bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4408: Mutant ABL1 is a genetic dependency in non-small cell lung cancer amenable to pharmacological intervention
Authors: Torres-Ayuso PEDRO , Testoni Ewelina , Stephenson Natalie L. , Marusiak Anna A. , Trotter Eleanor W. , Hudson Andrew , Hodgkinson Cassandra L. , Morrow Christopher J. , Dive Caroline , Brognard John 
Published: July 2016

Abstract
Non-small cell lung cancer (NSCLC) is the most frequent lung cancer subtype and it affects near 1.5 million patients worldwide annually. The lack of actionable mutations in NSCLC patients presents a significant hurdle in the administration of targeted therapies for this disease, and their identification is an urgent unmet need. Here we identify somatically mutated ABL1 as a genetic dependency that is required to maintain NSCLC cell survival. We demonstrate that NSCLC cancer cells with ABL1 mutations are sensitive to ABL inhibitors and we verify that the drug-induced effects on cell viability are specific to pharmacological inhibition of the ABL1 kinase. Consistent with structural modeling, we demonstrate that mutations in ABL1 identified in primary NSCLC tumors and a lung cancer cell line increase downstream pathway activation compared to wild-type ABL1. Finally, we show that imatinib suppresses lung tumor growth in vivo, specifically in lung cancer cells harboring a gain-of-function (GOF) mutation in ABL1. In summary, our results suggest that NSCLC patients with ABL1 mutations could be stratified for treatment with imatinib in combination with other therapies.
Citation Format: PEDRO Torres-Ayuso, Ewelina Testoni, Natalie L. Stephenson, Anna A. Marusiak, Eleanor W. Trotter, Andrew Hudson, Cassandra L. Hodgkinson, Christopher J. Morrow, Caroline Dive, John Brognard. Mutant ABL1 is a genetic dependency in non-small cell lung cancer amenable to pharmacological intervention. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4408.
Abstract 4415: CPAP contributes to HCC malignancy through regulating inflammatory pathways
Authors: Hung. Liang-Yi 
Published: July 2016

Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies, and the third most prevalent cause of cancer-related death worldwide. Its curative treatments are limited to liver resection and liver transplantation. In addition, HCC is characterized by hypervascular tumor which is described as a formation of many blood vessels during tumor growth. It has been shown that the transcription factors NF-κB and STAT3, both of which play an important role in the inflammatory pathway, are activated in HCC. Centrosomal P4.1-associated protein (CPAP) plays a vital role in centrosomal function and is identified as a transcriptional co-activator of NF-κB or STAT5. Our studies indicated that CPAP is overexpressed in HCC and involved in regulating the TNF-α-NF-κB and IL-6/STAT3 pathways. By reporter assay, Q-PCR, immunoblotting and ELISA analysis, we found that the activity of NF-κB or STAT3 is increased in HCC cells with CPAP overexpression upon TNF-α or IL-6 stimulation. Overexpressed GFP-CPAP significantly enhances NF-κB or STAT3-driven transcriptional activation and increases the expression of NF-κB or STAT3-targeted genes in response to TNF-α or IL-6 treatment. Furthermore, by immuoprecipitation and in situ PLA, CPAP could form a complex with NF-κB or STAT3. Expression of CPAP and NF-κB or STAT3 had a positive correlation in clinical HCC tissues. Interestingly, overexpression of GFP-CPAP augmented the expressions of pro-inflammatory cytokines and promoted tumor growth and metastasis in the orthotopic and splenic mouse models. The expression of CPAP was positively correlated with plasma proinflammatory cytokines expression in HCC patients. Our results suggest that CPAP participates in activating the TNF-α-NF-κB and IL-6/STAT3 pathways, which contributes to HCC malignancy.
Citation Format: Liang-Yi Hung. CPAP contributes to HCC malignancy through regulating inflammatory pathways. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4415.
