bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3049: Pathways of transformation in Kit-activated melanoma
Authors: Liang Ruixia 
Published: June 2012

Abstract
KIT-activated melanoma is a recently recognized distinct genetic form of melanoma characterized by constitutively activating KIT mutations. To understand the biology of KIT-activated melanoma, we sought to develop both in vitro and in vivo models. Mouse Kit L575P, the orthologue of human KIT L576P, a common KIT mutation found in human melanoma, was expressed in an immortalized but non-transformed mouse Ink4a/Arf-deficient melanocyte cell line. The resultant Kit L575P cell line exhibited increased proliferation, the ability to grow in soft agar and increased migration, indicating that the cells had been transformed by Kit L575P. Furthermore, when Kit L575P cells were injected subcutaneously into NOD/SCID/gamma(c) mice, tumors with all of the histological and clinical hallmarks of melanomas arose in 5 of 7 (71%) mice, while control cells harboring wild-type Kit failed to develop tumors. In addition to a subcutaneous tumor, 1 of 7 mice (14%) injected with Kit L575P cells developed metastatic disease to liver and lungs. Evaluation of signal transduction pathways downstream of constitutively activated Kit L575P revealed striking activation of the phosphatidyl inositol 3-kinase (PI3K) pathway. Inhibition of the PI3K pathway pharmacologically with the PI3K inhibitor LY294002 or genetically by engineering a second Kit mutation (Y719F) which abrogated binding of Kit L575P to the p85α subunit of PI3K, abolished the transformation phenotypes gained in the L575P single mutant. These studies validate this Kit L575P-activated model of melanoma and establish the PI3K pathway as a dominant signaling pathway downstream of Kit in melanoma. This model should be of further use in the pre-clinical evaluation of various therapeutic strategies in Kit-activated melanoma and for studying different aspects of the biology of Kit-activated melanoma.
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 3049. doi:10.1158/1538-7445.AM2011-3049
Abstract 3061: Somatic mutation profiling to tumor samples using OncoCarta Panel
Authors: Furuta Kazuyuki , Arao Tokuzo , Yanagihara Kazuyoshi , Sekijima Masaru , Nishio Kazuto 
Published: June 2012

Abstract
Clinical decision-making based on tumor genetic information have emerged as a key approach for targeted-based drugs in cancer therapy. New diagnostic approach is needed to profile for pivotal genetic mutations in multiple oncogenes simultaneously. In this study, we evaluated the validity and sensitivity of high-throughput mutation profiling approach, ‘OncoCarta Panel’, in cancer marker evaluation research. It enables us to simultaneously detect 238 mutations across 19 key oncogenes including ABL1, AKT1, AKT2, BRAF, CDK, EGFR, ERBB2, FGFR1, FGFR3, FLT3, HRAS, JAK2, KIT, KRAS, MET, NRAS, PDGFRA, PIK3CA and RET. We analyzed the somatic mutations using the OncoCarta Panel on 44 cancer cell lines and 41 clinical tumor samples. The 57% (n=25) of cancer cell lines contained one or more mutations among 44 cancer cell lines; EGFR (5/44), KRAS (13/44), BRAF (4/44), PIK3CA (3/44) and NRAS (3/44) mutations in lung, colorectal, gastric, liver and pancreatic cancer cell lines. Some samples exhibited co-occurring oncogene mutations which might modify the clinical response. In addition, this analysis was also able to perform for DNA isolated from formalin-fixed, paraffin-embedded samples. The obtained data were in concordance with the data from Sanger sequencing and Scorpions-ARMS PCR methods. The mutation was detectable even when the mutated DNA represented only 10% of the total DNA, and this was approximately 2.5-fold more sensitive than Sanger Sequencing. We conclude that the OncoCarta Panel is more rapid, sensitive and cost-effective method for mutation profiling than the commonly used Sanger sequencing.
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 3061. doi:10.1158/1538-7445.AM2011-3061
Abstract 3073: Isothermal whole genome amplification of FFPE samples to detect copy number changes in the progression from colonic adenoma to carcinoma
Authors: Hirsch Daniela , Stapleton Mark , Ried Thomas , Camps Jordi , Gaiser Timo 
Published: June 2012

