bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 921: Cdyl2 is a chromodomain protein involved in the maintenance of pluripotency of stem cells
Authors: Hattori Naoko , Kimura Kana , Taguchi Jumpei , Imai Toshio , Yamada Yasuhiro , Ushijima Toshikazu 
Published: July 2017

Abstract
Reader proteins of histone modifications are required to translate the information of histone marks into the cellular phenotypes, including pluripotency and malignancy. For example, a reader protein BRD4 has its target specificity and becomes a target of cancer therapy. Here, we aimed to identify reader proteins involved in the pluripotency of stem cells. Using the UCSC database, 11 genes coding chromo- or PHD-domain proteins were isolated as actively transcribed in mouse ES cells (ESCs). Among the 11 genes, Cdyl2, chromodomain protein Y-like2, was found to be down-regulated upon ESC differentiation using RT-qPCR. Immunofluorescence and ChIP assay revealed that Cdyl2 recognized H3K27me3 of the specific regions, including differentiation-associated genes. Cdyl2-knock-out ESCs could not survive after differentiation induced by LIF removal or retinoic acid because of the induction of apoptosis, indicating that Cdyl2 is important for normal differentiation of ESCs. ESC expressing exogenous Cdyl2 showed incomplete down-regulation of Oct-4 and Nanog by retinoic acid, and generated teratomas with an abnormal composition of three germ layers, showing perturbation of differentiation ability. Pathologically, aberrant expression of human CDYL2 was observed in breast cancer cell lines and primary breast cancers. Two breast cancer cell lines (MDA-MB-231 and MDA-MB-468) expressing exogenous CDYL2 showed enhanced attachment ability along with the up-regulation of integrin alpha-6 and integrin beta-1. The population of cancer stem cells, defined as ALDH positive cells, were increased in CDYL2-expressing MDA-MB-468 cells, showing that human CDYL2 is involved in proliferation of cancer stem cells. From these data, we conclude that, between self-renewal and differentiation of stem cells, mouse and human Cdyl2/CDYL2 is necessary for the implementation of the initial step of differentiation.
Citation Format: Naoko Hattori, Kana Kimura, Jumpei Taguchi, Toshio Imai, Yasuhiro Yamada, Toshikazu Ushijima. Cdyl2 is a chromodomain protein involved in the maintenance of pluripotency of stem cells [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 921. doi:10.1158/1538-7445.AM2017-921
Abstract 922: Delta133p53 represses p53-inducible senescence genes and enhances the generation of human induced pluripotent stem cells
Authors: Horikawa Izumi , Park Kye-yoon , Li Han , Isogaya Kazunobu , Hiyoshi Yukiharu , Anami Katsuhiro , Robles Ana I. , Mondal Abdul M. , Fujita Kaori , Serrano Manuel , Harris Curtis C. 
Published: July 2017

Abstract
p53 functions to induce cellular senescence and apoptosis, which can be incompatible with self-renewal of pluripotent stem cells such as induced pluripotent stem cells (iPSC) and embryonic stem cells (ESC). On the other hand, p53 regulates DNA damage response and repair and thus plays an essential role in maintaining genomic integrity and suppressing malignant transformation in iPSC and ESC. It remains to be elucidated whether and how p53 and its regulators contribute to balanced regulation between the self-renewing capacity and the genomic and functional integrity in these pluripotent stem cells. We hypothesized the involvement of Δ133p53, a physiological p53 protein isoform that inhibits the activity of full-length p53 (FL-p53), and here examined 12 lines of human iPSC and their original fibroblasts, as well as 3 human ESC lines, for endogenous protein levels of Δ133p53 and FL-p53, and mRNA levels of p53 target genes of different functions. While FL-p53 levels in iPSC and ESC widely ranged from below to above those in the fibroblasts, all iPSC and ESC lines expressed elevated levels of Δ133p53. The p53-inducible genes that mediate cellular senescence (e.g., p21WAF1 and miR-34a), but not those for apoptosis and DNA repair, were downregulated in iPSC and ESC. Consistent with these endogenous expression profiles, overexpression of Δ133p53 in human fibroblasts preferentially repressed the p53-inducible senescence mediators and significantly enhanced their reprogramming to iPSC. The iPSC clones derived from Δ133p53-overexpressing fibroblasts, when injected into immunodeficient mice, formed well-differentiated, benign teratomas, suggesting that Δ133p53 overexpression is non- or less oncogenic than total inhibition of p53 activities. Overexpressed Δ133p53 prevented FL-p53 from binding to the regulatory regions of p21WAF1 and miR-34a, providing a mechanistic basis for its dominant-negative inhibition. This study supports the hypothesis that upregulation of Δ133p53 is an endogenous mechanism that facilitates human somatic cells to become pluripotent without malignant transformation.
