bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5152: Zebrafish models of myeloid malignancies produced through tet2 and asxl1 genomic editing
Authors: Gjini Evisa , Mansour Marc , Sander Jeffry , He Shuning , Ko Myunggon , Zhou Yi , Rodig Scott , Joung Keith , Zon Leonard , Rao Anjana , Look Thomas 
Published: August 2015

Abstract
Myelodysplastic syndromes (MDS) are one of the most common and most difficult to treat of all hematologic malignancies. MDS are diverse clonal disorders of hematopoietic stem cells in the bone marrow that cause dysplastic differentiation in developing progenitors leading to ineffective hematopoiesis, dangerously low circulating blood counts, and evolution to acute myeloid leukemia (AML). We sought to create a faithful zebrafish model of MDS, to study the altered molecular pathways and mechanisms underlying this disease and to provide a means to identify synthetic lethal relationships that can be exploited with small molecule inhibitors to selectively eliminate the mutant cells. Somatic loss-of-function mutations of the Ten-ElevenTranslocation-2 (TET2) and Additional Sex Combs Like 1 (ASXL1) genes are the most frequent clonal somatically acquired genetic abnormalities that have been identified in human MDS and other myeloid malignancies, such as chronic myelomonocytic leukemia (CMML). To generate a zebrafish model of MDS with tet2 and asxl1 loss, we used genome-editing technology to disrupt the zebrafish tet2 and asxl1 genes. The resultant tet2m/m mutant zebrafish are viable and fertile and exhibited normal embryonic and larval hematopoiesis, but developed myelodysplastic syndrome progressing to anemia at 24 months of age. asxl1 m/m mutant zebrafish are embryonic lethal with bone malformations. asxl1 m/m embryos show reduced numbers of hematopoietic and progenitor stem cells (HSPCs), a phenotype which is rescued by Tet2 loss. Combined loss of tet2 and asxl1 in the zebrafish leads to CMML at 5 months of age. These zebrafish lines provide animal models for small molecule and genetic screens in definitive HSPCs to identify synthetic lethal relationships and to dissect the pathways in hematopoietic cells that are altered by loss of function of tet2 and asxl1.
Citation Format: Evisa Gjini, Marc Mansour, Jeffry Sander, Shuning He, Myunggon Ko, Yi Zhou, Scott Rodig, Keith Joung, Leonard Zon, Anjana Rao, Thomas Look. Zebrafish models of myeloid malignancies produced through tet2 and asxl1 genomic editing. [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 5152. doi:10.1158/1538-7445.AM2015-5152
Abstract 5170: The autotaxin-lysophosphatidic acid signaling pathways in ovarian carcinoma
Authors: Onalla Hadil , Tropé Claes , Reich Reuven , Davidson Ben 
Published: August 2015

Abstract
Ovarian carcinoma ranks as the fifth most common cancer among women. This is attributed to late presentation of the patients. The disease is characterized by widespread intraperitoneal metastases and accumulation of effusion fluids mainly in the peritoneal cavity
Lysophosphatidic acid (LPA) is a bioactive phospholipid with mitogenic and growth factor-like activities affecting cell invasion, cancer progression and resistance that act via specific cell-surface receptors present in many transformed cell types. LPA is produced by two main pathways, by PLA-2 and by Autotaxin (LysoPLD). Once its produced, it acts on six specific G protein coupled receptors, LPAR1-6. LPA has recently been implicated as a growth factor present in ascites of ovarian cancer patients. Previous studies have shown high levels of LPA in the effusions of ovarian carcinoma patients.
The aim of our study was to examine the role of ATX-LPA signaling in the progression of serous ovarian carcinoma. A total of 230 samples of serous ovarian carcinoma from the three different anatomic sites of the disease, were used .Effusion fluids were frozen and stored separately. All specimens were submitted for routine diagnostic purpose to the Division of Pathology at the Norwegian Radium Hospital during the period 1998-2008. mRNA levels of the six different LPA receptors were measured by RT-PCR, protein levels of Autotaxin were measured by Western blotting.
