bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3764: Modeling tumors in their environment
Authors: Delgado Juan , Yates James 
Published: August 2015

Abstract
Tumour microenvironment plays an important role in tumour growth. However, the composition and architecture of the tumour stroma varies dramatically across animal models and the clinic. In these animal models, not only the tumour formation, but the whole environment (stroma, mechanical stress…) is very different to the clinical tumour “context”. Nevertheless, explant models show a conserved stroma-tumour architecture. Keeping this in mind, we developed a mathematical model that not only captures tumour growth in animals, but may in the future also translate to patients.
We propose a multiscale model to mimic tumour microenvironment and tumour cell co-development. The model is an agent-based model. The agents (epithelial clusters) represent 10 cells each with 5 transit states (G1, S, G2M, Hypoxic and Necrotic). Also, stromal cells may be recruited, can migrate and deliver blood to the tumour. The transitioning probabilities across the cell cycle are characterised by a pure time delay, followed by an exponential decrease. Further, profiles of chemokines and oxygen are computed as an approximation of the Fick Diffusion equations. These profiles trigger cell recruitment and proliferation. Additionally, cells may undergo hypoxia and become necrotic. All this computed by the Gillespie algorithm method in a 3D lattice in matlab 13b.
The model successfully predicts tumour growth for a number of xenografted cell lines and explants of different cell origin. The patterns of the stromal architecture have been validated against IHC images from explant tumours at the end of study. For the validation, we developed an advanced imaging method to score tumour heterogeneity spatially from different immunostains.
By interrogating the model, we can demonstrate that explant tumours - unlike xenografts - are not completely out of the clinical “context”. Our model being able to mimic the different phenotypes of heterogeneity observed across explants of diverse tissue origins (or patients), demonstrates that this method is potentially very broad. In future versions, the model will include more characteristics of the stroma, which would help us understand reasons why patterns of the stromal complexity form and affect tumour development and its treatment; both in animal studies and the clinic. The model will be contrasted with clinical data.
Citation Format: Juan Delgado, James Yates. Modeling tumors in their environment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3764. doi:10.1158/1538-7445.AM2015-3764
Abstract 3776: HnRNP A1 regulates cell cycle and proliferation in oral squamous cancer cells
Authors: Yu Cheng , Guo Jihua , Jia Jun , Jia Rong , Fan Mingwen 
Published: August 2015

Abstract
Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in human head and neck neoplasms. Despite the improvement of therapeutic approaches, reducing high mortality is still the major challenge of OSCC. However, the molecular pathogenesis of OSCC remains largely unclear, which hinders the development of effective preventive and therapeutic methods. Alternative splicing of pre-mRNA has been implicated to be involved in tumorigenesis. Splicing factors play key roles in the regulation of alternative splicing. HnRNP A1 is an important multi-function splicing factor and closely related to tumorigenesis. It has been reported to be overexpressed in multiple types of tumors. However, the function of A1 in cell cycle and proliferation remains unclear. We found that hnRNP A1 was overexpressed in OSCC tissues and cells by immunohistochemistry and western blotting. Down-regulation of hnRNP A1 with siRNA significantly retarded the growth of OSCC cells and induced G2/M arrest. DNA chip assay showed that the expression of a number of target genes associated with G2/M phase are regulated by hnRNP A1. These findings suggest that hnRNP A1 plays key roles in the regulation of cell cycle progression and pathogenesis of OSCC.
Citation Format: Cheng Yu, Jihua Guo, Jun Jia, Rong Jia, Mingwen Fan. HnRNP A1 regulates cell cycle and proliferation in oral squamous cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3776. doi:10.1158/1538-7445.AM2015-3776
Abstract 3780: Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in osteosarcoma cells
Authors: Baranski Zuzanna , Booij Tijmen T.H. , Jong Yvonne de , Oosterwijk Jolieke van , Cleton Anne-Marie , Price Leo , Water Bob van de , Bovée Judith V.M.G. , Hogendoorn Pancras C.W. , Danen Erik 
Published: August 2015

