bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1436: Investigating the NAD metabolome in Ewing sarcoma
Authors: Mutz Cornelia N. , Ban Jozef , Niedan Stephan , Kauer Maximilian O. , Aryee Dave N.T. , Fuchs Dietmar , Heitger Andreas , Kovar Heinrich 
Published: May 2015

Abstract
Ewing Sarcoma (ES) is the second most common bone cancer in children and adolescents with a high metastatic potential. Tumor development is driven by the specific t(11;22)(q24;q12) chromosomal translocation resulting in generation of the chimeric transcription factor EWS-FLI1.
Recently, ES has been reported to be exquisitely sensitive to inhibitors of poly(ADP-ribose) polymerase 1 (PARP1). This enzyme uses NAD+ as substrate and was demonstrated to regulate EWS-FLI1 in a feed-back mechanism. Another major mammalian NAD+ consumer is the deacetylase SIRT1 which we observed to be highly expressed in ES metastases, validated with immunohistochemistry of 250 primary tumors and 30 metastases. PARP1 and SIRT1 play pivotal roles in coupling cellular metabolism to transcriptional gene regulation as well as to stress response. Both of them regulate pro-apoptotic transcription factors that are suppressed in ES including p53, FOXO1 and 3, and NFκB. It has been demonstrated that PARP1 activity is at least partially dependent on acetylation which is counteracted by SIRT1 activity. Severe cell stress such as DNA damage leads to massive activation of PARP1, thus resulting in depletion of the cellular NAD+ pool and finally cell death. Usually, NAD+ is regenerated from nicotinamide via NAMPT or from the reduction of pyruvate via LDHA (Warburg effect), but can also be synthesized de novo from tryptophan. Interestingly, the knockdown of EWS-FLI1 in ES cells comes along with increased TDO and suppressed KMO expression, both being critical enzymes in tryptophan metabolism and NAD+ de novo synthesis. As a consequence, cellular tryptophan consumption drastically increases, which might indicate a regulatory function of EWS-FLI1 in maintaining the balance of the cellular NAD+ metabolism. In addition, we observed a striking sensitivity of ES cells to interferon gamma treatment at very low doses (5U/ml) resulting in the induction of the tryptophan metabolizing enzyme IDO and the production of the immune-suppressive metabolite kynurenine. We are currently studying how these changes in tryptophan metabolism affect cellular NAD+ pools and SIRT1 and PARP1 activities in ES. This study serves for a better understanding of EWS-FLI1 and of the microenvironment in the post-translational control of SIRT1 and PARP1 regulated gene transcription, and the consequences for PARP1 and/or SIRT1 directed therapies of ES.
Supported by the Austrian Science fund, grant I1225-B19.
Citation Format: Cornelia N. Mutz, Jozef Ban, Stephan Niedan, Maximilian O. Kauer, Dave N.T. Aryee, Dietmar Fuchs, Andreas Heitger, Heinrich Kovar. Investigating the NAD metabolome in Ewing sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1436. doi:10.1158/1538-7445.AM2014-1436
Abstract 1440: Metabolic therapy reduces expression of PECAM-1/CD31 and decreases peritumoral edema in a mouse model of malignant glioma
Authors: Woolf Eric C. , Charlton Julie A. , Liu Qingwei , Turner Gregory , Preul Mark C. , Scheck Adrienne C. 
Published: May 2015

Abstract
Patients with malignant brain tumors have a median survival of approximately one year following diagnosis, regardless of currently available treatments which include surgery followed by radiation and chemotherapy. Improvement in the survival of brain cancer patients requires the design of new therapeutic modalities that take advantage of common phenotypes. One such phenotype is the metabolic dysregulation that is a hallmark of cancer cells. It has therefore been postulated that one approach to treating brain tumors may be by metabolic alteration such as that which occurs through the use of the ketogenic diet (KD). The KD is high-fat, low-carbohydrate diet that induces ketosis and has been utilized for the non-pharmacologic treatment of refractory epilepsy. We and others have shown that this diet enhances survival and potentiates standard therapy in mouse models of malignant gliomas, yet the anti-tumor mechanisms are not fully understood.