Results show that LPA2R is higher in effusion-derived tumor cells compared to solid lesions (p&lt;0.001), while the opposite was found for LPA3R (p&lt;0.001) and LPA6R (p&lt;0.001). Clinico-pathological analysis showed that LPA3R levels are significantly higher in pre-chemo patients (p = 0.038). LPA2R (p = 0.021) and LPA5R (p = 0.035) were found higher in cases with larger residual disease volume. LPA5R (p = 0.032) was higher in cases with primary chemo-resistance and LPA1R (p = 0.05) was marginally associated with better overall survival.
Autotaxin protein levels were lower in effusion-derived tumor cells compared to solid lesions (p&lt;0.001), yet higher levels of Autotaxin were found in peritoneal lesions compared to pleural ones (p = 0.033).
In this study we showed significant changes in mRNA LPAR levels and Autotaxin protein levels with the progression of the disease that correlates to clinic-pathological parameters.
To our best knowledge, this is the first description of the ATX-LPA signaling pathway in ovarian carcinoma with clinical relevance.
Citation Format: Hadil Onalla, Claes Tropé, Reuven Reich, Ben Davidson. The autotaxin-lysophosphatidic acid signaling pathways in ovarian carcinoma. [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 5170. doi:10.1158/1538-7445.AM2015-5170
Abstract 5173: Androgen receptor status is highly conserved during tumor progression of breast cancer
Authors: Grogg André , Pfaltz Katrin , Lädrach Claudia , Cihoric Nikola , Zweifel Martin , Tapia Coya F. M. 
Published: August 2015

Abstract
Introduction: Many clinical trails are ongoing targeting androgen receptor (AR) in breast cancer (BC). Anti-androgen therapy is increasingly accepted in BC patients since the new compounds have less androgenic side effects. The assessment of AR status is generally performed on the primary tumor even when treating metastatic disease. To the best of our knowledge, nothing is known regarding discrepancies of AR status between the primary tumor and the metastatic site. Therefore, we investigated AR status on a large cohort of primary BCs and matched metastases.
Method: A next-generation Tissue Microarray (ngTMA) was constructed harboring 356 primary BCs, 133 matched metastases and 11 recurrences. A commercially available monoclonal AR antibody (DAKO) was used to evaluate AR-Status by immunohistochemistry. AR positivity was defined as ≥1% of nuclear staining in tumor cells. The results of the primary tumor and metastases/recurrences were compared. Additionally, the results of AR status were correlated with other pathological tumor features.
Result: AR could be evaluated in 353/356 (99.2%) of primary BCs and a positivity was detected in 307 (87%). A discordant result was seen in 4.3% metastasized BC's with informative results (5/117). Three negative BCs were positive in the metastases representing 16.7% of all negative BCs with informative results (3/18). Two BCs were positive in the primary and negative in the metastases representing 2.0% of all positive BCs with metastases and informative results (2/99). No discrepancies were seen between primary and loco-regional recurrences. Further, AR expression was significantly correlated with a positive estrogen (p&lt;0.001) and progesterone receptor (p&lt;0.001) status and a low proliferation (≤15%) (p&lt;0.001). Negative AR status was significantly (p&lt;0.001) associated with a higher tumor grade. Triple negative BCs were in 11.4% AR positive (4/35).
Conclusion: AR positivity is frequent in primary BCs (87%) and AR status is highly conserved during tumor progression. In a small fraction AR status changes (4.3%) either from positive to negative status or vise versa. However, even AR status is highly preserved we would recommend reevaluation of the metastatic site in negative BC's since a positive AR status can be seen in 16.7% of this subgroup.
Citation Format: André Grogg, Katrin Pfaltz, Claudia Lädrach, Nikola Cihoric, Martin Zweifel, Coya F. M. Tapia. Androgen receptor status is highly conserved during tumor progression of breast 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 5173. doi:10.1158/1538-7445.AM2015-5173
Abstract 518: O-GlcNAcylation regulates breast cancer cell invasion via the NAD+-dependent deacetylase SIRT1
Authors: Ferrer Christina M. 
