bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4072: Direct transdifferentiation of glioblastoma cells to antigen-presenting cells: A novel immunotherapeutic approach
Authors: Sebastian Mathew , Le Son B. , Deng Changwang , Thomas Nagheme , Tran David D. 
Published: August 2018

Abstract
Cell-based immunotherapy has shown encouraging results in solid cancers. However, major limitations of this approach include difficulty with isolation and generation of effective antigen-presenting or immune effector cells and the high cost of cell-based vaccines. In glioblastoma (GBM), the most common and lethal brain cancer in adults, inadequate migration of immune cells across the blood-brain barrier represents another major obstacle to cell-based immunotherapy. One approach to overcome these barriers is to convert GBM cells directly into immune cells of interest. Transdifferentiation, the transformation of one cell type other than stem cells directly into another cell type without an intermediate pluripotent stage, has shown early promise in regenerative medicine, but has had a limited role as a cancer therapy, especially for solid tumors. This is in large part due to the laborious and time-consuming process of identifying master fate determinants of the cell types of interest in the transdifferentiation. To enable this novel application, we have developed and experimentally validated two tandem computational platforms, GeneRep and nSCORE. Applying this novel algorithm to large quantities of published and in-house gene expression datasets, we successfully predicted cell fate determinants of tens of different cell types with several having been validated in transdifferentiation experiments by others and us, such as the conversions of astrocytes to neuronal stem cells, of astrocytes to glioma stem-like cells, of fibroblasts to macrophages, etc. Here, we describe the process of combining a unique core set of hematopoietic stem cell, myeloid, and macrophage or dendritic cell (DC) fate determinants—some have not been described as critical in these cell fates—as predicted and highly ranked by GeneRep-nSCORE to efficiently transdifferentiate GBM cells into functional macrophages or dendritic cells, respectively, while neutralizing their malignant phenotype. This novel transdifferentiation has the potential for transformative impacts in many areas, including DC vaccine immunotherapy and cancer therapy in general, and pioneers the concept that solid tumor cells can be converted into another cell type, and not just any cell type, but one that potentially can elicit a therapeutic response against itself.
Citation Format: Mathew Sebastian, Son B. Le, Changwang Deng, Nagheme Thomas, David D. Tran. Direct transdifferentiation of glioblastoma cells to antigen-presenting cells: A novel immunotherapeutic approach [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 4072.
Abstract 4075: Role of yes-associated protein 1 (YAP1) in human pancreatic ductal adenocarcinoma initiation and progression
Authors: Yin Xue , Liu Jun , Akanuma Naoki , Nipper Michael , Wang Pei 
Published: August 2018

Abstract
Introduction: Understanding the molecular mechanisms underlying pancreatic ductal adenocarcinoma (PDAC) initiation and progression is an urgent need to achieve more effective diagnosis and treatment to this deadly cancer. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to study PDAC initiation and progression using normal human pancreatic cells. Methods: Normal human acinar cells or cells undergoing acinar-to-ductal metaplasia (ADM, AD cells) are isolated by fluorescence-activated cell sorting (FACS), and cultured in 3D-culture system. Lentivirus carrying either YAP1-mCherry are transduced into acinar cells to study whether YAP1 is sufficient to induce ADM or is required during TGFβ-induced ADM. Lentivirus carrying either shYAP1-mCherry or shYAP1-KrasG12D-mCherry are transduced into AD cells to study whether YAP1 is required for AD cell proliferation and Kras-induced prolonged proliferation. ChIP-PCR and genome-wide ChIP-seq will be used to identify the mechanism through which YAP1 promotes PDAC development and progression. Lentivirus carrying inducible shYAP1 will be transduced into cancer producing, engineered AD cells and orthotopically transplanted into SCID mice to investigate whether inhibiting YAP1 could suppress PDAC progression. Results: We already found that TGFβ could induce ADM and oncogenic Kras could maintain the proliferation capacity of AD cells. Also, TGFβ induces YAP1 expression and TGFβ inhibitor blocks YAP1 induction during ADM process, and deleting YAP1 will suppress Kras-induced over-proliferation in AD cells, suggesting that YAP1 plays an important role in ADM, and is downstream of TGFβ as well as Kras signaling. Conclusion and significance: Successful completion of the project will give us a better understanding of how YAP1 functions in human PDAC initiation and progression. It will provide us opportunities to develop new methods for early detection and treatment of PDAC.
