bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1000: PD-L1 binding peptide identified by phage peptide display inhibits PD-1/PD-L1 interaction and activates T cells
Authors: Gurung Smriti , Khan Fatima , Lee Soo-Woong , Yoon Jaewon , Lee Byungheon 
Published: August 2018

Abstract
Immune suppressive mechanism within the tumor microenvironment inhibits antitumor T cell function, leading to evasion of tumor from immune attack. One of the mechanisms is the up-regulation of programmed death-ligand 1 (PD-L1) expression on tumor cells which binds to programmed cell death protein 1 (PD-1) on activated T cells and inhibits T cell functions. Inhibiting the PD-L1/PD-1 interaction could reverse the tumor microenvironment and enhance the endogenous antitumor immune response. To identify a novel peptide that selectively binds to PD-L1, we screened a phage-displayed peptide library against cells transiently expressing PD-L1 at high levels. After multiple rounds of screening, selected phage clones were sequenced. Of these, two phage clones showed more selective binding to cells expressing PD-L1 compared to a control clone. The peptides displayed on the clones were synthesized for further study and named as PD-L1Pep-1 (9mer) and PD-L1Pep-2 (7mer). Fluorescein-conjugated PD-L1Pep-1 and PD-L1Pep-2 selectively bound to cells highly expressing PD-L1, whereas only negligible binding to cells expressing PD-L1 at low levels. The cell binding of the PD-L1-binding peptides was enhanced after treatment of cells with interferon-γ which is a potent inducer of PD-L1 in many types of cancer cells. FACS analysis showed that the pre-treatment of cells with an anti-PD-L1 antibody competed and reduced the cell binding of the PD-L1-binding peptides, suggesting the antibody and peptides bind to the same epitope on PD-L1. Co-culture experiments of CT26 mouse colon tumor cells with primary T cells isolated from a mouse spleen showed that, similar to the anti-PD-L1 antibody, the PD-L1-binding peptides increased the secretion of Interleukin-2 and interferon-γ by the T cells, indicating that the PD-L1-binding peptides can reactivate the T cells that were suppressed by the co-cultured tumor cells. In-vivo fluorescence imaging of BALB/c mice bearing subcutaneously transplanted CT26 mouse colon tumor cells showed tumor targeting ability of the PD-L1-binding peptides to PD-L1-expressing tumor. These findings suggest that PD-L1Pep-1 and PD-L1Pep-2 can inhibit PD-L1/PD-1 interaction and activate T cells in vivo and hold a potential as a cancer immunotherapeutic. Keywords: Colon tumor, immunotherapy, PD-L1, peptide, phage display
Citation Format: Smriti Gurung, Fatima Khan, Soo-Woong Lee, Jaewon Yoon, Byungheon Lee. PD-L1 binding peptide identified by phage peptide display inhibits PD-1/PD-L1 interaction and activates T 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 1000.
Abstract 1010: Establishing lobular-like and interlobular-like fibroblast cell lines from human breast reduction mammoplasties
Authors: Morsing Mikkel , Jafari Abbas , Kassem Moustapha , Petersen Ole William , Rønnov-Jessen Lone 
Published: August 2018

