bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4969: Impact of proteasome inhibition of caspase-8 regulation in cancer
Authors: Fiandalo Michael , Schwarze Steven , Kyprianou Natasha 
Published: August 2012

Abstract
Dissection of the extrinsic and intrinsic pathways of apoptosis has lead to the development of new anti-cancer therapeutic strategies. Strategies involve combination of a chemotherapeutic agent with a death inducing ligand, such as TNF-alpha Related Apoptosis Inducing Ligand (TRAIL) to induce apoptosis in cancer cells that are resistant to apoptosis. We recently demonstrated that proteasome inhibition sensitizes TRAIL resistant prostate cancer to TRAIL mediated apoptosis using both in-vitro and in-vivo models, by stabilizing the active p18 subunit of initiator caspase-8. Based on this data indicating a potential relationship between caspase-8 and the proteasome, we hypothesize that caspase-8 ubiquitination and targeting to the 26S proteasome regulates the extrinsic pathway of cancer cell apoptosis. This study pursues the impact of proteasome inhibition on caspase-8 stability, trafficking and activity following death receptor activation. The contribution of caspase-8 polyubiquitination in regulating the extrinsic pathway of apoptosis is determined, using subcellular fractionation, caspase-8 and polyubiquitin immunoprecipitation (IP), and fluorescent microscopy techniques in diverse experimental cell models. The cell lines analyzed include the TRAIL resistant LNCaP prostate cancer cell line and caspase-8 deficient neuroblastoma (NB7) cell line, engineered to re-express and test the wild-type and non-cleavable mutant forms of caspase-8. Our findings indicate that the non-cleavable forms of caspase-8 are capable of inducing apoptosis comparably to wild-type caspase-8 upon treatment with proteasome inhibitor and TRAIL. Moreover we provide evidence that caspase-8 polyubiquitination occurs following caspase-8 processing into its active subunits, processed caspase-8 accumulates at the DISC, and ultimately cycles into the cytosol for proteasomal degradation. This study identifies caspase-8 processing as a significant regulatory mechanism in apoptosis outcomes in cancer cells, but not required for caspase-8 activation. Together these data provide a better understanding of caspase-8 regulation that can be used as a platform for identifying new molecular targets such as E3 ligases responsible for caspase-8 regulation. Further defining caspase-8 regulation can lead to strategies that enhance efficacy of current therapies or lead to development of new more specific caspase-8 driven anti-cancer approaches. Funding provided by DOD GRANT USAMRMC PC073314
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4969. doi:1538-7445.AM2012-4969
Abstract 4971: The oncometabolite (R)-2-hydroxyglutarate modulates stress-induced caspase activity in glioma cells
Authors: Gilbert Misty , Liu Yinxing , Morris Andrew , Sunkara Manjula , Kyprinaou Natasha , Horbinski Craig 
Published: August 2012

Abstract
Point mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are present in the majority of WHO grade II and III gliomas, as well as secondary grade IV glioblastomas. These are gain-of-function mutations resulting in the neoenzymatic conversion of alpha-ketoglutarate into R-2-hydroxyglutarate (2HG), which is present in high concentrations (10-30 mM) in mutated gliomas. The mutation appears to be a favorable prognostic marker, suggesting better response to stressors like adjuvant radiation and chemotherapy; however, its effects on cell signaling and glioma cell death are not fully understood. In this study we investigated the impact of 2HG in glioma cell survival pathways. A single pulse of 2HG (30mM) increased phosphorylated Erk (p-Erk 1/2), but not pAkt, in the PTEN-intact glioma cell lines LN18 and LN229. Both p-Erk 1/2 and pAkt were unchanged in the PTEN-deficient cell lines U87 and U138. A single 2HG pulse, followed by prolonged withholding of medium changes, also enhanced caspase 3/7 activity in LN18 cells and LN229 cells, whereas it actually suppressed caspase 3/7 activity in U87 and U138 cells. Pretreatment with the MEK inhibitor UO126 prior to the 2HG pulse suppressed caspase 3/7 activity in LN18 cells, but not in LN229 cells. In U87 cells, the 2HG-induced suppression of caspase 3/7 activity was reversed by UO126, while no change was observed in U138 cells. These data indicate that 2HG can modulate stress-induced cell death in a MAPK/ERK-dependent manner, but that such modulation may vary greatly depending on the occurrence of other genetic aberrations in gliomas. Ongoing studies are pursuing potential mechanisms via which 2HG exerts such functionally divergent effects, aiming to develop better adjuvant therapeutic approaches for IDH-mutant gliomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4971. doi:1538-7445.AM2012-4971
Abstract 5046: miR-199a/125b inhibits tumor growth
Authors: Jiang Bing-Hua , He Jun , Xu Qing , Peiper Stephen , Liu Ling-Zhi 
Published: August 2012

