bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5550: Ingenol mebutate induces an early and inflammatory wound healing response in a human in vitro 3-D skin model
Authors: Litman Thomas , Høyer-Hansen Maria H. , Zibert John R. 
Published: August 2012

Abstract
Ingenol mebutate (IM, ingenol-3-angelate, PEP005) is a promising new agent for topical treatment of actinic keratosis (AK), a pre-malignant condition that if left untreated can develop into squamous cell carcinoma. A dual mechanism of action of IM has been suggested; this involves direct lesional cell death and PKC activation dependent, immune modulatory effects. The aim of this study was to investigate the mode of action of IM. We have previously compared IM's penetration through normal skin to a 3-D reconstructed human skin (RHS) model (EpiDermFT™, MatTek). A 10-fold higher permeability was found in RHS, which likely reflects the increased permeability of AK lesions. Therefore, we studied the effects of 0.05% IM gel in this model at different time points (0.5, 6, 24, and 96 h). The response parameters measured included cytotoxicity (MTT assay), cytokine secretion, as well as global transcriptomic profiling (Affymetrix GeneChip® Human Gene 1.0 ST arrays). Multivariate analysis, including principal component analysis, unsupervised hierarchical clustering, and gene ontology enrichment, revealed that the major effects of IM comprised: cell death, inflammation and a wound healing response. This was indicated by differential expression of e.g. CASP14, HAS2, several MMPs, SERPINs, ILs, and CCL20. We also observed regulation of many skin-specific genes, related both to epidermis development, such as keratinocyte differentiation, and to fibroblasts in dermis, reflecting the nature of the RHS. Furthermore, a transcription factor binding site (TFBS) analysis suggested ERK2 and PKC as relevant targets for IM. This is in accord with the drug's transient immune modulatory effect. Indeed, a specific, inflammatory response was observed already after 30 min treatment, and several genes, including MMP10 and IL1R2, displayed a time-dependent increase in expression, reaching a maximum at 24h returning to normal at 96h. A sustained effect was observed for more than 300 genes, most of which were down-regulated following IM treatment. In conclusion, IM displays pleiotropic effects, of which many are regulated on a transcriptional level. Our data suggest transient activation of in particular PKC and ERK2, with a link to cytokine release and wound healing response. The inflammatory reaction may subsequently contribute to the cell death observed after 24h treatment with IM.
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 5550. doi:1538-7445.AM2012-5550
Abstract 5551: Somatic mutations in KRAS, BRAF and PIK3CA genes in Chilean patients with sporadic colorectal cancer: Correlation with clinical and histological features
Authors: Hurtado Claudia , Zarate Alejandro , Wielandt Ana María , Carrillo Katya , Yamagiwa Ken , Kronberg Udo , Levican Jorge , Contreras Luis , Lopez-Kostner Francisco 
Published: August 2012

Abstract
Background: KRAS, BRAF and PIK3CA proto-oncogenes encode for proteins involved in epidermal growth factor receptor (EGFR) signaling pathways. Activating mutations in these genes may contribute to tumor development and induce resistance to biological therapies in patients with metastatic colorectal cancer (CRC). Furthermore, microsatellite instability (MSI) has been proposed as a prognostic and predictive marker in sporadic CRC. Patients and methods: In tumors of patients undergoing surgery for sporadic CRC at our institution, somatic mutations in KRAS, BRAF and PIK3CA genes were assessed by single-strand conformation polymorphism(SSCP) and direct sequencing. MSI analysis was performed using the 5 markers of the standard NIH panel. Clinical and histopathological data of the patients were obtained from our prospectively maintained database. Results: A total of 58 patients with a nearly equal gender distribution and a mean age of 62 years were included. A total of 31 mutations in 26 patients were identified. The frequency of mutations was 28% for KRAS, 9% for BRAF and 17% for PIK3CA. No difference was found in the mutation frecuency between the different tumor locations (42,1% in right colon vs. 46,2% in left colon/rectum, P= NS) or lymphnode status (37,5% in node positive vs. 50% in node negative tumors, P=0,346). Tumors with deeper invasion showed a higher frecuency of mutations, but this tendency did not reach statistical significance (32% in pT1-2 vs. 51% in pT3-4, P=0,157). In 26% of the patients, MSI-high was observed, more frecuently in tumors of the right colon (57,9% vs 10,3%, P&lt;0,001). Patients with BRAF mutations, a higher proportion of MSI-high was found compared to BRAF wildtype (27% vs. 2,3%, P=0,013). There was no correlation between the lymphnode positivity and MSI status. Conclusion: Our results show that the frequency of mutations in patients with sporadic CRC in Chile is similar to that described in other countries. The presence of MSI-high is correlated with tumors in the right colon and with mutations in the BRAF gene. The tendency of finding more mutations in locally advanced and node-negative tumors needs to be confirmed in future studies with a larger number of 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 5551. doi:1538-7445.AM2012-5551
Abstract 5552: Macrophages increase brain metastasis in a chick embryo model
Authors: Menen Rhiana , Kolostova Katarina , Bobek Vladimir , Hassanein Mohamed K. , Bouvet Michael , Hoffman Robert M. 
Published: August 2012

