bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4285: Impact of subsidies on cancer genetic testing uptake in Singapore
Authors: Li Shao Tzu , Yuen Jeanette , Zhou Ke , NGEOW JOANNE 
Published: July 2017

Abstract
Purpose: Previous reports cite high costs of clinical cancer genetic testing as main barriers to patient’s willingness to test. We report findings of a pilot study that evaluates how different subsidy schemes impact genetic testing uptake and total cost of cancer management.
Methods:We included all patients who attended the Cancer Genetics Service at the National Cancer Centre Singapore ( January 2014-May 2016). Two subsidy schemes, the blanket scheme (100% subsidy to all eligible patients), and the varied scheme (patients received 50%-100% subsidy dependent on financial status) were compared. We estimated total spending on cancer management from government’s perspective using a decision model.
Results: 445 patients were included. Contrasting against the blanket scheme, the varied scheme observed a higher attendance of patients (34 vs 8 patients per month), of which a higher proportion underwent genetic testing (5% vs 38%), while lowering subsidy spending per person (S$1098 vs S$1161). The varied scheme may potentially save cost by reducing unnecessary cancer surveillance when first-degree relatives uptake rate is above 36%.
Findings :Provision of subsidy leads to a considerable increase in genetic testing uptake rate. From the government’s perspective, subsidising genetic testing may potentially reduce total costs on cancer management. Understanding and overcoming barriers for cascade testing in first degree relatives can improve cost-savings.
Citation Format: Shao Tzu Li, Jeanette Yuen, Ke Zhou, JOANNE NGEOW. Impact of subsidies on cancer genetic testing uptake in Singapore [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4285. doi:10.1158/1538-7445.AM2017-4285
Abstract 43: ASN004, a novel 5T4-targeted Dolaflexin ADC, achieves complete regressions and tumor-free survivors in a broad variety of solid tumor models
Authors: Smith Roger A. , Zammit David J. , Reddy Sanjeeva P. 
Published: July 2017

Abstract
ASN004 is an Antibody Drug Conjugate (ADC) that targets the 5T4 oncofetal antigen (trophoblast glycoprotein). High expression of 5T4 is observed in a wide range of malignant tumors, while very limited expression is found in normal tissues. ASN004 incorporates a novel single-chain homo-dimer antibody, Fleximer® linker technology (Mersana Therapeutics), and several cytotoxic dolastatin (auristatin) analog warheads per ADC molecule with a drug/antibody ratio of ~15:1. ASN004 shows high affinity for the 5T4 antigen (Kd &lt; 30 pM) and 5T4-expressing tumor cells; rapid cellular internalization; and potent, selective cytotoxicity. ASN004 provides complete tumor regressions and tumor-free survivors in multiple tumor xenograft models, derived from human tumor cell lines having both high and low 5T4 expression levels. Tumor-free survivors were achieved at doses that are well-tolerated, based on xenograft body weight measures and exploratory toxicology studies in pharmacologically-relevant non-human primates. As well, tumor-free survivors were achieved in xenograft tumor models following administration of a single dose of ASN004, as low as 1 mg/kg iv. The broad activity of ASN004 has been demonstrated by its superior efficacy in a head-to-head study against trastuzumab-DM1, in a low-5T4, high-HER2 expressing tumor xenograft model. Finally, tumor xenografts that initially responded to ASN004 and later showed tumor regrowth, had not developed resistance and responded well to subsequent treatment with ASN004. Overall, ASN004 is demonstrated to be an ADC with high therapeutic potential in multiple tumor types, encompassing a wide range of 5T4-expression levels. IND-enabling toxicology studies are ongoing, in preparation for advancement to clinical studies in patients with solid tumors.
Citation Format: Roger A. Smith, David J. Zammit, Sanjeeva P. Reddy. ASN004, a novel 5T4-targeted Dolaflexin ADC, achieves complete regressions and tumor-free survivors in a broad variety of solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 43. doi:10.1158/1538-7445.AM2017-43
Abstract 4332: Interactome between vascular endothelial cells and Proneural glioma stem cells protects seeds for GBM recurrence from radiation therapy
Authors: Bastola Soniya , Pavlyukov Marat S. , Yamaguchi Shinobu , Wang Jun , Komarova Svetlana , kornblum Harley I. , Nakano Ichiro 
Published: July 2017