Abstract
Osteosarcoma is the most common primary bone malignancy with relatively high incidence in young people. Here, we found that expression of Aven was inversely correlated with metastasis-free survival in osteosarcoma patients and is increased in metastases compared to primary osteosarcoma biopsies. Also in chondrosarcoma, the second most common bone sarcoma, expression correlated with increased histological grade. Aven is an adaptor protein that has been implicated in anti-apoptotic signaling and serves as an oncoprotein in acute lymphoblastic leukemia. In human osteosarcoma cells, silencing Aven triggered a G2 cell cycle arrest. Chk1 protein levels were attenuated and ATR-Chk1 DNA damage response signaling in response to chemotherapy was abolished in Aven-depleted osteosarcoma cells while ATM, Chk2, and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven-controlled ATR-Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix-embedded cultures Chk1 inhibition effectively sensitized human osteosarcoma cells to chemotherapy. Together, these findings implicate Aven in ATR-Chk1 signaling and point towards Chk1 inhibition as a strategy to sensitize osteosarcomas to chemotherapy.
Citation Format: Zuzanna Baranski, Tijmen T.H. Booij, Yvonne de Jong, Jolieke van Oosterwijk, Anne-Marie Cleton, Leo Price, Bob van de Water, Judith V.M.G. Bovée, Pancras C.W. Hogendoorn, Erik Danen. Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in osteosarcoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3780. doi:10.1158/1538-7445.AM2015-3780
Abstract 3786: Novel regulation of cyclin D1 stability and the DNA damage response
Authors: Guessous Fadila , Heo Jinho , Vaddadi Naga , Abbas Tarek 
Published: August 2015

Abstract
Deregulation of the cell division cycle is critical for cancer development. Transition from G1 to S phase of the cell cycle is promoted by D-type cyclins (D1, D2 and D3). Cyclin D1 is a critical regulator of cell cycle progression due to its ability to activate cyclin dependent kinases (CDK) 4 and 6, which phosphorylate and inactivate the retinoblastoma protein (pRb) and activates the transcription factor E2F1 to promote the expression of genes essential for G1/S progression. Importantly, mutations in the tumor suppressor gene RB1 or inactivation of the RB tumor suppressor pathway occurs in almost all human malignancies and one such mechanism involves cyclin D1 overexpression. Even in cancer cells with amplified or elevated cyclin D1 mRNA, the Cyclin D1 protein rapidly declines as cells progress through the G1 phase of the cell cycle to reach undetectable levels in S-phase, and this is thought to be dependent on the Skp1-Cul1-F-box protein (SCF) E3 ubiquitin ligase complex. The identity of the E3 ubiquitin ligase that is specifically involved in downregulating cyclin D1 during S-phase of the cell cycle or the functional significance of cyclin D1 downregulation however, remains unknown, as recent genetic studies in mice demonstrated that the steady state levels or stability of cyclin D1 protein, are not altered following the inactivation of the known regulators of cyclin D1 stability. Using a genetic si-RNA-based screen, we have identified a novel E3 ubiquitin ligase; SCF-FBXW5, which specifically interacts with and downregulates cyclin D1 protein, both in unperturbed proliferating cancer cells and following DNA damage. Importantly, inactivation of this E3 ubiquitin ligase inhibits the proliferation of cancer cells primarily through cyclin D1-dependent inhibition of S-phase progression and sensitizes cancer cells to DNA damage induced by UV or ionizing radiation. These findings identify a novel axis of regulating cyclin D1 stability in cancer cells with implications for targeting this axis to inhibit cyclin D1-driven cancers.
Citation Format: Fadila Guessous, Jinho Heo, Naga Vaddadi, Tarek Abbas. Novel regulation of cyclin D1 stability and the DNA damage response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3786. doi:10.1158/1538-7445.AM2015-3786
Abstract 3799: Cordyceptin induces apoptosis through repressing hTERT expression and inducing extranuclear export of hTERT
Authors: Kim Nam Deuk , Kim Gi-Young , Choi Yung Hyun 
Published: August 2015

