bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 122: PARK2 is a negative regulator of Wnt and EGFR pathways in glioma
Authors: Xu Liang , Lin De-Chen , Chen Ye , Yan Haiyan , Hazawa Masaharu , Doan Ngan , Said Jonathan W. , Ding Ling-Wen , Liu Li-Zhen , Yang Henry , Yu Shi-zhu , Kahn Michael , Yin Dong , Koeffler Phillip 
Published: August 2015

Abstract
PARK2 is an E3 ubiquitin ligase whose dysfunction has been associated with the progression of autosomal recessive juvenile Parkinson's disease and human malignancies. However, its role in cancer remains to be explored. In this study, we report that PARK2 is frequently deleted and underexpressed in human glioma, and low PARK2 expression is associated with poor survival in cohorts of both low-grade glioma and glioblastoma multiforme (GBM). Functional studies revealed a tumor-suppressive role of PARK2 in GBM cells. Restoration of PARK2 significantly inhibited glioma cell growth both in vitro and in vivo, while depletion of endogenous PARK2 promoted cell proliferation. cDNA microarray analysis showed that PARK2 expression strongly altered the activity of both the Wnt and EGFR pathways. Immunoblot analysis confirmed that ectopic expression of PARK2 suppressed the intracellular levels of β-catenin, EGFR, as well as their down-stream targets including Cyclin D1, TCF4, c-Myc, p-AKT and p-S6K, etc. Notably, PARK2 physically interacted with both β-catenin and EGFR, and promoted their ubiquitination in an E3-ligase dependent manner. Similar to the ligase-dead PARK2 mutant (C431S), three PARK2 mutants harboring cancer-derived somatic mutations (T173A, T240M and P294S) showed decreased ability to ubiquitinate either β-catenin or EGFR proteins. We further found that PARK2 attenuated the cellular response to both Wnt3a and EGF stimulation, suggesting PARK2 is a negative regulator of both the Wnt and EGFR pathways. Lastly, inspired by these newly identified functions of PARK2, we tested and proved that the combination of small-molecule inhibitors targeting both Wnt-β-catenin and EGFR-AKT pathways synergistically impaired glioma cell viability. In aggregate, our findings uncover novel, cancer-associated functions of PARK2 and provide a potential therapeutic approach to treat glioma.
Citation Format: Liang Xu, De-Chen Lin, Ye Chen, Haiyan Yan, Masaharu Hazawa, Ngan Doan, Jonathan W. Said, Ling-Wen Ding, Li-Zhen Liu, Henry Yang, Shi-zhu Yu, Michael Kahn, Dong Yin, Phillip Koeffler. PARK2 is a negative regulator of Wnt and EGFR pathways in glioma. [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 122. doi:10.1158/1538-7445.AM2015-122
Abstract 1223: LIF is a novel negative regulator of p53 in colorectal cancers
Authors: Hu Wenwei , Yu Haiyang , Yue Xuetian , Zhao Yuhan , Zhang Cen , Young Ken , Liu Juan , Feng Zhaohui 
Published: August 2015