Abstract
Macrophages are known to promote tumor growth by various mechanisms. In the present study, we determined if macrophages could promote metastasis in the chick embryo models. The chorioallentoic membrane (CAM) of six chicken embryos was inoculated with 106 PC-3 human prostate cancer cells stably expressing GFP. Twelve hours later, 106 macrophages isolated from the peritoneal washings of three nude mice were added to the CAMs of three embryos. Embryo brains were removed on day 8 post-inoculation, and processed for cryosectioning. Imaging was performed using the IV-100 scanning laser microscope (Olympus Corp, Tokyo, Japan). Images were processed using Image J software in order to calculate the number, size, and total area of brain metastases in the control and macrophage groups. The macrophage group resulted in an average of 43.3 brain metastases compared to 5.5 in the control group (p=0.000001). There was also a significantly greater total metastatic area in the macrophage group of 504.8 mm2 compared to 100.5 mm2 in the control group (p= 0.000001). However, the control group showed a significantly larger size of individual metastases of 28.9 mm2 compared to 19.3 mm2 in the macrophage group (p= 0.0007). Macrophages, therefore, promote brain metastasis in the chick embryo model of human prostate 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 5552. doi:1538-7445.AM2012-5552
Abstract 5559: Detection of IDH1 mutation in the plasma of glioma patients
Authors: Boisselier Blandine , Labussiere Marianne , Rossetto Marta , Larraya Jaime Gallego Perez , Marie Yannick , Delattre Jean-Yves , Sanson Marc 
Published: August 2012

Abstract
Background IDH1 mutation is both a diagnostic and a strong prognostic factor in gliomas. In this work, we investigated the feasibility of detecting the IDH1 mutation in plasma of glioma patients. Patients and Methods The study was conducted in 31 controls and 80 glioma patients with known IDH1 status, and confronted with MRI data. Small Size DNA (ssDNA) was extracted from 4mL plasma and the IDH1R132H mutation was detected by a combination of COLD (co-amplification at lower denaturation temperature) and digital PCR. Results ssDNA concentration (150pb to 200pb) ranged from 0.1 to 6.6 ng/mL (median 1.2 ng/mL) in controls and 0.1 to 50.3 ng/mL (median 1.2 ng/mL) in patients. ssDNA concentration did not correlate with tumor volume in low grade glioma. In contrast, ssDNA concentration in high grade gliomas patients was significantly higher than in healthy controls and correlated with the enhancing volume V (V=0: 0.9 ng/ml [0.1-3.5]; V&lt; 10 cm3: 1.6 ng/ml [0.4-24.9]; V&gt;10 cm3: 14.0 ng/ml [0.6-50.3]). We then analyzed 39 patients (25 with R132H IDH1 mutated glioma, 14 with IDH1 wild type glioma) for the detection of IDH1 mutation on the ssDNA extracted from plasma. The mutation was detected in plasma DNA of 15 out of 25 patients (60%) with IDH1 mutated tumor, and in none of the 14 patients with IDH1 wild type tumor. The detection rate of IDH1 mutation in plasma was higher in high grade (12/17 patients (70.6%) and was correlated with the enhancing tumor volume. Interestingly all the mutant tumors with an enhancing tumor volume higher than 3.5 cm3 (9/9) were detected by digital PCR in plasma. Conclusions Our study shows that (i) tumor DNA is released in glioma patients; (ii) ssDNA concentration is correlated with enhancing tumor volume, and (iii) IDH1 mutation is detectable in plasma DNA. This represents the first step for developing a quantitative plasma biomarker that could be used to monitor glioma status.
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 5559. doi:1538-7445.AM2012-5559
Abstract 5560: PROX1 expression and function in malignant gliomas
Authors: Elsir Tamador , Qu Mingqi , Berntsson Shala , Olofsson Tommie , Ribom Dan , Orrego Abiel , Hedren Anna , deimling Andreas V. , Hartmann Christian , Lindström Mikael , Smits Anja , Nister Monica 
Published: August 2012