Abstract 4418: Identification and characterization of patient-derived PREX2 mutation in HCC
Authors: Chen Yen-Fu A. , Lee Kuo-Jui , Lin Yi-Hsiung , Li Chung-Hsien , Yen Chia-Hung , Lin Hui-Kuan , Chen Yi-Ming 
Published: July 2016

Abstract
Phosphatidylinositol 3,4,5-trisphosphate Rac exchange factor 2 (PREX2), a highly distributed GEF, is abundant in human cancer cells. Also, PREX2 is frequently mutated in melanoma, stomach, colorectal, and lung cancers. Recently, we identified HectH9 (homologous to E6AP carboxyl terminus homologous protein 9) is the E3 ligase of PREX2 and mediates its degradation. We found that PREX2 was overexpressed in HCC and associated with the following clinical characteristics: viral infection (P = 0.004), tumor size (P = 0.03) and AFP levels (P = 0.04). Results from multivariate logistic regression analysis indicated that PREX2 expression profoundly correlated with hepatitis B virus infection (odds ratio = 14.07, P = 0.01). Moreover, high-expression level of PREX2 in the tumor tissues was associated with poor survival (P = 0.02). In addition, we performed HaloPlex sequencing to analyze the PREX2 genome among tumorous, tumor-adjacent tissues and peripheral blood mononuclear cells from 68 HCC patients. Thirteen non-silent point mutations were detected in PREX2. Compared to wild-type PREX2, the S113R mutant displayed a weaker interaction with HectH9, a reduced ubiquitination level and prolonged half-life. Moreover, the S1113R mutant further enhanced AKT activation and cell proliferation. These results reveal a novel mechanism through which GNMT restrains AKT signaling and HCC tumorigenesis.
Citation Format: Yen-Fu A. Chen, Kuo-Jui Lee, Yi-Hsiung Lin, Chung-Hsien Li, Chia-Hung Yen, Hui-Kuan Lin, Yi-Ming Chen. Identification and characterization of patient-derived PREX2 mutation in HCC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4418.
Abstract 442: RASSF1A gene promoter methylation in primary tumors, adjacent morphologically normal tissues and plasma samples of patients with high grade serous ovarian cancer
Authors: Giannopoulou Lydia , Chebouti Issam , Pavlakis Kitty , Kasimir-Bauer Sabine , Lianidou Evi S. 
Published: July 2016

Abstract
Introduction: RASSF1A promoter methylation is frequent in high grade serous ovarian cancer (HGSC), the most common histological subtype. We examined RASSF1A promoter methylation in primary tumors, adjacent normal tissues and corresponding plasma samples of patients with HGSC, using real-time methylation specific PCR (real-time MSP) and methylation-sensitive high-resolution melting analysis (MS-HRMA).
Materials and methods: A training group of 78 primary HGSC FFPEs was first analyzed using both real-time MSP and MS-HRMA. Our validation group consisted of 61 primary HGSC FFPEs, 58 adjacent tissues (analyzed using both real-time MSP and MS-HRMA), and 59 corresponding plasma samples (analyzed using real-time MSP). The specificity of both assays was evaluated by analyzing a group of 16 fallopian tube samples from healthy individuals. OVCAR29 and IGROV1 cell lines were used as positive controls.
Results: In the training group, RASSF1A promoter methylation was detected in 33/78 (42.3%) by real-time MSP and in 33/78 (42.3%) by MS-HRMA (Agreement = 94.9%, P = 0.001, k = 0.895). The validation group results are shown in Table 1. According to the semi-quantitative MS-HRMA, RASSF1A promoter methylation was detected at significantly lower percentages in the adjacent morphologically normal tissues, compared to the paired primary tumors. In corresponding plasma samples, methylation was detected in 15/59 (25.4%) (Agreement with paired tumors = 60.7%, P = 0.259, k = 0.143). Both real-time MSP and MS-HRMA revealed no RASSF1A promoter methylation in the small group of normal fallopian tubes (n = 16).
Conclusion: RASSF1A promoter is highly methylated in primary tumors and at lower percentages in the adjacent normal tissues. In all cases, MS-HRMA gave comparable results with real-time MSP. Evaluation of the clinical significance of RASSF1A promoter methylation in corresponding plasma requires further investigation. Table 1RASSF1A promoter methylationMethodPrimary tumor samples (validation group) N = 61Adjacent tissues N = 58Agreement (paired samples, N = 57)Real time MSP25/61 (41%)17/58 (29.3%)48/57(84.2%), P = 0.001, k = 0.652MS-HRMA28/61 (45.9%)21/58 (36.2%)51/57(89.5%), P = 0.001, k = 0.782Agreement (methods)58/61(95.1%), P = 0.001, Cohen's kappa = 0.90050/58(86.2%),P = 0.001, Cohen's kappa = 0.689
Citation Format: Lydia Giannopoulou, Issam Chebouti, Kitty Pavlakis, Sabine Kasimir-Bauer, Evi S. Lianidou. RASSF1A gene promoter methylation in primary tumors, adjacent morphologically normal tissues and plasma samples of patients with high grade serous ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 442.