Abstract
Screening tumor genomes for somatic aberrations by aCGH is a commonly used high-resolution tool used both in research and clinical diagnostics. Unfortunately, the full utility of this technique is compromised with formalin fixed paraffin embedded (FFPE) tissue samples due to their inherently high degree of DNA degradation and the presence of DNA adducts acquired during the fixation and storage process. DNA degradation tends to worsen with storage time, making the analysis of archived samples even more challenging. We have developed a highly sensitive and robust whole genome amplification system for FFPE tumor samples that takes advantage of the proprietary Single Primer Isothermal Amplification (SPIA®) technology. The system uses 100 ng of routinely isolated FFPE DNA and produces 3-5 µg of DNA suitable for multiple downstream applications such as aCGH, enrichment strategies, and next generation sequencing (NGS). We evaluated the performance of the amplification system in the context of identifying aberrations by aCGH. Data will be presented that highlights the performance of the SPIA amplified material benchmarked against its unamplified counterpart along with the system's effectiveness on an array of sample qualities ranging from highly degraded FFPE DNA to highly intact FFPE DNA samples. Lastly, we employed the amplification system to examine the progression from adenoma to carcinoma using FFPE samples from human colon carcinomas within high-grade adenomas. Colonic epithelia gains numerous genetic alterations when degraded to dysplastic adenoma and then to cancer. While genetic alterations for each entity are well known, little data are available for combined lesions. Our results indicate that the SPIA amplified DNA performs equivalently to unamplified FFPE DNA in detecting copy number variations by aCGH, the system is suitable for a broad range of FFPE sample qualities, and is a flexible solution that allows for higher resolution analyses with NGS platforms.
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 3073. doi:10.1158/1538-7445.AM2011-3073
Abstract 3088: Regulation of tight junction protein claudin 1 mRNA expression by AU-rich element-binding (ELAV) proteins in colon cancer
Authors: Sharma Ashok , Singh Amar B. , Dhawan Punita 
Published: June 2012

Abstract
Tight junction associated proteins are key molecular components governing cellular adhesion, polarity and play critical roles in cellular proliferation via their functions as couplers of the extracellular milieu to intracellular signaling pathways. Claudin-1, a tight junction protein, expression is dysregulated in the majority of human colorectal carcinomas. We have previously reported that claudin-1 is regulated at post-transcriptional levels on treatment with HDAC inhibitor, TSA and its mRNA stability is modulated by 3’-UTR as the major mechanism underlying HDAC-dependent claudin-1 expression. It has putative AU-rich (ARE) cis-elements in its long 3’UTR (∼ 2.3Kb). Presence of a long 3’UTR is frequently indicative of post-translational regulation of gene expression via modulation of mRNA stability.
ELAV like RNA-binding proteins Hu antigen R (HuR) and tristetraprolin (TTP) associate with labile mRNAs bearing AU-rich elements located in the 3’ untranslated regions (3′-UTRs) and modulate their stability. We have identified putative AU rich elements in the proximal region of the claudin 1 3’-UTR and demonstrate that HuR interacts with these AU-rich elements. We further show a role of HuR and TTP during colon tumorigenesis and their ability to regulate Claudin-1 mRNA expression in presence TSA. We found that Claudin-1 mRNA was stabilized by HUR in both SW480 and SW620 cells, whereas its overexpression decreased the expression of TTP; We used a ribonomic approach to test the binding of HuR and TTP to claudin 1 3’UTR and their role in stabilization/destabilization of claudin-1 mRNA in the presence of TSA. On treatment with TSA the binding of HuR to claudin-1 3’UTR decreases while the binding of TTP increases correlating well with the rapid decay of claudin-1 mRNA in presence of TSA. Thus, our data suggest that claudin 1 is regulated via mRNA stability and a novel regulatory feedback loop between HuR and TTP in colon tumorigenesis.
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 3088. doi:10.1158/1538-7445.AM2011-3088
Abstract 3118: Regulation of SDF-1 (CXCL12) production by mesenchymal stromal cells
Authors: Amiri Sohrab 
Published: June 2012

