bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 501: A RET-related microRNA, miR-153-3p, acts as a tumor suppressor in medullary thyroid carcinoma (MTC) via S6K signaling
Authors: Joo Lauren Jin Suk , Weiss Jocelyn , Gill Anthony J. , Clifton-Bligh Roderick , Brahmbhatt Himanshu , MacDiarmid Jennifer A. , Gild Matti L. , Robinson Bruce G. , Sidhu Stan B. , Zhao Jing Ting 
Published: August 2018

Abstract
Background
Medullary thyroid carcinoma (MTC), which comprises 3-5% of all thyroid cancers, originates from a small population of neuroendocrine calcitonin C-cells of thyroid gland. Gain-of-function mutations of the human Rearranged during Transfection (RET) proto-oncogene have been recognized as the key driver of MTC tumorigenesis. RET has been targeted by tyrosine kinase inhibitors (TKIs), however with modest efficacy. Many of the microRNAs (miRNAs) identified in human genome have been associated with cancer and have prompted interest in the establishment of miRNA-based therapeutics. However miRNA studies in MTC has been hampered due to the lack of normal C-cell tissue as a differential expression comparator.
Aims
We aimed to characterize differentially expressed miRNAs, which play fundamental roles in MTC tumorigenesis and in modulation of TKI responses.
Methods
RET of human MTC cells were silenced using TKI, Cabozantinib, or siRNA. Small RNA sequencing was performed (AGRF) to identify differentially expressed miRNAs before and after RET inhibition. MiRNA effects on cell proliferation (MTS assay), cell cycle and apoptosis (flow cytometry, Western blot) were investigated with gain-of-function studies. For in vivo study, MTC xenografts were established and miRNAs were intravenously delivered using nanoparticle delivery vehicles invented by biotechnology company - EnGeneIC Ltd.
Results
miR-153-3p was identified to be under-expressed in MTC following RET inhibition. Restoration of miR-153-3p significantly reduced cell proliferation, induced G2 cell arrest and increased cell apoptosis. Furthermore, combined treatment of miR-153-3p and Cabozantinib caused greater cell proliferation inhibition compared to individual treatment. miR-153-3p targets ribosomal protein S6 kinase B1 (RPS6KB1) and reduced phosphorylation of Bcl-2 associated death promoter (BAD) protein. In vivo delivery of miR-153-3p significantly impeded tumor growth compared to scrambled sequence. Combination of miR-153-3p delivery and oral administration of Cabozantinib resulted in further tumor stabilization effect.
Conclusion
miR-153-3p reveals a significant tumor suppressive role in MTC via S6K signaling, demonstrating its important therapeutic potential for MTC patients.
Citation Format: Lauren Jin Suk Joo, Jocelyn Weiss, Anthony J. Gill, Roderick Clifton-Bligh, Himanshu Brahmbhatt, Jennifer A. MacDiarmid, Matti L. Gild, Bruce G. Robinson, Stan B. Sidhu, Jing Ting Zhao. A RET-related microRNA, miR-153-3p, acts as a tumor suppressor in medullary thyroid carcinoma (MTC) via S6K signaling [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 501.
Abstract 5010: Advantages in using orthotopic syngeneic tumor models to evaluate immune-based approaches for cancer treatment
Authors: Maubant Sylvie , Slos Philippe , Boisferon Marc Hillairet de , Bichat Francis , Mirjolet Jean-Francois 
Published: August 2018