Abstract 4426: The PEAK1/ZEB1/ITGA1 pathway mediates survival, stemness and TGFbeta-induced EMT in pancreatic cancer
Authors: Gharibi Armen , Kim Sa La , Brambilla Daniel , Adamian Yvess , Hoover Malachia , Lin Joy , Agajanian Megan , Wolfenden Laurelin , Kelber Jonathan A. 
Published: July 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States with a five-year survival rate of approximately 7%. Its highly invasive characteristics, lack of biomarkers for early detection, limited therapeutic targets and inherent resistance to chemotherapy are the central factors that lead to an overall poor prognosis for this malignancy. Since most cancer-related deaths are a result of metastatic tumors, we reasoned that our previously published proteomic signature of the cell pseudopodium (PD) may be a good pool from which to identify novel protein biomarkers or therapeutic targets in pancreatic cancer. We cross-referenced PD enriched proteins with Oncomine and identified 37 genes that are upregulated in pancreatic cancer. The function of integrin alpha 1 (ITGA1), a cell surface receptor for collagen and regulator of cell adhesion, has not been previously characterized in the context of PDAC. Our results indicate that ITGA1 is required for PDAC cell viability, promoting cell survival and tumor growth. We further analyzed ITGA1 cell-surface levels and discovered that ITGA1hi cells represent a subpopulation of Aldehyde Dehyrogenase high (ALDH1hi) cells, and that ITGA1 knockdown reduces the ALDH1hi cell population. One mechanism by which PDAC cells acquire metastatic potential is via epithelial-mesenchymal transition (EMT). Thus, we searched for prominent EMT genes among the top ITGA1 co-expressors using RNA-Seq data from the Cancer Bio Portal. Interestingly, ZEB1 (a transforming growth factor beta, TGFbeta, response gene and central regulator of EMT) and PEAK1 kinase (a protein we’ve shown to be required for pancreatic cancer progression and TGFbeta/ZEB1-induced EMT) co-expresses with ITGA1. We tested the function of ITGA1 on TGFbeta-induced EMT and found that ITGA1 is upregulated by TGFbeta during EMT, and required for metastasis and a complete EMT response to TGFbeta. We also demonstrate that PEAK1 is required for TGFbeta-induced ITGA1 in PDAC cells. Finally, we demonstrate that ITGA1 is responsible for collagen-induced spreading and an EMT-like shift in PDAC cell morphology. Taken together, these results point to a novel TGFbeta/PEAK1/ZEB1/ITGA1 signaling cascade that when targeted can abrogate PDAC cell survival, stemness, EMT and tumor growth/metastasis.
Citation Format: Armen Gharibi, Sa La Kim, Daniel Brambilla, Yvess Adamian, Malachia Hoover, Joy Lin, Megan Agajanian, Laurelin Wolfenden, Jonathan A. Kelber. The PEAK1/ZEB1/ITGA1 pathway mediates survival, stemness and TGFbeta-induced EMT in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4426.
Abstract 4428: Nestin suppression attenuates invasive potential of endometrial cancer cells by down regulating TGF-β signaling pathway
Authors: Bokhari Amber A. , Dorjbal Batsukh , Baker Tabari M. , Waheed Sana , Zahn Christopher M. , Hamilton Chad A. , Maxwell George L. , Syed Viqar 
Published: July 2016

Abstract
Nestin, an intermediate filament protein and a stem cell marker is expressed in several cancers. Little is known about the expression level and role of Nestin in endometrial cancer. Compared to immortalized endometrial epithelial cell line EM-E6/E7/TERT, endometrial cancer lines express high to moderate levels of Nestin. Endometrial tumors and tumor cell lines have a cancer stem-like cells population expressing CD133. The AN3CA and KLE cells showed more CD133+ cells and expressed Nestin at higher levels than Ishikawa cells. Knockdown of Nestin in AN3CA and KLE, and overexpression in Ishikawa cells was associated respectively with attenuation and enhancement of CD133+ cells. Knockdown of Nestin increased cells in G0/G1 phase and decreased in S phase, whereas overexpression decreased cells in G0/G1 phase and increased in S phase of cell cycle. Nestin knockdown cells showed increased expression of p21, p27 and PNCA and decreased expression of cyclin-D1 and D3. Nestin overexpression revealed an inverse expression pattern of cell cycle regulatory proteins. Nestin knockdown inhibited cancer cell growth and invasive potential by down regulating TGF-β signaling components, MMP-2, MMP-9, vimentin, SNAIL, SLUG, Twist, N-cadherin, and upregulating E-cadherin. Conversely, Nestin overexpression enhanced cell invasiveness by upregulating TGF-β signaling components, MMP-2, MMP-9, mesenchymal markers and downregulaing epithelial marker, E-cadherin. Nestin knockdown inhibited and overexpression promoted invadopodia formation and pFAK expression. Knockdown of Nestin significantly reduced tumor volume in vivo. Finally, progesterone and a nitric oxide donor inhibited Nestin expression in endometrial cancer cells. These results suggest that Nestin can be a therapeutic target for cancer treatment.
