bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4541: Binding and transcriptional activity of the androgen receptor isoforms in 22Rv1 prostate cancer cells
Authors: Mudryj Maria , Libertini Stephen J. , Chen Honglin , Al-Bataina Bushra , Kung Hsing-Jien , Ghosh Paramita M. 
Published: June 2012

Abstract
Prostate carcinoma (CaP) is a heterogeneous multifocal disease where gene expression and regulation is altered as the disease progresses but the androgen receptor (AR) continues to be a pivotal regulatory molecule. The 22Rv1 castrate resistant cell line, derived from the androgen dependent CWR22 xenograft model, continues to express the AR and remains androgen responsive. However, in additional to the full length AR, these cells also express several low molecular weight isoforms. These isoforms are the predominant (95%) forms present in the nucleus in castrate androgen levels. siRNA knockdown of all AR isoforms in castrate levels of androgen decreases cell growth indicating that AR is required for proliferation. Analysis of ChIP-promoter array data identified 128 binding sites (FDR&lt;=0.05) in Rv1 cells proliferating in androgen-depleted media. A closer examination of these 128 binding sites revealed that 20% of the sites showed exactly the same start and end position in the absence or presence of DHT. The remainder (80%) were within ∼35-1000bp upstream of the start position or downstream of the end position. Only 6% of the binding sites contained the palendromic consensus AR-response element and 48% contained the AR half-site motif. The 128 binding sites were associated with 118 genes. To define the role of AR binding in regulating transcription, the expression of 20 of the 118 genes was analyzed following knockdown of AR in castrate levels of androgen. One third of these genes are transactivated, while 1/3 are repressed, arguing that AR activating and repressing complexes co-exist in these cells. Notably the expression of CDKN1B (p27) RNA and protein is highly activated following AR knockdown, suggesting that AR-dependent repression of this cell cycle inhibitor may be important for proliferation of 22Rv1 cells.
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 4541. doi:10.1158/1538-7445.AM2011-4541
Abstract 4555: ERβ alters cell growth and the DNA damage response in lung cancer cells
Authors: Nikolos Fotis , Rajapaksa Gayani K. , Thomas Christoforos G. , Gustafsson Jan-Ake 
Published: June 2012

Abstract
Lung cancer is the leading cause of cancer deaths worldwide, in both men and women. Estrogen receptors that mediate the biological effects of estrogen and ant-estrogens are very important for the regulation of cell proliferation and differentiation in various human tissues. Recent data suggest that estrogen receptors may affect the initiation and progression of lung cancer. Here we show that estrogen receptor beta (ERβ) is expressed endogenously and it is localized in both cytoplasm and nucleus in the lung cancer cell line A549. Treatment of these cells with 17beta-estradiol does not alter the subcellular distribution of ERβ. Induction in the expression of ERβ in the same cells inhibits cell growth and modulates their resistance to cytotoxic chemotherapy in a ligand-independent manner. These results suggest ERβ as an important player in biology of lung cancer and a potentially useful component in the clinical management of the disease.
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 4555. doi:10.1158/1538-7445.AM2011-4555
Abstract 4576: IMGN853, an anti-Folate Receptor I antibody-maytansinoid conjugate for targeted cancer therapy
Authors: Ab Olga , Bartle Laura M. , Rui Lingyun , Coccia Jennifer , Johnson Holly A. , Whiteman Kathleen R. , Kellogg Brenda , Clancy Lauren , Sun Xiuxia , Goldmacher Victor S. 
Published: June 2012