Abstract
Introduction: The importance of epithelial-stromal interactions for tissue homeostasis and maintenance is well documented. We have recently provided evidence that two distinct fibroblast lineages in the human breast stroma, lobular and interlobular, respectively, can be prospectively isolated and stably propagated in serial-passage subculture. The aim of the present study was to generate immortalized and stable cell lines derived from lobular and interlobular fibroblasts with preserved lineage identity and functionality. The availability of such cell lines will allow for an as of yet unprecedented detailed characterization of mammary fibroblast lineages including their specific interactions with normal and malignant breast epithelium.
Results: Lobular- and interlobular-derived fibroblast cell strains in passage 8 were immortalized by retroviral introduction of human telomerase reverse transcriptase (hTERT) followed by neomycin selection. At abstract submission deadline, lobular and interlobular hTERT expressing fibroblasts had reached passage 56 corresponding to 60 and 100 population doublings, respectively, while mock-transfected controls had seized proliferating in passage 21. Lineage restriction of immortalized cells was maintained as lobular fibroblasts express higher levels of CD105 than interlobular fibroblasts. Also, lobular fibroblasts are able to undergo adipogenic and osteogenic differentiation upon relevant induction in culture, but fail to generate bone in an in vivo ectopic bone formation model, thus functionally distinguishing lobular fibroblasts from bone marrow-derived mesenchymal/skeletal stem cells. Upon co-culture with primary breast luminal progenitors, lobular fibroblasts support epithelial growth and branching morphogenesis, including correct apical-basal polarization.
Conclusion: Lobular and interlobular fibroblasts have been successfully immortalized while preserving both lineage restriction and functional characteristics of their primary counterparts. With 80% of breast cancers arising in lobular epithelium, these established fibroblast models may prove instrumental to unravel such focal susceptibility to breast cancer development.
Citation Format: Mikkel Morsing, Abbas Jafari, Moustapha Kassem, Ole William Petersen, Lone Rønnov-Jessen. Establishing lobular-like and interlobular-like fibroblast cell lines from human breast reduction mammoplasties [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 1010.
Abstract 1041: XenofilteR: Computational dissection of mouse and human reads in PDX and xenograft sequence data
Authors: Krijgsman Oscar , Kluin Roelof JC , Kemper Kristel , Kuilman Thomas , Ruiter Julian R. de , Iyer Vivek , Forment Josep V. , Cornelissen-Steijger Paulien , Rink Iris de , Brugge Petra ter , Song Ji-Ying , Klarenbeek Sjoerd , McDermott Ultan , Jonkers Jos , Velds Arno , Adams David J. , Peeper Daniel S. 
Published: August 2018

Abstract
Mouse xenografts from (patient-derived) tumors (PDX) or tumor cell lines are widely used as models to study various biological and preclinical aspects of cancer. However, analysis of their RNA and DNA profiles is challenging, because they comprise reads not only from the grafted human cancer but also from the murine host. The reads of murine origin can result both in the generation of false positives in mutation analysis of DNA samples and obscure gene expression levels when sequencing RNA. Therefore, we developed the open-source R-package XenofilteR, which separates mouse from human sequence reads based on the number of discordant base pairs between each read and the reference genomes. To assess the accuracy of XenofilteR, we generated sequence data by in silico mixing of mouse and human whole genome and whole exome DNA sequence data. This analysis revealed that XenofilteR removes &gt;99.9% of sequence reads of mouse origin while retaining sequence reads of human origin. The filtering allowed for mutation analysis of PDX samples with accurate variant allele frequencies, and retrieved all non-synonymous somatic mutations present in the original tumor. These findings were further validated in breast cancer and melanoma PDX samples, confirming the retrieval of accurate variant allele frequencies and somatic mutations. In conclusion, XenofilteR accurately dissects sequence reads from mouse and human origin in PDX sequence data, thereby outperforming currently available tools.
Citation Format: Oscar Krijgsman, Roelof JC Kluin, Kristel Kemper, Thomas Kuilman, Julian R. de Ruiter, Vivek Iyer, Josep V. Forment, Paulien Cornelissen-Steijger, Iris de Rink, Petra ter Brugge, Ji-Ying Song, Sjoerd Klarenbeek, Ultan McDermott, Jos Jonkers, Arno Velds, David J. Adams, Daniel S. Peeper. XenofilteR: Computational dissection of mouse and human reads in PDX and xenograft sequence data [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 1041.
Abstract 105: CADM1 is a TWIST1-regulated suppressor of melanoma invasion and survival
Authors: Hartsough Edward J. , Weiss Michele B. , Heilman Shea A. , Purwin Timothy J. , Kugel Curtis H. , Rosenbaum Sheera R. , Erkes Dan A. , Tiago Manoela , Chervoneva Inna , Aplin Andrew E. 
Published: August 2018