It has been previously shown that caloric restriction, which induces ketosis, reduces microvessel density in mouse and human brain tumor models, suggesting an anti-angiogenic effect. We now report that in animals fed KetoCal® (KC) (4:1 fat:protein/carbohydrates) ad libitum, peritumoral edema is significantly reduced early in tumor progression when compared to those fed a standard rodent diet (SD). Western blot analysis showed a reduction of platelet endothelial cell adhesion molecule 1 (PECAM1/CD31) in tumors from animals maintained on KC. These results were supported by immunohistochemical staining for CD31 which also revealed abnormal vessel structure in the tumors from animals fed SD but not in those fed KC, suggesting a normalizing effect by the KC. Furthermore gene expression profiling demonstrated that KC decreases expression of a group of genes involved in angiogenesis and vessel structuring including the genes encoding vascular endothelial growth factor B (VEGFB) and angiopoetin 1 receptor (TEK), integrin beta 1 (ITGB1), urokinase-type plasminogen activator (PLAU) and tissue inhibitor of metalloproteases 1 (TIMP1). Taken together our data suggests that KC alters the angiogenic processes involved in malignant progression of gliomas. A greater understanding of the effects of the ketogenic diet as an adjuvant therapy will allow for a more rational approach to its clinical use.
Citation Format: Eric C. Woolf, Julie A. Charlton, Qingwei Liu, Gregory Turner, Mark C. Preul, Adrienne C. Scheck. Metabolic therapy reduces expression of PECAM-1/CD31 and decreases peritumoral edema in a mouse model of malignant glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1440. doi:10.1158/1538-7445.AM2014-1440
Abstract 1441: Induction of cancer cachexia by inflammatory molecules in directed complementation tumor models
Authors: Liu Qing , Lerner Lorena , Siddiquee Zakir , Huang Lucia , Wang Ruojie , Tao Nianjun , Krieger Brian , Chiu Isabel , Gyuris Jeno 
Published: May 2015

Abstract
Cancer cachexia is a complex multi-factorial syndrome characterized by anorexia, body weight loss that is primarily due to the loss of skeletal muscle and adipose tissue, as well as systemic inflammation. It affects the majority of advanced cancer patients, being the cause of death in 20% to 40% of the cases. Although inflammation is recognized as an important component of cancer cachexia, the role of individual cytokines is poorly understood. Our analyses of inflammatory markers in two independent human cancer cachexia plasma collections identified several cytokines (GDF-15, Activin-A, IL-6 and IL-8) that are consistently upregulated in cancer cachexia patients. To examine the ability of these cytokines to induce cancer cachexia, we utilized an inducible breast cancer model as the background in which to create a panel of genetically-engineered mouse tumor models that overexpress targets of interests, namely GDF15, Activin A and IL-6. Such complemented tumor models present a unique preclinical opportunity for dissecting the role of candidate markers in vivo, in part because they were generated on a genetically homogeneous background, allowing the role of each individual target to be identified and differentiated.
Mice bearing tumors that overexpress each inflammatory marker were characterized for phenotypic manifestation of cachexia. Mice bearing tumors that overexpress GDF15 (or MIC-1, macrophage inhibitory cytokine-1) developed severe cachexia with a rapid onset of body weight loss as well as changes in body composition. Overexpression of Activin A or IL-6 induced partial body weight loss with a milder cachexia phenotype at concentrations significantly higher that seen in cachexic human patients, while mice bearing control tumors without the engineered expression of an inflammatory cytokine showed no detectable changes in either body weight or body composition.
These results indicate that the elevated expression of GDF-15 and to a lesser extent Activin A, and IL-6 can result in the development of cancer cachexia and may represent attractive therapeutic targets.