Abstract
Many human cancers of epithelial origin are associated with overexpression of epidermal growth factor receptor (EGFR) family. In particular, ERBB2 and ERBB3 overexpression are linked with cancer development and poor prognosis. Except ERBB2/ERBB3 gene amplification, other mechanism(s) of ERBB2 and ERBB3 overexpression remains elusive. Recent studies show that aberrant expressions of miRNAs are associated with cancer development. To identify specific miRNAs for regulating ERBB2 and ERBB3 expression, we find that miR-199a and miR-125b directly target ERBB2 and ERBB3, and are downregulated in ovarian tissues and cancer cells. Elevated reactive oxygen species (ROS) have been observed in tumor growth and drug resistance. Interestingly we show that increased ROS downregulate miR-199a and miR-125b for inducing ERBB2 and ERBB3 expression. ERBB2 and ERBB3 in turn activate AKT/P70S6K1/HIF signaling leading to tumor growth and angiogenesis. This study provides a novel mechanism of ERBB2 and ERBB3 regulation by miR-199a and miR-125b and new concept of ROS for inducing ERBB2 and ERBB3 in tumor growth and angiogenesis; and establishes a rationale for using miR-199a and miR-125b mimics and ROS scavengers as new therapeutic agents in the future.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5046. doi:1538-7445.AM2012-5046
Abstract 5048: Global microRNA expression array analysis and potential application in discovery of promising drugs for hematologic cancer
Authors: Shivapurkar Narayan M. 
Published: August 2012

Abstract
Hematologic cancers, the third most common cause of cancer deaths, will kill ∼50,000 Americans this year. Early diagnosis and innovative treatment has been proposed to result in cure. Bendamustine (BM) is a synthetic drug which is highly effective in broad range of hematologic cancers. The efficacy of the drug is attributed to the ability of the drug to induce apoptosis as well as to inhibit cell cycle. It was highly effective in patients whose disease is refractory to other established drugs. Gambogic acid (GA) is the major active component of gambose, the resin secreted from Garcinia hanburryi which also has strong ability to induce apoptosis as well as inhibit cell cycle. microRNAs (miRNAs) are master regulators of the gene expression. Neither BM nor GA had been previously reported for their effect on miRNA expression profiles in hematologic or other cancers. We have set up an innovative global miRNA expression analysis array. Using this miRNA expression array, we analysed global expression in leukemia cells in culture treated with or without treatment of MB or GA. Our data showed comparable inhibition of cell cycle and induction of apoptosis by both GA and BM at a dose of GA several folds lower than that of BM. Our data, based on miRNA expression analysis using genome-wide miRNA expression array showed five common miRNAs, found differentially expressed (more than 3 times up or down regulated compared to untreated group with p&lt;0.05) in both GA and BM treated groups. The data is particularly interesting, since these miRNAs have been reported to target and thus modulate expression of proteins of apoptotic pathway and senescence pathway. Out data suggest that drugs that induce apoptosis as well as inhibit cell cycle may have great therapeutic potential in hematologic cancers. Based on our data it appears that the drugs with anticancer properties may affect a common set or sets of miRNAs. To our knowledge, this constitutes the first report describing effect of both BM and GA on miRNA expression profile, not in just hematologic cancer but any cancer. Our study provides strong evidence to suggest that specific miRNA expression signature/s of hematologic cancer cells in culture following drug treatment should be further explored to screen promising drugs with higher anticancer properties.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5048. doi:1538-7445.AM2012-5048
Abstract 507: Nitrogen oxides-derived immunotherapy: Revealing cryptic melanoma-specific immune targets
Authors: Zhu Weidong , Eng Ashley C. , Olson Samuel Y. , Márquez-Garbán Diana C. , Garbán Hermes J. 
Published: August 2012