Abstract
Metastatic melanoma is the deadliest form of skin cancer; however, patients diagnosed and treated prior to metastatic dissemination have a good prognosis. The transcription factor, TWIST1 has been implicated in enhancing the migration and invasion of melanoma cells but the range of TWIST1-regulated targets is poorly described. In this study, we performed expression profiling to identify the TWIST1-regulated transcriptome. Gene ontology pathway analysis revealed that TWIST1 and epithelial to mesenchymal transition (EMT) were inversely correlated with levels of cell adhesion molecule 1 (CADM1). Chromatin immunoprecipitation (ChIP) studies and promoter assays demonstrated that TWIST1 physically interacts with the CADM1 promoter, suggesting TWIST1 directly represses CADM1 levels. Modulation of CADM1 resulted in significant effects on the migration and invasion of melanoma cells. In addition, elevated CADM1 elicited cell death in non-adherent conditions, an effect that could not be rescued with a pan-caspase inhibitor. Analyses suggest that CADM1 directed non-adherent cell death is associated with loss of mitochondrial membrane potential and subsequent failure of oxidative phosphorylation pathways. Furthermore, clinical data from TCGA indicates that CADM1 expression is correlated with better overall survival in patients. Together, these data suggest that CADM1 exerts tumor suppressive functions in melanoma by reducing invasive potential and may be a biomarker for improved survival of melanoma patients.
Citation Format: Edward J. Hartsough, Michele B. Weiss, Shea A. Heilman, Timothy J. Purwin, Curtis H. Kugel, Sheera R. Rosenbaum, Dan A. Erkes, Manoela Tiago, Inna Chervoneva, Andrew E. Aplin. CADM1 is a TWIST1-regulated suppressor of melanoma invasion and survival [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 105.
Abstract 1051: Mutation detection in patient-derived xenografts by WES and RNAseq
Authors: Qian Wubin , Li Henry Q.X. , Guo Sheng 
Published: August 2018

Abstract
Patient derived xenograft (PDX) is widely used in preclinical cancer research for drug efficacy evaluation, biomarker discovery and validation, drug mechanism and resistant mechanism study, tumor biology studies and so on. Many PDX libraries are now available to researchers1-4. A good library is composed of PDXs with high-quality characterization for genomics, pharmacology, histology, and clinical information associated with the originating patient tumors. Various technologies are used for genomic profiling of PDX models. For example, RNAseq is used for transcriptomic profiling to obtain data on gene expression, RNA-level mutations, gene fusion; whole exome sequencing (WES) is used to infer DNA-level mutations and gene copy numbers. In this study, we compared mutations inferred by RNAseq and WES for 600 PDX models with both datasets.
We found that about 50% of mutations detected by WES were uncovered by RNAseq. The other half are missing because these mutation alleles were covered by insufficient reads (&lt;5) or the mutations are located in poly-N regions, which make it hard to call mutations. By contrast, 99% of the RNAseq-based mutations were detected by WES. It is not surprising to see such difference. WES amplifies exons at DNA level, and is only affected by experimental variations such as hybridization efficacy. RNAseq yields more reads for genes with higher expression, therefore, mutations in genes with no or low expression cannot be reliably detected. Our results also indicate that there is limited RNA editing. We also examined mutation ratios and found good agreement between WES and RNAseq. Pearson's correlation coefficient is 0.91 and 0.81 between the two mutation ratios when homologous mutations are included and excluded, respectively.
Overall, our study shows that RNAseq data is reliable to infer mutations in highly expressed genes and can be readily used for such when WES data is not available.
References
1. Budinská E, Popovici V. The EurOPDX consortium: Sharing patient tumor-derived xenografts for collaborative multicentric preclinical trials. Molecular cancer therapeutics 2014;12:A8-A
2. Gao H, Korn JM, Ferretti S, Monahan JE, Wang Y, Singh M, et al. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nature medicine 2015;21:1318-25
3. Ledford, H. (2016). Us cancer institute to overhaul tumour cell lines. Nature, 530.
4. Guo, S., Qian, W., Cai, J., Zhang, L., Wery, J. P., & Li, Q. (2016). Molecular pathology of patient tumors, patient derived xenografts and cancer cell lines. Cancer Research, 76(16), 4619.
Citation Format: Wubin Qian, Henry Q.X. Li, Sheng Guo. Mutation detection in patient-derived xenografts by WES and RNAseq [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 1051.
Abstract 1058: CRLF1 promotes proliferation and metastasis in papillary thyroid carcinoma via activating MAPK/ERK and PI3K/AKT pathway
Authors: ZHONG QIAN , Yu Shitong , Huang Xiaoming , Zeng Musheng 
Published: August 2018

