic diacetylspermine production and response to drug treatment.
Citation Format: Thomas J. Velenosi, Kristopher W. Krausz, Frank J. Gonzalez. Characterization of diacetylspermine as a metabolic urinary biomarker in breast cancer using patient-derived xenografts [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 4366.
Abstract 4374: The role of glycine decarboxylase in neuroblastoma
Authors: Alptekin Ahmet , Ding Jane , Ye Bingwei , Ding Han-Fei 
Published: August 2019

Abstract
Neuroblastoma is the most common cancer in infants. While the low and intermediate risk groups of neuroblastoma patients have ≥90% five-year-survival rates, the high-risk group has only 40-50% five-year-survival rates despite multimodal therapies. Genomic amplification of the oncogene MYCN (a member of the MYC family of transcription factors) is a major cause of high-risk neuroblastoma and is strongly correlated with poor prognosis. A key function of MYCN is to promote cell growth and proliferation, which requires increased cellular metabolism to meet the biosynthetic demand for growth. Serine-Glycine-One-Carbon (SGOC) metabolism is particularly important in sustaining cell proliferation by producing amino acids for protein synthesis and one-carbon units for nucleotide production. We investigated the role of glycine decarboxylase (GLDC) in neuroblastoma. GLDC catalyzes the first reaction in glycine cleavage, which generates one-carbon unit and reduced NADH. Analysis of gene expression data from two cohorts of neuroblastoma patients showed that GLDC expression is correlated with advanced stages, high-risk disease and poor prognosis in neuroblastoma. We found that GLDC is required for neuroblastoma cell proliferation as silencing GLDC expression by shRNA induced G1 cell cycle arrest. Consistent with this observation, microarray gene expression profiling revealed that GLDC knockdown resulted in a significant decrease in the expression of E2F target genes. In addition, we obtained evidence that GLDC is a direct target gene of MYCN. Knockdown of MYCN expression reduced GLDC mRNA and protein expression, and overexpression of MYCN increased GLDC mRNA and protein levels. Moreover, chromatin immunoprecipitation with quantitative PCR demonstrated that MYCN binds to the GLDC promoter region. These findings suggest an important role of GLDC in driving neuroblastoma cell proliferation, which could be exploited as a therapeutic strategy against high-risk neuroblastoma with MYCN amplification.
Citation Format: Ahmet Alptekin, Jane Ding, Bingwei Ye, Han-Fei Ding. The role of glycine decarboxylase in neuroblastoma [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 4374.
Abstract 4382: Epigenetic deregulation in glycolysis genes for colorectal cancer
Authors: Chen KuoHsing , Lai Liang-Chuan , Lin Liang-In , Chang Hsien-Fang , Chao Yu-Liang , Lin Been-Ren , Liang Jin-Tung , Cheng Ann-Lii , Chuang Eric Y. , Yeh Kun-Huei 
Published: August 2019

Abstract
Background
Energy restriction may have influence on methylation of glycolysis genes and also be associated with decreased incidence of colorectal cancer (CRC) in Dutch Hunger Winter cohort. This study aimed to explore the roles of epigenetic deregulation in energy/glycolysis pathway for CRC.
Materials and methods
To perform a comprehensive analysis of methylation alterations in glycolysis pathway (67 genes in KEGG), we profiled 27 CRCs and 5 adjacent normal colon tissues (NTs) by using a powerful methylation array (Illumina Methylation EPIC Beadchips). We used Wilcoxon rank-sum test (p &lt; 0.05) and β value difference (≧ 0.2 or ≦ -0.2) to define the differential methylated genes (DMGs). We also searched the open datasets to find the shared DMGs in CRC. The shared DMGs were validated by pyrosequencing in our samples.
Results
We found 17 hypomethylation genes and 2 hypermethylation genes involved in
glycolysis pathway in our cohort. After comparing to the methylation profiles of CRC in 3 datasets (GSE42752, GSE25062 and TCGA), only hypermethylation of ALDH1A3 and hypomethylation of HKDC1 remained as shared DMGs. These findings were validated well by pyrosequencing in our cohort. The mRNA expression of HKDC1 and ALDH1A3 was negatively associated with the methylation status of each of them in TCGA dataset. RT-qPCR also showed the corresponding expression of HKDC1 and ALDH1A3 between CRCs and NTs.
Conclusion
Our study reveals that hypomethylation of HKDC1 and hypermethylation of ALDH1A3 exist in CRCs worldwide. Further exploratory study of biologic roles of them in CRC is ongoing.
Citation Format: KuoHsing Chen, Liang-Chuan Lai, Liang-In Lin, Hsien-Fang Chang, Yu-Liang Chao, Been-Ren Lin, Jin-Tung Liang, Ann-Lii Cheng, Eric Y. Chuang, Kun-Huei Yeh. Epigenetic deregulation in glycolysis genes for 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 4382.
Abstract 4419: Cell cycle analysis during TTF to exploit novel targets for increasing treatment efficacy
Authors: Slangen Paul , Gooijer Mark de , Tellingen Olaf van , Giladi Moshe , Borst Gerben 
Published: August 2019

Abstract
Cell cycle distribution and cell deathCell cycle distribution (index,%, t=12hrs)TreatmentControlTTFS10,5 ± 0.410.8 ± 0.5NSG229.9 ± 1.248.4 ± 0.9p&lt;0.05M6.3 ± 0.62.0 ± 0.2p&lt;0.05G153.0 ± 1.238.0 ± 0.8p&lt;0.05Cell death (%)TreatmentcontrolWee1TTFTTF+Wee1Cell count100+/-3.274.4 +/- 4.150.5 +/- 4.221.5 +/- 3.2SynergisticColony formation100 +/- 3.261.6 +/- 6.675.5 +/- 11.217.0 +/- 5.3Synergistic
While the effectiveness of TTFields is initially attributed to the effects of TTFields during cell division, recent studies have shown that TTFields additionally induce DNA damage and replication stress. We want to further exploit the working mechanism of TTFields, its effect on the cell cycle and identify targets to increase its efficacy.
A172 cells were synchronized in S-phase by double thymidine block. Six hours post-release (0h), cells were subjected to TTFields treatment (200kHz; 4,5V/cm pk-pk). Cell cycle analysis was performed by flow cytometry (PI, α-phospho-histone H3Ser10). Treatment of A172 cells synchronized in S phase with TTFields showed that TTFields cause an accumulation of cells in G2 phase, leading to delayed entry into mitosis and, subsequent lower entry into G1 (see table). Because this indication of G2 checkpoint activation we hypothesized the possible synergism between TTFields and Wee1 inhibition. A172 cells were simultaneously treated with TTFields (200kHz; 4,5V/cm pk-pk, 72hrs) and the Wee1 inhibitor (300nM, 72hrs). Cell survival was determined by automated cell counting (including Trypan Blue) and colony formation assay. We observed that abrogation of the G2 checkpoint by Wee1 inhibtion synergistically increases the efficacy of TTFields treatment (see table).
The underlying mechanism of the G2 checkpoint activation is subject of ongoing research. By any means, the combination of TTFields with the Wee1 inhibitor bypasses the G2 activation and causes a synergistic decrease in cell survival.
Citation Format: Paul Slangen, Mark de Gooijer, Olaf van Tellingen, Moshe Giladi, Gerben Borst. Cell cycle analysis during TTF to exploit novel targets for increasing treatment efficacy [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 4419.