bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1778: Nimotuzumab, a humanized antiepidermal growth factor receptor antibody, interacts with EGFRvIII
Authors: Jaramillo Maria L. , Grothe Suzanne , Baardsnes Jason , Banville Myriam , Paul-Roc Beatrice , Tikhomirov Ilia A. , Thompson Sean EL , O'Connor Maureen 
Published: February 2011

Abstract
Introduction: Glioblastomas frequently overexpress a variant form of EGFR, called variant III (EGFRvIII), which has an in-frame deletion of an 801-bp sequence in the extracellular domain. EGFRvIII does not bind EGF ligand but exhibits constitutive kinase activity that results in enhanced transformation, reduced apoptosis, and resistance to therapy. Nimotuzumab (Nmab) is an EGFR-targeting antibody that has demonstrated encouraging results in early clinical trials treating adult and pediatric brain tumors. Here we present data characterizing the interaction of Nmab with EGFRvIII.
Methods: Binding of Nmab to the extracellular domain of wtEGFR and EGFRvIII was first characterized by SPR biosensor analysis: Nmab was captured via its Fc domain and varying concentrations of EGFRvIII and EGFRwt were flowed. Flow cytometry analysis was subsequently performed using a parental U87MG glioblastoma cell line and derivatives which were engineered to overexpress either wtEGFR or EGFRvIII.
Results: Nmab bound EGFRvIII and EGFRwt with similar affinity, which was in the 10−8 M range. This KD is consistent with the previously reported affinity constant of Nmab for EGFRwt (Telavera et al, 2009). Binding was further analyzed by flow cytometry. Nmab bound both EGFRwt and EGFRvIII expressed on the surface of parental U87MG, U87MG EGFRvIII and U87MG wtEGFR cells. Additional data concerning effects of Nmab on EGFRvIII expressing cell lines will be presented.
Conclusion: Nmab binds to wtEGFR and EGFRvIII with similar affinity, which supports development of the antibody as a therapeutic for glioblastoma. In U87MG glioblastoma cells, synergistic activity of Nmab in combination with radiotherapy has been previously reported (Diaz Miqueli et al, 2009). Nmab is currently being tested in an advanced randomized study in the first line setting for the treatment of adult glioma. Nmab is being tested in combination with radiation plus temozolomide, vs radiation plus temozolomide alone, with preliminary results expected in the second half of 2010.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1778.
Abstract 1779: Serum level of DKK1 as a marker for predicting tumor recurrence of hepatocellular carcinoma
Authors: Tung Edmund KK , Mak Carmen KM , Lee Joyce MF , Li Jin J. , poon Ronnie TP , Lai Ching L. , Luk John MC , Ng Irene O. L 
Published: February 2011

Abstract
Dickkopf-1 (DKK1), an inhibitor of Wnt/beta-catenin signaling pathway, is upregulated in various cancers including HCC. However, the clinical significance of serum DKK1 in hepatocellullar carcinoma (HCC) remains to be determined. The objective of this study was to investigate the clinical significance of DKK1 and its prognostic value in predicting survival and tumor recurrence in human HCC. Two independent cohorts with 217 and 100 pairs of tumors and corresponding nontumor livers were employed for microarray analysis and real time-quantitative PCR (qPCR), respectively, to investigate the DKK1 transcript levels in human HCC samples. The serum levels of DKK1 were determined in 50 patients with early HCC, 50 patients with advanced HCC, 50 patients with cirrhosis, 50 hepatitis B virus (HBV) carriers, and 30 HCC patients after liver resection, using sandwich ELISA system. Transcript level of DKK1 in the human HCCs was found to be significantly upregulated as compared with the corresponding nontumorous livers in both microarray (P &lt; 0.001) and qPCR cohorts (P &lt; 0.001). Increased expression of DKK1 was associated with advanced tumor stage (P &lt; 0.001), venous infiltration (P &lt; 0.001), high serum alpha-fetoprotein (AFP) level (P &lt; 0.001). Higher level of DKK1 correlated with both poorer overall survival (P = 0.016) and tumor recurrence (P = 0.014). On the other hand, the serum DKK1 level in the group of HBV carriers without HCC (as control) was not significantly different from that of the cirrhosis group (P = 0.086). In contrast, the serum DKK1 level was significantly higher in patients with early HCC (P &lt; 0.001) and advanced HCC (P &lt; 0.001), as compared with the HBV carrier group. Furthermore, the serum DKK1 level in patients after liver resection was significantly reduced (P &lt; 0.001). Higher serum DKK1 level was associated with tumor recurrence (P = 0.046). To conclude, our data have demonstrated that tissue and serum DKK1 levels were significantly and progressively elevated during HCC formation and progression. DKK1 has prognostic role in predicting overall survival and disease-free survival of HCC patients, and serum DKK1 is a potential biomarker for predicting tumor recurrence.
(The study was supported in part by a grant from the NSFC/RGC Joint Research Scheme [N_HKU 716/06] and an RGC Collaborative Research Grant [HKU 1/06C]. IOLN is a Loke Yew Professor in Pathology)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1779.
Abstract 1787: Dual targeting of PI3K and mTOR results in synergistic growth inhibition in NSCLC cells
Authors: Chao Herta H. , Zito Christopher , Jilaveanu Lucia , Anagnostou Valsamo , Rimm David , Bepler Gerold , Camp Robert , Kluger Harriet M. 
Published: February 2011