Citation Format: Izumi Horikawa, Kye-yoon Park, Han Li, Kazunobu Isogaya, Yukiharu Hiyoshi, Katsuhiro Anami, Ana I. Robles, Abdul M. Mondal, Kaori Fujita, Manuel Serrano, Curtis C. Harris. Delta133p53 represses p53-inducible senescence genes and enhances the generation of human induced pluripotent stem cells [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 922. doi:10.1158/1538-7445.AM2017-922
Abstract 925: Tumorigenesis of murine iPS cell is prevented by iron depletion with downregulation of stemness markers
Authors: Katsura Yuki , Ohara Toshiaki , Kashima Hajime , Sato Hiroaki , Kato Takuya , Ninomiya Takayuki , Noma Kazuhiro , Tomono Yasuko , Tazawa Hiroshi , Kagawa Shunsuke , Shirakawa Yasuhiro , Fujiwara Toshiyoshi 
Published: July 2017

Abstract
Background: Iron plays a crucial role in the various metabolic pathways and it is essential for life. However excess of iron is known to cause cancer. There are many reports that iron depletion treatment indicates antitumor effect. Previously, we have confirmed that iron depletion treatment indicates antitumor effect against Cancer stem cell (CSC) model, miPS-LLCcm, which was converted from murine induced pluripotent stem cell (miPS cell) in Okayama university (Chen at el. PLOS ONE 2012), and also suppresses CSC markers. Many tumors contain phenotypically and functionally heterogenous cancer cells due to pluripotency of CSC. Although there are various theories about the origin of CSC, miPS has a pluripotency and regarded as the top of the hierarchy, it can be the candidate of the origin of CSC. miPS cell is known to form teratoma when inoculated into nude mouse because of its undifferentiated status. We hypothesized if we could suppress the stemness and tumorigenicity of miPS cell by iron depletion treatment, it can be applied to the therapy for CSC and undifferentiated status cancer cell. In this study, we investigated the stemness and tumorigenecity of miPS cell with iron depletion treatment.
Methods: We used miPS cell(cell name : iPS-MEF-Ng-20D-17) purchased from Riken Cell Bank(Japan). Deferasirox (DFX), an popular commercial available oral iron chelator was used for iron depletion treatment. Western blot analysis was done to examine the expression of the stemness markers including Nanog, Oct3/4, Sox2, Klf4, c-Myc. Subcutaneous model of miPS cell and miPS cell treated with DFX (50μM) were used in vivo study. Tumors were harvested for immunohistochemistry.
Results: Stemness markers of miPS cell were suppressed strongly by DFX in western blot analysis. DFX also suppressed the subcutaneous tumor growth. The average tumor volume of the control group was 665.3±430.8mm3 while that of the DFX treated group was 204.3±76.2 mm3(p&lt;0.05) on day 20. Immunohistochemistry of the tumor revealed the suppression of the stemness markers in the DFX treated group compared with the control group.