Published: August 2015

Abstract
Cancer cells increase nutrient consumption leading to the altered metabolic state known as the Warburg effect. One pathway dependent on glucose, glutamine and acetyl-CoA is the Hexosamine Biosynthetic Pathway (HBP). Increased flux through the HBP leads to elevated post-translation addition of O-linked-β-N-acetylglucosamine (O-GlcNAc) on a diverse population of nuclear and cytosolic proteins, many of which are implicated in cancer. Recently, our lab provided the first evidence that breast and prostate cancers increases total O-GlcNAcylation by increasing O-GlcNAc Transferase (OGT) levels. Importantly, reducing OGT activity inhibits cancer cell invasion in vitro and metastasis in vivo. OGT inhibition reduces breast and prostate cancer cell invasion through, in part, inhibition of the oncogenic transcription factor, FOXM1 and its transcriptional target matrix metalloproteinase 2 (MMP2). Here, we show that OGT regulation of FOXM1 and cancer cell invasion requires regulation of the NAD+-dependent deacetylase, SIRT1. SIRT1 is a NAD+-dependent deacetylase regulated by changes in energy metabolism and its levels have been found to be reduced during breast cancer progression. We demonstrate an inverse relationship between O-GlcNAcylation and SIRT1 protein level and activity in multiple breast cancer cells and show that SIRT1 regulation by O-GlcNAcylation occurs in an AMPK-dependent manner. Consistent with this idea that reducing O-GlcNAcylation increases SIRT1 activity, we found that reducing OGT levels results in increased NAD+ metabolite levels in breast cancer cells. Importantly, we demonstrate that SIRT1 is critical for OGT-mediated regulation of FOXM1 protein ubiquitination and proteosomal degradation as reducing SIRT1 levels or activity reverses OGT-mediated regulation of FOXM1 and invasion in aggressive triple negative breast cancer cells. Furthermore, we show that SIRT1 regulates FOXM1 to modulate its transcriptional target MMP2 to promote breast cancer cell invasion. Collectively, these data indicate that flux through HBP, via O-GlcNAcylation, connects this nutrient sensing pathways with SIRT deactylases to regulate cellular invasion signaling via regulation of FOXM1.
Citation Format: Christina M. Ferrer. O-GlcNAcylation regulates breast cancer cell invasion via the NAD+-dependent deacetylase SIRT1. [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 518. doi:10.1158/1538-7445.AM2015-518
Abstract 5185: Identification of BRIP1 as a novel marker of breast tumor malignancy in the Omani population
Authors: Gupta Ishita , Ouhtit Allal , Al-Riyami Marwa , Al Ajmi Adil 
Published: August 2015

Abstract
The rationale of the present study is based on the following observations made in Oman: 1) a significantly increasing number of younger females (25-40 years) present to the clinic with advanced stage of breast cancer (BC); 2) the rate of consanguinity is significantly high (∼50%); and 3) the transition from normal/benign to malignant phenotype of breast tumor requires the involvement of a subset of specific genes. The long-term objective of this study was to identify and validate the gene(s) that underpin BC malignant transformation using functional genomic approaches. RNA samples were isolated from 40 malignant breast tumor tissues and 40 normal/benign breast tissues and analyzed by microarray gene expression profiling. Among a number of differentially expressed genes, BRIP1 showing a 5-fold up-regulation was identified as a potential gene that might underpin the transition from the benign to the malignant phenotype. The differential expression of BRIP1 was structurally validated by RT-PCR using the remaining RNA of the same samples previously examined by microarray. Pathway analysis was carried out to predict the major functional pathways involving BRIP1 to other identified genes. Ongoing sequencing of these genes using DNA extracted from the same samples will ultimately identify any genetic alteration that can affect the normal function of these genes. Functional validation assays will validate further the physiological relevance of BRIP1 in tumor malignancy, and perhaps other novel gene(s) specific to BC in the Omani population. This study has identified BRIP1 as a novel potential marker for BC malignancy, and can be a potential biomarker for early diagnosis of BC and/or a target to pave the way towards the design of anti-BC therapeutic strategies.