Abstract
Leukemia inhibitory factor (LIF), a cytokine of the interleukin 6 superfamily,is involved in multiple biological functions. Recently, we identified that LIF is a p53 target gene which mediates the role of p53 in maternal implantation under normal physiological conditions in both mice and humans. However, to date, the role of LIF in tumorigenesis, especially colorectal cancers, is poorly understood. Here, we report that LIF is a negative regulator of p53; LIF downregulates p53 protein levels and function in transcriptional activity, apoptosis and senescence in human colorectal cancer cells. The downregulation of p53 by LIF is mediated by the activation of Stat3; blocking the Stat3 pathway largely abolishes the inhibitory effect of LIF on p53. We further identified that Stat3 transcriptionally induces ID1, the helix-loop-helix (HLH) protein inhibitor of differentiation and DNA binding to mediate its role in the negative regulation of p53. ID1 upregulates MDM2, a key negative regulator of p53, and promotes MDM2-mediated p53 protein degradation. We found that LIF is overexpressed in a large percentage of colorectal cancers. In turn, LIF overexpression promotes cellular resistance towards chemotherapeutic agents in cultured colorectal cancer cells and colorectal xenograft tumors in a largely p53-dependent manner. Furthermore, we found that overexpression of LIF is associated with a poor prognosis in colorectal patients. Taken together, LIF is a novel negative regulator of p53, overexpression of LIF is an important mechanism for the attenuation of p53, which promotes chemoresistance in colorectal cancers. Targeting LIF, Stat3 as well as ID1 to reactivate p53 is a potential therapeutic strategy to enhance chemosensitivity in colorectal cancer, especially in tumors with LIF overexpression.
Citation Format: Wenwei Hu, Haiyang Yu, Xuetian Yue, Yuhan Zhao, Cen Zhang, Ken Young, Juan Liu, Zhaohui Feng. LIF is a novel negative regulator of p53 in colorectal cancers. [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 1223. doi:10.1158/1538-7445.AM2015-1223
Abstract 1227: Differential efficacy of p53 restoration in induction and maintenance of senescence in premalignant and malignant cells
Authors: Harajly Mohammad , Zalzali Hassan , Ghayad Sandra , Ghamloush Farrah , Jabbour Mark , Basma Hussein , Tawil Ayman , Nawaz Zafar , Saab Raya H. 
Published: August 2015

Abstract
Restoration of p53 in tumors has been suggested as a possible therapeutic approach, based on preclinical in vivo and in vitro evidence of possible efficacy. However, the relationship between the timing of p53 restoration and its efficacy is still unclear. We now show that restoration of p53 in murine pre-malignant proliferating pineal tumors results in effective cell cycle exit and induction of cellular senescence, while p53 reactivation in established malignant pineal tumors does not impact cell proliferation, unless paired with DNA damaging therapies. This differential effect was not related to levels of p19Arf expression, as its expression was more pronounced in malignant tumors, nor to MAPK pathway activity. Interestingly, in premalignant lesions induced to senesce by p53 restoration, inactivation of p53 after senescence resulted in re-entry into the cell cycle, and rapid tumor progression. These findings were also validated in cell culture models of Cyclin D1-induced and RasV12-induced senescence in murine pineal cells and mouse embryo fibroblasts, respectively. Evaluation of a panel of human supratentorial primitive neuroectodermal tumors (sPNET), of which pineoblastoma is a subtype, showed low activity of the p53 pathway, while only one of 6 tumors had p53 deletion or mutation. Together, this data shows that restoration of the p53 pathway has different effects in premalignant versus invasive pineal tumors, where it may need to be paired with DNA damaging agents, to engage it in tumor suppression. Furthermore, p53 activation may need to be continually sustained for effective tumor suppression in such lesions undergoing senescence as a tumor suppressor mechanism. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene seems to be intact but the pathway inactive in the majority of examined tumors.
Citation Format: Mohammad Harajly, Hassan Zalzali, Sandra Ghayad, Farrah Ghamloush, Mark Jabbour, Hussein Basma, Ayman Tawil, Zafar Nawaz, Raya H. Saab. Differential efficacy of p53 restoration in induction and maintenance of senescence in premalignant and malignant 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 1227. doi:10.1158/1538-7445.AM2015-1227
Abstract 1254: Mitochondrial SOD2 regulates EMT and cancer stem cell-like cell populations
Authors: Whelan Kelly A. , Kinugasa Hideaki , Tanaka Koji , Srinivasan Satish , Guha Manti , St. Clair Daret , Klein-Szanto Andres , Avadhani Narayan , Diehl Alan , Rustgi Anil , Nakagawa Hiroshi 
Published: August 2015