Abstract
The PROX1 transcription factor, also known as Prospero in flies, plays a critical role in the development of various organs especially the lymphatic and central nervous systems. Mutations in Prospero induce brain tumor development in flies due to the lack of normal asymmetric neural stem cell division. Less is known about the expression and function of PROX1 in human brain tumors. First, we investigated expression of PROX1 using immunohistochemistry in 56 human astrocytic gliomas of different grades. PROX1 was found to be overexpressed in the majority of high grade tumors but not in grade I tumors or control tissue. Secondly, we addressed the prognostic value of PROX1 in a clinical cohort of patients with grade II gliomas (n=116). The number of PROX1 immunoreactive cells was used as a variable in survival analysis. Patients with tumors showing high PROX1 protein expression had poor outcome in the univariate analysis as well as in the multivariate analysis compared to those with low PROX1 expression. Thirdly, we found that PROX1 was expressed in glioma cell lines and we noted an apparent positive correlation between expression of PROX1 and the pluripotency factor SOX2. Depletion of SOX2 using siRNA inhibited glioma cell proliferation and reduced the levels of PROX1. Acute loss of PROX1 did not impair glioma cell proliferation in vitro. We conclude that PROX1 may constitute a useful tool for diagnosing and grading of astrocytic glioma distinguishing grade III and IV tumors from grade I and II tumors. PROX1 is also a novel predictor of survival for grade II 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 5560. doi:1538-7445.AM2012-5560
Abstract 5563: Comparative studies of TIMP-1 immunohistochemistry, TIMP-1 FISH analysis and plasma TIMP-1 in glioblastoma patients
Authors: Aaberg-Jessen Charlotte , Jensen Stine S. , Nielsen Signe L. , Pedersen Christian B. , Brünner Nils , Kristensen Bjarne W. 
Published: August 2012

Abstract
Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been associated with poor prognosis in various cancers as well as with resistance towards chemotherapy. In a previous study we found an association between a high immunohistochemical TIMP-1 protein level and a shorter survival for glioblastoma patients. The aim of the present study was to further evaluate TIMP-1 as a prognostic marker in gliomas by performing TIMP-1 fluorescence in situ hybridization (FISH) and by measuring TIMP-1 in plasma. TIMP-1 FISH analysis was performed on 33 glioblastoma biopsies in order to elucidate if the increased levels of TIMP-1 protein could be explained by gene amplification. Moreover, blood samples were collected from 43 patients (31 gliomas including 21 glioblastomas) prior to brain tumor surgery. The plasma TIMP-1 protein level was measured by ELISA. The results showed TIMP-1 FISH scores between 0.7 and 1.1, suggesting neither amplification nor loss of the TIMP-1 gene. The TIMP-1 level measured in plasma was not significantly higher than the TIMP-1 level measured in healthy matched controls. No correlation was identified between the immunohistochemical TIMP-1 levels and the FISH scores or the plasma TIMP-1 levels. In conclusion, TIMP-1 FISH scores or plasma TIMP-1 levels are without prognostic potential in gliomas. The present study suggests that the high immunohistochemical TIMP-1 protein levels in gliomas are not caused by TIMP-1 gene amplification. Moreover, TIMP-1 in plasma is low and not directly related to the tumor TIMP-1 level found by immunohistochemistry. The study suggests that TIMP-1 immunohistochemistry is the method of choice when using TIMP-1 as a biomarker in 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 5563. doi:1538-7445.AM2012-5563
Abstract 5566: Elevated CXCR4 expression is clinically correlated with advanced stage neuroblastoma: examination of its role as a possible therapeutic target
Authors: Carlisle Alex J. , Pawal Bruce , Carlisle Rosalind , Jagannathan Jayanti , Martinez Daniel , Zhao Huaqing , Wang Qun , Cole Kristina , Lyttle Christopher A. , Nguyen Nhu , Maris John M. 
Published: August 2012

