bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 196: Functional role of death-associated protein 3 in high grade gliomas of childhood
Authors: Vladimirova Valentina A. , Soerensen Niels , Pietsch Torsten 
Published: August 2014

Abstract
Background: High grade gliomas (HGG) are highly invasive tumors and respond poorly to conventional treatments. Although significant progress has been made in understanding the molecular pathways that lead to the development of HGG in adults, comparatively few data is available for gliomas of childhood. The death-associated protein 3 (DAP3) is localized on the chromosomal region 1q21-22 that has been previously described as a region of frequent chromosomal gain associated with poor outcome in HGG. Moreover, DAP3 has been reported to be overexpressed and to play anti-apoptotic role in invasive glioblastoma cells.
Methods: In the current study to investigate the functional role of DAP3 in pediatric versus adult HGG, we suppressed the endogenous DAP3 protein using DAP3-specific short hairpin RNA (shRNA) or chemical inhibitors of protein kinase C, and analyzed the phenotypic effect on glioma cell proliferation, migration, mitochondrial morphology and apoptosis.
Results: We found that knockdown of DAP3 by shRNA induced mitochondrial fragmentation and apoptosis in pediatric glioma cell lines while in adult glioma cell lines it suppressed cell proliferation and reduced mitochondrial potential without inducing mitochondrial fragmentation. Specific chemical inhibition of the two classical PKC isoforms (PKCα and PKCβ) significantly reduced the expression of DAP3 protein in both pediatric and adult glioma cell lines. The inhibition of PKCα changed cell morphology, mitochondrial status and significantly suppressed proliferation and migration of both pediatric and adult glioma cell lines without associated caspase activation indicating that DAP3 may mediate nonapoptotic form of cell death in HGG. The suppression of PKCβ rendered pediatric glioma cells more sensitive to the apoptotic effect of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) through a caspase-dependent process as compared with adult glioma cells suggesting a possible implication of DAP3 in intrinsic and extrinsic pathways for apoptosis in pediatric HGG.
Conclusion: Our findings confirmed the anti-apoptotic role of DAP3 in glioma cell biology suggesting that specific PKC isoforms mediated the DAP3 suppression of apoptosis in HGG and pointed out the specific functional role of this protein in mitochondrial maintenance. DAP3 may represent a novel target for the treatment of gliomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 196. doi:10.1158/1538-7445.AM2011-196
Abstract 1960: Phosphorylation of caspase-7 by p21-activated protein kinase (PAK)2 inhibits staurosporine-induced apoptosis of MCF-7 breast cancer cells
Authors: Zhu Feng , Li Xiang , Wen Weihong , Liu Kangdong , Malakhova Margarita , Peng Cong , Kim Hong-Gyum , Ma Weiya , Cho Yeon-Yong , Bode Ann , Dong Ziming , Dong Zigang 
Published: August 2014

Abstract
P21-activated kinase (PAK) 2, a member of PAK family of serine/threonine kinases, plays an important role in physiological processes such as motility, survival, mitosis, and apoptosis. However, the role of PAK2 in chemotherapy resistance, as well as cell proliferation, is not clear. In this report, we showed that the protein expression level of PAK2 is higher in human breast cancer cell lines and human breast invasive carcinoma tissues compared with adjacent normal breast tissues. Importantly, we found that PAK2 can bind with caspase-7 and phosphorylate caspase-7 at Ser30, Thr173 and Ser239. Phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis. Knocking down PAK2 expression can restore caspase-7 activity and promote apoptosis of MCF-7 breast cancer cells. Our data suggests that the highly expressed PAK2 mediates chemotherapy resistance in human breast invasive ductal carcinoma and that PAK2 is a novel target of chemotherapy for breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1960. doi:10.1158/1538-7445.AM2011-1960
Abstract 1966: Regulation of RKIP function by Helicobacter pylori in gastric cancer cells
Authors: Moen Erika , Anwar Talha , Wen Sicheng , Onikoyi Omobola , Moss Steven , Chatterjee Devasis 
Published: August 2014