Abstract
Cordycepin is an adenosine analog originally extracted from Cordyceps militaris that possesses many pharmacological effects including immune activation and antioxidant and antitumor effects. However, the underlying relationship between apoptosis and telomerase activity in response to cordycepin exposure has not been investigated. In this study, we found that cordycepin-induced apoptosis of human leukemia cells (H937 and THP-1 cells) was associated with inactivation of telomerase and downregulation of human telomerase reverse transcriptase (hTERT) as well as the transcription factors c-Myc and Sp1, which are required for basal transcription from the hTERT gene promoter. Cordycepin also attenuated the activation of phosphoinositide-3-kinase (PI3K)/Akt signaling, thereby reducing phosphorylation and nuclear translocation of hTERT. We further showed that the PI3K inhibitor LY29004 significantly decreased telomerase activity in cordycepin-treated cells and increased cordycepin-induced cell death. These findings demonstrate that cordycepin is cytotoxic to human leukemia cells and suppresses telomerase activity through transcriptional and post-translational suppression of hTERT by inactivating the PI3K/Akt signaling pathway.
Citation Format: Nam Deuk Kim, Gi-Young Kim, Yung Hyun Choi. Cordyceptin induces apoptosis through repressing hTERT expression and inducing extranuclear export of hTERT. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3799. doi:10.1158/1538-7445.AM2015-3799
Abstract 3819: A simple method for selectively isolating small size circulating cell-free DNA
Authors: Rodriguez Milka A. , Conroy Amanda , Li Wei wei 
Published: August 2015

Abstract
Elevated levels of circulating cell-free DNA (ccfDNA) in plasma/serum have been associated with several pathological and clinical disorders such as cancer. It was demonstrated that ccfDNA of clinical importance exists predominantly as ∼170 bp fragments in mononucleosomal complexes and isolation of this DNA is challenging. Traditional methods for isolation of ccfDNA have been unreliable since they cannot selectively capture small size DNA from mononucleosomes. Here we describe a simple and reliable method which can be used for selectively isolating ccfDNA from plasma/serum. Different amounts of HeLa mononucleosomes (10-500 ng) were spiked into 0.5 ml of bovine plasma to mimic ccfDNA. First, nucleosomal complexes were captured using size-fractionation magnetic beads. The DNA in the captured nucleosomal complexes was then purified with DNA purification beads. As a control, 500 ng of polynucleosomes (DNA size 2270 bps) were simultaneously spiked with mononucleosomes into 0.5 ml of plasma and subjected to the isolation procedures described above. Fluorescent quantification showed 70-100% recovery of DNA from plasma with the highest recovery (100%) at lower concentrations of spiked mononucleosomes (10 ng). Bioanalyzer results further showed that only 170 bp peak size fragments were present for mononucleosomes alone or for both mono- and poly-nucleosomes spiked into plasma. No peak was observed for polynucleosomes spiked into plasma. These results demonstrate that this method is highly selective and specific for isolation of small size ccfDNA generated from mononucleosomes in plasma and would benefit early cancer detection that uses ccfDNA as biomarkers.
Citation Format: Milka A. Rodriguez, Amanda Conroy, Wei wei Li. A simple method for selectively isolating small size circulating cell-free DNA. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3819. doi:10.1158/1538-7445.AM2015-3819
Abstract 382: Identification and characterization of circulating tumor cells with multiplexed Quantum Dot conjugated antibodies
Authors: Zhou Lanlan , Matthew Elizabeth M. , Dicker David T. , El-Deiry Wafik S. 
Published: August 2015

