bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3171: Stromal palladin is a poor prognostic marker in renal cell carcinoma
Authors: Gupta Vivekanand , Simons Jeffrey , Bassi Daniel , Al-Saleem Tahseen I. , Uzzo Robert G. , Cukierman Edna 
Published: June 2012

Abstract
Renal cell carcinoma (RCC) is a fatal disease in urgent need of novel diagnostic and treatment tools. Metastasis to the secondary site is the main cause of death in RCC. Although renal tumor cells are intercalated within a mesenchymal stromal microenvironment during RCC tumorigenesis, not much is known about this specific stroma. Therefore, questioning the specific importance of RCC's stroma is of noteworthy interest. In this study we questioned whether stromal and tumor components progress at similar rates and whether assessing rates of stromal progression are of clinical importance. Our experimental system uses fibroblasts harvested from patient matched normal kidney, as well as primary and secondary RCC surgical samples. We tested several stromal markers such as actin binding protein palladin, alpha-smooth muscle actin and fibronectin spliced form EDA, all known to be upregulated in tumor associated stroma, and uncovered that their expression levels depend on the production of stromal extracellular matrices (ECMs) using an in vitro 3-D stromal system derived from the harvested fibroblasts. In addition, using a well annotated tumor micro array, we specifically demonstrate that stromal palladin and α-SMA expression levels correlate to each other. Moreover, we observed that stromal palladin expression levels are indicative of poor outcomes in early non-metastatic RCCs. Here we not only introduce an in vitro 3-D stroma system which accurately mimics the in vivo features of human RCC-associated stroma, but we demonstrate a clinical relevance to assessing stromal activation in human pathological RCC samples. Results from this study underscore a distinctive clinical relevance to assessing stromal progression in renal cell carcinomas.
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 3171. doi:10.1158/1538-7445.AM2011-3171
Abstract 3172: Methylation portraits discriminate between hepatocellular carcinoma cases and controls
Authors: Guerrero-Preston Rafael , Soudry Ethan , Jaffe Andrew , Ili-Gangas Carmen , Brebi-Mieville Priscilla , Pérez Jimena , Zhong Xiaoli , Yang Quiang , Meltzer Stephen J. , Esteller Manel , Sidransky David 
Published: June 2012

Abstract
Background: Most genome-wide methylation studies have focused on technology to profile and identify therapeutic biomarkers in HCC. However, attempts to integrate these technologies to clinical and population based studies are still lacking.
Objective: Our aim was to identify existing methylation profiling technologies that can be used in translational epigenomic efforts.
Methods: We examined Quantitative Methylation specific PCR, oligonucleotide methylation tiling arrays (MeDIP-chip), and Methylation BeadChip arrays and their ability to distinguish between HHC cases and controls, a key goal in Phase I biomarker development trials. Scatterplots, histograms and heat maps of genome-wide DNA methylation array data were used to provide a snapshot of the differences in methylation patterns between tumor and normal samples.
Results: The representative tumor sample had a lower methylation score median and less significant genome-wide methylated probes (1,503) than either normal liver tissue samples (2,585 and 2,2887 respectively). RASSF1A and B4GALT1 had a sensitivity of 52%, a specificity of 100% and an AUC of 0.73 (RASSF1A) and 0.75 (B4GALT1). SSBP2 had a sensitivity of 38%, a specificity of 100% and an AUC of 0.58. A panel combining these genes with HCC risk factors had a sensitivity of 87%, a specificity of 100% and an AUC of 0.91.
Conclusions: We have shown that genome-wide and gene-specific methylation platforms, which interrogate gene promoter regions, can be used to examine novel biomarkers and differentiate HCC from normal liver tissue. Additional studies will confirm the value of using methylation-profiling technologies to evaluate these new markers as we move forward.
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 3172. doi:10.1158/1538-7445.AM2011-3172
Abstract 3194: Thymidine Kinase 1 staining aids in lung cancer prognosis
Authors: Alegre Melissa M. , Abegg-Lawrence Taylor , Alegre Ballantines F. , LaPorte Wesley D. , Yu Jessica , Weyant Michael , Robison Richard A. , O'Neill Kim L. 
Published: June 2012