Citation Format: Xue Yin, Jun Liu, Naoki Akanuma, Michael Nipper, Pei Wang. Role of yes-associated protein 1 (YAP1) in human pancreatic ductal adenocarcinoma initiation and 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 4075.
Abstract 408: Evidence of DLL4, NNAT, and SLC35C2 in suppression of breast cancer initiation, growth, and metastasis
Authors: Plasterer Cody , Lemke Angela , Murphy Dana , Bergom Carmen , Joshi Amit , Rui Hallgeir , Flister Michael J. 
Published: August 2018

Abstract
Breast cancer affects 1 in 8 women, resulting in 40,000 deaths annually. In most cases, a single cause of breast cancer cannot be found, but rather multiple environmental and genetic factors contribute to overall disease susceptibility. This, combined with complex gene interaction in both malignant tumor cells and nonmalignant tumor microenvironment (TME) cells, poses significant challenges in sifting through the many variants that contribute to the ~31% of breast cancer risk that is heritable. Here, we narrowed the regions associated with breast cancer risk on rat chromosome 3 (RNO3) by introgressing portions of RNO3 derived from the BN rat (protective strain) onto the genomic background of the SS rat (susceptible strain). These SS.BN3 congenics were then phenotyped for DMBA-induced mammary tumor incidence, latency, and multiplicity, which revealed two loci in close proximity that contribute to mammary tumor risk: chr3:95-130Mb (QTL1) and chr3: 154-177Mb (QTL2). By comparing these data with a previous study (Flister et al. Breast Cancer Res Treat. 2017 Aug;165(1):53-64.), we concluded that QTL1 is dependent on the host TME, whereas QTL2 directly modifies breast tumorigenesis and cancer cell proliferation. By combining the congenic mapping studies with genomic and transcriptomic sequencing, and functional analysis, we have now localized the top three candidate modifiers on RNO3: DLL4 (QTL1; TME modifier), NNAT (QTL2; cancer cell modifier), and SLC35C2 (QTL2; cancer cell modifier). Collectively, these data demonstrate the effects of several novel breast cancer modifiers, as well as highlight the potential interactions between modifiers of the malignant cancer cells and the nonmalignant host TME.
Citation Format: Cody Plasterer, Angela Lemke, Dana Murphy, Carmen Bergom, Amit Joshi, Hallgeir Rui, Michael J. Flister. Evidence of DLL4, NNAT, and SLC35C2 in suppression of breast cancer initiation, growth, and 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 408.
Abstract 4089: Establishment and long-term in vitro culture of organoids derived from human biliary tract carcinomas
Authors: Saito Yoshimasa , Muramatsu Toshihide , Sugiyama Yuko , Uchida Ryoei , Furukawa Ryo , Yoshikawa Nao , Yamaguchi Tomoko , Kanai Yae , Saito Hidetsugu 
Published: August 2018

Abstract
Background Biliary tract carcinomas (BTCs) are epithelial malignancies arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. Although patients with inoperable BTCs generally receive a chemotherapy regimen of gemcitabine and cisplatin, the effect of these drugs is limited and the 5-year survival rates of patients are very low. The newly developed 3D culture system known as “organoid culture” allows long-term expansion of stem cells into budding cyst-like structures (organoids) with properties resembling those of the original tissues. The aim of this study is to establish in vitro preclinical models for patients with BTCs using the organoid culture technology.
Methods We established organoids using cancer tissues obtained from patients with BTCs. Alterations of genome, gene expression profiles including microRNAs and drug sensitivity were analyzed in BTC organoids.