Citation Format: Qing Liu, Lorena Lerner, Zakir Siddiquee, Lucia Huang, Ruojie Wang, Nianjun Tao, Brian Krieger, Isabel Chiu, Jeno Gyuris. Induction of cancer cachexia by inflammatory molecules in directed complementation tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1441. doi:10.1158/1538-7445.AM2014-1441
Abstract 1443: A systematic approach to the metastatically relevant microRNA landscape
Authors: Mudduluru Giridhar , Abba Mohammed , Batliner Jasmin , Patil Nitin , Lunavat Taral R. , Scharp Maike , Leupold Jörg , Oleksiuk Olga , Buchhalter Ivo , Thiele Wilko , Rothley Melanie , Benner Axel , Sleeman Jonathan , Allgayer Heike 
Published: May 2015

Abstract
Distant metastasis is the major determinant of patient outcome in colorectal cancer. By systematically analysing the miR expression profiles of resected metastasis-, corresponding primary tumor and normal tissues of colorectal cancer patients, we were able to delineate a miR-signature indicative of the metastatically critical microRNA landscape. This “hot list” of miRNAs, including established metastasis-related miRs like the miR-34- and let -7 families, as well as rather novel miR-candidates like miR-552, -218, -135, -210 and -654, together with their putative common targets were bioinformatically predicted to regulate the most significant metastasis-associated signaling pathways currently known. We were able to show for the first time that miR-135b, miR-210 and the loss of miR-218 constitute a novel network that regulates both E- and N-cadherin expression, which is achieved, in part, via several novel common targets such as the recently described tumor suppressors SIAH1 and SETD2, and, most importantly, FOXN3 transcription factor. This is paralleled by a significant impact on migration, invasion, in vivo intravasation and metastasis in chicken embryo and mouse models. We conclude that miR-218 as a novel metastasis suppressor, and pro-metastatic miR-135b and miR-210, constitute one important novel network critical for metastasis, resulting from the first study to systematically suggest the microRNA-driven master pathways of metatasis from solid cancer tissues.
Citation Format: Giridhar Mudduluru, Mohammed Abba, Jasmin Batliner, Nitin Patil, Taral R. Lunavat, Maike Scharp, Jörg Leupold, Olga Oleksiuk, Ivo Buchhalter, Wilko Thiele, Melanie Rothley, Axel Benner, Jonathan Sleeman, Heike Allgayer. A systematic approach to the metastatically relevant microRNA landscape. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1443. doi:10.1158/1538-7445.AM2014-1443
Abstract 145: Fibulin-5 as a regulator of integrin-induced ROS production and potential target for pancreatic cancer
Authors: Topalovski Mary , Wang Miao , Brekken Rolf A. 
Published: May 2015

Abstract
Reactive oxygen species (ROS) function as signaling molecules in pathological and normal molecular pathways. Redox homeostasis is maintained by a balance between the ROS production and ROS scavenging capacity of the cell. Extracellular matrix (ECM) proteins such as fibronectin have been shown to induce ROS upon binding to cell surface integrins, such as α5β1 integrin. Solid tumors rich in ECM such as pancreatic ductal adenocarcinoma (PDAC) display with higher levels of ROS compared to normal tissue. An attractive strategy to improve therapeutic response in PDAC is to further increase the level of ROS, thereby producing irreversible stress to tumor cells and surrounding stromal cells. Furthermore, increased ROS production has been shown to enhance the efficacy of some chemotherapeutics and might also improve the potency of anti-angiogenic therapy.
We propose a novel function of the matricellular protein Fibulin-5 (Fbln5) is to regulate ROS levels during angiogenesis. Fbln5 is expressed highly in human PDAC tissue and in murine models of pancreatic cancer. We have seen that the genetic ablation of of Fbln5 results in decreased tumor growth in implant and genetic models of pancreatic cancer. Furthermore, this decrease in tumor growth is accompanied by a decrease in microvessel density. Our lab has discovered that Fbln5 reduces integrin-mediated ROS generation by competing with fibronectin for binding to α5β1 integrin. Fbln5 binds to α5β1 integrin via an RGD motif, mutation of which to RGE abolishes the Fbln5 - integrin interaction. Knock-in Fbln5RGE/RGE mice have been produced and crossed into the background of KIC mice (p48Cre/+; LSL- KrasG12D; Ink4a/Arflox/lox). By utilizing this in vivo model we will be able to elucidate the mechanism by which Fbln5 regulates tumor angiogenesis and specifically integrin-induced ROS production. In the present study, our goal is to investigate the molecular mechanism leading to increased ROS production in tumors in Fbln5RGE/RGE animals. These targeted experiments will advance our understanding of the biology of Fbln5 in pancreatic cancer and ultimately contribute to its development as a potential therapeutic target.