Abstract
Background:
Alterations of components in the PI3K/mTOR pathway can result in malignant transformation and are found in a multitude of human cancers including non-small cell lung cancer (NSCLC). Our purpose was to characterize expression of p85 and p110α PI3K subunits in NSCLC specimens and assess the association with mTOR expression, and to study the effects of co-inhibiting PI3K and mTOR in NSCLC cell lines.
Methods:
Using Automated Quantitative Analysis (AQUA), a novel method of in situ protein measurement, we quantified expression of PI3K subunits in two cohorts of 251 and 192 resected NSCLC specimens. AQUA scores were correlated with clinical and pathological variables and previously published AQUA scores for mTOR. We studied changes in viability of 6 NSCLC cell lines exposed to two PI3K inhibitors, LY294002 and NVP-BKM-120, alone and in combination with rapamycin, and assessed the activity of a dual PI3K/mTOR inhibitor, NVP-BEZ-235, which is in clinical development.
Results:
p85 and p110α tend to be co-expressed (p&lt;0.001), and higher expression of p85 was seen in adenocarcinomas than squamous cell carcinomas (SCC). High expression of p85 correlated with poor survival (p&lt; 0.0075). Expression of p110α correlated with mTOR (ρ=0.30). In 6 NSCLC cell lines (3 adenocarcinomas, 3 SCC) the addition of rapamycin to LY294002 or NVP-BKM-120 was highly synergistic. Of note, even small concentrations of rapamycin (1ηM) resulted in sensitization to the PI3K inhibitors, and similar reduction in viability was seen with the addition of 1ηM, 100ηM and 1000ηM of rapamycin. NVP-BEZ-235 was highly active in NSCLC cell lines with IC50s in the ηM range and resultant down-regulation of pAkt and pP70S6K.
Conclusions:
PI3K is associated with decreased survival in NSCLC, suggesting that it is a good drug target for this disease. Concurrent inhibition of PI3K and mTOR is synergistic in NSCLC cell lines. Dual inhibition of PI3K and mTOR by NVP-BEZ-235 is promising and should be further evaluated in clinical trials for patients with NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1787.
Abstract 1792: Association of enhanced IGF-1R signaling and HBV/inflammation with poor HCC prognosis
Authors: Chang Te-Sheng , Lee Kam-Fai , Tung Shui-Yi , Kuo Liang Mou , Huang Yen-Hua 
Published: February 2011