Abstract
Raf kinase inhibitory protein (RKIP) is a negative regulator of the mitogen activated protein kinase (MAPK) cascade initiated by Raf-1 and nuclear factor kappa B (NF-κB) and is an activator of apoptosis in human cancers. STAT3 (signal transducer and activators of transcription) is often constitutively phosphorylated in gastric cancer. RKIP is a negative regulator of STAT3 and has been positively correlated with a higher survival rate in gastric cancer patients (Chatterjee, et al., Clin. Cancer Res., 14:2994-3001, 2008). Helicobacter pylori (H. pylori) infection is associated with high levels of activated STAT3 as well as activation of the transcription factor NF-κB in gastric epithelial cells, through mechanisms involving macrophage-derived IL-6. H. pylori infection led to a dose- and time-dependent increase in STAT3 activation and Snail, a protein that is a negative regulator of RKIP transcription. In addition, H. pylori and IL-6 treatment stimulated the phosphorylation of RKIP in a protein kinase C- (PKC) dependent manner. Interestingly, H. pylori stimulated RKIP transcription which was enhanced in the presence of the histone acetyl transferase, CBP, and inhibited in the presence of the PKC inhibitor. Surprisingly, RKIP stimulated STAT3 transcription in gastric cancer cells, an effect that was reversed in the presence of CBP. After H. pylori infection, RKIP localized to the nucleus and enhanced H. pylori-mediated apoptosis. Collectively, these results indicate that RKIP function is regulated by phosphorylation after H. pylori infection and acetylation by CBP. Moreover, our study demonstrates that RKIP post translational modifications regulate apoptosis induction (via phosphorylation) and inhibition of cell survival (via acetylation) in gastric cancer. These results also suggest the existence of a feedback loop between RKIP, H. pylori infection and STAT3 in gastric cancer. Supported, in part, by NIH COBRE Investigator Award Grant P20 RR17695 (DC and SM).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1966. doi:10.1158/1538-7445.AM2011-1966
Abstract 197: Multi-cellular tumor spheroids in vitro model reveals a critical role of ERBB4 in survival of osteosarcoma
Authors: Hua Yingqi , Yang Yanwen , Hughes Dennis 
Published: August 2014

Abstract
Multi-cellular tumor spheroids (MCTS) model is an in vitro model holding an intermediate complexity between monolayer culture and solid tumor. It is cell-cell adhesion dependent and closely resembles avascular tumor regions and micrometastasis in pro-angiogenesis stage. Osteosarcoma (OS) is the most common malignant bone tumor with high incidence of early lung metastasis; therefore, multi-cellular tumor spheroid can be used to model its in vivo behaviors. Our group previously reported the expression profile of ERBB family in osteosarcoma tissue samples and cell lines. To further study ERBB pathways in osteosarcoma tumor spheroids, we generated OS tumor spheroids by plating cells on non-adherent poly-HEMA pre-coated dishes. Under anchorage-independent conditions, OS cells spontaneously generate multi-cellular spheroids to acquired anoikis resistant by cell-cell adhesion; blocking the formation of spheroids will result rapid cell death and increased PARP cleavage. MCTSs showed lower proliferation rate than monolayer culture, and they held a chemo-resistant phenotype, as shown by proliferation assay and subdiploid DNA content. Surprisingly, ERBB4 expression was up-regulated in non-adherent tumor spheroids compared with monolayer culture (1.2, 2.9, 6.3 fold respectively in 3 cell lines) while EGFR and ERBB2 did not. With knockdown of ERBB4 expression by shRNA, OS cells became less tolerant to anoikis and serum starvation, as shown by PARP cleavage and subdiploid DNA content. Moreover, knockdown of ERBB4 increased the chemo-sensitivity of OS cells against multiple chemotherapy including cisplatin, doxorubicin, and methotrexate (71%, 71%, 60% in survival compared to scramble control). In conclusion, our data showed that ERBB4 contributes to the tumorigenicity of osteosarcoma and plays a protective role against multiple exogenous apoptotic stimuli including matrix detachment, nutrition insufficiency and cytotoxic reagents. Although wildly expressed in osteosarcoma, the role of ERBB4 in tumor biology is largely unknown. These findings indicate that ERBB4 is a key factor regulating survival pathway of OS under various cellular stress condition. Thus, in primary osteosarcoma and metastatic lesion, ERBB4 might be a potential therapeutic target to facilitate multi-modal therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 197. doi:10.1158/1538-7445.AM2011-197
Abstract 1975: Discovery of a potent and selective Jak2 inhibitor that suppresses GM-CSF-induced STAT5 phosphorylation and Erythropoietin-induced reticulocytosis in vivo
Authors: Liu Liqin , Moody Gordon , Pistillo Jeanne , Emkey Renee , Yu Violeta , Doherty Elizabeth M. , Huang Xin , Kim Joseph L. , Sinclair Angus M. 
Published: August 2014

