bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4030: Loss of E-cadherin expression is a critical step for peritoneal metastasis of gastric cancer with sub-serosal invasion
Authors: Togano Shingo , Yashiro Masakazu , Kuroda Kenji , Okuno Tomohisa , Miki Yuichiro , Hirakawa Kosei , Ohira Masaichi 
Published: August 2018

Abstract
Background: Peritoneal metastasis is the most frequent type of metastasis in gastric cancer. However, the actual mechanisms responsible for this metastasis are not understood clearly. The process of peritoneal metastasis requires some steps including the detachment of cancer cells from the primary tumor. E-cadherin, a calcium-dependent cell-cell adhesion molecule, is known to mediate intercellular adhesion. We examined the correlation between peritoneal metastasis of gastric cancer and reduced E-cadherin expression.
Methods: A total of 694 gastric cancer cases of which were resected at our department was enrolled in this study. The expression of E-cadherin of gastric cancer cells was evaluated by immunohistochemical staining. We analyzed the correlation between the E-cadherin expression and clinicopathological features. A case with less than 50% of E-cadherin expression was defined as E-cadherin negative.
Results: Among the 694 cases, 232 cases were E-cadherin negative. 171 cases developed peritoneal metastasis. Among the 171cases, 88cases were E-cadherin negative. E-cadherin-negative cancer was significantly (p&lt;0.0001) associated with peritoneal metastasis. The 5-year survival rate of patients with E-cadherin-negative cancer (48.1%) was poor, in compared to that with E-cadherin-positive tumor (62.8%), while a multivariate analysis did not show significant difference. A multivariate analysis of sub-serosal invasion tumors (T3 stage tumor) indicated that only E-cadherin-negative was significantly associated with peritoneal metastasis (p=0.0005).
Conclusion: The loss of E-cadherin is a critical step in the promotion of cancer cells to a more malignant phenotype. E-cadherin is a useful prognostic factor for peritoneal metastasis in gastric carcinoma with sub-serosal tumor.
Citation Format: Shingo Togano, Masakazu Yashiro, Kenji Kuroda, Tomohisa Okuno, Yuichiro Miki, Kosei Hirakawa, Masaichi Ohira. Loss of E-cadherin expression is a critical step for peritoneal metastasis of gastric cancer with sub-serosal invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4030.
Abstract 4086: Efficient primary culture model of patient-derived epithelial cells from colorectal cancer using a ROCK inhibitor and feeder cells
Authors: Hong Hyekyung , Yun Nakhyeon , Kim Taewon , Lee Yeosong , Song Sujeong , Bae Jaemoon , Lee Wooyong , Cho Yongbeom 
Published: August 2018

Abstract
In vitro culture for patient-derived cells offers many advances in the development of novel therapies for colorectal cancer. Although various culture systems have been developed, experimental systems in which the long-term expansion of patient-derived epithelial cells still remained difficult. Here, we demonstrated that epithelial cells isolated from colorectal cancer patient-derived xenograft can be efficiently immortalized in conditioned medium from irradiated feeder cells containing a Rho kinase inhibitor Y-27632. Patient-derived tumor cells were rapidly proliferated to reach confluence in approximately 6 days. Short tandem repeat (STR) analysis of tumor tissue and cultured cells demonstrate that they have 13 identical STR loci and Amelogenin, Penta E, Penta D, D2S1338 and D19S433. The epithelial character was confirmed by staining for EpCAM, cytokeratin 20 and vimentin as a mesenchymal marker. Cells were continued to proliferate and formed well-defined tumor spheroids when transferred to 3D culture. To study the mechanism for promoting unrestricted cell proliferation, we investigated the expression of several cellular genes that fall into two designated pathways, induction of telomerase and cytoskeletal remodeling/p16 pathway. Moreover, patient-derived tumor cells were utilized for high-throughput screening of FDA approved drugs allowing detection of gene-drug associations. Collectively, we demonstrate that the long-term expansion of patient-derived tumor epithelial cells and these cells could be a useful tool in order to investigate a personalized treatment approach.
Citation Format: Hyekyung Hong, Nakhyeon Yun, Taewon Kim, Yeosong Lee, Sujeong Song, Jaemoon Bae, Wooyong Lee, Yongbeom Cho. Efficient primary culture model of patient-derived epithelial cells from colorectal cancer using a ROCK inhibitor and feeder cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4086.
Abstract 4191: Effect of a novel orally bioavailable CXCR4 inhibitor, AMD070, on the metastasis of oral cancer cells
Authors: Kuribayashi Nobuyuki , Uchida Daisuke , Kinouchi Makoto , Kuribayashi Kyoko , Hasegawa Tomonori , Yagisawa Shuma , Kawamata Hitoshi 
Published: August 2018