Abstract
The tumor microenvironment is made up of a number of cell types including neoplastic epithelial cells, myofibroblasts, smooth muscle cells, pericytes, adipocytes, endothelial cells and their precursors, fibroblasts and immune cells. The interaction between cellular components of the microenvironment is critical for processes such as tumor progression, growth, angiogenesis, and metastasis. Mesenchymal stromal cells (MSCs) are an important component of the tumor microenvironment with roles in key aspects of tumor development such as cell growth and metastasis. Stromal-derived factor -1 (SDF-1) has been identified as a key-signaling molecule in the interaction between MSCs and neoplastic cells. SDF-1 acting through its cognate receptors CXCR4 and CXCR7 is known to mediate diverse processes such as chemotaxis, angiogenesis, hematopoiesis, metastasis, and tumor growth. In this study, we investigated the regulation of SDF-1 production by MSCs.
We show that the tumor suppressor p53 is an important regulator of SDF-1 signaling in MSCs within the tumor stroma. A decrease in p53 function leads to increased SDF-1 production by MSCs and increased migration of MSCs in response to tumor cells. An improved understanding of the molecular mechanisms controlling SDF-1 production by MSCs may identify novel ways to therapeutically target tumor – stromal interactions.
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 3118. doi:10.1158/1538-7445.AM2011-3118
Abstract 3136: c-Kit / CD117 is a predictive prognostic marker for patients with basal-like breast cancer
Authors: Kashiwagi Shinichiro , Yashiro Masakazu , Takashima Tsutomu , Aomatsu Naoki , Kawajiri Hidemi , Tanaka Hiroaki , Onoda Naoyoshi , Nakata Bunzo , Ishikawa Tetsuro , Hirakawa Kosei 
Published: June 2012

Abstract
Purpose: The mortality of breast carcinoma is decreasing because of recent developments in diagnostic techniques and therapies; however, the mortality of the basal-like breast cancer (BLBC) remains poor. BLBC a poorly characterized subtype of tumor with no validated clinical assay to identify them. In breast cancer, although there were some reports of survival analysis regarding c-Kit expression, the significance of c-Kit expression is controversial. In addition, little is known about the c-Kit expression levels of BLBC. The aim of this study is to clarify the correlation between c-Kit and BLBC.
Experimental Design: A total of 667 patients who had undergone resection of a primary breast cancer at our institute were enrolled. ER, PR, HER2, EGFR, CK5/6 and c-Kit expression were assessed by immunohistochemistry. We examined the association between BLBC and other clinicopathologic variables, and evaluated the significance of c-Kit expression.
Results: Of informative 667 breast cancer cases, basal-like phonotype was 149 (78.4%) of 190 cases of triple-negative phenotype. c-Kit expression was found in 111 patients (16.6%), and it was significantly many results in BLBC (42/149, 28.2%) (p&lt;0.001). The c-Kit positive patients experienced significantly poorer outcomes in terms of overall survival (p&lt;0.001). In 149 patients with BLBC, a statistically significant difference was observed between c-Kit positive and negative in regard to the degree of high age (p=0.037), lymph node metastasis (p=0.008) and lymphatic invasion (p=0.017). In BLBC, cases with c-Kit expression showed a poor overall survival time (p&lt;0.001), and disease-free interval period (p&lt;0.001), and it was an independent indicator of a poor prognosis by multivariate analyses (p=0.024, OR=2.291).
Conclusions: c-Kit is one of predictive prognostic marker and molecular targets in BLBC.
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 3136. doi:10.1158/1538-7445.AM2011-3136
Abstract 315: Human metabotropic glutamate receptor 1 (GRM1) may be essential for melanoma cell survival and activation of angiogenic signaling
Authors: Wen Yu , Li Jiadong , Shin Seung-Shick , Chen Suzie , Goydos James 
Published: June 2012

