bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2085: Exploring mutation signatures in pediatric cancers
Authors: Lucas Francis A. San , Lupo Philip , Brown Austin , Scheurer Michael , Scheet Paul 
Published: August 2018

Abstract
Background: Mutation signatures have been catalogued across most common cancers, providing insights into their underlying mutational processes and suggesting strategies for categorization and subphenotyping. However, these analyses have been limited to mostly adult cancers, likely due to the relative rarity of pediatric analogs and a corresponding lower mutation burden of these tumors. Here we attempted to compare mutation signatures across several pediatric cancers, given these constraints, with their corresponding adult versions.
Data and Methods: From the ICGC data portal, we downloaded clinical and mutation data for pediatric brain (medulloblastoma, glioblastoma, neuroblastoma) and blood-based (acute lymphoblastic leukemia, acute myeloid leukemia) cancers. We also obtained data for related adult cancers, including glioblastoma and acute myeloid leukemia. For each cancer, we characterized mutation patterns using trinucleotides centered at somatic SNVs and then estimated the composition of underlying putative COSMIC mutation signatures. For cancers with low mutation rates (impeding estimates of mutation signatures), we grouped mutations from similar samples based on clinical and molecular statuses to infer mutation signatures.
Results: Each of the pediatric cancer types strongly exhibited the common cancer mutation Signature 1 (spontaneous deamination of 5-methylcytosine), as might be expected since it has been described across all adult cancer types. Further, pediatric acute myeloid leukemia and glioblastoma both harbored mutation signatures seen in their adult counterparts in addition to unexpected patterns of defective DNA mismatch repair and DNA double-strand break repair. Interestingly, for pediatric glioblastoma we identified Signatures 3, 8, 15 and 16, which were previously unidentified in adult glioblastoma and have been recently implicated in pediatric medulloblastoma.
Conclusion: Our findings may be influenced by the sparsity of mutations in pediatric cancers, highlighting the need for quantifying precision in measures of mutation signatures. This notwithstanding, from our initial observations, pediatric cancers appear to exhibit a more diverse set of mutation signatures than their adult counterparts. Further, pediatric cancers of different histologies, particularly those of brain cancers, may share molecular mechanisms more than currently believed.
Citation Format: Francis A. San Lucas, Philip Lupo, Austin Brown, Michael Scheurer, Paul Scheet. Exploring mutation signatures in pediatric 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 2085.
Abstract 2094: Pathology beyond 2D: Imaging and analysis of cells and the tumor microenvironment in three dimensions
Authors: Mansfield James R. , Wainright James , Bagnall Christopher , Wilde Geraint , Price Meredith , Willcox Benjamin E. , Browne Mark 
Published: August 2018

Abstract
The success of cancer immunotherapy treatments and the development of immuno-oncology into the “fifth pillar” of cancer treatment has fueled a rapid growth in interest into methodologies that investigate immune cells in the context of the tumor microenvironment. However, nearly all technologies that investigate the immune contexture of tumors either rely on homogenization or disaggregation of the sample and the concomitant loss of spatial relationships, or rely on a thin section (5 um or less), two-dimensional sample of a biopsy, which is a poor representation of an inherently three-dimensional structure. An image of a thin section will tend to over-estimate the numbers of proximal cells and underestimate the numbers of more distant cells due to sampling error. To address this, we have implemented an imaging system capable of 3D confocal and super-resolution imaging, tiling of large sample areas and imaging samples over time along with software for the visualization and analysis of the datasets.
We present here a series of examples showing the utility of 3D fluorescence imaging of labeled cells in thick (ca. 50 micron) FFPE tissue sections. By using a multimarker immunostaining scheme, this enables the phenotyping of cells within the tumor microenvironment and the calculation of distance metrics between cells in three dimensions. This methodology is an inherently better means of assessing cellular distributions in the tumor microenvironment and can give a much better representation of the complicated 3D structure of a tumor than imaging of thin sections.
Citation Format: James R. Mansfield, James Wainright, Christopher Bagnall, Geraint Wilde, Meredith Price, Benjamin E. Willcox, Mark Browne. Pathology beyond 2D: Imaging and analysis of cells and the tumor microenvironment in three dimensions [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 2094.
Abstract 2101: The growth of a xenograft breast cancer tumor model with engineered hyaluronan-accumulating stroma is dependent on hyaluronan and independent of CD44
Authors: Zhao Chunmei , Thompson Benjamin J. , Chen Kelly , Marella Mathieu , Zimmerman Susan , Kimbler Trevor , Blouw Barbara , Garrovillo Sheryl , Huang Lei , Radi Adrian , Huang Zhongdong , Shepard H. Michael , Rosengren Sanna , Thanos Christopher D. , Maneval Daniel C. 
Published: August 2018