Abstract
Essential thrombocythemia (ET), polythemia vera (PV) and myelofibrosis (MF) are myeloproliferative disorders (MPDs) characterized by a chronic excessive production of cells from one or more myeloid lineages and/or bone marrow fibrosis, and have the potential to progress to AML. Recently, gain-of-function mutations in intracellular tyrosine kinase Janus kinase 2 (Jak2) were identified to be associated with MPDs. Jak2 is a member of the Jak family of kinases including Jak1, Jak3, and Tyk2 and is the most proximal signaling component for a number of cytokine receptors. The most common Jak2 mutation identified in MPDs is a substitution of valine to phenylalanine at codon 617 (V617F) located in the pseudokinase domain, which results in the loss of its repressive function, and subsequently leads to the constitutive activation of Jak2 and downstream signaling pathways (STAT, MAP kinase, and PI3 kinase) which affect the survival, differentiation and proliferation of hematopoietic progenitors.
Highly selective Jak2 inhibitors may provide a better therapeutic window in chronic dosing settings (ET and PV patients) than non-selective Jak inhibitors. Here we report the discovery of a potent and highly selective Jak2 inhibitor, AMG-Jak2-01. In enzyme assays, AMG-Jak2-01 was potent (3 nM) and selective over other Jak family kinases (&gt; 2000-fold over Jak1, 10-fold over Jak3 and &gt; 400-fold over Tyk2). In isogenic BaF3 cell lines expressing constitutively active Jak kinases (Tel-Jak fusion), AMG-Jak2-01 showed over 40-fold Jak2 selectivity against Jak1 or Tyk2 and 10-fold selectivity against Jak3 based on the inhibition of STAT5 phosphorylation (pSTAT5 – detected with AlphaScreen®). In cytokine-stimulated primary PBMC or whole blood assays, AMG-Jak2-01 demonstrated more than 25-fold Jak2 selectivity over Jak1and Jak3 based on inhibition of pSTAT5 (detected by flow cytometry). In vivo, oral administration of AMG-Jak2-01 at 100 mg/kg for 1 hr inhibited GM-CSF-induced pSTAT5 by approximately 70% (p&lt;0.01) in a mouse peripheral blood pharmacodynamic assay. Finally, two doses of AMG-Jak2-01(100 mg/kg) given 4 hrs apart were able to suppress Epo-induced reticulocytosis in the mouse by 70% (p&lt;0.02).
In summary, we have discovered a potent Jak2 inhibitor, AMG-Jak2-01, which is selective over other Jak family members in both enzyme and cell-based assays and demonstrates inhibitory activity in GM-CSF-induced STAT5 phosphorylation and erythropoietin-induced reticulocytosis in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1975. doi:10.1158/1538-7445.AM2011-1975
Abstract 3927: Characterization of galectin 3 as a putative BRCA1/BARD1 ubiquitin E3 ligase substrate
Authors: Carvalho Renato S. , Costa Thales N. , Sweet Michael , Monteiro Alvaro NA , Carvalho Marcelo A. 
Published: August 2014