Citation Format: Mary Topalovski, Miao Wang, Rolf A. Brekken. Fibulin-5 as a regulator of integrin-induced ROS production and potential target for pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 145. doi:10.1158/1538-7445.AM2014-145
Abstract 148: Release of the TNF-family member BAFF by NK cells contributes to the resistance of chronic lymphoid leukemia cells to direct and Rituximab-induced NK reactivity
Authors: Wild Julia , Schmiedel Benjamin J. , Maurer Andreas , Raab Stefanie , Schneider Pascal , Salih Helmut R. 
Published: May 2015

Abstract
NK cells are cytotoxic lymphocytes that are particularly important for the immunosurveillance of leukemia. Due to their ability to mediate antibody-dependent cellular cytotoxicity (ADCC), NK cells substantially contribute to the therapeutic benefit of antitumor antibodies like Rituximab, which is a crucial component in the treatment of B cell malignancies. Available data indicate that the ability of NK cells to target malignant cells and to mediate ADCC is compromised in Chronic Lymphoid Leukemia (CLL), but the underlying mechanisms are still unclear (Jaglowski et al., Blood 2010). With the TNF family member B cell activating factor (BAFF) that regulates, among others, the proliferation and survival of B cells, we believe to have identified a factor which contributes to these clinical observations. We report that NK cells express BAFF on the mRNA level and release the protein in a soluble form with the levels depending on activation state. Notably, relevant BAFF surface expression was neither detected on resting nor activated NK cells. Using a tetrazolium salt based colorimetric assay we found that NK cell-derived BAFF enhances the metabolic activity of primary CLL cells. In addition, BAFF protects CLL cells from chemotherapy-induced cell death e.g. upon treatment with Fludarabine and Cyclophosphamide. Notably, the BAFF-specific antibody Belimumab, which is approved for the treatment of systemic lupus erythematosus, was found to block the leukemia cell-protective effects of BAFF and to restore the sensitivity of the leukemia cells to chemotherapy. Furthermore, BAFF was found to substantially reduce direct NK cell lysis and also Rituximab-mediated ADCC in cultures with primary CLL cells as measured by Europium cytotoxicity assays. Our data on the capacity of BAFF to enhance the metabolic activity of B-CLL cells and their resistance to NK cell cytotoxicity suggest its involvement in the compromised ability of NK cells to combat lymphoid as compared to myeloid leukemias (Pende et al., Blood 2005) and the reportedly impaired ability of NK cells to mediate ADCC upon Rituximab treatment in CLL. Furthermore, our findings point to a possible benefit of combinatory approaches employing Rituximab and Belimumab for immunotherapy of B cell malignancies.
Citation Format: Julia Wild, Benjamin J. Schmiedel, Andreas Maurer, Stefanie Raab, Pascal Schneider, Helmut R. Salih. Release of the TNF-family member BAFF by NK cells contributes to the resistance of chronic lymphoid leukemia cells to direct and Rituximab-induced NK reactivity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 148. doi:10.1158/1538-7445.AM2014-148
Abstract 1493: Specific miRNA signatures characterize different metastatic sites in clear cell renal cell carcinoma
Authors: Heinzelmann Joana , Stolzenbach Franzsika , Schneeweiss Robert , Wickmann Ulrike , Baumgart Sophie , Gajda Mieczyslaw , Stöckle Michael , Junker Kerstin 
Published: May 2015

Abstract
Background: MiRNAs are regulators of gene expression in tumorigenesis and progression. To identify miRNAs associated with metastasis miRNA expression in distant metastases was compared to primary clear cell renal cell carcinoma (ccRCC).