Abstract
Nitrogen oxides (NOx) can exert their relevant biological functions through two reversible molecular modifications: a) direct interaction with metals (nitrosation), and b) by interacting with thiols (s-nitrosylation); or irreversible modifications of aromatic amino acid residues such as tyrosine or phenylalanine (nitration). Any of these modifications have been demonstrated to affect the biological fate of the modified molecule or alter their functions. We have previously shown that these NOx-derived changes will trigger a myriad of modifications at the genetic, epigenetic and post-translational level in tumor cells resulting in a robust and effective therapeutic immune response against cancer cells. However, the molecular mechanisms and immune-related tumor targets remain elusive. Thus, we hypothesize that NOx-derived protein modifications (i.e., Tyrosine nitration) will differentially prime the immune system with otherwise subdominant antigens (cryptic) making them immune visible and triggering an effective anti-tumor immune response. We have tested this hypothesis using the well-characterized B16-C57BL/6 syngeneic and poorly immunogenic melanoma mouse model. NOx-modified and non-modified B16-F0 melanoma cell lysates were used to immunize naïve C57BL/6. Post-immunized sera was screened against SDS-PAGE resolved untreated B16-F0 lysates and human protein library micro array for differential recognition of immune cross-reactive of novel mouse and human melanoma targets by the mouse IgG fraction. Our results demonstrated the highly significant (p &lt;0.0001) IgG-associated immune recognition of five cross-reactive novel melanoma targets (in relative affinity decreasing order): 1) Golgi reassembly stacking protein 1 (GORASP1), 2) ArfGAP w/GTPase domain-ankyrin repeat and PH domain 1 (AGAP1), 3) Microtubule-associated protein tau (MAPT), 4) Mitochondrial ribosomal protein L46 (MRPL46), and 5) Protocadherin beta 6 (PCDHB6). Currently, we are evaluating the significance and functional activity of the identified targets and their isolated/purified specific immune effector (IgG) counterparts. In addition, we are characterizing the potential molecular and immunological mechanisms that might lead to the use of these novel melanoma-specific immune targets as diagnostic/prognostic and/or immunotherapeutic tools.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 507. doi:1538-7445.AM2012-507
Abstract 508: Correlation of antibody and T-cell responses against XAGE-1b in NSCLC patients
Authors: Ohue Yoshihiro , Eikawa Shingo , Mizote Yu , Matsumoto Hirofumi , Isobe Midori , Fukuda Minoru , Uenaka Akiko , Nakayama Eiichi , Oka Mikio 
Published: August 2012