Abstract
The abnormal accumulation of hyaluronan in the solid tumor microenvironment is associated with poor prognosis in several human cancers. Hyaluronan often accumulates in the tumor stroma. To understand the role of hyaluronan-accumulating stroma in tumor progression, we engineered a hyaluronan-producing fibroblast cell line 3T3HAS3 by lentiviral transduction of the human hyaluronan synthase 3 gene into Balb/c 3T3 cells. The 3T3HAS3 cells produced significant amounts of hyaluronan in vitro, which bind to the cell surface of the human breast cancer cell line MDA-MB-468. When co-grafted with MDA-MB-468 cells in nude mice, 3T3HAS3 significantly enhanced tumor growth. Immunohistochemical analysis of tumor xenografts showed that MDA-MB-468 cells were surrounded by hyaluronan-accumulating stroma, closely resembling the morphology observed in human breast cancer specimens. Tumor growth of this co-graft model required hyaluronan production from 3T3HAS3 cells, as demonstrated by the delayed tumor growth upon hyaluronan removal by expression of the human PH20 gene in 3T3HAS3 cells, or by systemic administration of PEGylated recombinant human PH20 (PEGPH20). In contrast, neither the expression of CD44, a well-characterized hyaluronan receptor, in tumor and stromal fibroblasts, nor the binding of hyaluronan to CD44 in MDA-MB-468 tumor cells was essential for tumor growth. Small scale screening of signaling changes in xenograft tumors suggested that the AMPK/mTOR pathway may respond to hyaluronan removal by PEGPH20. Collectively, these data demonstrate that the growth of an engineered breast cancer xenograft model with hyaluronan-accumulating stroma is dependent on hyaluronan, and that hyaluronan-CD44 interaction may not be the main mechanism through which hyaluronan promotes tumor progression in certain tumors.
Citation Format: Chunmei Zhao, Benjamin J. Thompson, Kelly Chen, Mathieu Marella, Susan Zimmerman, Trevor Kimbler, Barbara Blouw, Sheryl Garrovillo, Lei Huang, Adrian Radi, Zhongdong Huang, H. Michael Shepard, Sanna Rosengren, Christopher D. Thanos, Daniel C. Maneval. The growth of a xenograft breast cancer tumor model with engineered hyaluronan-accumulating stroma is dependent on hyaluronan and independent of CD44 [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 2101.
Abstract 2115: An authenticated in vitro model for prostate microenvironment studies utilizing prostate epithelial cells and stromal-derived cells
Authors: Rodriguez Luis G. , McDaniel Russell E. , Zhao Xiangshan , Zou Chaozhong 
Published: August 2018