Abstract
We have previously demonstrated that the stromal cell-derived factor (SDF)-1/CXCR4 system is involved in the metastasis of head and neck cancer. Additionally, it has been shown that the blockade of CXCR4 by subcutaneous daily injection with AMD3100, a CXCR4 antagonist, may be effective in preventing metastasis in CXCR4-related head and neck cancer. Recent investigations have suggested that AMD070, a novel orally bioavailable inhibitor of CXCR4, may be minimally invasive compared with AMD3100. In the present study, we examined the effect of AMD070 on metastasis induced by the SDF-1/CXCR4 axis in B88-SDF-1 oral cancer cells, which express high levels of SDF-1 and CXCR4. Although treatment with AMD070 did not affect the anchorage-dependent growth of B88-SDF-1 cells, it significantly suppressed the anchorage-independent growth. Moreover, the SDF-1/CXCR4-dependent migration and invasion of B88-SDF-1 cells was significantly inhibited following treatment with AMD070. Subsequently, we performed an experimental therapy using AMD070 to prevent the distant metastasis of B88-SDF-1 cells in vivo. Daily oral administration of AMD070 significantly inhibited the lung metastasis of B88-SDF-1 cells in nude mice. Furthermore, AMD070 treatment did not induce body weight loss despite the tumor bearing-condition of the mice. In addition, we could not detect the apparent macroscopic organ abnormalities associated with the daily oral administration of AMD070. These results indicated that AMD070 could be useful as a novel orally bioavailable inhibitor of oral cancer metastasis.
Citation Format: Nobuyuki Kuribayashi, Daisuke Uchida, Makoto Kinouchi, Kyoko Kuribayashi, Tomonori Hasegawa, Shuma Yagisawa, Hitoshi Kawamata. Effect of a novel orally bioavailable CXCR4 inhibitor, AMD070, on the metastasis of oral cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4191.
Abstract 4203: Alpha 9 nicotinic acetylcholine receptor promotes tumor progression in triple negative breast cancer
Authors: Kuo Yung-Che , Chu Jan-Show , Lee Kha-Liang , Wang Hsiao-Feng , Drew Victor James , Zhuang Wei-Zhan , Chen Chi-Long , Ho Yuan-Soon , Huang Yen-Hua 
Published: August 2018

Abstract
Purpose: To assess the potential therapeutic target on the alpha 9 nicotinic acetylcholine receptor (α9-nAChR) and the insulin-like growth factor (IGF)-I receptor (IGF-IR) for preventing distant metastasis in TNBC patients. Experimental Design: Expression levels of stemness-related genes, α9-nAChR and IGF-IR in clinical tissues (n = 67) were analyzed by RT-qPCR and the Pearson correlation analysis. The α9-nAChR, OCT4, IGF-1R, and p-IGF-1R protein in tissues were detected by immunohistochemical staining (n = 200). The effects of either α9-nAChR activation or IGF-1R transactivation on stemness expression in TNBC were examined using Western blot, ALDH activity assay with flow cytometry, shRNA silencing, wound closure/migration/invasion assay, as well as microCT scanning and IVIS assay for animal models. Results: A high positive correlation between the gene expression levels of OCT4/NANOG/CD24/CD44 and α9-nAChR/IGF-IR in human breast cancer tissues was observed. IGF-1R and OCT4 highly expressed in tumor part compared than that of in normal part. Moreover, IGF-1R positively correlated with OCT4 in tumor tissues. We also show that nicotine induced α9-nAChR activation trans-activates the expression of IGF-1R and pluripotent protein OCT4, which mediated stemness-related properties in TNBC cell lines. Our results reveal that knockdown α9nAChR and IGF-1R diminish the pernicious effects of nicotine, inhibit stemness activities, and suppress metastasis both in vitro and in vivo. Conclusions: A crosstalk between α9-nAChR and IGF-IR signal mediates the stemness-related properties and metastasis therefore convene poor prognosis in TNBCs.
Citation Format: Yung-Che Kuo, Jan-Show Chu, Kha-Liang Lee, Hsiao-Feng Wang, Victor James Drew, Wei-Zhan Zhuang, Chi-Long Chen, Yuan-Soon Ho, Yen-Hua Huang. Alpha 9 nicotinic acetylcholine receptor promotes tumor progression in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4203.
Abstract 4408: Development and validation of a serum miRNA biomarker panel for the detection of early stage lung cancer
Authors: Ying Lisha , Zou Ruiyang , Du Lingbin , Shi Lei , Zhang Nan , Jin Jiaoyue , Wu Junzhou , Zhang Fanrong , Chen Kaiyan , Yu Herbert , Mao Weimin , Su Dan 
Published: August 2018