Abstract
BACKGROUND: XAGE-1b is a cancer/testis antigen identified in lung cancer using autologous patient serum by SEREX. The expression of XAGE-1b is observed frequently in lung adenocarcinoma and rarely in some other tumors. Recently, we showed spontaneous T-cell response against XAGE-1b in XAGE-1b-antibody positive non-small cell lung cancer (NSCLC) patients. In this study, we analyzed the frequency of XAGE-1b-reactive CD4 and CD8 T-cells in NSCLC patients showing high, intermediate and low antibody responses. MATERIALS AND METHODS: Sera and PBMCs were obtained from NSCLC patients who visited Kawasaki Medical School Hospital between 2009 and 2011. Antibody response was determined for XAGE-1b protein by ELISA using O.D. values at 1:900 serum dilution and classified as high ≥ 3.0, 3.0 &gt; intermediate ≥ 1.0 and 1.0 &gt; low. CD4 and CD8 T-cell responses against XAGE-1b were examined by IFN-γ ELISA using 12- or 16-mer XAGE-1b-overlapping peptides (OLPs) spanning the entire XAGE-1b protein in antibody-positive patients. Cytotoxicity was analyzed determining GAPDH release by aCellaTox kit. RESULTS: The number of XAGE-1b-antibody positives was 29 (9.0%) of 323 NSCLC patients. Within those, the patients showing high, intermediate and low antibody response was 6, 11 and 12, respectively. The frequency of XAGE-1b-reactive CD4 T-cells in patients showing high, intermediate and low antibody response was 5.5 ±2.1 x 10-5, 1.5 ±0.7 x 10-5 and &lt; 1.1 x 10-5, respectively. The frequency of XAGE-1b reactive CD8 T-cells was 6.9 ±1.6 x 10-6, 4.6 ±1.6 x 10-6 and &lt; 1.1 x 10-6, respectively. The ratio of the CD8 T-cells recognizing XAGE-1b-expressing tumor to the XAGE-1b-peptide reactive CD8 T-cells in patients showing high and intermediate antibody responses was 60.0% and 14.3%, respectively. CONCLUSION: Our findings indicate correlation of antibody response to CD4 and CD8 T-cell responses against XAGE-1b in NSCLC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 508. doi:1538-7445.AM2012-508
Abstract 5085: TopModel: An online resource for predictive models in cancer
Authors: Szeto Christopher W. , Sokolov Artem , Benz Stephen , Stuart Joshua , Haussler David 
Published: August 2012

Abstract
One goal of characterizing the genome-wide landscape of cancer cells is to identify predictive signatures of onset, progression, and treatment outcomes. Many computational approaches have been developed to discover gene signatures with a range of success. The challenge still remains to identify the best approach that, when trained on one cohort, remains accurate in predicting outcomes on an unseen cohort. Thus far, no clear themes have emerged that might provide clues about which method works for a particular task. We have built a system called TopModel that facilitates the identification of top-performing machine-learning algorithms for a series of cancer-genomics challenges. The four components of the system include: 1) a benchmark that includes several cancer genomics datasets with outcome variables as targets to predict; 2) a database of results derived from the application of thousands of machine-learning and feature selection combinations; 3) a web interface that allows bioinformaticians to evaluate their own prediction results; and 4) a web interface that allows a biomedical researcher to upload data on a sample or set of samples in order to receive a report on the signatures predicted to exist in the sample(s). The cancer benchmark component provides a common ground for the development and evaluation of prediction methods for variables such as cancer subtype, drug response, survival, and others. Several datasets have been loaded including predicting survival in the TCGA cohorts, and the hundreds of drug sensitivities in several cancer cell line cohorts. We demonstrate the utility of the resource by comparing state-of-the art feature selection methods to a new approach that uses locality on a genetic interaction network. We evaluate the performance in terms of how well the features generalize across datasets as a trade-off to the accuracy of prediction. In addition to identifying high-value genome features, we explore the robustness of the cancer state in the absence of these features. We simulate gene knock outs by disconnecting these features in our pathway models, inferring the pathway interaction network in the absence of these features, and then reassessing using the top-performing predictive models of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5085. doi:1538-7445.AM2012-5085
Abstract 509: Immunoglobulin reactivity analysis of chronic lymphocytic leukemia patients unveils Lymphocyte Cytosolic Protein 1 (LCP1) as a novel CLL exosome antigen
Authors: Dubovsky Jason A. , Andritsos Leslie A. , Blum William , Johnson Amy , Muthusamy Natarajan , Byrd John C. 
Published: August 2012