Citation Format: Yuki Katsura, Toshiaki Ohara, Hajime Kashima, Hiroaki Sato, Takuya Kato, Takayuki Ninomiya, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Tumorigenesis of murine iPS cell is prevented by iron depletion with downregulation of stemness markers [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 925. doi:10.1158/1538-7445.AM2017-925
Abstract 933: Bcl-xL overexpression promotes tumor aggressiveness
Authors: Tupone Maria Grazia , Trisciuoglio Daniela , Desideri Marianna , Martile Marta Di , Gabellini Chiara , Buglioni Simonetta , Salvo Laura De , Alessandrini Gabriele , D'Aguanno Simona , Bufalo Donatella Del 
Published: July 2017

Abstract
Bcl-xL is an antiapoptotic protein highly expressed in cancer and contributes to tumor initiation and progression by promoting cell survival. It also promotes tumor angiogenesis and metastasis. By using M14 melanoma and ADF glioblastoma cell lines and their derivative bcl-xL overexpressing clones, in the current study, we investigated the role of bcl-xL in aggressive features of melanoma and glioblastoma models. We found that in both models, bcl-xL overexpression increased in vitro cell migration and invasion and facilitated tumor cells to form de novo vasculogenic structures. Furthermore, bcl-xL overexpressing cells exhibited significantly higher tumorsphere formation capacity, reflecting the self-renewal activity, and expressed high levels of some stem cell markers, supporting the concept that bcl-xL plays essential roles in the maintenance of cancer stem cells phenotype. Forced expression of bcl-xL in melanoma cells also increased vascular endothelial growth factor (VEGF) and matrix metalloprotease-2 (MMP-2) expression, and the activation of hypoxia-inducible factor 1 (HIF-1), a key pathway involved in melanoma vascularization and aggressiveness. On the contrary, no differences were observed after bcl-xL overexpression in glioblastoma model, in terms of HIF-1 expression and activity, and VEGF protein secretion. Immunohistochemical analysis revealed that the expression of the vascular markers, and the vasculogenic mimicry were upregulated in the bcl-xL overexpressing xenografts derived from both tumor histotypes. The work presented here brings further support to the understanding of the malignant actions of bcl-xL both in melanoma and glioblastoma, and in particular to the concept that bcl-xL contributes to the aggressiveness of these two tumor histotypes by promoting invasion, migration, vasculogenic mimicry and cancer stem cells phenotype. It also indicates a cell type-specific effect of bcl-xL on HIF-1/VEGF axis.
Citation Format: Maria Grazia Tupone, Daniela Trisciuoglio, Marianna Desideri, Marta Di Martile, Chiara Gabellini, Simonetta Buglioni, Laura De Salvo, Gabriele Alessandrini, Simona D'Aguanno, Donatella Del Bufalo. Bcl-xL overexpression promotes tumor aggressiveness [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 933. doi:10.1158/1538-7445.AM2017-933
Abstract 944: Chemokine receptor signaling as a new tool to improve lung cancer diagnostics and therapy
Authors: Nagy-Major Katalin , Sänger Jörg , Kulkarni Harshad R. , Fix Peter , Kunze Almut , Lupp Amelie , Bonnet Reiner , Seeger Werner , Baum Richard P. , Grabowski Patricia , Savai Rajkumar 
Published: July 2017

Abstract
Background: The tumor microenvironment plays a critical role in cancer development, progression, and control. We demonstrated in vitro and in vivo that a bidirectional crosstalk between tumor-associated macrophages and cancer cells via CCR2-CCL2 and CX3CR1-CXCL1 signaling is fundamental for lung cancer growth and metastasis offers new treatment concepts.
Aim: Our working hypothesis is to develop a new platform for specific chemokine receptor (CCR2) PET imaging and a range of theranostic applications in lung cancer. For this purpose, we planned to define the CCR2 expression in NSCLC as well as in SCLC, tumor cells as well as immune/inflammatory cells.
Material and Methods: This is a multicenter trial with patients from Zentralklinik Bad Berka GmbH (n =100 NSCLC, n=100 SCLC). All patients gave informed consent according to the declaration of Helsinki. FFPE material was available in all cases. CCR2 CXCR4 and CX3CR1 expression was determined by immunohistochemistry with the avidin-biotin-peroxidase-complex.
Results: Analyzing 96 NSCLC (47 adenocarcinoma, 49 squamous cell carcinoma) and 45 SCLC tumor samples, we found CXCR4 and CCR2 chemokine receptor expression in tumor, immune and inflammatory cells. In NSCLC, co-expression between CCR2 and CXCR4 staining was very high concerning their expression on tumor cells rising with higher tumor stages, proliferation rate and grading. CCR2 expression in immune cells was restricted to lower stages; the same pattern could be observed in 45 SCLC tumor samples where CCR2 expression on immune cells was found especially in limited disease rather than in metastatic disease; CXCR4 expression in tumor cells was found to be high in all stages of SCLC. To evaluate the therapeutic efficacy of CCR2 antagonism in vivo, we injected LLC1 s.c. into WT mice treated with CCR2 antagonist (RS504393) or vehicle. Notably, tumor growth was significantly inhibited in CCR2 antagonist-treated mice as compared with vehicle-treated mice.
Discussion: Our preliminary results show a significant portion of CCR2 positive tumors - NSCLC as well as SCLC which would qualify for a CCR2-based imaging as well as - demonstrated in our mice models - CCR2 inhibitory strategies. This should be evaluated in further preclinical trials.