Abstract
Lung cancer kills more patients than breast, colon, prostate, melanoma, and kidney cancers combined. One way to improve the high lung cancer mortality rate is through early detection and better prognosis. There have been attempts to establish spiral CT scan imaging protocols or early detection assays to improve the diagnosis of lung cancer. Although these detection methods show merit, they are often costly, and are only useful for a subset of the potential lung cancer population such as high-risk smokers. One biomarker that shows promise is Thymidine Kinase 1 (TK1). Recently, it has been demonstrated that TK1 has diagnostic potential in both small cell and non-small cell lung cancer. Therefore, the present study was conducted to elucidate whether TK1 could be used in early detection and lung cancer prognosis. Five tissue microarrays (TMA) including a lung carcinoma screen, lung adenocarcinoma grade III, large cell carcinoma, small cell carcinoma, and one normal lung TMA consisting of 376 lung cancer tissue cores from 172 patients and 63 control lung tissue cores from 22 normal individuals, were stained with a TK1 monoclonal antibody produced by our lab. Mesothelioma and some of the lung cancers including squamous cell, small cell, adenosquamous cell, undifferentiated, adenocarcinoma, and bronchioloalveolar carcinoma stained positive for TK1. Papillary carcinoma, sarcoma, neuroendrocrine carcinoma, and undifferentiated large cell carcinoma showed considerably less TK1 staining. Normal and inflammatory lung tissue showed zero to minimal staining which was significantly different from positively stained lung cancer tissue. There are various increasing grades of squamous cell carcinoma patients from grade I, I-II, II, II-III and III. There was a definitive increase in TK1 staining as the grade of the lung tumor increase. A similar pattern was found with adenocarcinoma tissue grade II, II-III, and III; the more progressive the tumor, the more intense the TK1 staining. This preliminary data supports further investigation of TK1 as a marker for early detection and prognosis of numerous lung cancer subtypes.
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 3194. doi:10.1158/1538-7445.AM2011-3194
Abstract 3195: HMGA1 and HMGA2 over-expression in human lung carcinoma
Authors: Piscuoglio Salvatore , Pallante Pierlorenzo , Cappuzzo Federico , Zlobec Inti , Lugli Alessandro , Fusco Alfredo , Terracciano Luigi M. 
Published: June 2012

Abstract
Background: Lung cancer is the leading cause of cancer death worldwide with an overall 5-year survival rate of only 15%. Therefore, research focusing on lung carcinogenesis is strongly needed. High mobility group A (HMGA) proteins play an important role in the regulation of transcription, differentiation, and neoplastic transformation. The HMGA gene family includes HMGA1, which encodes the HMGA1a and HMGA1b protein isoforms, and HMGA2, which encodes HMGA2. These chromatin-binding proteins function in transcriptional regulation and recent studies also suggest a role in cellular senescence. HMGA1 proteins also appear to participate in cell cycle regulation and malignant transformation, whereas HMGA2 has been implicated primarily in the pathogenesis of benign mesenchymal tumors.
Aims: The aim of this study was to investigate on the potential role of HMGA 1 and 2 in lung carcinogenesis.
Materials and methods: A tissue microarray (TMA) including normal and neoplastic non-small cell lung cancer (NSCLC; n=454) tissues was constructed and HMGA1 and 2 analyzed by immunohistochemistry. HMGA1 was detectable in a 454 patients and HMGA2 in 409 patients, respectively. Immunoreactivity was scored semi-quantitatively by evaluating the number of positive tumor cells over the total number of tumor cells. Scores were assigned using 5% intervals and ranged from 0% to 100%. Median protein expression levels were used as cut-off scores to define protein marker positivity and the findings were associated with clinical-pathological parameters.
Results: HMGA1 and A2 are over-expressed in NSCLC tissues compared to normal lung (p&lt;0,001), and more specifically, the HMGA2 expression is significant higher in non-adenocarcinomas than in adenocarcinomas (p&lt;0,001. A significant relationship between HMGA2 over-expression and tumor grade (p&lt;0,013), cN stage (p&lt;0,037), cM stage (p&lt;0,002), pT stage (p&lt;0,003), pM stage (p&lt;0,002), and recurrence (p&lt;0,002). Additionally, HMGA1 over-expression showed a significant relationship with gender (p&lt;0,003), tumor grade (p&lt;0,028), pT stage (p&lt;0,006) and recurrence (p&lt;0,002).
Conclusion: HMGA1 and A2 over-expression seems to play an important role in lung carcinogenesis and additional studies are needed to demonstrate a potential prognostic impact of HMGA1 and HMGA2 expression in NSCLC.
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 3195. doi:10.1158/1538-7445.AM2011-3195
Abstract 3208: Impact of targeted therapy on circulating tumor cells in metastatic breast cancer treated by first-line chemotherapy: IC 2006-04 study
Authors: Pierga Jean-Yves , Hajage David , Bachelot Thomas , Delaloge Suzette , Brain Etienne , Campone Mario , Asselain Bernard , Mathiot Claire , Bidard François-Clément 
Published: June 2012