Abstract
Chronic lymphocytic leukemia (CLL) is incurable accumulation of malignant clonal B lymphocytes in the blood, bone marrow, lymph nodes, and spleen. A hallmark of CLL is profound immunosupression mediated by a litany of costimulatory, cytokine, and exosome signals within the microenvironment. One of the most promising recent advances in this disease has been the development of membrane targeted immunotherapeutics such as the monoclonal antibodies rituximab and alemtuzumab. However, a shortfall of most current and experimental immunotherapeutics is the reliance upon cluster of differentiation (CD) antigens that are also common to a variety of healthy tissues. Moreover, the non-obligate nature of many CD markers renders them susceptible to shedding and down- modulation in resistant CLL cases. In recent studies, we and others have identified endogenous adaptive immune responses against known CLL specific antigens such as ROR1. Curiously, this effect appears biased to tumor relevant antigens with defined malignant signaling. Using retrospective antigen identifications as proof of principle, we sought to further investigate humoral reactivity against autologous CLL membrane associated antigens to identify novel targets for immunotherapy. Mass spectroscopic analysis of CLL membrane antigens targeted by patient derived serum IgG repeatedly identified LCP1 as a lymphocyte specific target. Confirmation by immunoblot and ELISA revealed that CLL patients maintain elevated LCP1 IgG response despite an inability to respond to common vaccine antigens such as tetanus toxin, suggesting continued antigenic stimulation. Flow cytometry, RT-PCR, immunoblot, and confocal microscopic analyses revealed few differences in LCP1 protein levels, glyocoslyation, transcripts, and localization between healthy and malignant B lymphocytes. Given the potential for CLL exosomes to provide a vehicle for continued antigenic stimulation as well as a target for future therapeutics we investigated their LCP1 content. We found that LCP1 is an integral component of CLL exosomes and that production of LCP1-laden exosomes is increased upon CLL stimulation. Ongoing studies aimed at addressing the potential role of exosomal LCP1 in CLL will be discussed. Supported in part by NIH and D. Warren Brown Foundation
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 509. doi:1538-7445.AM2012-509
Abstract 5094: Genome-wide molecular profiles of undifferentiated pleomorphic sarcoma and leiomyosarcomas
Authors: Silveira Sara Martoreli , Villaces Rolando Andre Rios , Cunha Isabela Werneck , Lopes Ademar , Rogatto Silvia Regina 
Published: August 2012

Abstract
Malignant soft-tissue sarcomas are a heterogeneous group of mesenchymal cancers accounting for 1% of all malignant tumors in adult. These tumors are classified according their differentiation status. Undifferentiated high-grade spindle/pleomorphic sarcoma (UPS) presents a clinically aggressive behavior with frequent development of distant metastases and recurrence after surgery. The genome profile of 20 UPS and 17 leiomyossarcomas (LMS) was evaluated by array CGH and correlated with the clinical course and histopathological findings. Array CGH was done using the Human 44K Agilent oligoarrays according to manufacturer's instructions. Data were extracted using the Feature Extraction software, version 10.7, and analyzed by Nexus Software v 6.0 (BioDiscovery), with a FASST2 (Fast Adaptive States Segmentation Technique 2) algorithm. DNA copy number alterations were compared with a reference dataset of healthy Brazilian individuals and with Database of Genomic Variants. DNA from UPS presented 1406 CNAs and from LMS showed 625 CNAs. However, the genomic profile revealed striking similarities between both tumors that were indistinguishable by unsupervised hierarchical cluster analysis. In UPS samples, genomic gains were mainly found on chromosomes 1 and 7 (79 and 65 events, respectively), while recurrent losses encompassing chromosomes 1 and 12 (49 and 43 events, respectively). Recurrent gains on chromosomes 5 and 17 (28 and 30 events, respectively) and losses on chromosomes 2 and 10 (29 and 28 events, respectively) were frequently found in LMS. Gains on 2q11.1-q11.2 (P=0.031) and losses on 21p11.1 (P=0.001) were significantly detected in patients with UPS alive with the disease and alive without the disease, respectively. In LMS, gains in 1q and 11q (P=0.02 and P=0.043), as well as losses in 17q25 (P=0.05) were associated with tumor recurrence. Non-supervised hierarchical clustering revealed three groups. Cluster 2 was characterized by retroperitoneal tumors (P=0.04) and cluster 3 included both, LMS and UPS, from extremities (P=0.032). None exclusive alteration was verified for cluster 1. In addition, losses on 3p12.1-p11.2 found in UPS and gains on 1q21.3 and 11q13.2-q13.3 in LMS were associated significantly with reduced patient survival (P&lt;0.05). These data suggest a very complex interplay between UPS and LMS, providing new hints about the pathobiology of these tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5094. doi:1538-7445.AM2012-5094