Citation Format: Ishita Gupta, Allal Ouhtit, Marwa Al-Riyami, Adil Al Ajmi. Identification of BRIP1 as a novel marker of breast tumor malignancy in the Omani population. [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 5185. doi:10.1158/1538-7445.AM2015-5185
Abstract 5211: In vivo fluorescence and spectral microscopy of the effects of aerobic exercise on tumor oxygenation and perfusion in breast cancer
Authors: Lee Jennifer A. , Wiggins Jennifer M. , Rice Lori P. , Siemann Dietmar W. 
Published: August 2015

Abstract
Abnormal tumor angiogenesis leads to inefficient blood flow and inhibited delivery of oxygen, resulting in a hypoxic tumor microenvironment. In radiation therapy the presence of oxygen is necessary to impart lasting damage to cancer cells, therefore the modulation of tumor hypoxia has been an important focus to improve radiation therapy outcome. While strategies such as hyperbaric chambers and hypoxic cell radiosensitizers or cytotoxins have shown merit, their success in the clinic has been limited. A potential method to increase oxygenation and decrease hypoxia in a tumor mass that is safe and well-tolerated is aerobic exercise. For cancer patients, the benefits of exercise in a palliative setting are well known, however the effects of exercise on tumor microvasculature and blood flow have not been extensively characterized.
In vivo microscopy of microvessel function in preclinical models is a useful tool for the study of tumor vascular structure and function. The combination of hyperspectral imaging of hemoglobin (Hb) saturation and first-pass fluorescence (FPF) imaging of blood transit time in the murine dorsal skinfold window chamber has been previously used to characterize tumor angiogenesis, wound healing and the response of tumor microvasculature to vascular targeting agents. Hb saturation imaging reveals the oxygenation of blood within microvessels while FPF imaging gives information regarding blood flow and network connections by recording a fluorescent contrast agent as it is injected into circulation. In the present study, this combination imaging technique is used to evaluate the impact of treadmill running on tumor blood flow and microvessel oxygenation in real time. 4T1 mammary tumors were initiated in nude mice bearing titanium window chambers. Once tumors reached a volume of ∼5mm3, mice were subjected to daily treadmill running for 5-7 consecutive days (30 min, 15-18 m/min, 10° incline). As a sedentary control, mice were placed on a stationary treadmill for equivalent periods of time. Combination imaging was performed daily to monitor microvessel oxygenation and blood flow. On the first day of exercise, imaging was performed both before and after animals were exercised. Preliminary results indicate that following one bout of exercise, tumor perfusion is increased, however there was no significant correlation between exercise and tumor microvessel oxygenation.
Citation Format: Jennifer A. Lee, Jennifer M. Wiggins, Lori P. Rice, Dietmar W. Siemann. In vivo fluorescence and spectral microscopy of the effects of aerobic exercise on tumor oxygenation and perfusion in breast 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 5211. doi:10.1158/1538-7445.AM2015-5211
Abstract 5251: TaqMan® rare mutation assays for QuantStudio® 3D digital PCR system
Authors: Laig Marion , Ho Brian , Majumdar Nivedita S. , Lac Le T. , Chan Frances , Sathiyaa Ramesh , Russel Iain , Cifuentes Paco , Straub Ted , Varma Kamini , Keys David 
Published: August 2015

Abstract
Detection and quantification of mutant alleles in tumor tissue allow for research disease monitoring and the research of drug efficacy. Detection of emerging secondary mutations in the same tumor tissue causing resistance to potential treatment will help guide decisions on future treatment plans. A less invasive research method than using tumor tissue is testing for the presence of mutations in circulating free DNA (cfDNA).