Abstract
As non-invasive real-time liquid biopsy, circulating tumor cell (CTC) detection and characterization is one of the most active areas in translational cancer research, with 627 clinical trials having that include analysis of CTCs as a biomarker. We used breast cancer cells, prostate cancer cells and melanoma cells spiked into normal donor whole blood and captured with high porosity micro-filters followed by immunofluorescence staining. DAPI, CD45 conjugated with QDot525, CK8/18/19 conjugated with QDot605 and high molecular weight-melanoma associated antigen (HMW-MAA) conjugated with QDot705 were stained to identify CTCs. ER conjugated with QDot800 and PSA conjugated with QDot655 were stained to characterize CTCs. The CTC recovery rate was compared with the report from the US Food and Drug Administration- approved CellSearch® system (Veridex). Multiplexed tumor marker staining results were compared with single staining with fluorescently-labeled secondary antibody. Our study demonstrates that CTC multiplexed analysis has the potential for further genetic characterization of CTCs and offers potential insights into therapeutic targeting and resistance mechanisms.
Citation Format: Lanlan Zhou, Elizabeth M. Matthew, David T. Dicker, Wafik S. El-Deiry. Identification and characterization of circulating tumor cells with multiplexed Quantum Dot conjugated antibodies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 382. doi:10.1158/1538-7445.AM2015-382
Abstract 3822: SOX17 gene promoter methylation in high-grade serous epithelial ovarian cancer
Authors: Giannopoulou Lydia , Chebouti Issam , Pavlakis Kitty , Kasimir-Bauer Sabine , Lianidou Evi S. 
Published: August 2015

Abstract
Introduction: Impaired DNA methylation patterns hold promise as cancer biomarkers. SOX17, a member of the SOX family of transcription factors, is conserved in many species and plays critical roles in the regulation of development and stem/precursor cell function, at least partly through repression of the canonical Wnt/beta-catenin signaling pathway. Global analysis of CpG island hypermethylation and gene expression in colorectal cancer cell lines revealed that SOX17 gene silencing is associated with DNA hypermethylation. We have already shown that this gene is hypermethylated in circulating tumor cells and circulating tumor DNA of patients with breast cancer (Chimonidou et al, Clin Chem 2011, Chimonidou et al, Clin Chem, 2013). High grade serous ovarian cancer (HGSC) is the most common histological subtype of ovarian cancer, with a worse disease prognosis and overall survival. In this study, we investigated for the first time the status of SOX17 promoter methylation in patients with high grade serous ovarian cancer.
Materials and methods: HGSC tumors (FFPEs) from ovarian cancer patients belonging to an independent group (n = 78) and a training group (n = 47) were analyzed.
For the evaluation of the specificity of our results, a small group of 10 corresponding normal tissues from the first ten individuals of the training group was also analyzed. Genomic DNA was isolated from all samples, and then was modified by Sodium Bisulfite (SB). All SB converted DNA samples were analyzed by a real time Methylation Specific PCR (MSP) assay, for detecting SOX17 promoter methylation. The IGROV1 ovarian cancer cell line was used as a positive control in all procedures.
Results: In the training group, SOX17 promoter methylation was detected in 25/47 ovarian tumor samples (53.2%) and in 5/10 corresponding normal tissues. The same 5/10 matched pathological samples of the training group, were also found methylated for the SOX17 gene. In the independent group, SOX17 promoter methylation was observed in 61/78 tumor samples (78.2%).
Conclusion: Our results indicate for the first time that SOX17 promoter methylation is a frequent event in high grade serous ovarian cancer. Further investigation is required to determine the prognostic significance of SOX17 promoter methylation status in ovarian cancer and correlate these findings with patients’ clinicopathological characteristics.
Citation Format: Lydia Giannopoulou, Issam Chebouti, Kitty Pavlakis, Sabine Kasimir-Bauer, Evi S. Lianidou. SOX17 gene promoter methylation in high-grade serous epithelial ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3822. doi:10.1158/1538-7445.AM2015-3822
Abstract 3829: DNA methylation profile in papillary thyroid cancer according to BRAF (V600E) mutation
Authors: Beltrami Caroline Moraes , dos Reis Mariana Bisarro , Barros-Filho Mateus Camargo , Marchi Fabio Albuquerque , Kuasne Hellen , Ambatipudi Srikant , Herceg Zdenko , Kowalski Luiz Paulo , Rogatto Silvia Regina 
Published: August 2015