Abstract
BARD1 (BRCA1-associated ring domain 1) was originally identified in a yeast-two-hybrid screen as a binding partner of BRCA1. The functional heterodimer BRCA1/BARD1 is required for several of the cellular and tumor-suppressor functions of BRCA1. Both proteins interact through the N-terminal RING domain to form a heterodimeric E3 ubiquitin ligase that constitutes the major catalytic activity of the BRCA1-BARD1 complex. BARD1 is also associated to p53-mediated apoptosis, in a BRCA1-independent manner. The carboxy terminus of BRCA1 is highly acidic and contains two tandem BRCA1 C-terminal (BRCT) domains, which are characteristic of members of a large superfamily of proteins involved in DNA repair and cell cycle checkpoint control. These domains are protein-protein interacting regions that mediate the association with a number of other proteins with a role in DNA replication, DNA damage repair pathway, transcription, cell cycle control, and ubiquitination. BARD1 also contains two tandem BRCT repeats at its C-terminus, a region shown to bind serine-phosphorylated peptides in vitro. In order to identify putative interaction-proteins with BARD1 C-terminal region we performed a yeast-two-hybrid screening using BARD1 BRCT tandem domain (aa 554-777) to screen a human testis cDNA library. We identified, among other hits, a cDNA coding for galectin 3 C-terminal region, residues 170-250 (OMIM 153619). Galectin 3 is a galactoside binding protein involved in several cellular processes including apoptosis control and RNA splicing. Moreover there are evidences that galectin 3 variants are correlated with tumor development and progression in breast and thyroid cancer. We confirmed galectin 3/BARD1 interaction by conducting co-immuneprecipitation analysis of ectopically expressed BARD1 and galectin-3 in HEK293T cells. The interaction between endogenous galectin 3 and BARD1 were validated in HeLa nuclear extracts. Using the same approach we co-immuneprecipitated BRCA1 and galectin-3, suggesting the presence of BRCA1, BARD1 and galectin-3 in the same complex. Interestingly the galectin 3 observed in this complex corresponds to a mono-ubiquitinated form, corroborating the idea that galectin 3 is a putative natural target of BRCA1-BARD1 heterodimer E3 ubiquitin ligase.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3927. doi:10.1158/1538-7445.AM2011-3927
Abstract 3929: ADA3, a component of ATAC complex regulates DNA damage response
Authors: Mirza Sameer , Mohibi Shakur , Gurumurthy Channabasavaiah B. , Katafiasz Bryan J J. , Zhao Xiangshan , Bele Aditya , Band Hamid , Band Vimla 
Published: August 2014

Abstract
Our long term research goal is to understand the biochemical mechanism of immortalization of human epithelial cells that represents early step in cancer progression. Over the years, we have generated several epithelial cell immortalization models, using viral oncogenes, mutated cancer genes, as well as radiation treatment of cells. In one of such immortalization model, we identified alteration/deficiency in activation (ADA3) protein as a novel human papilloma virus E6 oncoprotein binding protein, and as a regulator of p53 function. We and others have shown that human ADA3 protein is an essential component of various Histone acetyl transferase complexes (HATs) and thus controls transactivation of various transcriptional factors.
To gain insight into the physiological importance of ADA3, we established a conditional knockout mouse model and showed that loss of ADA3 led to embryonic lethality at an early stage of development. Using ADA3lox/lox mouse embryonic fibroblast (MEF) cell lines, we further showed that ADA3 plays an important role in DNA damage and repair pathway. Adenovirus cre-mediated deletion of ADA3 led to a global reduction of histone acetylation, severe G2/M cell cycle arrest, various aberration in nuclear structures, and massive chromosome aberration. Significantly, cells lacking ADA3 showed defects in recruitment of DNA repair associated proteins, BRCA1 and 53BP1 to the DNA damage foci. These results implicate ADA3 as a major cell cycle and DNA repair response regulating protein. These findings in the context of oncogenesis and chemotherapy will be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3929. doi:10.1158/1538-7445.AM2011-3929
Abstract 3936: Identifying molecular subgroups of gliomas in formalin fixed paraffin embedded material
Authors: Gravendeel Lonneke A. , de Rooi Johan J. , Erdem Lale , Eilers Paul H. , Kros Johan M. , Sillevis Smitt Peter A. , van den Bent Martin J. , French Pim J. 
Published: August 2014