Abstract
Epithelial-mesenchymal transition (EMT) is involved in cancer cell invasion, metastasis and treatment failure. EMT may promote conversion of a subset of cancer cells defined by low expression of CD44 (CD44L) to those with high expression of CD44 (CD44H), the latter associated with increased malignant properties of cancer cells. Triggered by a variety of stimuli such as transforming growth factor (TGF)-β, hypoxia and chemoradiation, EMT may be activated in cancer cells via stress-induced reactive oxygen species (ROS) in the tumor microenvironment. Excessive ROS may cause cell death or senescence; however, cells undergoing EMT may require a physiological level of ROS. It remains elusive as to how cellular antioxidant capabilities may influence EMT. Mitochondrial superoxide dismutase 2 (SOD2) is frequently overexpressed in oral and esophageal cancers. Here, we investigated mechanisms of SOD2 transcriptional regulation in EMT as well as the functional role of this antioxidant in EMT. Using well-characterized genetically engineered oral and esophageal human epithelial cell lines coupled with RNA interference (RNAi) and flow cytometric approaches, we find that TGF-β stimulates EMT, resulting in conversion of CD44L to CD44H cells, the latter of which display SOD2 upregulation. SOD2 induction in transformed cells was concurrent with suppression of TGF-β-mediated induction of both ROS and senescence. SOD2 gene expression appeared to be transcriptionally regulated by NF-κB and ZEB2, but not ZEB1. Moreover, SOD2-mediated antioxidant activity may restrict conversion of CD44L cells to CD44H cells at the early stages of EMT. In aggregate, this study provides novel mechanistic insights into the dynamic expression of SOD2 during EMT and delineates a functional role for SOD2 in EMT, influencing distinct CD44L and CD44H subsets of cancer cells that have been implicated in oral and esophageal tumor biology.
Note: This abstract was not presented at the meeting.
Citation Format: Kelly A. Whelan, Hideaki Kinugasa, Koji Tanaka, Satish Srinivasan, Manti Guha, Daret St. Clair, Andres Klein-Szanto, Narayan Avadhani, Alan Diehl, Anil Rustgi, Hiroshi Nakagawa. Mitochondrial SOD2 regulates EMT and cancer stem cell-like cell populations. [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 1254. doi:10.1158/1538-7445.AM2015-1254
Abstract 1275: Chemotactic factors underlying tumor infiltration by immunocompetent cells in colorectal cancer
Authors: Cremonesi Eleonora , Amicarella Francesca , Padovan Elisabetta , Muraro Manuele G. , Mele Valentina , Zajac Paul , Hirt Christian , Droeser Raoul , Oertli Daniel , Zuber Markus , Adamina Michel , Rosso Raffaele , Garzon Jesus G. , Borsig Lubor , Spagnoli Giulio C. , Iezzi Giandomenica 
Published: August 2015

Abstract
Colorectal cancer (CRC) is a leading cause of cancer related death. Several studies have convincingly showed that CRC infiltration by immunocompetent cells and, in particular, cytotoxic CD8+ T cells, IFN-γ-producing cells, Foxp3+ regulatory T cells and CD16+ MPO+ neutrophils, is significantly associated with prolonged patient survival. However, the factors driving these cell populations into the tumor site remain to be elucidated. We are investigating the chemokine/chemokine receptor network promoting CRC infiltration by immune cells associated to favorable prognosis.
We have analysed the expression of a panel of genes encoding for 39 chemokines and for 7 markers identifying specific immune cell types in 58 freshly excised specimens of CRC and corresponding control colonic tissues. In parallel, chemokine receptor profiles on clinically relevant immunocompetent cell populations have been characterized by flow cytometry.
Our results suggest that tumor infiltration by immunocompetent cells associated to favorable prognosis is linked to the expression of three main chemokine patterns: 1) CCL3, CCL5, CXCL9, and CXCL10 capable of recruiting cytotoxic CD8+ and IFN-γ producing T cells; 2) CCL22 and CXCL12 attracting Foxp3+ regulatory T cells; 3) CXCL2, CXCL5 and CXCL8 inducing migration of CD16+ MPO+ neutrophils. We have started to investigate the chemokine sources. CRC cells purified from tumor specimens were found to express chemokines potentially recruiting T and myeloid cells, including CCL3, CCL5, CXCL9, CXCL10, CXCL12, and CXCL2, CXCL5, CXCL8. The stimuli driving chemokine expression by tumor cells remain however to be clarified and are currently under investigation.
Citation Format: Eleonora Cremonesi, Francesca Amicarella, Elisabetta Padovan, Manuele G. Muraro, Valentina Mele, Paul Zajac, Christian Hirt, Raoul Droeser, Daniel Oertli, Markus Zuber, Michel Adamina, Raffaele Rosso, Jesus G. Garzon, Lubor Borsig, Giulio C. Spagnoli, Giandomenica Iezzi. Chemotactic factors underlying tumor infiltration by immunocompetent cells in colorectal 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 1275. doi:10.1158/1538-7445.AM2015-1275
Abstract 1279: Expression of B7-H5 in human pancreatic caner
Authors: Zhu Yuwen , Byers Joshua , Paniccia Alessandro , Kaplan Jeffrey , Koenig Michelle , Schulick Richard , Edil Barish 
Published: August 2015