We created a research tool for mutation detection at a sensitivity level of 1% and below. This allows researchers to find correlation between types of mutations and types of tumors and determination of potential secondary mutations.
The tool combines TaqMan® SNP Genotyping Assays with digital PCR. A set of assays was optimized for use in digital PCR with the QuantStudio® 3D Digital PCR System. In digital PCR, partitioning the sample into many individual reaction wells facilitates detection and quantification of rare mutant alleles. TaqMan® SNP Genotyping Assays ensure reliable discrimination of mutant and wild-type allele.
Our initial set of 38 assays covers mutations commonly found in tumor tissues: BRAF V600E, mutations in EGFR exons 19, 20 and 21, KRAS codons 12 and 13, PIK3CA exons 9 and 20, and the JAK2 V617F mutations.
All assays were wet-lab tested at a 10% mutation rate and a 1% mutation rate using mutant plasmid spiked into wild-type genomic DNA. Additionally, selected assays were tested at the 0.1% mutation rate using mutant cell lines spiked into wild-type genomic DNA.
Wet-lab results confirm that all assays showed superior performance discriminating mutant and wild-type alleles. Mutant alleles were successfully detected as low as 0.1%.
For Research Use Only. Not for use in diagnostic procedures.
Citation Format: Marion Laig, Brian Ho, Nivedita S. Majumdar, Le T. Lac, Frances Chan, Ramesh Sathiyaa, Iain Russel, Paco Cifuentes, Ted Straub, Kamini Varma, David Keys. TaqMan® rare mutation assays for QuantStudio® 3D digital PCR system. [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 5251. doi:10.1158/1538-7445.AM2015-5251
Abstract 5255: miR-21 expression in HER2-positive breast cancer and prediction of resistance to adjuvant trastuzumab
Authors: Nielsen Boye S. , Balslev Eva , Poulsen Tim S. , Nielsen Dorte , Moller Trine S. , Mortensen Christiane E. , Holmstrom Kim S. , Hoegdall Estrid 
Published: August 2015

Abstract
Trastuzumab is established as standard care for patients with HER2-positive breast cancer both in the adjuvant and metastatic setting. However, approximately 50% of the patients do not respond to the trastuzumab therapy, and therefore new predictive biomarkers are highly warranted. MicroRNAs (miRs) constitute an interesting group of biomarkers and their cellular expression can be determined in tumor samples by in situ hybridization (ISH) analysis. miR-21 is highly prevalent and up-regulated in breast cancer and has been linked to drug resistance in clinical and in vitro settings. To determine expression patterns of miR-21 in high-grade breast cancers, we examined miR-21 expression in 22 HER2-positive tumors and 15 HER2-negative high-grade tumors by ISH. The histological examination indicated that patient samples could be divided into 3 major expression patterns: miR-21 predominantly in tumor stroma, predominantly in cancer cells or in both stromal and cancer cells. There was no obvious difference between the HER2-positive and HER2-negative tumors in terms of the miR-21 expression patterns and intensities. To explore the possibility that miR-21 expression levels and/or cellular localization could predict resistance to adjuvant trastuzumab in HER2-positive breast cancer patients, we analyzed additional 16 HER2-positive tumors from patients that were treated with trastuzumab in the adjuvant setting. Eight of the 16 patients showed clinical recurrence and were considered resistant. Examination of the miR-21 expression patterns and intensities revealed no association between the miR-21 scores in the cancer cell population (p = 0.69) or the stromal cells population (p = 0.13) and recurrent disease after adjuvant trastuzumab. Thus, our findings suggest that elevated miR-21 expression does not predict resistance to adjuvant trastuzumab.
Citation Format: Boye S. Nielsen, Eva Balslev, Tim S. Poulsen, Dorte Nielsen, Trine S. Moller, Christiane E. Mortensen, Kim S. Holmstrom, Estrid Hoegdall. miR-21 expression in HER2-positive breast cancer and prediction of resistance to adjuvant trastuzumab. [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 5255. doi:10.1158/1538-7445.AM2015-5255