bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2108: Detection and molecular profiling of leptomeningeal disease in melanoma
Authors: Smalley Inna , Evernden Brittany , Law Vincent , Kenchappa Rajappa , Puskas John , Ryzhova Elena , Tran Nam , Etame Arnold , Sahebjam Solmaz , Magliocco Anthony , Forsyth Peter , Smalley Keiran S. 
Published: August 2018

Abstract
Approximately 5% of melanoma patients develop leptomeningeal disease (LMDz), a highly symptomatic complication with a dismal survival of 8-10 weeks. The aim of this study was to determine whether diagnosis and personalized treatment for melanoma-LMDz could be improved by assessing patient-derived cerebrospinal fluid (CSF) specimens. Circulating tumor cells in CSF (CSF-CTCs) were detected by Veridex CellSearch® System and the circulating melanoma cell kit, based on anti-CD146 and anti-high molecular weight melanoma associated antigen (HMW-MAA-PE (MEL-PE)). Of the 12 patients with definitive LMDz diagnosis, all but 1 patient (92%) had CSF-CTCs (range 23-3055 CTCs/ml). In contrast, only 3/8 (37%) melanoma patients without LMDz diagnosis had CSF-CTCs detected, with significantly lower CTC counts per ml CSF (range 0.13-0.6 CTCs/ml). Ex vivo studies of CSF uncovered that although patient-derived CSF does not appear to act as a chemo-attractant or a stimulant of invasion to initiate melanoma migration to the leptomeninges, it significantly reduced the ability of BRAF inhibitors to induce apoptosis in established melanoma cell lines (p&lt;0.005). Patient-derived CSF composition is complex but includes many growth factors and mediators of adhesion and TGFβ signaling. In melanoma cells, the CSF stimulated signaling through mTOR/AKT and STAT. BRAF inhibition amplified these signals further. We show that ex vivo expansion of isolated CSF-CTCs is possible for ~25% of samples, in the presence of FBS, FGF and EGF. At this time, there is a very limited understanding of the mechanisms underlying melanoma metastasis to the leptomeninges, a truly devastating and rapidly terminal complication of melanoma. This is the first report of patient-derived CSF eliciting a protective effect in melanoma cells, suggesting melanoma cells find a protective niche in the central nervous system. Furthermore, we demonstrate that patient-derived CSF biopsies serve as a critical tool for improving diagnosis and personalized treatment for melanoma-LMDz patients.
Citation Format: Inna Smalley, Brittany Evernden, Vincent Law, Rajappa Kenchappa, John Puskas, Elena Ryzhova, Nam Tran, Arnold Etame, Solmaz Sahebjam, Anthony Magliocco, Peter Forsyth, Keiran S. Smalley. Detection and molecular profiling of leptomeningeal disease in melanoma [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 2108.
Abstract 2111: The tumor microenvironment of preclinical tumor models may have an impact on the therapeutic index of nanotherapeutics
Authors: Ferretti Stephane , Beckmann Nicolau , Holzer laura , Obrecht Michael , Berger Marjorie , Jensen Michael Rugaard 
Published: August 2018