Citation Format: Amber A. Bokhari, Batsukh Dorjbal, Tabari M. Baker, Sana Waheed, Christopher M. Zahn, Chad A. Hamilton, George L. Maxwell, Viqar Syed. Nestin suppression attenuates invasive potential of endometrial cancer cells by down regulating TGF-β signaling pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4428.
Abstract 4442: Very low methylation is a novel epigenetic regulatory mechanism in normal tissues and predisposes to hypermethylation in cancer
Authors: madireddi priyanka , Jelinek Jaroslav , Lee Justin , Sato Takahiro , Issa Jean-Pierre 
Published: July 2016

Abstract
High level DNA methylation of promoter CpG Island (CGI) represses gene expression. However, low-level CGI methylation is usually not distinguished from complete absence of methylation. Here we show that Very Low Methylated Regions (VLMRs 1-20%) on promoter CGIs are present in up to 20% of human and mouse genes and negatively correlate with gene expression in all tissues examined. In vitro, low-level methylation directly represses reporter gene expression; an effect mediated by methyl-CpG-binding proteins as transient knockdown of MBD4 reverses this repression. In vivo VLMR genes are enriched for polycomb occupancy but can also occur in H3K4me3 occupied promoters, where it correlates with gene repression independent of polycomb complex binding. VLMRs in promoter CGIs in healthy WBCs are 19 fold and 65 fold more likely to gain hypermethylation in Acute Myelogenous Leukemia and Myelodysplastic Syndrome patients respectively compared to unmethylated CGIs (&lt;1%). Our study reveals a novel epigenetic control mechanism that has strong effects on gene expression in normal tissues and accounts for most of the gene specificity of hypermethylation in cancer.
Citation Format: priyanka madireddi, Jaroslav Jelinek, Justin Lee, Takahiro Sato, Jean-Pierre Issa. Very low methylation is a novel epigenetic regulatory mechanism in normal tissues and predisposes to hypermethylation in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4442.
Abstract 4450: Silencing NKD2 by promoter region hypermethylation promotes esophageal cancer progression by activating Wnt signaling
Authors: Guo Mingzhou , Cao Baoping , Yang Weili , Jin Yongshuai , Zhang Meiying , He Tao , Zhan Qimin , Herman James G. , Zhong Guanglin 
Published: July 2016

Abstract
Background: Despite the use of surgery or chemoradiotherapy to treat, esophageal cancer, its prognosis still remains poor, with a 5-year survival below 15%. Recent insights into the epigenetic mechanisms associated with multi-step carcinogenesis provide new opportunities to develop novel effective targeted therapies for esophageal squamous cell carcinoma. Naked cuticle homolog 2 (NKD2) was found frequently methylated in human breast cancer. The epigenetic changes and mechanisms of NKD2 in human esophageal cancer remain unclear. Methods: Nine esophageal cancer cell lines and 154 cases of primary esophageal cancer samples were analyzed using methylation specific PCR, immunohistochemistry, western blot, flow cytometry techniques and a xenograft mouse model. Results: Loss of NKD2 expression and complete methylation were found in KYSE150 and TE1 cells. Reduced expression and partial methylation were observed in KYSE30, KYSE70, KYSE410, KYSE140 and COLO680 cells. High level expression and unmethylation were detected in KYSE450 and TE8 cells. Re-expression of NKD2 was induced by 5-aza-2’-deoxycytidine in NKD2 unexpressed or reduced cells. NKD2 was methylated in 53.2% (82/154) of human primary esophageal cancer samples, and promoter region hypermethylation was associated with reduced expression of NKD2 significantly (p&lt;0.01). NKD2 methylation was associated with TNM stage and lymph node metastasis (p&lt;0.01). The results suggest that NKD2 is regulated by promoter region methylation and methylation of NKD2 may serve as a prognostic marker in esophageal cancer. Our further studies demonstrate that NKD2 suppresses cell proliferation, colony formation, cell invasion and migration, as well as induces G1/S check point arrest in esophageal cancer cells. NKD2 suppressed xenograft tumor growth and inhibited Wnt signaling in human esophageal cancer cells. Conclusions: NKD2 is frequently methylated in human esophageal cancer, and the expression of NKD2 is regulated by promoter region methylation. NKD2 suppresses esophageal cancer progression by inhibiting Wnt signaling both in vitro and in vivo.