Abstract
Immune checkpoint modulators are now accepted as the fourth pillar of cancer care for both solid tumors and hematological malignancies. In addition to CTLA-4, PD-1 or PD-L1 targeting antibodies, novel immune-oncology targets are currently tested in patients but also new strategies such as bispecific T cell engagers or cell therapies including CAR-T cells. Some of them have been already approved. Prediction of preclinical models is still a long-standing debate, even more when considering modulators of the immune system. Despite significant progresses made in humanized mouse model field during the last decade, having a complete and stable immune system comprising both lymphoid and myeloid subpopulation is not yet possible. Syngeneic tumors thus remain the model of choice to interrogate and better understand the mechanisms of action of new compounds targeting immune cell interactions. In order to improve prediction and relevance of these syngeneic models, orthotopic (OT) models were developed in parallel of standard subcutaneous (SC) models. Here, comparison of regular SC versus OT engraftments are provided. Various models, such as EMT-6 (breast), MBT-2 (bladder) as well as RenCa (kidney) will be described in addition to other OT models like Hepa1-6 (liver) or PAN-02 (pancreas) models. In addition to growth characteristics using imaging for OT models, antitumor efficacy of CTLA-4 and PD-1 targeting antibodies will be detailed for both SC and OT models. One of the most interesting model is MBT-2 (bladder) for which response to CTLA-4 targeting antibody is changing depending engraftment site: significant increase in survival was evidenced for the OT model (treated to control ratio (T/C) of 285%) and only moderate efficacy was observed for the SC model (T/C = 66%). For the PD-1 targeting antibody, OT injection seemed to be the preferential site to observe increased efficacy. Attempting to correlate immune profile and response to treatment, differences in immune infiltrate between OT and SC tumors will also be presented.
Citation Format: Sylvie Maubant, Philippe Slos, Marc Hillairet de Boisferon, Francis Bichat, Jean-Francois Mirjolet. Advantages in using orthotopic syngeneic tumor models to evaluate immune-based approaches for cancer treatment [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 5010.
Abstract 5085: CXCR2 signaling in pancreatic cancer induces a tumor supporting inflammatory phenotype of the cancer-associated fibroblasts
Authors: Awaji Mohammad , Varney Michelle , Purohit Abhilasha , Batra Surinder , Singh Rakesh 
Published: August 2018

Abstract
Pancreatic cancer (PC) remains one of the deadliest types of solid malignancies. Making progress in dealing with PC starts by understanding the complex interaction of cellular components in the tumor microenvironment and identifying the crucial checkpoints for tumor progression and metastasis. Desmoplasia and inflammation are two major hallmarks of PC. Cancer-associated fibroblasts (CAFs) are known for inducing fibrosis in several pathologies of the pancreas including PC. Recent reports have described that CAFs can assume the fibrosis-inducing phenotype, when close or have a direct contact with tumor cells, or a tumor-promoting inflammatory phenotype, through distant paracrine signaling. Known for their role in recruiting granulocytes and inducing angiogenesis, CXC chemokines (1-3 and 5-8) contain a conserved motif of Glutamic acid-Leucine-Arginine (ELR) and signal through CXCR1/2 chemokine receptors. In PC, ELR+ chemokines produced by malignant cells and stromal cells contribute to tumor growth, angiogenesis, and tumor-supporting immunosuppression. The deletion of CXCR2 in the genetically engineered PC mouse model (KC) promoted fibrosis and tumor metastasis.
Taken together, we hypothesize that ELR+ chemokines signaling through CXCR2 may trigger the inflammatory phenotype of CAFs in PC that promotes tumor growth and progression. Utilizing unidirectional coculture studies, incubating CAFs in conditioned media of PC cells inhibited their growth, decreased the expression of the fibrotic CAFs-associated markers such as αSMA and collagen I, and increased the expression of immunosuppressive cytokines and tumor-promoting chemokines including IL-4, IL-10, IL-13, and CXCL7. Treating CAFs with exogenous ELR+ chemokines (CXCL1 and CXCL8) exhibited a similar phenotype. Furthermore, treating CAFs with exogenous ELR+ chemokines or PC cells conditioned media in the presence of pharmacological inhibitors of CXCR2 rescued this phenotype. In summary, we believe that ELR+ chemokine signaling through CXCR2 induces the inflammatory phenotype of CAFs that promotes immunosuppression, tumor growth, and tumor progression of PC.
Citation Format: Mohammad Awaji, Michelle Varney, Abhilasha Purohit, Surinder Batra, Rakesh Singh. CXCR2 signaling in pancreatic cancer induces a tumor supporting inflammatory phenotype of the cancer-associated fibroblasts [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 5085.
Abstract 5113: Spontaneous tumors in aging colonies of C57BL/6J mice
Authors: Schile Andrew , Dion Stephanie , Imai-Leonard Denise , Doty Rosalinda 
Published: August 2018