Abstract
Lung cancer is the most prevalent cancer and leading cause of cancer death worldwide. Low-dose spiral computed tomography (LDCT) scan is being recommended as a screening test for smokers in the U.S. However, the poor specificity (73% specificity at 94% sensitivity) of LDCT has raised significant concern for its high chance of false positive (96% of LDCT positives are benign nodules). This study aims to develop a blood (serum) miRNA based molecular diagnostic test for the detection of early stage lung cancer. In the discovery phase, more than 400 miRNAs were profiled with MiRXES's qPCR based high throughput assay platform through a highly defined Chinese male smoker case-control cohort (n=424) where the cases were collected from Zhejiang Cancer Hospital and the controls were collected from the LDCT screening program in Zhejiang province, China. 29 miRNA biomarkers with p-value (FDR) &lt; 0.01 and more than one z-score (standardized score) difference were identified and validated in another Chinese case-control cohort (n=432) collected from similar sources and a Caucasian case-control cohort (n=218) collected from EU and US. 18 out of the 29 miRNA biomarkers were validated in both cohorts (p-value &lt; 0.01 and z-score &gt;0.4). With multiple time of two-fold cross-validation, 5 miRNAs were found to be minimally required to form the biomarker panel for the accurate prediction of early stage lung cancer and the panel gives 0.984 (95% CI 0.973-0.991) AUC for the discovery cohort, 0.936 (95% CI 0.912-0.957) AUC for the Chinese validation cohort and 0.970 (95% CI 0.939-0.986) AUC for the Caucasian validation cohort. The 5-miRNA biomarker panel were then further validated in three additional Asian cohorts: a Chinese cohort collected from the similar sources (0.973, 95% CI 0.950-0.986, AUC), a Chinese cohort collected from independent sources (0.916, 95% CI 0.852-0.949, AUC) and a Singaporean cohort (Chinese, Malay and Indian population) (0.911, 95% CI 0.822-0.963, AUC).
Citation Format: Lisha Ying, Ruiyang Zou, Lingbin Du, Lei Shi, Nan Zhang, Jiaoyue Jin, Junzhou Wu, Fanrong Zhang, Kaiyan Chen, Herbert Yu, Weimin Mao, Dan Su. Development and validation of a serum miRNA biomarker panel for the detection of early stage lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4408.
Abstract 45: Snai2 is a new target to mediate glucocorticoid signaling on breast cancer cell migration
Authors: Ling Jun , Singhal Adit , Lopez-Dee Zenaida P. , Porreca Brittany , Sprague Trinity 
Published: August 2018