Abstract
Papillary thyroid cancer (PTC) is the most common cancer in endocrine system which accounts for the majority component of thyroid cancer during the past decades. PTCs usually are indolent and curable with 5-year survival rate over 95%. However, some of PTCs will dedifferentiate and become aggressive with a poor prognosis. Current established biomarkers may not fully explain the mechanisms of the development of PTC. Therefore, it is still urgent to find novel biomarkers of PTC to better predict patients' prognosis and lead to the personalized therapies for PTC patients. By analyzing The Cancer Genome Altas (TCGA) database, we identified Cytokine Receptor Like Factor-1(CRLF1) as a potential oncogene. We identified CRLF1 is highly expressed in papillary thyroid carcinoma (PTC) compared with normal thyroid tissues both at mRNA and protein level. High CRLF1 level was associated with aggressive clinicopathological features and worse disease-free survival rate. By loss-of-function and gain-of-function assays, we found that CRLF1 not only boosts capacity of cell migration and invasion in vitro, but promotes tumor growth both in vitro and in vivo. Besides, CRLF1 can induce epithelial-mesenchymal transitions. Overexpressing CRLF1 could activate ERK1/2 and AKT pathways. The oncogenic effects induced by CRLF1 were suppressed by treating the cells with the MEK inhibitor U0126 or the AKT inhibitor MK-2206. These results suggest an oncogenic role CRLF1 plays in PTC tumorigenesis by regulating MAPK/ERK and PI3K/AKT signaling pathways. These results suggest that CRLF1 is a potential biomarker in PTC patients and it may be a valuable therapeutic target for PTC in the future.
Citation Format: QIAN ZHONG, Shitong Yu, Xiaoming Huang, Musheng Zeng. CRLF1 promotes proliferation and metastasis in papillary thyroid carcinoma via activating MAPK/ERK and PI3K/AKT pathway [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 1058.
Abstract 1062: Downregulation of miR-200c stabilizes XIAP mRNA and contributes to invasion and lung metastasis of bladder cancer
Authors: Tian Zhongxian , Jin Honglei , Li Jingxia , Huang Chao , Huang Chuanshu 
Published: August 2018

Abstract
Our previous studies have demonstrated that X-linked inhibitor of apoptosis protein (XIAP) plays a regulatory role in cancer invasion via mediation of RhoGDIα protein SUMOylation at Ser138 in colorectal cancer HCT116 cells. However, the alteration/association of XIAP in invasion, progression, and lung metastasis of bladder cancer (BC) as well as the molecular mechanisms leading to this XIAP alteration during BC development have not been explored yet. Herein, we found that XIAP was overexpressed in human high grade BCs, high metastatic human BC T24T cells, and in mouse invasive BCs. Mechanistic studies indicated that XIAP overexpression in the highly metastatic T24T cells was due to increased mRNA stability of XIAP in comparison to the parental non-metastatic T24 cells. Results from XIAP mRNA stability regulation revealed that miR-200c was profoundly downregulated in T24T cells and in highly invasive BCs, and that such miR-200c downregulation was mediated by CREB inactivation. Furthermore, miR-200c downregulation reduced its binding to the 3'-UTR region of XIAP mRNA, and resulted in its mRNA stabilization, protein overexpression, and invasive capabilities in T24T cells. Moreover, our results from XIAP-specific shRNA and miR-200c ectopic expression showed that suppression of XIAP profoundly attenuated lung metastasis of T24T cells in nude mice. In conclusion, our findings demonstrate the molecular basis leading to XIAP overexpression and the crucial role of XIAP in BC invasion in vitro and lung metastasis in nude mice.
Citation Format: Zhongxian Tian, Honglei Jin, Jingxia Li, Chao Huang, Chuanshu Huang. Downregulation of miR-200c stabilizes XIAP mRNA and contributes to invasion and lung metastasis of bladder 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 1062.
Abstract 1066: L1CAM as a pivotal mediator for disease progression and prognostic biomarker in gastric cancer patients
Authors: Okugawa Yoshinaga , Toiyama Yuji , Mohri Yasuhiko , Yamamoto Akira , Shigemori Tsunehiko , Yin Chengzeng , Narumi Aya , Ide Shozo , Kitajima Takahito , Yasuda Hiromi , Fujikawa Hiroyuki , Hiro Junichiro , Yoshiyama Shigeyuki , Ohi Masaki , Tanaka Koji , Araki Toshimitsu , Kusunoki Masato 
Published: August 2018