Abstract
Circulating tumor cells (CTC) have been reported to be a prognostic marker in metastatic breast cancer. This study was designed to test whether changes in CTC counts during treatment are associated with outcome of first-line chemotherapy with/without targeted therapy.
Methods: CTC were counted (CellSearch®) at baseline, before cycle 2 (C2) and C3/4 in 267 metastatic breast cancer patients. Usual prognostic variables, serum tumor markers, tumor response according to RECIST criteria and events were prospectively registered and compared with CTC status and outcome over time.
Results: Median follow-up was 16 months, 45 patients (17%) had HER2 positive tumor and received trastuzumab, 55 (21%) had triple negative tumor, 125 received bevacizumab associated with CT. Baseline CTC positivity (65%; ≥1CTC/7.5ml threshold, 45% ≥5CTC/7.5ml threshold) was correlated with tumour markers, bone/liver involvement and number of metastatic sites, as well as performance status but was not statistically different according to breast cancer subtypes (hormone-positive, HER2-positive or triple-negative). At multivariate analysis, CTC ≥5CTC/7.5ml was an independent prognostic factor for progression-free survival (PFS), RR=1.9 (CI95% 1.26-2.88), p=0.002, with triple negative status, poor performance status and elevated CEA. For overall survival, CTC ≥5CTC/7.5ml was an independent prognostic factor with triple negative status and poor performance status (RR=2.41, p=0.02). Changes with a threshold ≥5CTC/7.5ml, between baseline and Cycle 2 were highly correlated with both PFS (p=5e-07) and OS (p=3e-07). Persistent CTC positivity at C2 was associated with lower tumor response (p=4e-03). Among CTC-positive patients at baseline treated by chemotherapy only, chemotherapy/bevacizumab and chemotherapy/anti-HER2, CTC counts decreased respectively below the ≥5CTC/7.5ml positivity threshold before cycle 2 in 53%, 64% and 83% of patients, and before cycle 3 or 4, in 62%, 77% and 100% of patients (p=0.04). Prognostic value of CTC count at baseline and C2 remained in all subgroups.
Conclusions: CTC count appeared to decrease more markedly in the patients who received also bevacizumab or trastuzumab. However, CTC remain a reliable independent prognostic marker in metastatic breast cancer treated by first-line chemotherapy with/without targeted therapy.
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 3208. doi:10.1158/1538-7445.AM2011-3208
Abstract 3210: Profiling of DNA methylation signature for different phases of prostate cancer development
Authors: Chang Michelle , Liem Natalia , Goh Liang Kee , Kalaw Emarene , Lim Pei Li , Geronimo Carla , Sim Allen , Huang Hong Hong , Chong Tsung Wen , Tan Puay Hoon , Soong Richie , Cheng Christopher , Sim Hong Gee 
Published: June 2012