Abstract
Steroid hormone receptors such as estrogen and progesterone receptors are well studied in breast cancer pathology; they are also used as drug targets for breast cancer therapy in the clinic. In contrast, glucocorticoid (GC) as a ubiquitous stress activated steroid hormone is less investigated in breast cancer. However, GC is frequently used as a co-treatment for breast cancer chemotherapy that generates some controversial effects to even promote cancer progression or recurrence in certain subtypes of breast cancer. To address this clinical issue, we focused on investigating the specificity of GC signaling on breast cancer cell behaviors in this study. When breast cancer cells were treated by dexamethasone (Dex), they were more responsive to cell migration (measured by electric cell-substrate impedance sensing, ECIS) than the effects on cell proliferation and apoptosis, wherein MDA-231 (triple negative breast cancer) cell was more sensitive to Dex than MCF7 cell (luminal A subtype). Further gene expression analysis by qRT-PCR microarray revealed that the glucocorticoid receptor (GR) responsive gene patterns are different between these two subtypes of breast cancer cells. One of remarked changes was that Snai2 (a zinc finger transcriptional factor) was highly activated in both cell lines. Western blotting analysis confirmed that MDA-231 cells have much higher basal level of Snai2 but with less fold increase upon Dex treatment than MCF-7. GR response elements (GREs) were also identified in the promoter region of Snai2, thus confirming Snai2 as a new target gene of GR in breast cancer. When Snai2 was knocked out by CRISPR, it was found that the basal migration rate was decreased in both cell lines. More importantly, their response rates to Dex treatment were also decreased as compared to the wild type cells. These decreases in cell migration are similar to those treated by GR antagonist RU486, thus confirming that Snai2 is a mediator to regulate the effects of GC/GR signaling on breast cancer cell migration. In summary, this study identified Snai2 as a new target gene of GR to regulate cell migration and potentially metastasis in response to GC signaling. The differential regulation of different subtypes of breast cancer cells by GC signaling was also confirmed. (+ equal contribution; * Corresponding author).
Citation Format: Jun Ling, Adit Singhal, Zenaida P. Lopez-Dee, Brittany Porreca, Trinity Sprague. Snai2 is a new target to mediate glucocorticoid signaling on breast cancer cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 45.
Abstract 4500: BET proteins regulate hyaluronan synthases in pancreatic ductal adenocarcinoma
Authors: Kumar Krishan , Ebine Kazumi , Pham Thao , Shang Meng , Munshi Hidayatullah G. 
Published: August 2018

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with an extensive desmoplasia which is composed of multiple extracellular matrix components, including collagen, fibronectin, laminin, and hyaluronan (HA). Inhibitors targeting bromodomain and extra-terminal (BETi) proteins have emerged as potential therapeutic agents and are in clinical trials for a range of malignancies. We have previously shown that BETi attenuate fibrosis in vivo by decreasing collagen expression; however, the effect of BETi on HA has not been previously evaluated. Increased HA, which is synthesized by HA synthases (HAS), is associated with poor outcome in PDAC. Targeting HA has been postulated to provide a potential therapeutic opportunity to overcome PDAC chemo-resistance. Preclinical data have demonstrated that enzymatic degradation of HA with PEGPH20 remodels the tumor microenvironment, decreases the interstitial pressure and enhance the drug entry in tumors. Several ongoing clinical trials are evaluating PEGPH20 in combination with chemotherapies. We now report that BET inhibitors markedly decrease expression of HAS2 and HAS3, which are overexpressed in PDAC.
Purpose: The aim of this study is to investigate the role of BET proteins in HA synthesis.
Methods: mRNA expression levels HAS2 and HAS3 were determined in a panel of 7 PDAC cell lines by quantitative real-time RT-PCR. Protein expression was determined by western blotting.
Results: We found that treatment with BET inhibitors decrease the expression of HAS2 and HAS3 in all cell lines. Furthermore, siRNA mediated knockdown of individual BET proteins demonstrated that HAS2 is primarily regulated by BRD2, while HAS3 is primarily regulated by BRD4.
Conclusion: Our results demonstrate that BET proteins play a role in HA synthesis by regulating expression of HAS2 and HAS3 enzymes.
Citation Format: Krishan Kumar, Kazumi Ebine, Thao Pham, Meng Shang, Hidayatullah G. Munshi. BET proteins regulate hyaluronan synthases in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4500.
Abstract 4553: A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint
Authors: Koopmans Iris , Samplonius Douwe F. , Ginkel Robert J. van , Wierstra Peter J. , Heskamp Sandra , Bremer Edwin , Helfrich Wijnand 
Published: August 2018