Abstract
ABSTRACT Purpose: Recent evidence suggests that expression of CXCR4 is associated with the growth and progression of neuroblastoma. The purpose of this study was to determine the value of CXCR4 as in independent predictive biomarker and evaluate its potential as a therapeutic target in neuroblastoma. Experimental Design: mRNA Expression profiling was performed on 101 diagnostic neuroblastoma primary tumor samples using Affymetrix oligonucleotide arrays. CXCR4 expression was stratified by risk and stage, and statistically significant differences in mRNA levels were determined. Protein expression profiling was performed by conducting immunohistochemical analysis of CXCR4 expression in 92 neuroblastoma tumors on a tissue microarray constructed at Children's Hospital of Philadelphia (CHOP); expression levels were stratified by stage and compared to determine significant correlations. To examine the role of CXCR4 in neuroblastoma progression, the selective CXCR4 inhibitor AMD3100 was used to observe the effect of CXCR4 inhibition on the growth of neuroblastoma cells in culture and in mice. Results: CXCR4 expression was significantly higher in stage 1 vs. ganglioneuroma tumors, as assessed at the protein level (P&lt;0.0001), and in stage 4 tumors vs. stage 1 tumors, at both the mRNA and protein levels (P&lt;0.01). Additionally, a comparison of CXCR4 transcriptional expression in patient tumors stratified by risk revealed greater CXCR4 expression in high-risk groups compared to low and intermediate groups (P&lt;0.002); interestingly, CXCR4 protein expression was not associated with overall survival or progression-free survival (PFS). Treatment of neuroblastoma cells with AMD3100 inhibited growth of these cells in culture and in mouse xenografts. Conclusion: We conclude that increased levels of CXCR4 expression are associated with advanced tumor stage and a high risk population in neuroblastoma patients, demonstrating the clinical value of CXCR4 as an independent biomarker for risk classification and patient stratification; additionally, CXCR4 should be considered a novel and viable candidate for targeted therapeutic intervention in neuroblastoma 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 5566. doi:1538-7445.AM2012-5566
Abstract 557: Fluorescence in situ hybridization versus qPCR as means to detect Merkel cell polyomavirus in Merkel cell carcinoma
Authors: Haugg Anke M. , Rennspiess Dorit , zur Hausen Axel , Speel Ernst-Jan M. , Cathomas Gieri , Becker Jürgen C. , Schrama David 
Published: August 2012