Abstract
Previously we reported (O. Ab; EORTC, 2010) that an antibody-maytansinoid conjugate (AMC) composed of an anti-FOLR1 antibody conjugated to the cytotoxic maytansinoid, DM4, via the disulfide-containing linker, SPDB, was potent in killing FOLR1-expressing cancer cells in vitro and in vivo. In light of the favorable results noted, we assessed the optimal antibody, linker, and maytansinoid agent for an AMC targeting FOLR1, as reported here.
Antibody selection. Anti-FOLR1 antibodies were generated by immunizing mice with human FOLR1-expressing cells, and a panel of FOLR1-specific antibodies was identified by flow cytometry binding assay. Several FOLR1-antibodies with high binding affinity to both human and monkey FOLR1 were chosen for further evaluation and were humanized using ImmunoGen's resurfacing technology.
Antibodies were conjugated to DM1 via the non-cleavable SMCC linker and the conjugates tested for activity against FOLR1-positive KB cells in vitro and in vivo. All conjugates had comparable cytotoxic potencies in vitro. However, the in vivo anti-tumor activity of one conjugate, M9346A-SMCC-DM1, was significantly better than that of SMCC-DM1 conjugates of other FOLR1 antibodies. Based on this finding, the M9346A antibody was chosen for further development.
Linker/maytansinoid selection. The M9346A antibody was linked to DM1 or DM4 via the disulfide-containing cleavable linkers SPP, SPDB or sulfo-SPDB, or via the non-cleavable SMCC linker. We compared the in vitro cytotoxic activities of these conjugates on KB, Igrov-1 and Jeg-3 cell lines. The conjugates with cleavable linkers displayed markedly greater in vitro activities than the SMCC conjugate. We then examined the in vivo activities of the conjugates in FOLR1-positive KB- and Ovcar 3-tumor models. Again, we found that the conjugates with cleavable linkers were more active in vivo than the noncleavable conjugate. Among the conjugates with cleavable linkers, the sulfo-SPDB-DM4 conjugate was the most active conjugate against the Ovcar-3 model, it had activity comparable to that of the SPDB-DM4 conjugate against KB tumors, and both were more active than the SPP-DM1 conjugate in the two xenograft models.
Taking into consideration that sulfo-SPDB-DM4 was the most efficacious design in vivo and the potential of the hydrophilic sulfo-SPDB-linker to enable better activity against PgP-expressing cells (previously reported data), M9346A-sulfo-SPDB-DM4 was selected to be the candidate for development and designated IMGN853. IMGN853 is a promising candidate for the treatment of FOLR1-expressing tumors.
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 4576. doi:10.1158/1538-7445.AM2011-4576
Abstract 4597: Chemopreventive and chemotherapeutic potential of blueberry and black raspberry against lung cancer using mouse models
Authors: Gupta Ramesh C. , Jeyabalan Jeyaprakash , Kausar Hina , Aqil Farrukh , Vadhanam Manicka V. , Ravoori Srivani 
Published: June 2012

Abstract
Berries, particularly blueberry (BB), black raspberry (BRB), are gaining increased attention for their chemopreventive and chemotherapeutic activities and have been tested in limited clinical studies with mixed results. Previous studies with strawberry and BRB failed to elicit protection against NNK/PAH-induced lung carcinogenicity in the A/J mice (the Stoner studies). However, a low dose of a mixture of different berries (BB, BRB, blackberry, and strawberry) elicited modest inhibition of cigarette smoke-mediated lung carcinogenicity in our study. In this study we investigated chemopreventive and chemotherapeutic activities of BB and BRB using two different animal models: To determine the DNA adduct-inhibiting potential female A/J mice were provided AIN-93M diet or diets supplemented with lyophilized powder of BB or BRB (5% each, w/w) and then challenged with continuous low doses of dibenzo-[a,l]pyrene (DBP) by subcutaneous polymeric implants (two, 20 mm long, 1.4 mm dia; DBP load 5%). Three weeks later animals were euthanized and the target tissue (lung) DNA was analyzed by 32P-postlabeling assay. The DNA adduct burden (as adducts/109 nucleotides) in animals receiving the BB (67 ± 16), BRB (68 ± 9) diets was found to be unaffected compared with control diet (54 ± 17), indicating that the berry bioactives were ineffective against the DNA adduct-forming ability of DBP under the conditions used. To determine the chemotherapeutic potential, female nude mice received AIN-93M (control) diet or diet supplemented with a mixture of BB and BRB (2:1) and 4 days later inoculated with human lung cancer A549 cells (3×106 cells). Four weeks into the ongoing study, the berry diet has shown significant (nearly 60%) inhibition of the lung tumor xenograft (186 ± 117 versus 79 ± 47). The anti-tumor activity elicited by the berry diet in xenograft model is consistent with the anti-tumor activity of anthocyanidins reported by us in cell culture and nude mice (Kausar et al. AACR 51: 1884, 2010). In conclusion, our data suggest that the anti-lung cancer potential of the berries may be associated with mechanisms other than inhibition of carcinogen-induced DNA adducts. (Supported from CA-118114, KLCRP and Agnes Brown Duggan Endowment).
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 4597. doi:10.1158/1538-7445.AM2011-4597
Abstract 4623: Capsaicin represses transcriptional activity of β-catenin in human colorectal cancer cells
Authors: Lee Seong-Ho , Richardson Raphael L. , Baek Seung J. 
Published: June 2012