Abstract
Prostate cancer is the third most common cancer in Singaporean men. Compared to Western countries, the prostate cancer incidence is lower in Asian countries but recent data suggest that incidence is increasing, especially in rapidly urbanized countries. Recent studies provide evidence that methylated genes can be useful and promising molecular biomarkers for detection of prostate cancers. The aim of our study is to identify a panel of global gene methylation signatures that are unique and specific for different phases of prostate cancer development and different prostate cancer phenotypes. This may thus differentiate cancers from non-cancers, and aggressive cancers from indolent ones. We have profiled methylation of genes using the Illumina's GoldenGate Methylation System. The Standard GoldenGate Methylation Cancer Panel I (Illumina Inc, San Diego, CA) spans 1,505 CpG loci selected from 807 genes that have been shown in literature to play important roles in cancer. Methylation levels of candidate genes were quantified in 28 benign tissues without prostate cancer, 52 tissues of Gleason score 3+3, 66 tissues of Gleason score 4+x and 37 tissues of Gleason score 5+x. DNA used for the assays were obtained from laser capture microdissected paraffin embedded archival tissues. Interestingly, our results showed that 28 different CpG loci were methylated in Gleason 3+3 prostate cancer tissues compared to benign prostatic hyperplasia tissues that were used as controls. In addition, methylation levels in prostate cancer samples of high Gleason index (4+x and 5+x) were significantly higher than the paired prostate cancer samples of low Gleason index (3+3) in at least 10 candidate genes. These genes include VIM (p-value 3.59E-08), ASCL2 (p-value 1.71E-09), DAB2IP (p-value 6.55E-08) and FRZB (p-value 6.44E-08). Together with bioinformatics and quantitative methylation-specific PCR, we identified a set of potentially phenotype-specific gene methylation signatures in Asian men. Our studies contributed to the improvement of diagnostic capability for prostate cancer beyond available tumour markers such as PSA as it is a more sensitive molecular correlate.
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 3210. doi:10.1158/1538-7445.AM2011-3210
Abstract 3211: FGFR1 and FGFR2 gene copy number variations in prostate cancer
Authors: Otte Marcus , Kanchev Ivan , Sharp Michael C. , Alvarez John , Winkler Hans , Platero Suso 
Published: June 2012

Abstract
Patients with hormone refractory prostate cancer (HRPC) have very few clinical options. A bottle neck in development of new therapies is the poor understanding of the molecular basis of hormone independency. A pathway thought to be important in this progression is FGFR. Amplification of FGFR1 has been observed in breast cancer and has led to the hypothesis that it is involved in Tamoxifen resistance (Turner et al., 2010). Here we evaluated the copy number variations (CNV) of the gene loci of FGFR1 (8p12) and FGFR2 (10q26) by dual color FISH in FFPE tissue of recurrent PC patients (n=28), non-recurrent PC patients (n=15), PC patients undergoing palliative RPE (n=15), patients with benign prostate hyperplasia (n=17) and tumor free tissue samples (n=12). We analyzed CNV between different clinical patient subgroups. Two types of CNV for the gene loci of FGFR1 and FGFR2 were observed. Either the gene dose of the target gene locus occurred to be amplified or the gene dose was elevated due to polysomy of the respective chromosome. Furthermore patients with CNV of FGFR1 or FGFR2 exhibited in 40-50% intra tumor heterogeneity by presenting normal cells and cells with CNV. FGFR1 gene dose elevations (either due to gene locus amplification or polysomy of chromosome 8) were observed in 7% (1/15) of patients without recurrence but in 49% (17/35) of the patients with recurrence. Also, in patients undergoing palliative RPE 75% (12/16) of the patients exhibited FGFR1 gene dose elevation. In the case of FGFR2, gene dose elevations (gene locus amplification or polysomy of chromosome 10) were observed in none of the patients without recurrence but in 13% of the patients with recurrence and in 20% of patients undergoing palliative RPE. In the control groups such variations were not found. Interestingly, the gene dose variations differed in the prostate cancer patients depending on their hormone sensitivity. 47% (7/15) of hormone refractory patients and 30% (6/20) of the hormone sensitive patients showed elevated FGFR1 gene dose, for FGFR2, 30% and 20% of the respective subgroups were affected. In summary we conclude that this is first evidence that CNV of FGFR1 and FGFR2 might have implications for hormone resistance in PC.
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 3211. doi:10.1158/1538-7445.AM2011-3211
Abstract 3227: Bioactivity and metabolic stability of indirubins
Authors: Merz Karl-Heinz , Cheng Xinlai , Eisenbrand Gerhard 
Published: June 2012