Results We were successful in establishment and long-term in vitro culture of five organoid lines derived from human BTCs including intrahepatic cholangiocarcinoma, gallbladder cancer and neuroendocrine carcinoma of the ampulla of Vater. These BTC organoids can be stably cultured over a year, whereas organoids derived from non-cancer bile duct and gallbladder tissues ceased proliferating after 15 passages or six months. H&E staining and immunohistochemistry of BTC organoids and the primary tissues demonstrated that BTC organoids closely recapitulate the histopathological features of the primary tumors. The tumor suppressor microRNA miR-34a was suppressed in organoids derived from one case of intrahepatic cholangiocarcinoma, and enforced expression of miR-34a markedly suppressed the growth of these organoids with down-regulation of its target oncogenes. We also examined the effect of the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-Aza-CdR) on BTC organoids. Treatment with 5-Aza-CdR suppressed the proliferation of all BTC organoids by inducing an anti-viral immune response including activation of interferon-responsive genes.
Conclusions Studies using organoids derived from various BTC cases could potentially pave the way for development of precision medicine for patients with BTCs. These preclinical models for refractory cancers may fill the gap between basic cancer research and patients trials and allow personalized cancer therapy.
Citation Format: Yoshimasa Saito, Toshihide Muramatsu, Yuko Sugiyama, Ryoei Uchida, Ryo Furukawa, Nao Yoshikawa, Tomoko Yamaguchi, Yae Kanai, Hidetsugu Saito. Establishment and long-term in vitro culture of organoids derived from human biliary tract carcinomas [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 4089.
Abstract 4095: Active Kras induced metaplasia progression toward gastric neoplasia is suppressed by MEK inhibition during gastric carcinogenesis
Authors: Choi Eunyoung , Engevik Amy C. , Goldenring James R. 
Published: August 2018

Abstract
Intestinal type gastric cancer develops within metaplastic mucosal fields and development of gastric neoplasia represents the most prominent example of gastric cancer developing within the morphologic changes of metaplasia. Recent investigations have noted activation of Ras activity in up to 40% of human gastric cancers and suggest. Our recent study has suggested that chief cells might be an origin of gastric cancer using a mouse model, Mist1-CreERT2;LSL-KRas(G12D) mouse (Mist1-Kras). The Mist1-Kras mice rapidly developed SPEM and IM within 3 months and invasive metaplasia within 4 months following induction of constitutively-active Kras(G12D) expression in the chief cells in the mouse stomach. We also observed regression of metaplasia by targeting downstream mediators of Kras signaling using a MEK inhibitor, Selumetinib. We therefore have now investigated how the progression and proliferation of metaplasia can be controlled. In this study, we have established metaplastic organoid lines (Meta3 and Meta4) from Mist1-Kras mouse stomach mucosa at 3 or 4 months after tamoxifen induction. We examined these organoids to understand the mechanisms of metaplasia progression through MEK inhibition. Both Meta3 and Meta4 organoids have formed distinguishable glandular structures in 3D cultures and maintained a stable phenotype observed in metaplastic glands in the Mist1-Kras mouse stomachs. The MEK inhibition with Selumetinib in the metaplastic organoids inhibited growth, but promoted differentiation of metaplastic cells toward intestinal absorptive cells with elaboration of an apical brush border. Single cell RNA sequencing data revealed that Meta-4 have distinct characteristics that differ from Meta3. In 3D culture, Meta4 organoids developed more aggressive phenotypes than Meta3 and expressed Cortactin, which has critical roles in cancer cell migration and metastasis. Cortactin localized at the lamellipodia in monolayer culture of Meta4. Meta4 organoids treated with Selumetinib produced significantly fewer colonies in soft agar and resulted in loss of lamellipodia localization of Cortactin. Our results indicate that gastric carcinogenesis can be controlled by a MEK inhibitor, Selumetinib, and support the concept that growth of pre-neoplastic metaplasia and early stage gastric cancer in humans might be controlled with administration of Selumetinib.
Citation Format: Eunyoung Choi, Amy C. Engevik, James R. Goldenring. Active Kras induced metaplasia progression toward gastric neoplasia is suppressed by MEK inhibition during gastric carcinogenesis [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 4095.