Abstract
Background/Aims: Although significant progress has been made in the diagnosis and treatment of Gastric cancer (GC) patients, GC is the second leading cause of cancer-related deaths worldwide. Identification of critical factors driving the progression of metastasis and new prognostic biomarkers are urgently required to improve both early detection of recurrence and prognosis of patients with advanced GC. L1 cell adhesion molecule (L1CAM) has been observed to be highly expressed in several types of tumors, which may play a vital role in tumor progression. The present study investigated the clinical significance of L1CAM, in the development and progression of gastric cancer.
Experimental Design: At first, the effects of L1CAM alteration were investigated using proliferation, migration, invasion, and anoikis and xenograft model. Next, we analyzed L1CAM expression in surgical tissue speciemens from 131 gastric cancer patients (Cohort 1) by quantitative real-time reverse transcription-PCR and 309 patients (Cohort 2) by immunohistochemistry.
Results: Knockdown of L1CAM using small interfering RNA in GC cell lines resulted in reduced cell proliferation, invasion, migration, and anoikis in gastric cancer cells. Furthermore, Knockdown of L1CAM inhibited metastasis in a xenograft model. Interestingly, L1CAM expression in cancer tissues was significantly higher in patients with lymph node metastasis and distant metastasis. The expression of L1CAM was significantly associated with poor prognosis. Furthermore, L1CAM emerged as an independent prognostic predictor and a predictor of lymph node metastasis in GC patients.
Conclusions: Our data highlight that L1CAM appear to play an important role in disease development and L1CAM expression may serve as a novel predictor for the identification of patients who are at high risk for tumor recurrence and strict surveillance in curative GC patients.
Citation Format: Yoshinaga Okugawa, Yuji Toiyama, Yasuhiko Mohri, Akira Yamamoto, Tsunehiko Shigemori, Chengzeng Yin, Aya Narumi, Shozo Ide, Takahito Kitajima, Hiromi Yasuda, Hiroyuki Fujikawa, Junichiro Hiro, Shigeyuki Yoshiyama, Masaki Ohi, Koji Tanaka, Toshimitsu Araki, Masato Kusunoki. L1CAM as a pivotal mediator for disease progression and prognostic biomarker in gastric cancer patients [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 1066.
Abstract 107: Interaction of BIR domain of XIAP with Sp1/E2F1 activates MMP2 and bladder cancer cell invasion by inhibiting src protein translation
Authors: Hua Xiaohui , Xu Jiheng , Jin Honglei , Huang Chuanshu 
Published: August 2018

Abstract
X-linked inhibitor of apoptosis protein (XIAP) is important in the regulation of cancer cell biological behaviors. However, little is known about the molecular mechanism by which the XIAP domains promote aggressive tumor behavior in human bladder cancer (BC). Herein, we discovered that ectopic expression of the BIR domains of XIAP rescued the MMP2 activation and human BC invasion in human BC cells with XIAP deletion. Interestingly, Src expression was upregulated in XIAP/BIR domain-deficient cells, whereas restoration of BIR domain in XIAP-deletion cells recused Src expression. Moreover, knockdown of Src reversed the defects of MMP2 activation and BC invasion in XIAP-deficient BC cells, revealing that Src acts as a XIAP downstream negative regulator for MMP2 activation and BC invasion. Mechanistic studies revealed that the regulatory effect of the BIR domains of XIAP on Src expression was due to directly inhibition of its protein translation by upregulation of miR-203 resulting from activation of the transcription factors Sp1 and E2F1, while the BIR domains of XIAP was found to interact with both Sp1 and E2F1 to activate these transcription factors. Overall, our studies demonstrate that BIR domain of XIAP is able to bind to Sp1 and E2F1 leading to their transcriptional activation, resulting their targeted miR-203 transcription, consequently directly targets the 3'-UTR of src mRNA and therefore attenuating SRC protein translation, and activating MMP2 and BC invasion.
Citation Format: Xiaohui Hua, Jiheng Xu, Honglei Jin, Chuanshu Huang. Interaction of BIR domain of XIAP with Sp1/E2F1 activates MMP2 and bladder cancer cell invasion by inhibiting src protein translation [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 107.