Abstract
Hepatocellular cell carcinoma (HCC) associated with chronic HBV hepatitis tends to have a more unfavorable prognosis. Recently, a global transcriptome analysis by Boyault's group suggested that HBV infection would result in chromosome instability and activation of insulin-like growth factor receptor (IGFR)/AKT signaling pathway (but not the β-catenin pathway) of a subgroup of HCC. As both chronic inflammation and viral infection have been demonstrated to be important promoters for HCC tumorigenesis, we investigated the potential effects of HBV and chronic inflammation on the activation of IGF signaling pathway. By using the paired HBV- positive and HBV-negative HCC cell lines (HepG2.2.15 (HBV+) vs. HepG2 (HBV-); and Hep3B (HBV+) vs. Huh7 (HBV-)), we found the increased expression of IGF1 receptor at both gene (by RT PCR) and protein levels (by Western blotting) in HBV-positive HCC cell lines. Meanwhile, the IGF-1R activation signaling (such as phospho-IGF-1R and phospho-Akt) was also significantly increased in HBV-positive HCC cell line (Hep3B vs. Huh7). To further examine the role of inflammatory cytokine(s) in IGF-1 signaling of HCC cells, increasing dilution folds of LPS (lipopolysaccharide)- stimulated monocyte-differentiated U937 cell condition medium (U937-CM) were added in culture medium for treatment of HepG2 and HepG2.2.15 cells. By Western blotting analysis, the chronic inflammation condition showed enhancement of the IGF-1R protein expression in the HepG2.2.15 while comparing with the HepG2 cells. These observations suggested that the inflammatory stress may further elevate the IGF-1R expression in HBV-positive HepG.2.2.15 cell line. The associated clinical implication was further evaluated by high throughput tissue microarray. Our results revealed a negative correlation between phospho-IGF-1R expression and disease-free survival. In summary, our work showed that both HBV and chronic inflammation promoted IGF-1R activation signaling which may result in the poor prognosis of a subgroup of HCCs. The underlying mechanism(s) contributing the IGF-1R-mediated signal to the ominous disease outcome still needs further investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1792.
Abstract 1806: Efficacy of MM121 in ER+ and triple negative breast cancer studies
Authors: Nie Lin , Burenkova Olga , Adams Sharlene , Kalra Ashish , Fulgham Aaron , Xiao Dongmei , Grantcharova Viara , Onsum Matt , Wille Lucia , Moulis Sharon , Garcia Gabriela , Moyo Victor , Kubasek Bill , Nielsen Ulrik 
Published: February 2011

Abstract
In women, breast cancer is among the most common cancers and the fifth most common cause of cancer deaths. Due to the heterogeneity of the disease, 10-year progression free survival can vary widely with stage and type from 98% to 10%. We present data showing that MM-121, a fully human monoclonal anti-ErbB3 antibody, is efficacious in studies of both hormone dependent (ER+) and triple negative (ER-,PR-, Low Erb2) breast cancer lines that express the molecular profile consistent with MM-121 response (co-expression of ErbB3 and HRG).
Using a combination of computational and experimental approaches, ErbB3 was identified as a critical transducer of oncogenic signaling leading to the development of MM-121, a first in class anti-ErbB3 antibody. We have previously demonstrated that MM-121, when used as a single agent, inhibits heregulin-induced signaling events in human cancer cell lines. Moreover, MM-121 caused dose-dependent inhibition of tumor growth in multiple xenograft models of human cancer, including ovarian, renal cell, pancreatic, lung, and prostate cancer.
Estrogen dependent, or ER+ breast cancers, make up about 80% of breast cancers. A standard treatment for ER+ breast cancer includes hormone therapy; however a substantial number of ER+ breast cancers eventually develop resistance requiring additional treatments. Here we show that in ER+ breast cancer cells, MM-121 can block HRG induced ErbB3 activation and VEGF secretion as well as HGF induced pErbB3 in vitro. Additionally, in ER+ breast cancer xenograft models, MM121 is effective in combination with both chemotherapy agents and targeted therapies and may be effective in ER+ breast cancers that are refractory to hormone treatment.
The triple negative breast cancers are characterized by poor prognosis, aggressiveness, and reduced responsiveness to standard treatments. MM-121 used as a single agent therapy was able to suppress tumor growth in triple negative primary human tumors, when grown as xenografts suggesting that MM-121 monotherapy may be clinically efficacious in triple negative breast cancers.
Together, these data suggest that MM-121, when used as a single agent or in combination with other therapies, could offer significant clinical benefit to both ER+ and triple negative breast cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1806.
Abstract 1810: PTEN association with mTOR pathway activation and outcomes in bladder cancer
Authors: Orloff Mohammed , Elson Paul , Yang Yi-Ran , Eng Charis , Hansel Donna E. 
Published: February 2011