Citation Format: Mingzhou Guo, Baoping Cao, Weili Yang, Yongshuai Jin, Meiying Zhang, Tao He, Qimin Zhan, James G. Herman, Guanglin Zhong. Silencing NKD2 by promoter region hypermethylation promotes esophageal cancer progression by activating Wnt signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4450.
Abstract 4455: DNA methylation as biomarkers to predict early recurrence of T1-2N0 lung cancer
Authors: Chen Chen , Yang Andrew , Danielle Devlin , Rodgers Kristen , Huang Peng , Lu Zhihao , Griffin Candace , Lee Beverly , Battafarano Richard , Yu Fenglei , Wang Tza-Huei , Baylin Stephen , Herman James , Hulbert Alicia , Brock Malcolm 
Published: July 2016

Abstract
Purpose: Many patients die of recurrent NSCLC. Current clinical and molecular tests fail to predict patients at high risk for recurrence. We investigated the relationship between gene promoter methylation and recurrence of NSCLC and its prediction accuracy.
Materials and Methods: We prospectively enrolled patients who underwent surgery for T1-2N0 NSCLC. We collected primary tumors, regional lymph nodes (RLN) and mediastinal lymph nodes (MLN). A total of 112 patients were included; cases (n = 39) and controls (n = 73) were defined based on cancer recurrence within 40 months of surgery. Promoter methylation of eight cancer-related genes (CDO1, TAC1, SOX17, p16, CDH13, RASSF1A, APC and MGMT) was obtained by using nanoparticle-based DNA extraction followed by qMSP. Logistic regression analysis adjusted by age, gender, race, tumor size and pack year was used to study the relationship between the gene promoter methylation and the risk of recurrence of NSCLC; machine learning assessed its prediction accuracy.
Results: Cases had significantly higher p16 methylation levels than controls in all three tissue types by univariate and multivariate analysis after adjusting for confounders (age, gender, race, tumor size, smoking history, and other gene methylation levels). SOX17 was significantly methylated among cases in both RLN and MLN samples, and remained significant in MLN after adjusting for confounders. Table 1 shows the prediction accuracy of p16 and SOX17 using tumor tissue alone and combined with RLN and/or MLN. Prediction accuracies were increased after adding biomarkers from lymph nodes.
Conclusion: Increased methylation status in the promoter region of p16 and SOX17 is associated with an increased risk of cancer recurrence among patients with T1-2N0 NSCLC treated with curative resection. Adding molecular analyses of lymph nodes to primary tumor samples significantly increased the diagnostic accuracy of predicting recurrence in these patients. Table 1.Prediction accuracy using tumor and combined with RLN and/or MLN.Tissue SamplesSensitivitySpecificityPPVNPVTumor0.410.840.520.76Tumor+RLN0.680.960.900.84Tumor+MLN0.560.880.710.79Tumor+RLN+MLN0.690.900.790.85
Citation Format: Chen Chen, Andrew Yang, Devlin Danielle, Kristen Rodgers, Peng Huang, Zhihao Lu, Candace Griffin, Beverly Lee, Richard Battafarano, Fenglei Yu, Tza-Huei Wang, Stephen Baylin, James Herman, Alicia Hulbert, Malcolm Brock. DNA methylation as biomarkers to predict early recurrence of T1-2N0 lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4455.