Abstract
Our group has demonstrated that ectopic expression of murine GRM1 results in transformation of mouse melanocyte cells, and we have found that human GRM1 is ectopically expressed in more than 60% human melanomas. We recently reported on the results of a Phase 0 preclinical trial targeting GRM1 signaling using a glutamate release-inhibitor, Riluzole. We demonstrated inhibition of signaling through the PI3K/AKT and MAPK pathways and a reduction in tumor size in 40% of patients treated. To better examine the mechanisms of Riluzole treatment effect and to begin to understand the function of GRM1 signal transduction in melanoma, cell lines that over-express GRM1 (UACC903 G2 and UACC903G4) were constructed using the native, low GRM1-expressing, UACC903 human melanoma cell line. We found that UACC903G2 and G4 cells produce elevated levels of GRM1 and were much more sensitive to treatment with 25uM Riluzole than the vector transfected control cell line UACC903V1. We also found that UACC903G2 and G4 cells produced much larger tumors in nude mice than the vector control cells. Tumors formed by UACC903G2 and G4 xenografts also do not demonstrate areas of hemorrhage necrosis as is found in UACC903V1 xenografts, and there are significantly more tumor blood vessels in the GRM1-overexpressing xenograft tumors. To confirm the angiogenic effect of GRM1 over-expression in UACC903 cells, an endothelial cell migration assay was performed. We found that culturing UACC903G2 and G4 cells in serum-free basic medium stimulated HMVECnd endothelial cell migration, an effect not seen with the vector control UACC903V1 cells. We next examined whether increased GRM1 expression in UACC903 cells resulted in the release of angiogenesis factor(s) from these cells. An angiogenesis antibody array (from Affymetrix) experiment was performed and we found that the conditioned medium from UACC903G2 and G4 cells had significantly higher levels of IL8 and VEGF (angiogenesis promoters), but decreased level of TIMP-2 and TIMP-1 (angiogenesis inhibitors) as compared to the conditioned medium from the UACC903V1 vector control cells. We conclude that over-expression of human GRM1 promotes proliferation, activates angiogenesis signaling, and renders cells more susceptible to the inhibitory effects of the glutamate-release inhibitor Riluzole. Further experiments examining the molecular mechanism of GRM1 in cell survival and angiogenesis are need to better understand the mechanisms at work.
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 315. doi:10.1158/1538-7445.AM2011-315
Abstract 3166: Lung cancer bio-signatures in plasma based on the analysis of mouse models
Authors: Taguchi Ayumu , Politi Katerina , Pitteri Sharon J. , Lockwood William W. , Faça Vitor M. , Sage Julien , Kemp Christopher J. , Varmus Harold E. , Hanash Samir M. 
Published: June 2012