Abstract 4098: New strategy of drug response assessment using PDX organoid platform for non-resectable pancreatic cancer
Authors: Jeon A-Ra , Choi Sun Il , Park Sang-Jae , Han Sung-Sik , Kong Sun-Young , Kim Min Kyeong , Lee Yu-sun , Im Jieun , Lee Min Kyeong , Park Sang Hyun , Kim Joon-Ki , Yoon Kyong-Ah , Koh Young-Hwan , Lee Ju Hee , Lee Woo Jin , Woo Sang Myung , Kim Yun-Hee 
Published: August 2018

Abstract
To develop an efficient drug screening platform which overcomes the difference of drug response between initial screening and clinical trial stage is a pivotal issue for drug discovery. The patient-derived Xenograft (PDX) model has been reported as a screening system to reflect the microenvironment and heterogeneity of tumor. However, in pancreatic cancer that 80 % of patients is non-resectable, PDX is not be suitable for an initial screening model in terms of economic- and time cost of mouse-based amplification system as well as the lack of obtaining pancreatic tumor tissue from fine needle biopsy or percutaneous gun. To overcome this limitation, here we newly suggested organoids system, miniature organ culture on a dish, that are generated from tumor tissues of orthotopic PDX model, which has the advantages of reflection of each patient's characteristics as well as amplification of limited tumor tissue. Besides, it is possible to screen of drug responsibility with a little number of cells. 12 organoids derived from PDX using needle or gun biopsy tumor tissues showed EpCAM overexpression and each unique morphological phenotype. Moreover, from drug responsibility test, H #43 and H #44, an organoids derived from a gemcitabine-sensitive patients, were highly responsible to gemcitabine, whereas the organoids from gemcitabine-resistant patients, G #20 and H #19 showed a strong resistance to gemcitabine as measuring the IC50 value. In addition, combined treatment with gemcitabine and abraxane to the G #13 model which has no clinical information of drug response due to early death, it inhibited organoid formation significantly, showing a combination index below 1, which was proved through in vivo (PDX) validation. Taken together, the PDX-Organoid system might be able to reflect primary tumor characteristics as well as to overcome the quantitative limitations of the specimen and time cost, and thereby it is possible to predict drug response early in vitro, making it very efficient as an anti-cancer drug development platform for pancreatic cancer.
Citation Format: A-Ra Jeon, Sun Il Choi, Sang-Jae Park, Sung-Sik Han, Sun-Young Kong, Min Kyeong Kim, Yu-sun Lee, Jieun Im, Min Kyeong Lee, Sang Hyun Park, Joon-Ki Kim, Kyong-Ah Yoon, Young-Hwan Koh, Ju Hee Lee, Woo Jin Lee, Sang Myung Woo, Yun-Hee Kim. New strategy of drug response assessment using PDX organoid platform for non-resectable pancreatic 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 4098.
Abstract 4102: Surgical imaging of pancreatic cancer using near infrared fluorescent hyaluronic acid nanomaterials
Authors: Qi Bowen , Crawford Ayrianne , Cohen Samuel , Hollingsworth Michael , Mohs Aaron M. 
Published: August 2018

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) has an overall 5-year survival rate for all patients of approximately 7.1%. Surgery only increases the long-term survival rate of PDAC to 12.1%. Survival could potentially be increased with better detection of pancreatic cancer during surgical resection by improved margin detection, more effective debulking of disseminated disease, and earlier detection. In this work, we utilized nanoparticle formulations of the near infrared fluorophore indocyanine green (ICG) to provide optical detection of pancreatic tumors in an orthotopic, syngeneic mouse model of PDAC.
Methods: ICG was physico-chemically entrapped nanoparticles derived from amphiphilic hyaluronic acid, termed NanoICG and compared to ICG alone. Cytotoxicity and immunotoxicity of the imaging agents were determined by in vitro methods, while blood biochemistry, cell counts, and toxicological pathology, were examined in vivo. The ability to detect PDAC was determined in PDAC cells originating from KPC mice that were implanted orthotopically into syngeneic C57 mice. Contrast enhancement was determined using a combination of image-guided surgery systems and whole animal imaging systems.