Abstract
The C57BL/6J inbred mouse strain is widely used to study the effects of aging. We have documented 51 spontaneous tumors (39 malignant and 12 benign) as part of a recent effort to establish large colonies of male and female C57BL/6J mice for aging research. Forty six of the tumors were diagnosed in mice submitted for histopathology from typical aging colonies maintained throughout a range of ages (6-18 months) that roughly correspond to 30 - 56 years of age in humans; the remaining cases were from much smaller cohorts aged past 18 months. Sarcomas represented the largest category of malignant tumors (20/51). There were 6 cases (5 male, 1 female) of hemangiosarcoma (4 on the neck, 1 on the liver, and 1 on the ear) and 6 multicentric histocytic sarcomas (4 male, 2 female). Four cases (1 male, 3 female) of rhabdomyosarcoma (2 on the head, 2 on the leg) were also seen. The remaining sarcoma diagnoses included one osteosarcoma (female; leg), one chondrosarcoma (male; ear), and two sarcomas not otherwise specified (both female; one leg, one lateral abdomen). Hematological malignancies constituted the second largest category (9/51), including 7 multicentric lymphomas (3 male, 4 female), a uterine lymphoma, and a multicentric plasma cell tumor (1 male). The four skin malignancies included two melanomas (male: head; female: tail/anus) and two squamous cell carcinomas (male: jaw; female: leg). Three mammary cancers were observed in females, including an adenoacanthoma and two adenocarcinomas, one of which had lung metastases. An ovarian dysgerminoma was the only germ cell tumor documented. The Harderian gland (a lacrimal duct of the eye) was the site of two carcinomas (male) and six adenomas (5 male, 1 female). Other benign tumors included a tail fibroma (male), two pulmonary adenomas (1 male, 1 female), one mammary fibroadenoma (female), a myoepithelioma of the leg (female), and a keratoacanthoma of the paw (female). Tumor incidence was very low overall, representing &lt;0.1% of the mice present on an average week during the typical range of ages (6-18 months) in the aging colonies. Overall, the median age of diagnosis was 239 days for females and 427 days for males. These results should help to define the spectrum of tumors that develop in colonies of C57BL/6J mice that approximately correspond in age to middle-aged humans.
Citation Format: Andrew Schile, Stephanie Dion, Denise Imai-Leonard, Rosalinda Doty. Spontaneous tumors in aging colonies of C57BL/6J mice [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 5113.
Abstract 5169: Novel target molecules for treatment of cancer of unknown primary
Authors: Fujita Yoshihiko , Sakai Kazuko , Velasco Marco De , Kurata Takayasu , Hayashi Hidetoshi , Nakagawa Kazuhiko , Nishio Kazuto 
Published: August 2018

Abstract
We have previously been involved in a multicenter clinical study to predict the primary site of cancer of unknown primary site (CUP) for a site-specific therapy. Based on the microarray analysis of gene expression pattern, we not only predicted the primary site for each CUP patient but also extracted 44 up-regulated genes common to each CUP showing over 2.5-fold change compared to normal tissue (lymph node). To identify genes related to CUP development among these candidate genes, we performed cell-based siRNA screening and estimated to what extend A549 cells reduce the ability of migration, and found 4 genes, GRN, MIF, PRKDC, PSMB4. Konckdown of each of these genes suppressed metastasis of implanted cells from a footpad to a popliteal lymph node. Inhibitors for PRKDC (NU 7441) and PSMB4 (bortezomib) also suppressed the metastasis of parental A549 cells in vivo, suggesting the involvement of these genes in metastasis.
As there is no standard treatment for CUP, drugs targeting immune checkpoints, such as PD-1 or IDO, may reveal promising antitumor activity for CUP. Recent studies suggest that expression levels of PD-L1 (a PD-1's ligand) or IDO may be a biomarker of patient response to anti-PD-1 or anti-IDO therapy, respectively. We analyzed the expression of PD-L1 and IDO for the CUP tissues and found several patients with high expression of either or both proteins who may be most likely respond to these novel immunotherapies.
Citation Format: Yoshihiko Fujita, Kazuko Sakai, Marco De Velasco, Takayasu Kurata, Hidetoshi Hayashi, Kazuhiko Nakagawa, Kazuto Nishio. Novel target molecules for treatment of cancer of unknown primary [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 5169.
Abstract 5175: Advancing the molecular understanding of stage I colorectal cancer
Authors: Dunne Philip , Loughrey M B. , Coleman H G. , McBride R , Campbell J , Alderdice M , Redmond K L. , McArt D G. , Isella C , Leedham S , Maughan T , Lawler M , consortium S:CORT 
Published: August 2018