Abstract
Prostate cancer remains one of the most common cancers diagnosed in men and one of the leading causes of cancer death in men. Tumor development and progression have been shown to be highly influenced not simply by the genetic makeup of a cell, but by its surrounding stroma, particularly fibroblasts. It has been demonstrated that prostate cancer-associated fibroblasts (CAFs, which are located marginal to the prostate tumor), differ from prostate normal-associated fibroblast (NAFs, which are located distal to the prostate tumor), on their contribution to tumor progression. However, human prostate cancer in-vitro model systems have focused largely on prostate cancer epithelial cells exclusively. A need exists for a more physiologically relevant human cell model system to study prostate cancer progression within the context of its tumor microenvironment. In this study, we utilized prostate cancer-associated fibroblasts (CAFs), prostate normal-associated fibroblasts (NAFs) and normal prostate epithelial (PrE) cells; all three lines were immortalized by hTERT (human telomerase reverse transcriptase) alone and they were continuously passaged for at least 15 passages without any indications of a decrease in growth rate. All cell lines express appropriate specific cell lineage markers for either fibroblasts or epithelial cells. Fibroblasts expressed TE7 and alpha smooth muscle actin (a-SMA), while prostate epithelial cells expressed cytokeratin 5, low levels of prostate specific antigen (PSA) and high levels of p63 throughout their continuous passage; all characteristics in accord with their primary cell counterparts. Next, cell proliferation was measured for various prostate-derived epithelial cells under the influence of CAFs and NAFs cells. Normal prostate epithelial cell proliferation was inhibited and produced a visible morphological change in the cells in the presence of CAFs or CAF-conditioned medium. Meanwhile, the effects of stromal cells on prostate cancer cells was cell line dependent, demonstrating both promotion and inhibition of growth of selected cancer cells. Surprisingly, both CAFs and NAFs promoted cancer cell growth, but CAFs promoted a greater increase in cell proliferation than NAFs in some cancer cell lines. This study demonstrates that these three hTERT immortalized cells from human prostate are a valuable model system for the study of prostate cancer cell progression and tumor micro environment studies.
Citation Format: Luis G. Rodriguez, Russell E. McDaniel, Xiangshan Zhao, Chaozhong Zou. An authenticated in vitro model for prostate microenvironment studies utilizing prostate epithelial cells and stromal-derived 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 2115.
Abstract 2123: Myeloma derived macrophage inhibitory factor regulates BMSC IL6/8 via cMYC
Authors: Piddock Rachel E. , Marlein Christopher R. , Abdul-Aziz Amina , Auger Martin J. , Bowles Kristian M. , Rushworth Stuart A. 
Published: August 2018

Abstract
Background
Multiple Myeloma (MM) is a plasma cell malignancy dependent on the bone marrow microenvironment. Macrophage inhibitory factor (MIF) acts directly on malignant plasma cells affecting homing and chemotherapy resistance, however the adaptive effect that MM derived MIF has on the tumor microenvironment is not yet defined. Here we investigate the function of MM derived MIF in the MM microenvironment by examining its effects on bone marrow mesenchymal stromal cells (BMSC).
Methods
Primary MM and BMSC were obtained from patient bone marrow. Proteome Profiler Human XL Cytokine Array was used. Inhibitors including JQ1 were
purchased from Merck. In-vivo experiments were performed using 8-10 week old NSG mice.
Results
First we injected 1 x 106 MM.1S MIF-knock down (KD) cells or MM.1S control-KD cells (containing the pCDH-luciferase-T2A-mCherry construct) into the tail vein of 6-8 week old NSG mice. MIF-KD in MM cells resulted in animals with significantly reduced tumor burden and improved overall survival. To further investigate the role of MIF in regulating the BM microenvironment we stimulated primary human BMSC with biologically appropriate doses of recombinant MIF and then used Human XL Cytokine Array and cytokine specific ELISA to assay the supernatant from these MIF stimulated BMSC. Results show that MIF induces IL-6 and IL-8 protein secretion from primary BMSC. To examine the mechanism of action of these observations we used a panel of inhibitors to screen for potential pathways responsible for MIF induced BMSC derived IL-6 and IL-8 expression. The c-Myc inhibitor JQ1 inhibited MIF induced IL-6 and IL-8 expression. Next, we looked at whether c-Myc regulates BMSC pro-tumoral interleukin production in-vivo. We injected NSG mice via the tail vein with human myeloma cell line U266 and then randomized animals to two groups; treating with either JQ1 (50mg/kg, IP) or alternatively vehicle control for 5 days, after which bloods were taken
to assess murine IL-6 levels (IL-8 is deleted from the mouse genome). Results show that murine IL-6 was significantly reduced in the JQ1 treated animals (carrying human MM) compared to vehicle control treated animals.
Summary
MM derived MIF is pro-tumoral through induction of c-Myc and downstream IL-6 and IL-8 in the BMSC of the tumor micro-environment. Identification of this novel pro-tumoral crosstalk mechanism which exists between MM and the bone marrow stroma provides scientific rationale for the clinical evaluation of new therapeutic targets in MM.
Citation Format: Rachel E. Piddock, Christopher R. Marlein, Amina Abdul-Aziz, Martin J. Auger, Kristian M. Bowles, Stuart A. Rushworth. Myeloma derived macrophage inhibitory factor regulates BMSC IL6/8 via cMYC [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 2123.
Abstract 215: Reconstructing the Barrett's-dysplasia-adenocarcinoma sequence from patient-matched stem cells
Authors: Xian Wa , Zhang Yanting , Duleba Marcin , Wang Shan , McKeon Frank 
Published: August 2018