Citation Format: Katalin Nagy-Major, Jörg Sänger, Harshad R. Kulkarni, Peter Fix, Almut Kunze, Amelie Lupp, Reiner Bonnet, Werner Seeger, Richard P. Baum, Patricia Grabowski, Rajkumar Savai. Chemokine receptor signaling as a new tool to improve lung cancer diagnostics and 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 944. doi:10.1158/1538-7445.AM2017-944
Abstract 947: CXCR4 in combination with immune check point inhibition in ovarian cancer mouse model demonstrates potential for novel therapeutic strategies
Authors: Starbuck Kristen , McGray Robert , Masoumi-Moghaddam Samar , Francois Ariel , Odunsi Kunle , Zsiros Emese 
Published: July 2017

Abstract
Chemokine CXCL12 and its receptor CXCR4 are the most highly expressed chemokine axis in serous ovarian cancer. CXCR4 promotes tumor growth, angiogenesis, and metastasis. High CXCR4 expression is associated with poor survival, making it an attractive therapeutic target. The objective of this study was to establish an immune competent murine ovarian cancer model with high CXCR4 expression and to test single agent CXCR4 blockade and combination therapy to optimize emerging treatment strategies for future clinical trials. CXCR4 expression was evaluated by flow cytometry in ID8, ID8-VEGF, IE9-MP1, BR5, BR5-Akt, BR5-C2k, and BR5-Kras mouse ovarian cancer cell lines as well as IE9-MP1 tumor samples. Subsequently an exploratory study was undertaken utilizing the ID8 immune competent mouse model to assess the efficacy of AMD3100, the only commercially available CXCR4 inhibitor, alone and in combination with bevacizumab and anti-PD-1. Immune analysis of circulating lymphocytes by flow cytometry was performed during treatment to monitor changes of immune cell subsets. Surface expression of CXCR4 receptor was minimal in ID8 (1.6%), ID8-VEGF (0.9%), IE9-MP1 (1.8%), BR5 (0.9%), BR5-Akt (1.2%), BR5-C2k (2.3%), and BR5-Kras (1.1%), however intracellular staining revealed widespread CXCR4 expression in ID8 (99.6%), ID8-VEGF (99.7%) BR5 (96.7%), BR5-Akt (94.3%), BR5-C2k (98.2%), and BR5-Kras (98.7%) cell lines. Using the ID8 intraperitoneal ovarian cancer mouse model in C57BL/6J mice, treatment with immunotherapy significantly increased cell surface expression of CXCR4 from 2% in the control group to 79.6-91.8% in the treatment group. Treatment with AMD3100 as a single agent showed no improvement in survival over control. However, AMD3100 in combination with anti-PD-1 therapy significantly improved survival. The addition of bevacizumab demonstrated no further survival benefit and bevacizumab as a single agent showed no improvement in survival over control, either alone or in combination with anti-PD-1. Analysis of circulating lymphocytes revealed a trend toward higher CD4 to CD8 ratio in mice who were treated with anti-PD1 therapy. Targeting the CXCL12-CXCR4 axis in combination with other immunotherapies such as immune checkpoint inhibitors is a novel therapeutic strategy which may provide benefit over single-agent immunotherapy and warrant investigation in a clinical trial.
Citation Format: Kristen Starbuck, Robert McGray, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros. CXCR4 in combination with immune check point inhibition in ovarian cancer mouse model demonstrates potential for novel therapeutic strategies [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 947. doi:10.1158/1538-7445.AM2017-947
Abstract 971: Genome directed diagnosis informs clinical cancer care
Authors: Penson Alexander , Camacho Niedzica , Varghese Anna M. , Abeshouse Adam , Razavi Pedram , Syed Aijazuddin , Zehir Ahmet , Schultz Nikolaus , Solit David B. , Hyman David , Taylor Barry S. , Berger Michael F. 
Published: July 2017

Abstract
Cancer treatment is primarily guided by the organ of origin, which despite extensive histopathological and clinical evaluation, remains ambiguous in many cases and may be inaccurate in cases of occult primary. We determine the extent to which routine prospective tumour sequencing, combined with conventional histopathology, can be used to infer the tumor type and thereby direct clinical decisions.
Characteristic patterns of somatic mutations, broad and focal copy number alterations, structural rearrangements, mutational signatures, and other facets acquired from prospective tumor sequencing can inform the tissue of origin classification of patient disease. Such prospective sequencing of active cancer patients presents an opportunity to guide diagnosis and therapy beyond the identification of individual biomarkers of treatment response. Probabilistic classification allows for systematic combination of genome-directed diagnosis with conventional histopathology and clinical history in the course of disease management.