Material and methods: Total RNA of 27 primary ccRCC samples and 25 distant metastases (lung, bone and brain) was isolated from formalin-fixed paraffin-embedded (FFPE) samples Microarray analyses were performed for a global miRNA expression profiling. Results were validated by qPCR. For miRNA target identification a ccRCC cell line (786-O) was transfected with miRNAs differently expressed in metastatic primary tumors and metastases.
Results: We identified 9 miRNAs (including miR-30c and miR-126) with a similar expression in metastatic primary ccRCC and distant metastases from different metastatic sites compared to non-metastatic primary ccRCC. 11 miRNAs (including miR-10b and miR-204) were differently expressed in distant metastases compared to primary ccRCC. Furthermore, each metastatic site is characterized by a specific miRNA signature. Results were verified on selected miRNAs using qPCR. In vitro studies identified potential miRNA targets and associated metastasis related pathways.
Discussion: These data suggest that miRNAs play an important role in metastatic processes of ccRCC. Furthermore, our results regarding different metastatic sites suggest two important statements. Specific miRNAs characterize distant metastases in general. On the other hand, miRNA expression is associated with specific conditions at different metastatic sites. Thus, the data presented in this study give the base for a better understanding of the involvement of miRNAs as regulators of metastasis which opens new possibilities for new targeted therapy options.
Citation Format: Joana Heinzelmann, Franzsika Stolzenbach, Robert Schneeweiss, Ulrike Wickmann, Sophie Baumgart, Mieczyslaw Gajda, Michael Stöckle, Kerstin Junker. Specific miRNA signatures characterize different metastatic sites in clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1493. doi:10.1158/1538-7445.AM2014-1493
Abstract 1495: Identification of markers for the presence of lymph nodes metastasis in patients with oral squamous cell carcinomas
Authors: Zamunér Fernando Tadeu , Maia Danielle Calheiros Campelo , Carvalho André Lopes , Vettore André Luiz 
Published: May 2015

Abstract
INTRODUCTION: Oral cancer is the most common subset of head and neck squamous cell carcinomas (OSCC). These tumors often have an aggressive clinical outcome hallmarked by a propensity for local invasion and regional nodal metastasis. The presence of metastatic disease in cervical lymph nodes is an important prognostic factor and it influences in the choice of the therapeutic strategy to be adopted. Thus, the identification of molecular markers able to select patients who are at high risk for lymph node metastasis and/or locoregional recurrence could be of great value. Recent studies have shown that microRNAs can be regulators of the tumor metastasis process by the activation of various signaling pathways involved in this process being useful in diagnosis, determination of disease prognosis and prediction of therapeutic response. PURPOSE: to identify microRNAs expressed in OSCC associated with the presence of lymph node metastasis. METHODS: Tumor samples were obtained from patients diagnosed with OSCC at the Head and Neck Surgery Department, Cancer Hospital of Barretos. For microRNA microarrays experiments, total RNA from 32 tumor samples (12 without lymph node metastasis and 12 with metastasis) was extracted labelled and hybridizated Analysis of microarray data was performed using GeneSpring GX 12.0 and R program. RESULTS: This analysis allowed the identification of six microRNAs differentially expressed in the comparison between metastatic and non-metastatic OCCS cases. These microRNAs will be validate and selected by qRT-PCR in an independent cohort of OSCC patients and correlate the molecular data with the clinical features of the patients.
Financial Support: FAPESP
Note: This abstract was not presented at the meeting.
Citation Format: Fernando Tadeu Zamunér, Danielle Calheiros Campelo Maia, André Lopes Carvalho, André Luiz Vettore. Identification of markers for the presence of lymph nodes metastasis in patients with oral squamous cell carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1495. doi:10.1158/1538-7445.AM2014-1495