Abstract
Rapid development in nanotechnology allows the incorporation of multiple therapeutic agents (e.g. liposomes) into nanoparticle with a size range from 1 to 1000 nm. These nanocarrier systems provide new approaches to treat aggressive malignancy. Nano-based delivery systems hold an advantage over traditional small molecule therapy in that they can deliver drugs preferentially to tumors due to the enhanced permeability and retention (EPR) effect. On one hand, high permeability of the tumor vessels and a lack of functional lymphatic vessels results in the EPR effect, driving nanoparticle extravasation. On the other hand, these phenomena lead to high interstitial fluid pressure (IFP), limiting nanoparticle extravasation. In this study, we have used dynamic-contrast enhanced (DCE) MRI with small (Dotarem, 5 nm) and large (Vistarem, 25 nm) contrast agents (CAs) to examine tumor vessel permeability in SJSA-1 osteosarcoma tumor-bearing rats. An inversion-recovery true fast imaging with steady state precession (TrueFISP) was employed to determine the transfer constant Ktrans in subcutaneous and intra-tibia tumor models. When the tumor cells were injected in both niches within the same animal, Ktrans was significantly lower in intra-tibia tumors with both CAs, and blood vessels significantly less and larger compared to subcutaneous tumors. Moreover, Ktrans negatively correlated with tumor bioluminescence for the intra-tibia model, suggesting that EPR decreased inversely with tumor size, while the opposite was noticed for the subcutaneous tumors. These data demonstrate for the first time that the EPR of tumors with a similar size within the same animal can be influenced by the microenvironment. Moreover, they show that the therapeutic index of a nanotherapeutics may be different if it's determined with either an orthotopic or ectopic model.
Citation Format: Stephane Ferretti, Nicolau Beckmann, laura Holzer, Michael Obrecht, Marjorie Berger, Michael Rugaard Jensen. The tumor microenvironment of preclinical tumor models may have an impact on the therapeutic index of nanotherapeutics [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 2111.
Abstract 2128: Autocrine fibronectin inhibits breast cancer metastasis
Authors: Shinde Aparna , Abdullah Ammara , Solorio Luis , Wendt Michael 
Published: August 2018

Abstract
The processes of the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are strongly linked to breast cancer metastasis via their ability to generate cells of increased invasive capacity and enhanced tumor-initiating phenotypes. Numerous growth factors, cytokines and chemotherapies present in the tumor microenvironment are capable of inducing EMT, but the role of extracellular matrix (ECM) components in this process remains less well understood. Analysis of the METABRIC dataset strongly linked high-level FN expression to decreased patient survival. However, in vitro analysis of the MCF-10A progression series indicated that autocrine FN expression was associated with nonmetastatic cells. Therefore, we utilized differential bioluminescent imaging to track the metastasis of these isogenic epithelial and mesenchymal cells within heterogeneous primary tumors. Using this approach, we demonstrate that tumor cells expressing autocrine FN display a constitutively mesenchymal phenotype and are incapable of completing the metastatic process, even when grown within a tumor containing epithelial tumor cells. Importantly, depletion of FN allows tumor cells to exit their mesenchymal state, regain epithelial characteristics and initiate tumor growth in a metastatic microenvironment. Using a tessellated three-dimensional polymer scaffolding, we show that depletion of FN or pharmacologic inhibition of focal adhesion kinase prevents mesenchymal tumor cells from producing structural fibrils and thus supporting the growth and migration of metastatic-competent epithelial tumor cells. Finally, dynamic FN coating of this 3D growth scaffold resulted in formation of a functionalized fibrillar FN network that was sufficient to induce transient EMT events as metastatic cells migrated along FN fibrils. Taken together, our data indicate that autocrine expression of FN by tumor cells supports a stable mesenchymal phenotype limiting their metastatic potential. Instead, this tumor cell-derived production of fibrillar FN acts in a paracrine fashion to support transient EMT events in metastatic competent cells within a heterogeneous tumor microenvironment.
Citation Format: Aparna Shinde, Ammara Abdullah, Luis Solorio, Michael Wendt. Autocrine fibronectin inhibits breast cancer metastasis [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 2128.
Abstract 2159: Use of in vitro cell sheet engineering as a chemotherapeutic model for epithelial cancer
Authors: Kim Eun Hye , Lee Jaewang , Shin Daiha , Park Sunwoo , Kwon Minsu , Roh Jong-Lyel 
Published: August 2018