Abstract
Glioblastoma (GBM) is the most aggressive form of intracranial tumors. Despite multimodal treatment strategies that include surgical resection, radiation and chemotherapy, most patients survive for less than two years. GBM cells tend to invade into adjacent normal brain tissues and therefore, cannot be completely resected by surgery. These remaining tumor cells are the “seeds” to escape post-surgical therapies, thereby giving rise to recurrent tumors during or after treatment. The exact mechanisms by which these seeds contain pre-existing resistant cells, and/or gain resistance to therapy remain elusive. Recent findings demonstrated that communication between normal and GBM cells play physiological roles in tumor initiation and progression. Here, we aim to determine how vascular endothelial (VE) cells affect GBM recurrence in response to radiotherapy. To this end, we first assessed the effect of secreted factors from VE cells on patient-derived GBM neurospheres in vitro by using their conditioned medium (CM). GBM neurospheres promoted their growth with CM from VE cells. qPCR and FACS exhibited that the CM treatment preferentially protected CD133+ population in GBM neurospheres that otherwise were depleted by irradiation treatment. Furthermore, RNA sequencing of VE cells and A2B5-expressing GBM stem-like cells directly isolated from GBM and epilepsy patients demonstrated that only tumor-derived VE cells and GBM stem-like cells express a high level of a secreted factor Endocan (ESM1) and its receptor CD11a, respectively. Preferential expression of CD11a in perivascular GBM cells was also confirmed by immunocytochemistry. Further, we found that recombinant Endocan is able to promote GBM neurosphere growth in vitro after irradiation and protected them from irradiation-induced aggressive mesenchymal transition of these cells. Taken together, these results demonstrate a potential role of a crosstalk between peri-vascular GBM stem-like cells and their adjacent VE cells, via the ligand-receptor interaction mechanism. This interactome network may help Proneural GBM stem cells to escape from radiation therapy, thereby reinitiating the tumor as recurrence via an Endocan-CD11a signaling. Hence, targeting Endocan in endothelial cells or CD11a in GBM cells may have potential as a novel efficacious strategy for preventing recurrence.
Citation Format: Soniya Bastola, Marat S. Pavlyukov, Shinobu Yamaguchi, Jun Wang, Svetlana Komarova, Harley I. kornblum, Ichiro Nakano. Interactome between vascular endothelial cells and Proneural glioma stem cells protects seeds for GBM recurrence from radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4332. doi:10.1158/1538-7445.AM2017-4332
Abstract 4334: Interleukin-6 is a key player in stroma-induced resistance to chemotherapy for gastric carcinomas
Authors: Ham In-Hye , Lee Dakeun , Jin Hyejin , Son Sang Yong , Kim Yong Bae , Han Sang-Uk , Hur Hoon 
Published: July 2017