Abstract
Capsaicin is a pungent ingredient in chili red peppers and has been linked to suppression of growth in various cancer cells. However, the underlying mechanism(s) by which capsaicin induces growth arrest and apoptosis of cancer cells is not completely understood. In the present study, we investigated whether capsaicin alters β-catenin signaling in human colorectal cancer cells in vitro. Exposure of human colorectal cancer cells to capsaicin suppressed cell proliferation. Transient transfection with β-catenin responsive reporter gene indicated that capsaicin suppressed transcriptional activity of β-catenin. Capsaicin treatment resulted in a decrease of intracellular β-catenin levels and a reduction of β-catenin transcripts. These results were confirmed by a reduced luciferase reporter activity driven by β-catenin promoter. In addition, capsaicin destabilized β-catenin through enhancement of proteosomal-dependent degradation. Western blot and immunoprecipitation studies indicated that capsaicin treatment disrupted interaction of TCF-4 and β-catenin and suppressed TCF-4 expression. This study identifies an important capsaicin-mediated pathway that contributes to anti-cancer activity of human colorectal cancer cells.
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 4623. doi:10.1158/1538-7445.AM2011-4623
Abstract 4625: Curcumin suppresses the expression of HER-2 gene and interferes with redox regulated pathways in SK-BR-3 breast cancer cells
Authors: Thomas T.J. , Venkiteswaran Sripriya , Thomas Thresia , Yang PingAr , Hsu Hui-Chen 
Published: June 2012

Abstract
Curcumin (diferuloylmethane), a polyphenolic phytochemical, is the major pigment in turmeric, a popular spice in Oriental cuisine. Curcumin is known for its anti-inflammatory, antioxidant, and anti-carcinogenic properties. We studied the effect of curcumin on cell growth, gene regulation, cell cycle and cell signaling parameters in a HER-2 over-expressing human breast cancer cell line, SK-BR-3. Curcumin inhibited the growth of SK-BR-3 cells with an IC50 value of 5 ± 1 µM, as determined by trypan blue exclusion assay at 48 and 72 h. In contrast, measurement of apoptosis, using the APO-BRDU assay, showed &lt; 5% apoptosis after exposing SK-BR-3 cells to 5 µM curcumin for 24, 48, or 72 hours. Apoptosis increased to ∼ 80% at 25 µM concentration. To understand the basis of these phenomena, we examined the effects of curcumin on several molecular parameters. At 25 µM concentration, curcumin suppressed the expression of HER-2 gene by a significant 70% (P&lt;0.005) at 16 and 24 hours after treatment, as measured by real time qPCR assay. Curcumin further caused a 2- to 4-fold increase in p21 and p27 mRNA levels. Twenty five µM concentration of curcumin also suppressed the expression of cyclin B1, cyclin D1 and cyclin E mRNA levels. In addition, curcumin arrested cells in the G2/M phase of cell cycle, and decreased cyclin A, cyclin B1 and cyclin E protein levels. At 10 to 50 µM concentrations, curcumin also caused a decrease in phospho-HER-2 and total-HER-2 protein levels. Pre-treatment with the anti-oxidant glutathione partially reversed apoptosis induced by curcumin and restored HER-2 and cyclin D1 protein levels. These results indicate that the apoptotic effects of curcumin on HER-2 over-expressing breast cancer cells result from interference with redox-mediated cell growth regulatory pathways. Increased levels of glutathione attenuated the effects of curcumin, an important consideration for translational research and clinical trials on curcumin. Since some of its growth inhibitory effects can be restored by exogenous glutathione, cellular redox status is an important factor in curcumin sensitivity of breast cancer cells.
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 4625. doi:10.1158/1538-7445.AM2011-4625
Abstract 4717: Final results from the Phase I study of MetMAb, a monovalent antagonist antibody to the receptor Met, dosed as single agent and in combination with bevacizumab in patients with advanced solid malignancies
Authors: Moss Rebecca A. , Bothos John G. , Patel Premal H. , Peterson Amy C. , Eppler Steve , Bai Shuang , Nijem Ihsan , Desnoyers Luc , Kaur Surinder , Zha Jiping , Yu Wei , Simpson Joe , Ratain Mark J. , Tan Antoinette R. , Stein Mark N. , Mehnert Janice M. , Salgia Ravi 
Published: June 2012