Results: Neither Empty NP of NanoICG affected metabolic activity toward healthy pancreatic epithelial or pancreatic adenocarcinoma cells and NanoICG displayed did not have capacity to act as a chemoattractant. In vivo, NanoICG (normalized to maximum allowed ICG dose) did not alter blood biochemical markers including HGB, ALB, ALP, ALT, AMY, BUN, GLOB, and TP or cell counts including, WBC, RBC, PLT, or HCT. Histological examination showed no toxicity related to the administration of contrast agents in liver, lung, spleen, or kidneys. In the syngeneic, orthotopic PDAC model, NanoICG accumulated significantly within the pancreas and had a 2.1-fold stronger signal compared to ICG alone. Considering contrast within PDAC compared to uninvolved healthy pancreas, NanoICG was 2.34-fold stronger (P&lt;0.05), while contrast between PDAC and healthy pancreas with ICG was minimally detectable. Using near infrared fluorescence microscopy, area strong signal from NanoICG localized to areas of PDAC.
Conclusions: NanoICG exhibited improved efficacy at detecting pancreatic tumors in an orthotopic pancreatic cancer model with negligible NP-derived toxicity, which shows NanoICG as a promising agent in pancreatic tumor diagnosis and surgical resection. Further research is being performed to minimize clearance organ uptake.&lt;!–EndFragment–&gt;
Citation Format: Bowen Qi, Ayrianne Crawford, Samuel Cohen, Michael Hollingsworth, Aaron M. Mohs. Surgical imaging of pancreatic cancer using near infrared fluorescent hyaluronic acid nanomaterials [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 4102.
Abstract 4114: Development and application of 18F-labeled Tenascin-C aptamer for cancer imaging
Authors: Park Jun Young , Cho Ye Lim , Chae Ju Ri , Chu Ga Eul , Cho Won Gil , Kim Sang Wun , Kang Won Jun 
Published: August 2018

Abstract
Aptamers are synthetic single-stranded DNA or RNA that can be held together with complementary sequences by base-pairing. Tenascin-C is an extracellular matrix protein that is overexpressed in cancer tissues. Herein, we investigate the biological characteristics of Tenascin-C aptamer as potential tumor imaging agents. Cy5 or F-18 labeled Tenascin-C aptamers were prepared through hybridization-based labeling method using complementary oligonucleotide platform. Immunoblot analysis was performed on U-251 MG, U-87 MG, C6 and NCI-H460 cell lines to confirm the expression of tenascin-C. In vitro binding specificity of Tenascin-C aptamers was evaluated using confocal microscopy. In vivo biodistribution properties and PET Imaging of the 18F-labeled Tenascin-C were determined in C6 tumor-bearing nude mice. High levels of tenascin-C protein were detected in C6, U-251 MG. and U-87 MG cell lines. However, tenascin-C protein levels were undetectable in NCI-H460 cells. Confocal fluorescence microscopy images showed that Cy5-labeled Tenascin-C aptamer bound specifically to tenascin-C protein expressing cell lines including C6, U-251 MG and U-87 MG, however, not bound to NCI-H460 cells. Tumor uptake of 18F-labeled Tenascin-C aptamer was 1.64 ± 0.36 at 30 min after injection in C6 tumor xenografts. C6 tumors were clearly visualized by microPET imaging in a tumor-bearing mouse at 60 after injection. Tenascin-C aptamer was successfully labeled with F-18 labeled complementary oligonucleotide by base-pair hybridization. In vitro data showed that the cODN platform-hybridized Tenascin-C aptamer was selectively bound to target tumor cells. In addition, C6 tumor xenografts in mice were clearly visualized on microPET imaging. Our study demonstrated that Tenascin-C may be a useful target molecule for the imaging of malignant gliomas.
Citation Format: Jun Young Park, Ye Lim Cho, Ju Ri Chae, Ga Eul Chu, Won Gil Cho, Sang Wun Kim, Won Jun Kang. Development and application of 18F-labeled Tenascin-C aptamer for cancer imaging [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 4114.