Abstract
Introduction: Both esophageal and gastric adenocarcinoma (EAC; GAC) evolve from intestinal metaplasia (Barrett's and gastric IM, respectively) in a multi-decade and multi-step process involving transitions through low- and high-grade dysplasia often referred to as the “Correa Sequence”. In early stage EAC, each of these lesions can be seen co-existing in the 2-D topology of the distal esophagus. We have adapted methods we originally developed for cloning normal stem cells of the gastrointestinal tract to capturing stem cells of each of these lesions. We anticipate that a clonal analysis of these stem cells will reveal key steps in the evolution of highly lethal EAC.
Methods: Libraries of stem cell clones were generated from a series of patient-specific endoscopic biopsies derived from normal, Barrett's, dysplasia, and EAC. Single cell-derived clones were analyzed by in vitro differentiation, whole genome expression analysis, and SNP-based copy number variation.
Results: Highly undifferentiated, ground state stem cells were cloned from multiple endoscopic biopsies of patients with early EAC. Based on sampling site and adjacent biopsy histology, tissue corresponding to normal esophagus, gastric epithelia, Barrett's, and EAC were taken in these biopsies dissociated for stem cell cloning. All the clones derived showed unlimited proliferative potential and the ability to differentiate to normal or diseased epithelia in vitro. Thus the normal esophageal and gastric stem cells gave rise to squamous and gastric epithelia, the Barrett's stem cells yielded intestinal metaplasia, and dysplastic and EAC clones yielded highly proliferative and disordered epithelia marked by a loss of cell polarity. In contrast to the germline genotypes of the normal stem cells, those from Barrett's, dysplasia, and EAC sustained increasingly large numbers of copy number variation events, single nucleotide variations, and chromosomal aneuploidies. Significantly, all single cell-derived clones of EAC yielded “intestinal” adenocarcinoma following xenografting to immunodeficient mice. We are presently exploiting the genomic alterations present in hundreds of sample clones from each patient to reconstruct the evolutionary events that accompanied the progression to a highly lethal cancer.
Conclusions: Stem cells from all stages of lesions along to the path to epithelial cancers can be cloned and independently propagated to yield insights into the evolution of cancer. In addition, these cloned cells should enable insights into intratumor heterogeneity, therapy resistance, and drug discovery.
Citation Format: Wa Xian, Yanting Zhang, Marcin Duleba, Shan Wang, Frank McKeon. Reconstructing the Barrett's-dysplasia-adenocarcinoma sequence from patient-matched stem 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 215.
Abstract 2165: Mini-patient-derived xenograft sensitive assay: A rapid systemic detection method for assessment of cancer therapeutics
Authors: Pan Xiaoqing , Zhang Feifei , Long Yuan , Liu Hui , Guo Lin , Cheng Jijun , Wen Danyi 
Published: August 2018

Abstract
Patient-derived xenografts (PDX) have a high predictive power for efficacy of anticancer therapeutics. Limitations such as engraftment failure and time consuming for establishment and expansion of PDX models for drug efficacy testing need to be overcome for immediate application in patient decision-making for therapeutics. We developed a rapid in vivo drug sensitivity assay system so-called OncoVee® Mini-PDX, in which patient-derived tumor cells were arrayed within hollow fiber capsules in vivo over 7 days and screened against clinical relevant regimens. For validation study, the Mini-PDX was assessed by comparing the drug response in PDX tumor-bearing mice to response in Mini-PDX (capsule-containing) mice. The correlation between PDX tumorgrafts assay and Mini-PDX assay was evaluated using PDX models generated from 21 cancer patients. In the 21 cases, the overall predictive accuracy of the PDX assay for sensitivity was 69% and resistance was 88%, respectively. We also extended the approach to the patients with advanced malignancies. We report clinical cases in which Mini-PDX guided treatment improved the outcomes of treated cancer patients. In sum, Mini-PDX assay based on the capsule implantation was developed and optimized for quick assessment of the chemosensitivity of patients' cancers and found to be compatible with that of PDX tumorgrafts assay. This method hold promise for application of personalized chemotherapy for cancer patients.
Citation Format: Xiaoqing Pan, Feifei Zhang, Yuan Long, Hui Liu, Lin Guo, Jijun Cheng, Danyi Wen. Mini-patient-derived xenograft sensitive assay: A rapid systemic detection method for assessment of cancer therapeutics [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 2165.
Abstract 2168: Anti-cancer drug sensitivity assay using in vitro primary culture cells
Authors: Fujino Shiki , Miyoshi Norikatsu , Ohue Masayuki , Saso Kazuhiro , Mizushima Tsunekazu , Doki Yuichiro , Mori Masaki 
Published: August 2018