Abstract
Genetically engineered mouse models of cancer have been shown to recapitulate many of the molecular and biological features of human cancer. To identify plasma proteins that show altered abundance during lung cancer development, we applied in-depth quantitative proteomic analysis to plasma from three mouse models of lung adenocarcinoma driven by mutant EGFR, Kras or induced by urethane exposure; a mouse model of small cell lung cancer (SCLC); models of pancreatic, ovarian, colon, prostate and breast cancer; and two mouse models of inflammatory disease as confounders. Plasma proteins from mice with disease and age-matched littermate controls were analyzed by mass spectrometry (MS). Whole cell lysates and conditioned media from 12 lung adenocarcinoma cell lines were also analyzed by MS to identify enriched proteins in conditioned media in common with proteins with increased levels in plasmas from lung tumor bearing mice.
Proteins corresponding to 3744 non-redundant IPIs (International Protein Index) that represented protein products from 2260 unique genes were quantified in one or more experiments. Unsupervised hierarchical clustering of plasma proteins revealed clustering of the four lung cancer models and the two breast cancer models, suggesting that protein signatures in the blood are organ-type specific. Fifty-eight percent of the elevated proteins in plasmas from mice with lung adenocarcinoma were identified in conditioned media of one or more human lung cell lines. A biosignature based on plasma proteins regulated by the Titf1/Nkx2-1 transcription factor was identified in plasmas from mouse models of lung adenocarcinoma. In addition, protein network analysis showed that many proteins whose abundance is altered in the plasma of the lung cancer mouse model engineered to express mutant human EGFR are associated with EGFR. A plasma protein signature that is enriched in proteins associated with neuroendocrine development was also identified in a SCLC model. Exploratory studies in human lung cancer and control plasmas of candidate markers identified in mouse models yielded altered levels in lung cancer plasmas concordant with findings in mouse models.
Our studies of mouse models have identified plasma based signature for lung cancer that reflect developmental and signaling pathways applicable to human lung 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 3166. doi:10.1158/1538-7445.AM2011-3166
Abstract 317: 1q32.1 and 16q21 genomic alterations implicate KIF14/MDM4/PIK3C2ß and CDH11 as independent prognostic markers of relapse in localized Ewing Family of Tumors
Authors: Ayala Fernanda R.R , da Cunha Isabela Werneck , Yoshimoto Maisa , Zielenska Maria , Squire Jeremy Andrew , Soares Fernando Augusto 
Published: June 2012

Abstract
EWS-ETS genetic fusion appears to be the initiating mechanism behind Ewing Family of Tumors (EFT) pathogenesis; however, progression of the disease is dependent on additional genetic alterations. Using the Progenetix database, we identified mainly alterations at 1q, and at 16q, as the most recurrent genetic alterations in EFT without consistency as markers of relapse. Clinic features of a large genotype cohort of 135 patients with EFT were retrospectively reviewed from A.C. Camargo hospital records. Tissue microarrays (TMA) were built for multi-color interphase fluorescent in situ hybridization (iFISH) analysis of aberrations at 1q32.1 (KIF14/MDM4/PIK3C2ß) and 16q21 (CDH11) using in-house probes. Gains were defined by the presence of more than three hybridization signals per interphase nucleus with simultaneous intact centrosome signal occurring in more than 5% of tumor nuclei. Losses were indicated by one target signal with the intact centrosome signals in more than 30% of nuclei. The frequencies of gene copy number alterations (CNA) were compared with clinical parameters and follow-ups. Statistical analyses were performed by SPSS program. A p-value of less than 0.05 was considered significant.
CNA analysis showed gains at 1q32.1 in 15/128 (11.7%) cases, while abnormalities at 16q21 were seen in 24/118 (20.3%) patients, split into two groups. One group of patients, 11/118 (9.3%), showed only hemizygous deletion, whereas, the other group with 13/118 (11%) patients showed gain. A significant association between 1q32.1 gains and 16q21 losses (p=0.029) was detected, but not a significant clinical synergism when interacting at the same patient. Univariate analyses showed gains at 16q21 (p=0.029) or at 1q32.1 (p=0.005) associated with tumor relapse in the localized disease subgroup. Disease-free survival curves represented these gained regions as unfavorable outcome parameters (p&lt;0.05) for EFT patients. The multivariate model confirmed 1q32.1 or 16q21 gains as independent prognostic markers for relapse. Hence, copy number gains at 1q32.1 and 16q21 constitute valuable markers of relapse in localized EFT. Genomic alterations of the critical genes in these chromosomal regions probably activate key downstream target genes of distinct pathways, which thus lead to an intricate molecular mechanism for EFT growth and aggressiveness.
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 317. doi:10.1158/1538-7445.AM2011-317