Abstract
Background: The receptor tyrosine kinase Met and/or its ligand, hepatocyte growth factor (HGF), are frequently over-expressed in cancers. Aberrant Met activation can enhance invasion, proliferation, and survival and may promote angiogenesis. MetMAb was uniquely engineered as a recombinant, humanized, monovalent monoclonal antibody to act as an antagonist of HGF-induced Met signaling.
Materials and Methods: This 3+3 dose-escalation study consisted of three phases: 1) dose-escalation evaluating 1, 4, 10, 15, 20 and 30 mg/kg IV Q3W; 2) expansion at 15mg/kg IV Q3W; and 3) combination testing MetMAb, at 10 and 15mg/kg IV Q3W, plus bevacizumab (15mg/kg Q3W). Pre- and post- dose serum was collected for evaluation of pharmacodynamic biomarkers that could be affected by inhibition of Met and/or VEGF signaling.
Results: 43 patients were treated in this study (21 in escalation, 13 in expansion, and 9 in combination). MetMAb has a half-life of approximately 11 days, and there were no apparent PK interactions with bevacizumab. MetMAb was generally well tolerated, both alone and in combination. The most frequent treatment-related adverse events included: fatigue, peripheral edema and hypoalbuminemia. In patients treated with the combination, no Grade 3-5 treatment-related adverse events were reported; a Grade 1, and dose-limiting adverse event of hemoptysis was reported in a patient who had central-necrosis of pulmonary metastases. A patient with gastric carcinoma achieved a complete response after 4 cycles of single-agent MetMAb; this patient came off study after 10 cycles with a sustained complete response.
Conclusions: MetMAb, when administered as a single-agent, or in combination with bevacizumab was generally safe and well tolerated. A Phase II trial testing MetMAb in combination with bevacizumab and paclitaxel in patients with triple negative breast cancer is currently ongoing, while a Phase III trial testing MetMAb in combination with erlotinib in advanced NSCLC patients is planned.
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 4717. doi:10.1158/1538-7445.AM2011-4717
Abstract 4732: Cis-expression QTL analysis of established risk variants for colorectal cancer
Authors: Loo Lenora W.M , Cheng Iona , Tiirikainen Maarit , Lum-Jones Annette , Seifried Ann , Dunklee Lucas M. , Gallinger Steve , Thibodeau Stephen N. , Casey Graham , Marchand Loic Le ,   Colon Cancer Family Registry
Published: June 2012