Abstract
Primary culture of cancer cells derived from an individual patient's tumor provides important information regarding the tumor character. We established a novel culture method for primary colorectal cancer (CRC) with phenotypic heterogeneity as a human tumor model, named isolated tumor-derived cancer cells (iCCs). The success rate of iCC growth in vitro was 100%, passage was 90%, and establishment of a xenograft model from iCC was 80%. The gene expression of the cultured cells was similar to the clinical tumors, and exhibited a ductal structure of the tumor in the xenograft model even after several passages. The present in vitro analyses allow us to predict the clinical efficacy of chemotherapeutic drugs. For this purpose, we examined the sensitivities of iCCs isolated from patients. In this study four patients with distant metastasis received FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) chemotherapy according to the treatment guidelines, and in vitro drug sensitivity was evaluated using the cultured cells, compared with each parental tumor in the individual clinical course. It is a model to predict the effect of chemotherapy to the individual tumor. Our results showed that the effect of chemotherapy was poor in three patients and good in one patient. In their clinical courses, the tumor size increased in two patients and decreased in two patients. In vitro drug sensitivity results reflected the clinical course in three of the four patients. In conclusion, our primary culture model is a novel tool for the prediction of anti-cancer drugs in the clinical courses.
Citation Format: Shiki Fujino, Norikatsu Miyoshi, Masayuki Ohue, Kazuhiro Saso, Tsunekazu Mizushima, Yuichiro Doki, Masaki Mori. Anti-cancer drug sensitivity assay using in vitro primary culture 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 2168.
Abstract 2172: Dying tumor cells (tumor debris) stimulate the growth of 4T1 breast cancer tumor in female athymic nude mice
Authors: Roomi M Waheed , Niedzwiecki Aleksandra , Rath Matthias 
Published: August 2018

Abstract
Current cancer therapies are based on chemotherapy and radiation. These therapeutic approaches can initially reduce the tumor mass or tumor burden by killing tumor cells. It has been postulated that the resulting dying tumor cells, or tumor debris, can act as sources of tumor stimulation on surviving cells leading to reappearance of the cancer, and thereby drastically reducing the survival rate. In our study we investigated whether 4T1 debris induced by chemotherapeutic agent docetaxel would affect breast tumor growth in female nude mice. Female athymic nude mice were divided into three groups: Group 1 was inoculated with 4T1 cells; Group 2 with 4T1 cells together with their debris and Group 3 with debris alone. All mice were fed a regular diet. After four weeks, the mice were sacrificed; tumors were excised, weighed and processed for histology and immunohistochemistry for inflammation parameters. Tumor weight significantly increased in Group 2 mice compared to the control Group 1. Group 3 mice developed no tumors. Although the tumor histology for both Groups 1 and 2 were similar, there were significant differences in inflammatory parameters in the two groups. Tumors developed in Group 2 mice had intense staining patterns for TNF-alpha, IL-6, Ki-67, i-Nos and VEGF compared to tumors in the control Group 1. Our results show that dying cells from docetaxel treatment, or tumor debris, had stimulatory effect on growth of breast cancer 4T1 cells in nude mice which was associated with increased inflammation. This study represents a novel method to evaluate the effects of chemotherapy or radiation on surviving tumor cells and to investigate the effect of various inhibitors on the growth recurrence.
Citation Format: M Waheed Roomi, Aleksandra Niedzwiecki, Matthias Rath. Dying tumor cells (tumor debris) stimulate the growth of 4T1 breast cancer tumor in female athymic nude 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 2172.