Abstract
Epithelial cancer is grown in the in vivo microenvironment mixed of keratinocytes, fibroblasts and matrix, vessels, and immune cells. The current in vitro 2-dimensional (2D) models for anti-cancer drug testing are commonly performed on a physical basis, resulting in significant difference from elucidating the real in vivo effects. To resolve the experimental gap, the 3D models have been developed to mimic the in vivo cancer microenvironment, while there is a lack of specific models for epithelial origin tumors. Therefore, we developed a new 3D model of using the in vitro cell sheet engineering for epithelial cancers and compared the results of several chemotherapeutic drug testing among in the 3D model, spheroid culture, and 2D-dish cell culture. The cell sheet included epithelial and subepithelial layers consisting of keratinocytes overlying the mixture of fibroblasts and endothelial progenitors. The spheroids of green fluorescent protein-tagged epithelial cancers were placed at the interface of epithelial and subepithelial layers. The spheroids with mixture of cancers and fibroblasts or cancer-associated fibroblasts (CAF) were made by the conventional hanging-drop method, and the 2D was simply seeded in the culture dish. The cell growth, viability, and hypoxia were calculated by cell counting kit (CCK), live/dead assay, propidium iodide and LOX-1 staining. The morphology, invasion, and mRNA and protein expressions were also compared among the different in vitro models. The results of live/dead assay and CCK showed higher viabilities in the cell sheet-based models before and after treatment with chemotherapeutic drugs. TGF-β and epithelial-mesenchymal transition-related mRNA and proteins were highly expressed in tumors growing in the cell sheet. Further, the incorporation of CAF into the cancer spheroids appeared to less decrease viable cancer cells by chemotherapeutic agents compared to the use of no or normal fibroblasts. Tumor angiogenesis and hypoxia were also apparently observed in the cell sheet model, which partly contributed to relative resistance to chemotherapeutic drugs. Taken together, the cell sheet-based cancer model might be applied to the in vitro observation of epithelial cancer growth and invasion, and anti-cancer drug testing.
Citation Format: Eun Hye Kim, Jaewang Lee, Daiha Shin, Sunwoo Park, Minsu Kwon, Jong-Lyel Roh. Use of in vitro cell sheet engineering as a chemotherapeutic model for epithelial 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 2159.
Abstract 2164: Conditional tumor cell reprogramming: From in vitro sensitivity to in vivo PDX modeling
Authors: Long Yuan , Van Loc , Xi Song , Li Le , Zheng Yuhui , Ling Ying , Zhang Feifei , Cheng Jijun , Wen Danyi 
Published: August 2018

Abstract
Tumor cell immortalization through conditional reprogramming, particularly from limited biopsy specimen, is an invaluable tool to generate propagating tumor cells for cell-based diagnostics, drug sensitivity assay and bio-banking in vitro. We have successfully reprogrammed primary tumor cells from a number of unreported tumor types, including lung carcinoma and adenoid cystic carcinoma, towards immortalization. The propagating cells exhibited typical colonized growth, which is well maintained upon cryo-frozen. In some cases, the cells can be passaged for multiple times and likely become useful cell lines. Like primary tumor cells, conditional reprogrammed tumor cells are reliable to test drug sensitivity in vitro. We attempt to extend conditional reprogrammed tumor cells to reconstitute and grow PDX models in vivo for testing drug efficacy. Preliminary data indicate that, in a 7-day in vivo assay utilizing hollow-fiber tubes grown subcutaneously in mouse, which we call OncoVee Mini-PDX, conditional reprogrammed tumor cells, like primary tumor cells and PDX tumor cells, can be successfully used to test drug efficacy in vivo. In summary, this study explores and evaluates applications of conditional reprogrammed tumor cells in drug efficacy tests both in vitro and in vivo.
Citation Format: Yuan Long, Loc Van, Song Xi, Le Li, Yuhui Zheng, Ying Ling, Feifei Zhang, Jijun Cheng, Danyi Wen. Conditional tumor cell reprogramming: From in vitro sensitivity to in vivo PDX modeling [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 2164.
Abstract 2166: Dasatinib displays antitumor efficacy in an orthotopic xenograft mouse model of histiocytic sarcoma
Authors: Takada Marilia , Smyth Lauren , Yuzbasiyan-Gurkan Vilma 
Published: August 2018