Abstract
Introduction Gastric carcinomas (GCs) are known to progress through the interaction between cancer cells and the tumor stroma. Moreover, recent molecular analysis revealed that the expression of stroma-related genes was significantly associated with poor response to chemotherapy in GCs. However, the specific targets to inhibit the interaction between stroma and cancer cells and to reverse stroma-induced chemoresistance have never been suggested in GCs.
Experimental procedures The gene expression in the biopsied GCs tissues from 10 patients, who were treated with preoperative chemotherapy, was analyzed using Nanostring analyzer. We compared the expression pattern of genes involved in the cancer progression panel between chemotherapy response and non-response groups. In addition, we investigated the level of serum interleukin-6 (IL-6) in 39 GCs patients, who underwent curative gastrectomy and postoperative adjuvant chemotherapy. GCs patients were subclassified into recurrence and non-recurrence groups, and the level of IL-6 was compared between two groups. We performed cell proliferation assay, qRT-PCR, ELISA and Western blot to investigate the role of cancer-associated fibroblasts(CAFs)-produced IL-6 on the chemoresistance.
Summary of the new data For pretreated biopsied tissues of patients with preoperative chemotherapy, the expression of IL-6 gene in non-response group was significantly higher than response group. In addition, for patients with postoperative adjuvant chemotherapy, the serum level of IL-6 in GCs patients with recurrence was higher than patients without recurrence. Moreover, In vitro studies demonstrate that co-culture with CAFs increased chemoresistance of various GCs cell lines to 5-fluouracil (5-FU) and CAFs-derived IL-6 activated the membrane gp130 and the STAT3 signal pathway in GCs cell lines. When anti-IL-6R monoclonal antibody was added to 5-FU for GCs cell lines in co-culture with CAFs, activation of STAT3 was significantly reduced and apoptosis markers efficiently induced.
Conclusion Our study showed that the stroma-induced IL-6 is a key player in the resistance to chemotherapy in GCs. We convinced that the interaction between stroma cells and cancer cells could be inhibited by blockade of IL-6 signal pathway. We suggest the use of IL-6 inhibitor as therapeutic agent to enhance the response to chemotherapy in GCs.
Citation Format: In-Hye Ham, Dakeun Lee, Hyejin Jin, Sang Yong Son, Yong Bae Kim, Sang-Uk Han, Hoon Hur. Interleukin-6 is a key player in stroma-induced resistance to chemotherapy for gastric carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4334. doi:10.1158/1538-7445.AM2017-4334
Abstract 4340: RHBDF2 in stromal fibroblasts mediates TGF-β signaling and enhances gastric cancer cell invasion via intercellular crosstalk
Authors: Ishimoto Takatsugu , Miyake Keisuke , Yashiro Masakazu , Eto Tsugio , Izumi Daisuke , Arima Kota , Baba Yoshifumi , Watanabe Masayuki , Hirakawa Kosei , Baba Hideo , Tan Patrick 
Published: July 2017

Abstract
Background: Cancer-associated fibroblasts (CAFs) have been reported to promote various types of tumor through secretion of soluble factors. However, there have been no systematic studies of CAFs in diffuse-type gastric cancers (DGCs). We investigated the characteristics and functional roles of CAFs in DGCs using comprehensive genomic approach.
Methods: We established primary fibroblasts, normal fibroblasts (NFs) and CAFs from more than 100 tissue samples from GC patients. NFs/CAFs were subjected to Exome and RNA sequencing, and the possible candidates for functional assay were selected from among the acquired comprehensive data. The candidate molecules were examined the functional roles for GC tumor progression by in vitro assays.
Results: CAFs exhibited an invasive molecular pattern and acquired motility in extracellular matrix (ECM). We identified RHBDF2 as a mediator of TGF-β signaling and an enhancer of CAF motility. RHBDF2 silencing in CAFs significantly decreased their motility stimulated by TGF-β1 in ECM, whereas NFs transfected with the RHBDF2 expression vector displayed a greater motility in ECM than did control NFs. RHBDF2 silencing also decreased type I TGF-β receptor (TβRI) cleavage through tumor necrosis factor (TNF)-α converting enzyme (TACE) activity and attenuated the invasive molecular pattern of CAFs. Consequently, high-motility CAFs confer on DGC cells the ability to invade the ECM. Furthermore, simultaneous treatment with interleukin (IL)-1α, IL-1β and TNF-α resulted in a strong induction of RHBDF2 expression in NFs. The expression of these cytokines in GC tissues was associated with poor prognosis in GC patients.
Conclusion: These findings highlight the underlying mechanism whereby DGC cells take advantage of CAFs to acquire invasiveness.
Citation Format: Takatsugu Ishimoto, Keisuke Miyake, Masakazu Yashiro, Tsugio Eto, Daisuke Izumi, Kota Arima, Yoshifumi Baba, Masayuki Watanabe, Kosei Hirakawa, Hideo Baba, Patrick Tan. RHBDF2 in stromal fibroblasts mediates TGF-β signaling and enhances gastric cancer cell invasion via intercellular crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4340. doi:10.1158/1538-7445.AM2017-4340
Abstract 4342: Loss of MSLN impairs pancreatic cancer growth in the peritoneal cavity
Authors: Rudloff Michael W. , Arons Danielle , El-Behaedi Salma , Albalawy Rakan , Alewine Christine 
Published: July 2017