Abstract
Background: There are ~1.4 million cases of colorectal cancer (CRC) annually worldwide. Bowel cancer screening (BCS) detects cancers and high-risk adenomas earlier; previously stage I accounted for 12% of CRC, but 42% of screen-detected cancers are now stage I. This study is based on the hypothesis that within the early lesions detected by BCS there are "hopeful monsters"; a term used to describe highly aggressive tumours that are simply being caught earlier while they are still potentially curable. Colorectal tumour evolution models have proposed the “Big Bang” of tumour growth, where a single expansion in adenoma development dictates disease outcome. In line with the “hopeful monsters” theory, this model reason that some tumours are “born-to-be-bad” from the earliest point in CRC tumour evolution.
Aims: This proposal aims to develop a molecular stratifier of lethal vs non-lethal early-invasive disease based on comprehensive molecular pathological profiling, improved biological understanding and multiple tiers of validation to inform the management of CRC disease at the earliest stage. Methods: In contrast to stage II-IV CRC, there are limited stage I molecular studies, reducing opportunities to identify lethal early-disseminating tumours in patients who account for ~50% of screen-detected cancers. This study is undertaking collection and molecular profiling of a cohort of retrospective stage I tissue (n=200), enriched for patients that experienced relapsed, to identify factors associated with early-dissemination.
Results: Pathological characterisation of the stage I cohort indicated that histological factors such as fibroblast content or depth of invasive front are not associated with eventual metastatic relapse. Unsupervised analysis highlighted a detectable shift in transcriptional signalling between recurrent and non-recurrent samples. Further supervised analysis indicates that intrinsic “stem-like” factors may be more prognostic than extrinsic factors in stage I.
Conclusions: In order to find any effective treatment you have to first understand the biology underpinning disease. Given the increasing numbers of early stage patients being diagnosed as a result of BCS, and the paucity of tissue cohorts and focussed molecular studies of stage I CRC, this study aims to increase our understanding of specific factors underpinning prognosis at this early stage.
Citation Format: Philip Dunne, M B. Loughrey, H G. Coleman, R McBride, J Campbell, M Alderdice, K L. Redmond, D G. McArt, C Isella, S Leedham, T Maughan, M Lawler, S:CORT consortium. Advancing the molecular understanding of stage I colorectal 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 5175.
Abstract 520: circEPSTI1 as a prognostic marker and mediator of triple-negative breast cancer progression
Authors: Chen Bo , Huang Xiaojia , Wei Weidong , Tang Hailin , Xie Xiaoming 
Published: August 2018

Abstract
Purpose: Circular RNAs (circRNAs) represent a class of non-coding RNAs which play a vital role in modulating gene expression and several pathological responses. However, it is largely unknown about the expression profile and function of circRNAs in triple negative breast cancer (TNBC). In the current study, we investigated the expression profile of human circRNAs in TNBC tissues and identified circEPSTI1 (hsa_ circRNA_000479) as one circRNA significantly upregulated.
Experimental Design: We performed circular RNAs microarray assay to screen circular RNAs expression profiles of TNBC and further investigated circEPSTI1. We observed the effect of circEPSTI1 on proliferation, clonal formation and apoptosis of TNBC by knockdown of circEPSTI1 in three TNBC cell lines. According to the MREs analysis and luciferase reporter assay, we found circEPSTI1 could bind to miRNAs as a miRNA sponge and the co-target gene of miRNAs and performed xenografts in mice to confirm our findings. We evaluated circEPSTI1 levels of 240 TNBC patients by ISH.
Results: We found that knockdown of circEPSTI1 could inhibit TNBC cell proliferation and induce apoptosis. In vitro and in vivo experiments implicated that circEPSTI1 could bind to miR-4753 and miR-6809 as miRNAs sponge to regulate BCL11A expression and affect TNBC proliferation and apoptosis. High level of circEPSTI1 was correlate with shorter survival in TNBC patients.
Conclusions: The circEPSTI1-miR-4753/6809-BCL11A axes can affect the proliferation and apoptosis of triple negative breast cancer through the mechanism of competing endogenous RNAs. Meanwhile, our results provide circEPSTI1 as an independent prognostic marker for survival in patients with TNBC.
Citation Format: Bo Chen, Xiaojia Huang, Weidong Wei, Hailin Tang, Xiaoming Xie. circEPSTI1 as a prognostic marker and mediator of triple-negative breast cancer progression [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 520.
Abstract 5348: Single-cell analysis of mutational heterogeneity in acute myeloid leukemia tumors with high-throughput droplet microfluidics
Authors: Eastburn Dennis J. , Pellegrino Maurizio , Sciambi Adam , Treusch Sebastian , Xu Liwen , Durruthy-Durruthy Robert , Gokhale Kaustubh , Jacob Jose , Chen Tina X. , Oldham William , Matthews Jairo , Kantarjian Hagop , Futreal Andrew , Patel Keyur , Jones Keith W. , Zehnder James L. , Takahashi Koichi 
Published: August 2018