Abstract
Histiocytic sarcoma (HS) is an orphan hematological malignancy with an incidence of less than 1% of all non-Hodgkin's lymphoma, affecting both children and adults. It is a highly metastatic disease, and can affect any organ in the body including spleen, lungs, bone marrow, liver and lymph nodes. It is associated with a poor prognosis as treatment options are scarce and responses are short lived. Dogs spontaneously develop a similar form of HS with an appreciable frequency, and therefore present a unique translational model to investigate better treatments. Preliminary data from in vitro studies identified dasatinib, a multi tyrosine kinase inhibitor, as a highly potent drug against HS cell lines derived from tumors in dogs, but non-toxic to normal normal tissue surrogate fibroblasts. The current study was undertaken to evaluate if the efficacy of dasatinib could be re-capitulated in an in vivo orthotopic xenograft model of HS. The mouse model was generated in NOD-SCID mice by surgical injection of HS cells, transfected with a luciferase reporter construct, into their spleen. Tumor growth was monitored using In Vivo Imaging System. Mice were treated with 30 mg/kg of dasatinib intraperitoneally once a day or vehicle control, with five mice in each group. Dasatinib treated mice had a significantly decreased tumor growth rate in comparison to untreated mice. Most importantly, treatment with dasatinib significantly increased their survival time. All mice from the vehicle control group reached humane endpoints for euthanasia by day 27, while treated mice were clinically stable at day 53, with the difference in survival being highly significant (p&lt;0.0001). In conclusion, here we report the first orthotopic xenograft mouse model of HS, that offers the possibility to test therapeutic response to novel agents, such as dasatinib. Our findings indicate that dasatinib is a promising treatment option for HS, and provide a rational for the initiation of clinical trials.
Citation Format: Marilia Takada, Lauren Smyth, Vilma Yuzbasiyan-Gurkan. Dasatinib displays antitumor efficacy in an orthotopic xenograft mouse model of histiocytic sarcoma [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 2166.
Abstract 2182: DigiPico: A whole-genome sequencing approach to investigate microscopic residual chemotherapy resistance disease in ovarian cancer
Authors: KaramiNejadRanjbar Mohammad , Fotso Donatien Chedom , Zheng Yuhao , Yau Christopher , Ahmed Ahmed 
Published: August 2018

Abstract
Microscopic residual chemotherapy resistance disease (MRCD) following cancer therapy predisposes to recurrence. Genome analysis of MRCDs could, therefore, give insights into evolutionary mechanisms that might govern this process. However, to date, this has largely been restricted to studies utilizing targeted sequencing of known somatic mutations due to the challenges of whole-genome sequencing of subnanogram quantities of DNA. A previous report showed that obtaining accurate whole-genome sequencing is possible from as little as 10 to 20 cells with the added advantage of obtaining reconstructed long fragment reads. Adopting this technology, we were able to optimize a procedure to accurately obtain high-quality whole-genome sequencing data from minimally available clinical samples such as MRCDs, termed DigiPico. Using DigiPico, we were able to perform sequencing on several post-chemotherapy MRCDs and single tumor islets from a high-grade serous ovarian cancer (HGSOC) tumor. The data were found to be highly accurate, with over 96% of the single-nucleotide polymorphisms (SNPs) being detected in DigiPico sequencing results despite the extremely low amount of material available. Moreover, we found that DigiPico can be used for calculation of allele fractions with a consistency rate of up to 84% as opposed to a consistency rate of only 47% for when a standard multiple displacement amplification of similar amount of DNA is used during library preparation. The high-quality allele fraction information from DigiPico was then used to predict the copy number variation (CNV) in these clinical samples. Here, we showed the power of DigiPico for accurate SNP calling and CNV prediction from post-chemotherapy MRCDs and single tumur islets of a HGSOC tumor, the latter of which is extremely important for studying HGSOC as these tumors often show a great degree of structural alterations. This information can now be used for better understanding of how MRCDs might be able to remain unharmed during the course of chemotherapy and initiate recurrence after completion of treatment, which in turn can allow us to design better treatment strategies for HGSOC patients.
Citation Format: Mohammad KaramiNejadRanjbar, Donatien Chedom Fotso, Yuhao Zheng, Christopher Yau, Ahmed Ahmed. DigiPico: A whole-genome sequencing approach to investigate microscopic residual chemotherapy resistance disease in ovarian 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 2182.
Abstract 2187: A rapid autopsy program for cancer research
Authors: Beach Thomas G. , Sue Lucia I. , Serrano Geidy E. , Intorcia Anthony , Walker Jessica , Glass Michael , Callan Michael 
Published: August 2018