Abstract
Background: We have recently identified increased mTOR pathway activation in urothelial carcinoma of the bladder (UCC). We next sought to determine the relationship of PTEN, an upstream negative mediator of the mTOR pathway, to mTOR activity and outcomes in UCC patients.
Methods: Patients with UCC (n=118) were examined for PTEN expression, including intensity of expression (0 no expression, 1+ low, 2+ moderate, 3+ intense expression) and predominant subcellular localization (nuclear, non-nuclear). Results were correlated with the presence of lymph node (LN) metastases, recurrence-free survival (RFS) and overall survival by univariate and multivariate analysis. PTEN intron/exon mutational analysis was performed by denaturing gradient gel electrophoresis (DGGE) and mutational status was correlated with PTEN protein expression in a subset of 91 specimens.
Results: The majority of patients (91/118; 81%) demonstrated moderate to intense expression of PTEN, with PTEN loss in only 2 patients. PTEN was primarily localized to the nucleus in 30/116 (26%) patients, with some level of nuclear PTEN staining in 74/116 (64%) of patients. In LN metastases, reduced PTEN intensity was associated with an increased percentage of phospho-mTOR cells (p=0.02). PTEN mutational analysis identified 3 variants (c.132C&gt;T, c.511C&gt;G, c.892C&gt;G) which were associated with absent PTEN protein expression and diffuse phospho-mTOR expression. Reduced RFS was correlated with positive surgical margins (p=0.09), carcinoma in situ (p=0.09) and nuclear PTEN (p=0.08). Reduced overall survival was significantly associated with metastases (p=0.04) and nuclear PTEN expression (p=0.04). Stepwise multivariable analysis showed an association between reduced RFS and LN metastases (p=0.03), carcinoma in situ (0.05) and nuclear PTEN (p=0.07).
Conclusions: Alterations in PTEN expression and subcellular localization appear to mediate mTOR pathway activity in bladder cancer cells, although few mutations appear to account for reduced PTEN expression. Nuclear localization of PTEN is a relatively new finding and its function in mediating cancer behavior is under investigation. Our finding of worsened outcomes with nuclear PTEN localization warrant further functional investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1810.
Abstract 183: Global knock-down of the cancer epigenome
Authors: Hou Pei-Chi Peggy , Yen Ching-Chu , Lee Kuan-Der , Chang Hao-Chun , Cheng Chao-Min , Lin Yi-Shiuan , Sun H. Sunny , Chang Yu-Sun , Huang Tim H.-M. , Hsiao Shu-Huei , Tsai Shaw-Jenq , Leu Yu-Wei 
Published: February 2011

Abstract
Aberrant DNA methylation within the promoter regions is associated with the tumorigenesis, yet no whole epigenomic targeting method has been developed to target all of the aberrant loci. We then aimed to establish a global epigenomic targeting method to efficiently against specific cancer cells. To identify and target all the methylation differences between the estrogen receptor (ER) expressing (MCF7, ER+) versus the nonexpressing (MDA-MB-231, ER−) breast cancer cells, a methylation subtraction method was established. Identified targets was validated by high-throughput sequencing and quantitative PCR, and the efficiency of targeting was validated by the cell death phenotype, increased DNA methylation and reduced expression in the target genes. Targeted methylation within these identified loci specifically killed the MDA-MB-231 cells but not the MCF7 cells either in culture or the tumors grown in immuno-deficient mice. To narrow down the number of targets, we identified and targeted 19 of the estrogen receptor-governed loci that were hypomethylated in the MDA-MB-231, implicating their role in the survival and malignance of these ER− cells. The targeted methylation was sufficient to kill the ER− cells in culture. Among these 19 loci, targeted ENSA methylation alone was sufficient to kill the MDA-MB-231 cell specifically in culture as well as in immuno-deficient mice. Overall, a global targeted methylation methodology was established that could be used to identify and target the methylation differences between two cells. These results indicated that the developed global knock-down method might serve as a whole genome validation and therapeutic alternatives. (Supported in part by NSC 97-2320-B-194-003-MY3, NSC 98-3112-B-194-001 and NSC 97-2627-B-006-003)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 183.
Abstract 1844: No evidence for genetic factor increasing renal cell cancer risk in Hereditary Leiomyomatosis and Renal Cell Cancer syndrome
Authors: Koski Taru A. , Vahteristo Pia , Näätsaari Laura , Kiuru Maija , Karhu Auli , Herva Riitta , Sallinen Satu-Leena , Vierimaa Outi , Björck Erik , Richard Stéphane , Gardie Betty , Bessis Didier , Glabeke Emmanuel Van , Blanco Ignacio , Houlston Richard , Senter Leigha , Hietala Marja , Aittomäki Kristiina , Aaltonen Lauri A. , Launonen Virpi , Lehtonen Rainer 
Published: February 2011