Abstract
Indirubins are known to induce cell cycle arrest in G1/S and/or G2/M followed by apoptosis and potently inhibit proliferation of human tumor cells. In general, they have unfavorable pharmacokinetic properties as a consequence of poor solubility, resulting in low bioavailability. They are CYP450 substrates, undergoing deactivating metabolic transformations by formation of hydroxylated metabolites, especially in 6- and 7’-positions. The antiproliferative activity of these metabolites was decreased or nearly completely abrogated.
To improve metabolic stability and solubility, novel indirubins were synthesized: hydrophilic N-methylpiperazinoethyl (E748) or N,N-dimethylaminophenyl groups were attached to the indirubin core by a 5-carboxamide anchor (E748 and E 744, respectively) or by a 3’-oxime ether link (E857). Moreover, to block 7’-hydroxylation, 7’-aza-5-methylindirubin (E844) was synthesized. Compounds were incubated in vitro with liver microsomes and metabolites were analyzed. E844 yielded as main metabolites 7’-aza-5-methyl-6-hydroxy-indirubin and 7’-aza-5-hydroxymethyl-indirubin. E748 yielded the 7’-hydroxy derivative as main metabolite. In contrast to E748, E744 did not appear to undergo detectable metabolic transformation. In addition, E857 and its water soluble hydrochloride (E857a) were not found to be hydroxylated at the respective bisindole positions. Main biotransformation of E857 rather occurred in the side chain, resulting in the formation of N- methylpiperazinoethyl-N-oxide. In contrast to E 857, the hydrochloride E857a was found hydroxylated at the methylpiperazino group.
The results demonstrate that deactivating metabolic transformation of indirubins can be mitigated by introducing N-atoms into the bisindole core, and/or by directing metabolic attack into the 3’ side chain, through attachment of hydrophilic substituents. In summary, the metabolic stability of the bisindole pharmacophore can be increased by appropriate molecular modifications that also improve pharmacokinetics.
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 3227. doi:10.1158/1538-7445.AM2011-3227
Abstract 3236: Role of mouse and human CYP2A enzymes in the bioactivation of the tobacco-specific lung procarcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
Authors: Ding Xinxin , Zhou Xin 
Published: June 2012

Abstract
NNK is a potent lung procarcinogen. Previously, we have demonstrated that NNK-induced lung tumorigenesis depends on target-tissue metabolic activation by pulmonary P450 enzymes. The aim of this study is to test the hypotheses that 1) mouse CYP2A5 plays an essential role in NNK bioactivation in the lung, and 2) transgenic expression of human CYP2A13, known to be selectively expressed in the respiratory tract, and be the most efficient enzyme for NNK metabolic activation in vitro, can increase the rates of NNK metabolic activation in the mouse lung. We determined the rates of in vitro formation of 4-oxo-4-(3-pyridyl)-butanal (OPB), representing the reactive intermediate that can lead to the further formation of O6-mehtylguanine (O6-mG) DNA adduct, in liver and lung microsomes of wild-type, Cyp2a5-null, and CYP2A13-humanized (CYP2A13-transgenic/Cyp2a5-null) mice. We found that, in both liver and lung microsomes, the loss of CYP2A5 resulted in significant decreases in the rates of formation of OPB; whereas, the gain of CYP2A13 led to recovery of the microsomal activity in the lung, but not in the liver. Furthermore, we observed that the levels of O6-mG, the DNA adduct known to be most highly correlated with incidences of lung tumor formation, were significantly higher in the lungs of the CYP2A13-humanized mice, than in the Cyp2a5-null mice. In control experiments, rates of systemic clearance of NNK and its major circulating metabolite, NNAL, were confirmed to be not different among the three mouse strains. These results indicate that CYP2A13 can catalyze NNK bioactivation in vivo, and they support the idea that CYP2A13 genetic polymorphisms can influence the risks of tobacco-induced lung tumorigenesis in humans. (Supported in part by NIH grant CA092596)
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 3236. doi:10.1158/1538-7445.AM2011-3236