Abstract
Mesothelin (MSLN) is a cell surface glycoprotein that is expressed in at least 85% of pancreatic adenocarcinoma but not on cells of the healthy pancreas nor in the parenchyma of other vital organs. Due to this differential expression, MSLN has been used as a target for various antibody based treatments and cancer vaccines. The physiologic role of MSLN is unknown. Previous reports have suggested that overexpression of MSLN may increase tumorigenicity and metastatic potential of pancreatic adenocarcinoma. To further define the role of MSLN in this disease, we deleted MSLN from the human pancreatic cancer cell line, KLM1, using CRISPR/Cas9 gene editing. Successful deletion of MSLN was confirmed via flow cytometry and immunoblotting. Furthermore, KLMΔMSLN cells were rendered invulnerable to the MSLN-targeted immunotoxin, RG7787, which depends on the presence of surface MSLN for cytotoxicity. In cell culture, KLMΔMSLN cells grew at the same rate as control cells. KLMΔMSLN formed subcutaneous tumors in nude mice with the same frequency as control cells and these tumors grew at the same rate. However, when nude mice were inoculated with KLMΔMSLN or control cells intraperitoneally, a marked decrease in tumor burden was observed in cells lacking MSLN. In summary, we have engineered a pancreatic cancer cell line that lacks MSLN and demonstrated that loss of MSLN impairs tumor growth and spread specifically within the peritoneal cavity. Further experiments are in progress to identify the factors contributing to this phenotype.
Citation Format: Michael W. Rudloff, Danielle Arons, Salma El-Behaedi, Rakan Albalawy, Christine Alewine. Loss of MSLN impairs pancreatic cancer growth in the peritoneal cavity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4342. doi:10.1158/1538-7445.AM2017-4342
Abstract 4350: Cell-of-origin differentiation stages define methylation-based subtypes of human colorectal cancer
Authors: Bormann Felix , Rodríguez-Paredes Manuel , Bergman Yehudit , Linhart Heinz G. , Lyko Frank 
Published: July 2017

Abstract
Introduction: Colorectal cancer accounts for a significant fraction of cancer-related mortalities, but has proven to be surprisingly refractory to consensus pathological and molecular subclassification. Similarly, little is known about the molecular profiles of colorectal cancer cells-of-origin. DNA methylation is an important epigenomic marker of cellular identity and can therefore be used to infer cancer cells-of-origin.
Methods: Infinium 450k data from colorectal cancer samples provided by “The Cancer Genome Atlas” was applied to a consensus clustering algorithm. The identified epigenetic subgroups were tested for features including well established clinical parameters or subgroup specific gene expression. Additionally, the subgroups were compared with Infinium 450k data of non-malignant colorectal adenomas. Finally, clinical significance was addressed by testing for subgroup specific overall survival rates.
Results: Analysis of the TCGA dataset defined 5 distinct epigenetic subtypes of human colorectal cancer. These subgroups showed an overlap to the microsatellite instability phenotype and the CpG island methylator phenotype. Gene expression based analysis revealed that the subtypes also form a continuum of epigenetic programs reflecting various intestinal crypt cell differentiation stages. Patient survival correlated with the differentiation stage, with a particular poor prognosis for patients with stem cell-related signatures. Interestingly, its prognostic potential outperformed a recently established gene expression-based classifier. Finally, non-malignant colorectal adenomas could be classified into the same methylation subtypes, reflecting their shared cell-types of origin with carcinomas
Conclusion: Our results establish a novel and clinically relevant approach for colorectal cancer classification and illustrate how differences in the cell-type of origin shape the tumor methylome.
Citation Format: Felix Bormann, Manuel Rodríguez-Paredes, Yehudit Bergman, Heinz G. Linhart, Frank Lyko. Cell-of-origin differentiation stages define methylation-based subtypes of human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4350. doi:10.1158/1538-7445.AM2017-4350
Abstract 4354: Methylation-mediated silenced PYCARD plays a key role in human prostate cancer
Authors: Fukushige Shinichi , Miyauchi Toshiya , Okubo Teppei , Mitsuzuka Koji , Arai Yoichi , Horii Akira 
Published: July 2017