Abstract
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary tumor predisposition syndrome with fumarate hydratase (FH), which encodes a tricarboxylic acid cycle enzyme fumarase, as the predisposing gene. The HLRCC family members carry heterozygous germline mutations of the FH gene and the tumors often harbor a second hit making the growth fumarase deficient. The phenotype includes benign cutaneous and uterine leiomyomas as well as renal cell cancer (RCC). The HLRCC related RCCs usually belong to histological papillary type II subtype and are solitary, unilateral and aggressive. The benign leiomyomas are the most common manifestation of the syndrome affecting almost all FH mutation carriers whereas the renal cell cancer phenotype affects only about 20% of the HLRCC families. Interestingly, majority of the families with multiple renal cell cancer cases have concentrated in Finland and the U.S. Why the malignant phenotype affects only a part of the HLRCC patients is unknown. There is no genotype-phenotype correlation and type or site of the FH mutation does not affect the phenotype. The fumarase enzyme activity levels do not correlate with the phenotype either. Thus it is possible that the appearance of RCC requires, in addition to FH mutation, another genetic factor. To search for such a factor in four Finnish HLRCC families with multiple RCC cases we performed genome wide linkage and/or identical by descent (IBD) analyses. After finemapping procedures the only region compatible with linkage was the FH locus itself in 1q43. The genes of the region were screened but no pathognomonic mutations were found. Although these results do not exclude the existence of a genetic RCC risk modifier in HLRCC, the role of FH mutations behind RCC tumors is emphasized. Counseling and genetic testing should be available for HLRCC family members and the FH mutation carriers should be carefully followed up to enable early detection and treatment of the aggressive cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1844.
Abstract 1852: A novel role for the 185delAG BRCA1 mutant protein, BRAT, in ovarian cancer pathology
Authors: Linger Rebecca J. , Kruk Patricia A. 
Published: February 2011

Abstract
Objective: Familial history is the strongest risk factor for developing ovarian cancer (OC). Studying risk-associated BRCA1 truncation mutations, such as the founder mutation 185delAG, may reveal signaling pathways important in OC etiology. Normal human ovarian surface epithelial (HOSE) cells expressing the 185delAG mutant, BRAT, exhibit phenotypic changes due possibly in part to up-regulation of maspin, a tumor suppressor important in apoptosis, invasion, and metastasis that exhibits unique up-regulation in some cancer types. In the current study, we wish to determine BRAT's impact on expression and activity of matrix metalloprotease 1 (MMP1), another key player in invasion and metastasis, and the mechanism of this modulation.
Methods: HOSE, breast epithelial cells, and breast cancer cells transiently and stably expressing the 185delAG mutation were analyzed for differential target gene expression by semi-quantitative and real time PCR. SiRNA transfection was performed to achieve knockdown of c-Jun. Western blotting was used to evaluate MMP1 and c-Jun protein levels. FRET ELISA was performed on conditioned media to evaluate levels and functionality of secreted MMP1. Cells were treated with cisplatin and subjected to MTS assay to evaluate chemosensitivity.
Results: BRAT-expressing HOSE cells exhibited enhanced MMP1 mRNA expression. Higher levels of pro-MMP1 protein were detected by Western blotting of conditioned media. FRET ELISA revealed total MMP1 (pro and active forms) was also higher in BRAT-expressing cells, and that MMP1 in the conditioned media was functional. c-Jun knockdown diminished MMP-1 expression and secretion in HOSE. Expression of BRAT in normal breast and breast cancer cell lines failed to significantly alter chemosensitivity or MMP1 expression levels.
Conclusion: Normal HOSE cells expressing the BRAT mutation exhibit c-Jun-dependent changes in expression of MMP1. Further investigation is warranted to elucidate the mechanism of this change since increased expression of this gene may represent an initial step forward on the continuum of malignant transformation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1852.