Abstract
Introduction: Genome-wide association studies of colorectal cancer have identified 18 risk variants that explain ∼25% of the hereditable risk of colorectal cancer. These variants are located in intronic, inter-genic or gene-desert regions. To uncover whether some of these variants may have a regulatory function on the expression of near-by genes, we conducted expression quantitative trait loci (eQTL) analyses of these 18 regions.
Methods: DNA and RNA were extracted from 40 fresh-frozen paired colon tumor (microsatellite stable and CpG island methylator phenotype-negative) and adjacent normal tissue samples collected by the Colon Cancer Family Registry. Whole genome gene expression assessment was performed in the tumors and adjacent normal tissue with the Affymetrix GeneChip Human Exon 1.0 ST array. Genome-wide SNP data was generated with DNA extracted from the same normal tissue samples using the Affymetrix Genome-Wide Human SNP 6.0 array. Partek software was used to compare the expression levels by genotype for each gene spanning a 2 Mb region up- and down- stream of each of the 18 established risk variants for colorectal cancer.
Results: Three of the 18 risk variants (rs10795668, rs4444235, rs9929218) demonstrated significant cis-eQTLs (FDR q-values&lt;0.05). Specifically, differential gene expression was observed in genes neighboring rs10795668 at 10p14 (ATP5C1, q=0.024), rs4444235 at 14q22.2 (DLGAP5, q=0.041), and rs9929218 at 16q22.1 (NOL3, q=0.017; DDX28, q=0.046). In particular, DLGAP5 (discs, large (Drosophila) homolog-associated protein 5) at 14q22.2 and NOL3 (nucleolar protein 3) at 16q22 are interesting candidate genes for colorectal cancer. DLGAP5 encodes for a microtubule-associated protein and functions as a mitotic regulator that has been reported to be overexpressed in colon tumors. NOL3 (nucleolar protein 3) encodes for an anti-apoptotic protein that down-regulates the expression of caspase 2 and 8, and p53. NOL3 also appears to be overexpressed in colorectal tumors.
Conclusion: In summary, these findings suggest putative functional activities for three established colorectal risk variants and highlight potentially interesting candidate genes for this malignancy. If confirmed, these results may help explain the total genetic risk of the disease, as well as further our understanding of the underlying biology of colorectal 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 4732. doi:10.1158/1538-7445.AM2011-4732
Abstract 4756: Exome sequencing of 81 neuroblastomas identifies a wide diversity of somatic mutation
Authors: Pugh Trevor J. , Lawrence Michael , Sougnez Carrie , Getz Gad , Attiyeh Edward , Hogarty Michael , Diskin Sharon , Yael Mosse , Diamond Maura , Asgharzadeh Shahab , Sposto Richard , Wei Jun S. , Badgett Thomas , London Wendy B. , Gastier-Foster Julie , Smith Malcolm A. , Gerhard Daniela S. , Seeger Robert , Khan Javed , Meyerson Matthew L. , Maris John M. ,   NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative
Published: June 2012

Abstract
Neuroblastoma (NBL) is a cancer arising from the peripheral nervous system and is the most common solid tumor outside the brain in infants and children. Despite improved treatment over the past 20 years, only 45% of those with high-risk disease survive emphasizing the need for new molecular targets for therapy. To identify genetic mutations that encode such targets, we present an analysis of 162 whole exome sequences from 81 tumor/normal pairs from high-risk NBL patients (N=27 with MYCN amplification). From each sample, genomic DNA fragments encoding 185,961 exons from 18,380 genes were isolated using in-solution hybrid capture and sequenced using the Illumina sequencing platform to a median of 195X coverage. A wide diversity of somatic variation was observed with non-silent mutation counts ranging from 5 to 149 per tumor (median=24). Novel hyper-mutation phenotypes (&gt; 125 candidate coding somatic mutations) were observed in four tumors including one case with both a deletion and a truncating mutation in MLH1. Several genes were mutated across the set at a statistically significant level including ALK (6 tumors, q=0.006) and PTPN11 (3 tumors, q=0.012). There are 27 other genes with candidate mutation frequencies in the 4-10% range, but no single gene identified to date with a mutation frequency &gt;10%. Importantly, multiple paired blood samples (acquired at diagnosis) have sufficient numbers of circulating tumor DNA to potentially interfere with our SNV detection algorithm; refinement of the analytic pipeline using SNP-derived “contamination” metrics is ongoing. We anticipate validating candidate somatic candidates using an orthogonal genotyping method and further defining their true frequency in an expanded sample set that includes non-high-risk cases as well. Finally, we plan a concerted effort to catalogue potentially detrimental germline variations in order to further extend our understanding of the heritable component of NBL.
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 4756. doi:10.1158/1538-7445.AM2011-4756