Abstract
Background: Merkel cell polyoma virus (MCPyV) is detected in 80% of Merkel cell carcinomas (MCC). The clonal integration and tumor specific mutations in the large T Antigen (LTAg) gene strongly implicate an oncogenic impact of the virus. To date the relationship between the viral presence and cancer induction, development or clinical prognosis is discussed controversial. Yet almost all studies are based on quantitative virus detection e.g. PCR or qPCR. Material and Method: In order to gain additional information about the quality of the viral presence on the single cell level we performed FISH analysis of formalin fixed and paraffin embedded (FFPE) MCCs (n= 62) on tissue micro arrays (TMA), determined the FISH pattern and correlated the results of the FISH analysis with the qPCR data. We grouped the MCCs according to different FISH evaluations and correlated them with the respective qPCR data on the basis of a determined cut-off. MCPyV FISH was established using the MKL-1 cell line which harbors integrated copies of MCPyV DNA. For MCPyV-qPCR the LT3 primer pair was used on whole tissue sections. Results: MCPyV-FISH on FFPE MKL-1 cells revealed punctate signals compatible with viral integration. The MCPyV FISH positive MCC cores (76%) mainly revealed two different signal patterns: a punctate pattern (85%) which correlated with a moderate relative viral presence and in some areas the punctate pattern was combined with a diffuse pattern (15%) indicating the episomal presence of the virus which is linked to viral replication. If a pattern mixture was seen this was associated with very high qPCR values. Comparing MCPyV FISH and qPCR data the results correlated highly with 83 % in the MCPyV positive evaluated group, whereas the negative group showed a concordance of 93 %. The mean of the qPCR values of all MCPyV positive cores differed significantly from the negative cores (p= 0.0076). The FISH signals were in some tumor areas from the same patient heterogenic in intensity, pattern and localization. Conclusion: While the qPCR using the LT3 primer pair was highly sensitive to detect MCPyV sequences in the respective MCC cases, the MCPyV FISH analysis highly concordantly revealed the quality of the viral presence, i.e. viral integration or episomal presence and morphological sublocalization in the tissues.
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 557. doi:1538-7445.AM2012-557
Abstract 5573: Nuclear IGF-1R expression as a prognostic factor in cervical cancer patients
Authors: Tanioka Maki , Sudo Tamotsu , Obayashi Chiho , Matsumoto Koji , Fujiwara Kiyoshi , Negoro Shunichi , Minami Hironobu 
Published: August 2012

Abstract
Background: Insulin-like growth factor-1 receptor (IGF-1R) is an unusual transmembrane receptor in that both α and β subunits, regulated by IGF-1, translocate from the membrane to the nucleus and then bind to DNA, increasing gene transcription. Insulin receptor substrate-1 (IRS-1), a docking protein for IGF-1R, also traffics to the nucleus and then activates promoters of cell cycle progression genes. We studied the prognostic significance of nuclear and membranous IGF-1R and nuclear IRS-1 in cervical cancer, previously unreported. Methods: We retrospectively reviewed all patients (pts) with stage Ib2-IIb disease who received platinum-based neoadjuvant chemotherapy (NAC) at Hyogo Cancer Center between 2002 and 2009. Age, performance status, FIGO stage, histology, tumor size, pelvic lymph nodes on MRI, squamous cell carcinoma (SCC) antigen level, hemoglobin levels before NAC, chemotherapeutic agents and chemotherapy cycles were evaluated. Paraffin-embedded pretreatment tissue was stained immunohistochemically with an anti-IGF-1Rβ (Cell signaling, MA) or anti-IRS-1 (Millipore, MA) rabbit polyclonal antibody. IGF-1R and IRS-1 expressions were scored from 0 to 3 according to frequency and intensity. All slides were reviewed by a single pathologist. We analyzed prognostic factors associated with overall survival by a Cox proportional-hazards model. Results: A total of 128 pts (median age 57 years) were identified. The majority had stage II (61%) and SCC (69%). Median tumor size was 40 mm. Overall response rate to NAC was 59%, and median follow-up was 34 months. Nuclear and membranous IGF-1R and nuclear IRS-1 expressions were scored as 0/1-2/3 in 49/60/19 pts, 97/12/19 pts, and 65/41/22 pts, respectively. Multivariate analysis revealed that nuclear IGF-1R expression (HR, 2.6; P= .035 for score 1-3 vs. 0) and age &lt;40 (HR, 2.6; P= .026) were independently associated with worse overall survival. Neither membranous IGF-1R nor IRS-1 expression had a prognostic impact on survival. Conclusions: Nuclear IGF-1R is commonly expressed in cervical cancer and is an independent prognostic factor, unlike membranous IGF-1R or nuclear IRS-1. Approaches that block the translocation of IGF-1R from the cell membrane to nucleus might hold promise for the treatment of cervical 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 5573. doi:1538-7445.AM2012-5573