Abstract
Epigenetic gene silencing by aberrant DNA methylation leads to loss of key cellular pathways in tumorigenesis. In order to analyze effects of DNA methylation in prostate cancer, we constructed LNCaP-derived human prostate cancer cells that can induce global reactivation of hypermethylated genes by the methyl-CpG targeted transcriptional activation (MeTA) method. In MeTA, a cassette construct of MBD2-derived methyl-CpG binding domain (MBD) with NFκB-derived transcriptional activation domain is transfected into cancer cells. Then expressed MBD domain specifically binds to the hypermethylated promoter regions, and NFκB transcriptional activation domain recruits p300/CREB-binding protein (CBP) and reactivates hypermethylation-mediated silenced genes. A cell proliferation assay indicated that MeTA suppressed the growth of LNCaP cells. Furthermore, both flow cytometry and TUNEL assays demonstrated that MeTA induced apoptosis. In order to search genes responsible for apoptosis, we performed gene expression microarray analysis of MeTA-uninduced and -induced LNCaP cells: Five genes encoding apoptosis-inducing factors upregulated two-fold or more in accordance with the induction of MeTA; PYCARD (PYD and CARD domain containing), TNFRSF25 (tumor necrosis factor receptor superfamily 25), HRK (harakiri, BCL2 interacting protein), BIK (BCL2 interacting killer), and CIDEA (cell death-inducing DFFA-like effector a). These genes also contained CpG islands (CGIs) within ± 1,000-bp of the transcription start site. We focused on PYCARD and TNFRSF25 because these two genes upregulated 10-fold or more in accordance with the induction of MeTA. We found that both genes were hypermethylated and showed low expression levels in LNCaP prostate cancer cells, whereas only PYCARD was unmethylated in RWPE-1 normal prostate epithelial cells. We further analyzed primary prostate cancer tissues and found tumor-specific promoter hypermethylation of PYCARD in 53.8% (7/13; P &lt; 0.01). These results suggest that methylation-mediated silencing of PYCARD contributes to escape from apoptosis in human prostate cancer, and MeTA may provide important clues to analyze changes in cancer cell phenotypes by DNA methylation alterations.
Citation Format: Shinichi Fukushige, Toshiya Miyauchi, Teppei Okubo, Koji Mitsuzuka, Yoichi Arai, Akira Horii. Methylation-mediated silenced PYCARD plays a key role in human prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4354. doi:10.1158/1538-7445.AM2017-4354
Abstract 4373: SOX2-related gene signature predicting the prognosis in head and neck squamous cell cancer
Authors: Eun Young-Gyu , Lee Young Chan , Hwang Jun Eul 
Published: July 2017

Abstract
Purpose: Numerous studies have indicated that Sex-determining region Y-box 2 (SOX2) is involved in many squamous cell carcinomas. However, the role of SOX2 in head and neck squamous cell carcinoma (HNSCC) remains unclear. Therefore, we investigated whether activation of SOX2 is significantly associated with prognosis in HNSCC.
Methods: Gene expression signature reflecting SOX2 activation was identified in HNSCC cohort, and patients were stratified into two groups according to this signature: SOX2-high group or SOX2-low group. Validation of the signature was sought in two independent patient groups. The association between the signature and prognosis of patients was assessed.
Results: The SOX2-low group was associated with poor prognosis for HNSCC in three independent patient cohorts. In a multivariate analysis, the impact of the SOX2 signature on overall survival (OS) was independent of other clinical variables [hazard ratio (HR), 1.45; 95% confidence interval (CI), 1.09 - 1.92; P=0.01]. In patients who received radiotherapy (RT), SOX2-low group had significantly poor OS than those in SOX2-high group.
Conclusions: SOX2-low signature is associated with poor prognosis in patients with HNSCC and could be used to predict patients who would benefit from RT.
Note: This abstract was not presented at the meeting.
Citation Format: Young-Gyu Eun, Young Chan Lee, Jun Eul Hwang. SOX2-related gene signature predicting the prognosis in head and neck squamous cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4373. doi:10.1158/1538-7445.AM2017-4373