Abstract
PD-L1-blocking antibodies produce significant clinical benefit in selected cancer patients by reactivating functionally-impaired anticancer T cells. However, their efficacy is potentially reduced by ‘on-target/off-tumor' binding to PD-L1 widely expressed on normal cells. This lack of tumor selectivity potentially induces a generalized activation of all antigen-experienced T cells as is evidenced by frequent autoimmune-related adverse events during and after treatment. To address these issues, we constructed a tetravalent bispecific antibody (bsAb), designated PD-L1xEGFR, to direct PD-L1-blockade to EGFR-expressing cancer cells and thus reactivate anticancer T cells more selectively. The IC50 of PD-L1xEGFR for binding to EGFR+ cancer cells was ~140 fold lower compared to an analogous PD-L1-blocking bsAb of irrelevant target antigen specificity (PD-L1xMock). Importantly, treatment with PD-L1xEGFR selectively enhanced activation status, INF-γ production, and activity of anti-CD3xanti-EpCAM-redirected T cells in presence of EGFR+/EpCAM+, but not EGFR-/EpCAM+ carcinoma cells. Similarly, capacity of PD-L1xEGFR to promote proliferation and IFN-γ production by CMVpp65-specific CD8+ effector T cells was enhanced in the presence of EGFR+/CMVpp65+ cancer cells. In contrast, the clinically-used PD-L1-blocking antibody MEDI4736 (durvalumab) promoted T cell activation indiscriminate of EGFR expression on cancer cells. Additionally, in tumor-bearing mice 111In-PD-L1xEGFR showed a significantly higher tumor uptake compared to 111In-PD-L1xMock. In conclusion, PD-L1xEGFR blocks the PD-1/PD-L1 immune checkpoint in an EGFR-directed manner, which promotes a more selective reactivation of anticancer T cells. This novel targeted approach may be useful to enhance efficacy and safety of PD-1/PD-L1 checkpoint blockade in EGFR-overexpressing malignancies.
Citation Format: Iris Koopmans, Douwe F. Samplonius, Robert J. van Ginkel, Peter J. Wierstra, Sandra Heskamp, Edwin Bremer, Wijnand Helfrich. A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4553.
Abstract 4600: Biomarker analysis in circulating cell-free DNA in patients treated with sorafenib for advanced hepatocellular carcinoma
Authors: Park Sook Ryun , Oh Chung Ryul , Kong Sun-Young , Kim Min Kyeong , Yoon Kyong-Ah , Cho Eun-Hae , Lee Junnam , Kang Jihoon , Ryoo Baek-Yeol 
Published: August 2018

Abstract
Purpose: We evaluated the potential role of Vascular Endothelial Growth Factor-A (VEGFA) amplification and genome-wide copy number variations (CNVs) using circulating cell-free DNA (cfDNA) as predictors of treatment outcome in hepatocellular carcinoma (HCC) patients treated with first-line sorafenib. Methods: Among 184 patients from a prospective biomarker cohort, who had started sorafenib between April 2015 and May 2016, 151 eligible patients were included in the analysis. Plasma cfDNA was extracted from peripheral blood in patients before starting sorafenib or healthy donors. Plasma VEGFA-to-EIF2C1 ratios (the VEGFA ratios) were determined using droplet digital polymerase chain reaction. We applied low depth whole genome sequencing in cfDNA to find CNVs and developed I-score to express genomic instability, which was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. Results: The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; p&lt;0.0001). Patients who had progressive disease with sorafenib as best tumor response had significantly higher cfDNA levels (0.82 vs. 0.63 ng/μL; p=0.006) and I-scores (3,405 vs.1,024; p=0.0017) than those who achieved disease control. The disease control rate was 52.0% for the cfDNA-high group (above the median) vs. 75.0% for the cfDNA-low group (p=0.003), and 49.3% for the I-score-high group (above the median) vs. 77.6% for the I-score-low group (p=0.0003). The cfDNA-high group also had significantly worse TTP (median, 2.2 vs. 4.1 months; HR=1.71; p=0.002) and OS (median, 4.1 vs. 14.8 months; HR=3.50; p&lt;0.0001) than the cfDNA-low group. Similarly, the I-score-high group had poorer TTP (median, 2.2 vs. 4.1 months; HR=2.09; p&lt;0.0001) and OS (median, 4.6 vs. 14.8 months; HR=3.35; p&lt;0.0001). In the multivariate analyses, cfDNA remained an independent prognostic factor for OS (p&lt;0.0001), and I-score for both TTP (p=0.011) and OS (p=0.010). Although the VEGFA ratio was significantly higher in HCC patients than in healthy controls (2.50 vs. 2.17; p&lt;0.0001), it was not significantly associated with treatment outcomes. Conclusions: Pretreatment cfDNA concentration and genome-wide CNVs in cfDNA are potential biomarkers predicting treatment outcomes in advanced HCC patients receiving first-line sorafenib.
Citation Format: Sook Ryun Park, Chung Ryul Oh, Sun-Young Kong, Min Kyeong Kim, Kyong-Ah Yoon, Eun-Hae Cho, Junnam Lee, Jihoon Kang, Baek-Yeol Ryoo. Biomarker analysis in circulating cell-free DNA in patients treated with sorafenib for advanced hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4600.