Abstract
Background: Thyroid cancer is an important health burden and the endocrine neoplasia with highest incidence in worldwide. Papillary thyroid cancer (PTC), the most common thyroid malignancy, is frequently associated with BRAF V600E mutation. This mutation occurs in around 45% of PTC cases and it has been associated with aberrant gene methylation. This finding suggests an association between genetic and epigenetic alterations in tumor development. The goal of this study was to evaluate the methylation profile in PTC samples according to BRAF mutation.
Patients and Method: Forty-two PTC were included in this study (28 positive for BRAF V600E mutation). Normal and tumoral samples were obtained from patients submitted to total thyroidectomy and radioiodine therapy. The pyrosequencing method was used to detect and quantify the BRAF V600E mutation in tumor samples. The methylation analysis was performed by microarray platform Methylation 450 Human Infinium®BeadChip (Illumina), according to the manufacturer's recommendations. The data were normalized and analyzed using SVA, wateRmelon and LIMMA package. It was considered only probes with Delta-Beta (β) = 0.1 and p value ≤ 0.001. Integrative analyses were performed using expression data generated from previous analysis. The findings were compared with 56 samples from The Cancer Genome Atlas (TCGA). Genes enrichment to biological pathways were performed using Ingenuity Pathway Analysis software.
Results: It was identified 404 differentially methylated probes (291 hypomethylated and 113 hypermethylated) of which 195 were validated by TCGA. After the integrative analysis with expression data, nine TOP genes (INF2, TACSTD2, RAB15, TM7SF4, GJB3, CDSN, BHLHE41, GTF2IRD1, CXXC5) were selected with hypomethylation and overexpression. Three of them, BHLHE41, CDSN and INF2, were enriched to cancer and endocrine system disorders pathways (P = 4,47×10−2), highlighting the relevance of these genes in PTC
Conclusion: This study point out putative drivers in PTC according to BRAF mutation revealing epigenetic mechanisms that contributes with cell proliferation and aggressiveness in thyroid carcinoma.
Citation Format: Caroline Moraes Beltrami, Mariana Bisarro dos Reis, Mateus Camargo Barros-Filho, Fabio Albuquerque Marchi, Hellen Kuasne, Srikant Ambatipudi, Zdenko Herceg, Luiz Paulo Kowalski, Silvia Regina Rogatto. DNA methylation profile in papillary thyroid cancer according to BRAF (V600E) mutation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3829. doi:10.1158/1538-7445.AM2015-3829
Abstract 3908: Periostin mediated TNFα and IL-17 induced collagen deposition: Potential role in liver fibrosis
Authors: Tiriveedhi Venkataswarup 
Published: August 2015

Abstract
Background: The pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, and interleukin (IL)-17, have been implicated in the pathogenesis of liver fibrosis. In this study, we investigated the role of TNFα and IL-17 towards induction of profibrotic factor, periostin.
Methods: HepG2 cells were cultured and treated with inflammatory cytokines, TNFα and IL-17. Computational promoter sequence analysis of the periostin promoter was performed to define the putative binding sites for transcription factors. Transcription factors were analyzed by Western blot and Chromatin Immunoprecipitation. Periostin and transcription factor expression analysis was performed by RT-PCR, Western blot, and fluorescence microscopy. Type I collagen expression from fibroblast cultures was analyzed by Western blot and Sircol soluble collagen assay.
Results: Activation of HepG2 Cells with TNFα and IL-17 enhanced the expression of periostin (3.5 and 4.4 fold, respectively p&lt;0.05) compared to untreated cells. However, combined treatment with both TNFα and IL-17 at similar concentration demonstrated a 13.3 fold increase in periostin (p9.1 fold, p&lt;0.01), indicative of a direct fibrogenic effect of TNFα and IL-17.
Conclusion: TNFα and IL-17 induced fibrogenesis through cJun and STAT-3 mediated expression of profibrotic biomarker, periostin. Therefore, periostin might serve as a novel biomarker in early diagnosis of liver fibrosis.
Note: This abstract was not presented at the meeting.
Citation Format: Venkataswarup Tiriveedhi. Periostin mediated TNFα and IL-17 induced collagen deposition: Potential role in liver fibrosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3908. doi:10.1158/1538-7445.AM2015-3908