Abstract
The B7-H5/CD28H pathway is the most recently identified costimulatory pathway of the B7 family. Here we investigated how the ligand B7-H5 is expressed in normal human pancreas tissues, as well as its expression changes in pancreas cancer. By immunohistochemical (IHC) staining of frozen specimens from patients undergoing pancreatic resection, we found that B7-H5 protein was constitutively expressed on normal ductal epithelium within the pancreas. Other cell types from normal pancreas, like acinar cells or islet cells, did not express B7-H5. In adenocarcinoma, B7-H5 staining was decreased or absent, though normal ducts adjacent to tumors were highly B7-H5-positive. No B7-H5 protein was found on other cancer types such as neuroendocrine tumors. Our study suggests that loss of the B7-H5 signal might contribute to immune evasion of pancreatic ductal adenocarcinoma.
Citation Format: Yuwen Zhu, Joshua Byers, Alessandro Paniccia, Jeffrey Kaplan, Michelle Koenig, Richard Schulick, Barish Edil. Expression of B7-H5 in human pancreatic caner. [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 1279. doi:10.1158/1538-7445.AM2015-1279
Abstract 1289: Renal cell carcinoma patients have altered HLA expression patterns which show correlations to clinical parameter
Authors: Goebel Steffen , Bluemke-Anbau Karen , Altermann Wolfgang , Bilkenroth Udo , Meye Axel , Fuessel Susanne , Kehlen Astrid , Lautenschlaeger Christine , Melchior Andres , Fornara Paolo , Taubert Helge 
Published: August 2015

Abstract
The aim of this study was to evaluate altered HLA (Human Leukocyte Antigen) expression patterns of renal cell carcinoma (RCC) patients and healthy control persons (blood donors).
Peripheral blood samples from RCC patients and from healthy controls were investigated for the incidence of HLA groups. The frequency of HLA groups was analyzed statistically and correlated with relevant clinical data. In addition, HLA subtypes were analyzed for RCC patients and for healthy blood donors. A multidimensional statistical comparison was performed. An update of the follow up for RCC patients was conducted in 2014.
After following the CD45 autoMACS depletion protocol, we identified CTCs in 96 out of 233 peripheral blood samples (41%), which originated from 81 out of 154 (53%) RCC patients. We detected two HLA groups, HLA-Cw*07 and HLA-DRB1*04 that were significantly higher in healthy controls than in RCC patients (p &lt; 0.05), respectively. In a Kaplan-Meier survival analysis these results were confirmed (p &lt; 0.05). On the one hand, RCC patients had less alleles HLA-Cw*07 (p &lt; 0.05; χ2-test) and HLA-DRB1*04 (p &lt; 0.05; χ2-test) compared to healthy blood donors. On the other hand, RCC patients showed an increased occurrence of the allele HLA-Cw*12 compared to healthy blood donors.
There are HLA groups that occur less often in RCC patients than in healthy controls. But it needs larger study populations and further immunological studies to investigate if special HLA-types can have a protective effect against RCC carcinogenesis. Occurrence of the alleles HLA-Cw*07, and HLA-DRB1*04 was significantly altered in RCC patients compared to healthy blood donors and may change the risk to suffer from a RCC.
The integration of our results in systematic functional studies will help to earlier identify persons with an increased risk of RCC development and may have an impact in future patient care.
Citation Format: Steffen Goebel, Karen Bluemke-Anbau, Wolfgang Altermann, Udo Bilkenroth, Axel Meye, Susanne Fuessel, Astrid Kehlen, Christine Lautenschlaeger, Andres Melchior, Paolo Fornara, Helge Taubert. Renal cell carcinoma patients have altered HLA expression patterns which show correlations to clinical parameter. [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 1289. doi:10.1158/1538-7445.AM2015-1289
Abstract 1294: Identification of tumor-specific antigens associated with RET/PTC3 expression
Authors: Sponton Laura , Cosma Gabriela , Mendonca Mark , Giovarelli Mirella , Eisenlohr Laurence Crane 
Published: August 2015