Abstract
Many new technologies, such as genomics, transcriptomics, proteomics and metabolomics, are directed at molecular-level analyses of high-quality human normal and diseased tissues. At present, however, the relative lack of suitable tissue for this work is a critical roadblock to the full utilization of these new methods. Tissue is traditionally collected at the time of therapeutic surgical interventions, such as biopsy, or at the time of death, by autopsy. Biopsy is only done on individuals with disease and therefore normal control tissues are only obtained by chance. Biopsy tissue is often completely used for diagnostic purposes or is insufficient in quantity to constitute a shared resource, or for studies of intra-tumoral heterogeneity. Metastatic tissue is often not biopsied, precluding analysis of its evolving molecular changes. Both diseased and normal control tissue could potentially be obtained at autopsy, but autopsy tissue is generally only suitable when it is rapidly obtained after death. The Brain and Body Donation Program (BBDP) in Sun City, Arizona, is a not-for-profit longitudinal clinicopathological study of aging and is the world's only consistently-rapid autopsy program (3 h median). Board-certified pathologists diagnose all tissue microscopically. Many cases have both primary and metastatic tumor tissue. Both fresh-frozen & formalin-fixed samples are saved. All subjects are research volunteers with comprehensive clinical documentation. Our informed consent allows wide sharing of tissue and data, including with for-profit companies. More than 100 cancer autopsies have been done; fixed and frozen tissue is available from more than 25 cancer types, many of which have both primary and metastatic tumor tissue. Normal control tissue is available from more than 40 tissue types and RNA quality is high (Walker DG et al, Cell Tissue Bank 2016 17(3):361-75). The BBDP is listed on the NCI Specimen Resource Locator, and inquiries may be made directly to our website, www.brainandbodydonationprogram.org.
Citation Format: Thomas G. Beach, Lucia I. Sue, Geidy E. Serrano, Anthony Intorcia, Jessica Walker, Michael Glass, Michael Callan. A rapid autopsy program for cancer research [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 2187.
Abstract 2192: Single-molecule single-cell DNA sequencing identifies ongoing copy number evolution in BRCA breast cancers
Authors: Du Haowei , Davis Alexander , Gao Ruli , Colic Medina , Sei Emi , Hu Min , Barrera Angelica Gutierrez , Casasent Anna , Albarracin Constance , Arun Banu , Navin Nicholas E. 
Published: August 2018

Abstract
BRCA2 germline mutation carriers have a lifetime risk of 72% for developing invasive breast cancer. Although BRCA2 has been implicated in double-stranded break repair, the role of this mutation in genome evolution and maintaining genome instability during the expansion of the primary tumor mass is not well understood. To investigate these questions, we developed a novel method for single-cell, single-molecule (SCSM) sequencing. SCSM uses a Tn5 transposase to directly fragment and ligate adapters for PCR amplification, thereby omitting the whole-genome-amplification (WGA) step, which introduces technical noise into single-cell sequencing datasets. This approach provides single-molecule data by positional barcoding, reducing WGA artifacts that are typically associated with amplification bias. We further utilize a dual-barcoding approach and acoustic liquid transfer technology to increase throughput (N=384) and reduce cost to $1 per cell using nanoliter volumes. We applied SMSC to sequence copy number profiles from ~1000 single cells from two patients with BRCA2-positive breast tumors. In both cases we identified several major clonal subpopulations that shared a set of truncal CNAs, suggesting that they evolved from a single normal epithelial cell in the breast, not multiple initiating cells. We also identified many small subclonal CNAs that further diversified the major clones, which suggests that copy number evolution was ongoing during the expansion of the primary tumor mass. These data demonstrate the technical feasibility of SMSC sequencing, and further show that minor copy number evolution is ongoing in BRCA-positive breast cancer patients.
Citation Format: Haowei Du, Alexander Davis, Ruli Gao, Medina Colic, Emi Sei, Min Hu, Angelica Gutierrez Barrera, Anna Casasent, Constance Albarracin, Banu Arun, Nicholas E. Navin. Single-molecule single-cell DNA sequencing identifies ongoing copy number evolution in BRCA breast 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 2192.