Abstract
To make possible the routine characterization of genetic diversity within cancer cell populations, we developed a novel two-step microfluidic droplet workflow that enables efficient and massively-parallel single-cell PCR-based genomic barcoding for single-cell DNA sequencing applications. We demonstrate that the two-step microfluidic approach is required for robust DNA amplification on thousands of individual cells per run with high coverage uniformity and low allelic dropout of targeted genomic loci. To apply our single-cell sequencing technology to human tumor samples, we developed a targeted panel to partially sequence 26 genes frequently mutated in acute myeloid leukemia (AML) including TP53, DNMT3A, FLT3, NPM1, NRAS, IDH1 and IDH2. Using this panel, we were able to sensitively identify SNV and indel-defined clones within AML samples and assess their distribution at the time of diagnosis, remission and relapse. We also used single cell SNVs to monitor host and donor cell populations during bone marrow transplantation (BMT), which allowed us to accurately evaluate engraftment and disease relapse. Collectively, our single-cell data indicates that clonal populations inferred from VAFs obtained from bulk sequencing data may not fully resolve the heterogeneity within tumors; moreover, the single-cell nature of our approach enabled the unambiguous identification of multiple co-occurring mutations within subclones that is not possible with bulk measurements. Collectively, our results show a greater degree of heterogeneity in AML tumor samples than is commonly appreciated with traditional sequencing paradigms and demonstrate the value of single-cell analysis for AML.
Citation Format: Dennis J. Eastburn, Maurizio Pellegrino, Adam Sciambi, Sebastian Treusch, Liwen Xu, Robert Durruthy-Durruthy, Kaustubh Gokhale, Jose Jacob, Tina X. Chen, William Oldham, Jairo Matthews, Hagop Kantarjian, Andrew Futreal, Keyur Patel, Keith W. Jones, James L. Zehnder, Koichi Takahashi. Single-cell analysis of mutational heterogeneity in acute myeloid leukemia tumors with high-throughput droplet microfluidics [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 5348.
Abstract 5359: Regulatory germline variants in 10,389 adult cancers
Authors: Huang Kuan-lin , Weerasinghe Amila , Wu Yige , Liang Wen-wei , Mashl R. Jay , Reynolds Sheila , Houlahan Kathleen E. , Oak Ninad , Atlas The Cancer Genome , Lazar Alexander J. , Wendel Michael C. , Khurana Ekta , Plon Sharon , Chen Feng , Gerstein Mark , Shmulevich Ilya , Ding Li 
Published: August 2018

Abstract
Previous studies of rare germline variants in cancer has largely been limited to the coding regions of known predisposition genes. The TCGA PanCanAtlas Germline Working Group is analyzing germline predisposing variants of 10,389 cases in 33 cancer types. We deployed more than 121,000 virtual machines running for over 600,000 hours on the ISB Cancer Genome Cloud to conduct massively parallel variant calling and analyses, and the resulting data are shared with scientists across institutions worldwide. Carriers of the functional regulatory variants add on to the 8.9% of cases carrying known pathogenic variants. Burden analyses reveal enrichment of rare variants in the 3'UTR region of NHP2 and POLH. Further, we observed variants aggregating in conserved regions of selected microRNA families that are also affected by somatic mutations, including mir-17 and mir-29. We nominate regulatory variants by using GWAVA and FunSeq2 corroborated with their enrichment in cancer. The prioritized variants are then further evaluated by further co-occurrence of two-hit events and expression changes in their respective tumor samples. Finally, we examine ancestries, familial history and age at onset for carriers of these variants. Overall, we aim to discover and establish the role of regulatory germline variants in oncogenesis.
Citation Format: Kuan-lin Huang, Amila Weerasinghe, Yige Wu, Wen-wei Liang, R. Jay Mashl, Sheila Reynolds, Kathleen E. Houlahan, Ninad Oak, The Cancer Genome Atlas, Alexander J. Lazar, Michael C. Wendel, Ekta Khurana, Sharon Plon, Feng Chen, Mark Gerstein, Ilya Shmulevich, Li Ding. Regulatory germline variants in 10,389 adult cancers [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 5359.