Abstract
Gliomas are the most common primary brain tumors with heterogeneous morphology and variable prognosis. Histological classification, combined with the patients’ prognostic features, often guides treatment decisions. Unfortunately, differences in histology are subtle and therefore, diagnosis is subject to a large interobserver variability. To improve classification, we did expression profiling on fresh frozen tumor material of 276 glioma samples of all histological subtypes. This resulted in seven molecular subgroups, which correlated significantly better with survival than histology.
When validated in prospective studies these molecular clusters could contribute to clinical decision making. However, there is a lack of fresh frozen glioma material, and until now clinical studies have been performed on formalin fixed paraffin embedded (FFPE) material. Therefore, we would like to see whether our molecular clusters are reproducible in FFPE material.
Expression profiling was performed on 57 paired snap-frozen/FFPE glioma samples of all histological and molecular subtypes and three non-diseased brain samples. We collected FFPE material from the same patients that were included in our previous study (Gravendeel et al. Cancer Res 2009). FFPE expression profiling was performed using Hu_Ex_1.0_st “exon” arrays (Affymetrix) in combination with Nugen WT-Ovation technology (FFPE V2 and Exon modules).
FFPE expression profiles were assigned to a molecular cluster based on its nearest centroid using the 20.000 most variably expressed exons.
Preliminary analysis indicates that approximately 75% of all samples were assigned to the correct molecular cluster. Survival data confirmed that the molecular clusters identified using FFPE material retained significant prognostic value, similar to those obtained using fresh frozen material (p=0.0016).
Our data indicate that exon arrays in combination with Nugen WT technology are a suitable platform to perform expression profiling on FFPE samples. We are currently expanding our dataset to include FFPE samples from a large phase III European trial.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3936. doi:10.1158/1538-7445.AM2011-3936
Abstract 3955: Epigenetic silencing of microRNA-34b/c plays a pivotal role in pathogenesis of small-cell lung cancers
Authors: Tanaka Norimitsu , Toyooka Shinichi , Soh Junichi , Maki Yuho , Muraoka Takayuki , Ueno Tsuyoshi , Aokage Keiju , Asano Hiroaki , Tsukuda Kazunori , Yamane Masaomi , Oto Takahiro , Miyoshi Shinichiro 
Published: August 2014

Abstract
Background: Lung cancer is the leading cause of cancer-related death in the world. Small-cell lung cancer (SCLC) accounts for approximately 13% of lung cancers. Although chemotherapy results in initially high response rates, survival of patients with extensive stage disease is dismal. MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes that regulate cell proliferation and apoptosis. Recent studies have shown that, in cancer cells, expression of some miRNAs is silenced with DNA methylation in promoter region. Aberrant methylation of miR-34b/c has been reported in human malignancies, but not in SCLCs, causing up-regulation of oncogenes. In this study, we investigated the methylation and expression status of the miR-34b/c and the anti-proliferative effect by induction of miR-34b/c in SCLCs.
Methods: We examined 11 SCLC cell lines and 6 resected primary SCLC tumors (one tumor treated with preoperative chemotherapy and five without preoperative chemotherapy). Methylation and expression status of miR-34b/c were determined by methylation-specific PCR and quantitative PCR, respectively. Colony formation assay was applied to examine the anti-proliferative effect by induction of miR-34b/c and scramble sequence control with plasmid vector. The ability of cell migration was examined using cell migration assay.
Results: Aberrant methylation of miR-34b/c was found in 7 (64%) of 11 SCLC cell lines and 3 (50%) of 6 primary SCLC tumors. Expression of miR-34b/c in all methylation cell lines was silenced and restored with 5-aza-2’-deoxycytidine treatment, indicating that methylation caused gene silencing. Ectopic induction of miR-34b/c gene in SCLC cell line (H1048) showed significant inhibition of colony formation compared with induction of control vector, demonstrating anti-proliferative effect of miR-34b/c on SCLC. The cell migration was also significantly inhibited by induction of miR-34b/c in SCLC cell line tested.
Conclusion: Our results demonstrated that miR-34b/c methylation is frequent in SCLCs and induction of miR-34b/c inhibits the cell proliferation and migration, resulting that miR-34b/c silencing plays an important role in pathogenesis of SCLCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3955. doi:10.1158/1538-7445.AM2011-3955