Using more than 10,000 tumors collected from advanced cancer patients at our institution and sequenced using a comprehensive cancer panel (MSK-IMPACT) encompassing 341 genes, we have developed a probabilistic classifier that infers the tumor type from nine broad categories of genomic aberrations. Scores from a RandomForest classifier are calibrated to correspond to the probability for each of the 22 interrogated tumor types. In 18% of all cases, a prediction is made with very high confidence (greater than 99%), of which just over 99% agree with the existing diagnosis. The classifier has been used to guide clinical decision making, including re-diagnoses that distinguish between a recurrence and a new primary, spare or encourage surgery, facilitate access to FDA-approved molecularly targeted drugs and prompt germline genetic testing.
We demonstrate that genome-directed diagnosis, based on alterations routinely identified from prospective sequencing, can inform clinical cancer care with the potential to improve patient outcomes.
Citation Format: Alexander Penson, Niedzica Camacho, Anna M. Varghese, Adam Abeshouse, Pedram Razavi, Aijazuddin Syed, Ahmet Zehir, Nikolaus Schultz, David B. Solit, David Hyman, Barry S. Taylor, Michael F. Berger. Genome directed diagnosis informs clinical cancer care [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 971. doi:10.1158/1538-7445.AM2017-971
Abstract 988: Effect of a supervised exercise intervention on sarcopenic obesity and metabolic syndrome in prostate cancer patients: A randomized pilot study
Authors: Kiwata Jacqueline L. , Dorff Tanya B. , Schroeder E. T. , Dieli-Conwright Christina M. 
Published: July 2017

Abstract
Purpose: Prostate cancer survivors (PCS) on androgen deprivation therapy (ADT) experience adverse side effects such as skeletal muscle loss and adiposity gain, together called sarcopenic obesity, and changes in cardiometabolic factors that increase risk of metabolic syndrome (MetS). Resistance exercise can increase skeletal muscle mass, but no exercise interventions to date in PCS on ADT have concomitantly improved sarcopenic obesity and cardiometabolic risk factors. Utilizing a 12-week intervention of progressive resistance exercise designed to target skeletal muscle mass, this ongoing pilot trial investigates sarcopenic obesity and as a secondary analyses, MetS components, in PCS on ADT.
Methods: Eighteen PCS (65.6±8.8 yr) on current or previous ADT were recruited from the USC Norris Comprehensive Cancer Center and randomized to resistance training (RT; n=9) or a control stretching program (CS; n=9). Body composition, measured through dual-x-ray absorptiometry, and MetS outcomes, including waist circumference, blood pressure, fasting blood glucose, triglycerides and HDL, were assessed at baseline and after the 12-week intervention. Appendicular skeletal muscle index (ASMI), a common index of sarcopenia, was calculated from body composition. RT performed a supervised total-body resistance exercise and stretching program 3 times/week. CS performed home-based stretching 3 times/week. Baseline differences were tested with univariate ANOVA. Differences in all outcomes were tested with 2(group) x 2(time) ANOVA.
Results: No significant differences in ADT duration, Gleason score, body fat, skeletal muscle mass, or MetS components were found between groups at baseline (P&gt;0.05). RT program compliance was 98.3%, while CS program compliance was 75.5%. Post-intervention, significant increases were observed in RT compared to CS for appendicular skeletal mass (mean±SE; 0.8±.4 kg; P=0.04) and ASMI (0.3±.1 kg/m2; P=0.041). A nonsignificant decrease in body fat (%) was observed in RT compared to CS (1.3±.7 %; P=.067; d=0.89). No differences were found in MetS components.
Conclusions: While 12 weeks of resistance exercise in PCS on ADT improved skeletal muscle mass, no changes in adiposity and MetS variables were observed. Future interventions are needed for PCS to determine the optimal exercise prescription to target both sarcopenic obesity and cardiometabolic risk factors.
Citation Format: Jacqueline L. Kiwata, Tanya B. Dorff, E. T. Schroeder, Christina M. Dieli-Conwright. Effect of a supervised exercise intervention on sarcopenic obesity and metabolic syndrome in prostate cancer patients: A randomized pilot study [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 988. doi:10.1158/1538-7445.AM2017-988