Abstract
Relocated in transformation/papillary thyroid carcinoma, RET/PTC3 (RP3) is a fusion oncogene that causes a form of papillary thyroid cancer (PTC). In addition to driving transformation, the constitutively active kinase precociously phosphorylates itself as well as other intracellular proteins, thereby providing tumor-specific targets for the adaptive immune system.
PTCs are known to have the ability to escape the immune system driving a dysregulation of the activity of several cell populations involved in the immune response. Indeed we found that mice immunized with RP3+/MHC class II+ cells produce dramatically fewer IFNg-secreting CD4+ T cells compared to mice immunized with RP3-/MHC class II+ counterparts as measured in the spleens.
We demonstrated the immunogenicity of RP3 with reactivity in both BALB/c and C57BL/6 mice to RP3/IEd- and RP3/CIITA-expressing cells. Also, we observed immunogenicity of RP3-derived phosphopeptides in ELISpot assays, supporting the hypothesis that the aberrant autophosphorylation of RP3 is a source of tumor-specific immunogenicity.
Finally, utilizing a RP3-expressing vaccinia vector for immunization of C57BL/6 mice, we identified peptide sequences that appear to be immunogenic on the basis of unique conformation of the fusion protein that impacts antigen processing.
Taken together these results could pave the way for better vaccine approaches without accompanying autoimmunity.
Citation Format: Laura Sponton, Gabriela Cosma, Mark Mendonca, Mirella Giovarelli, Laurence Crane Eisenlohr. Identification of tumor-specific antigens associated with RET/PTC3 expression. [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 1294. doi:10.1158/1538-7445.AM2015-1294
Abstract 1297: Increases in the numbers of myeloid-derived suppressor cells in Egyptian children with acute lymphoid leukemia
Authors: Salem Mohamed L. 
Published: August 2015

Abstract
Background: Acute lymphoblastic leukemia (ALL) or acute lymphoid leukemia is an acute form of leukemia. Although the mechanism behind the relapse in ALL is not clearly known, one possible mechanism could be the accumulation of immune regulatory cells, in particular myeloid-derived suppressor cells (MDSCs). We and others have reported that MDSCs cause suppression of host immune responses through several mechanisms. Aim: The main goal of this study was to determine whether these cells accumulate in ALL patients and whether they are affected by chemotherapy. Materials and Methods: Upon informed consent, patients with B-Linage Acute Lymphoblastic Leukemia “B-ALL” (n = 20) were recruited in this study along with healthy volunteers (n = 20). Patients included in this study were risk stratified according to risk classification system and treated according to treatment protocols including high risk pre B-ALL protocol, standard risk pre B-ALL. MDSCs were characterized as HLA-DR-Lin-CD33+CD11b+ cells. Results: Our preliminary results showed significant increases in the numbers of myeloid population with MDSC-like phenotype in B-ALL patients at different stages of chemotherapy treatment when compared with healthy control volunteers (Mean = 1.01%). The increases in the numbers of these cells were higher after treatment of the patients with induction chemotherapy. Further, the increased numbers of MDSCs associated with high numbers of circulating leukemic stem cells (LSCs). Conclusion: Our preliminary data suggest that cells with MDSCs like-phenotype emerge in ALL patients and possibly play a critical role in establishing an immune suppressive environment in children with ALL. Further research is needed to determine if circulating MDSCs like-phenotype populations are a immunosuppressive and whether they can be modulated.
Acknowledgment:
This work has been supported by a grant (ID# 5245) funded from the Science and Technology Development Fund (STDF), Ministry of Scientific Research and Technology, Egypt to Mohamed L. Salem, the Principal investigator of this project.
Note: This abstract was not presented at the meeting.
Citation Format: Mohamed L. Salem. Increases in the numbers of myeloid-derived suppressor cells in Egyptian children with acute lymphoid leukemia. [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 1297. doi:10.1158/1538-7445.AM2015-1297