bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4967: Array-based genomic resequencing of acute myeloid leukemia
Authors: Yamashita Yoshihiro , Ueno Toshihide , Soda Manabu , Mano Hiroyuki 
Published: June 2012

Abstract
Somatic mutations within cancer-related genes play a central role in the pathogenesis of many human malignancies, as clearly demonstrated for the cases with mutated RAS and EGFR. Although a new generation of sequencing technologies is now available, whole-genome resequencing of many samples remains a demanding task. DNA microarray-based sequencing is suitable for analysis of multiple samples. However, currently available platforms are limited in the number of nucleotides that each array is able to probe. To overcome such limitations, we have now developed extra-large DNA arrays (“wafers”) for resequencing the human genome, in a collaborative study with Perlegen Sciences, Inc. With its capacity to assay ∼9 Mbp, we could place, on the array, oligonucleotides to interrogate sequence alterations at protein-coding exons and exon-intron boundaries for 5648 human genes that are possibly involved in malignant transformation mechanism. To identify transforming mutations in acute myeloid leukemia (AML), hybridization of genomic DNA from CD34-positive blasts of AML (n = 19) or myeloproliferative disorder (MPD) (n = 1) to the arrays revealed a total of 9148 nonsynonymous nucleotide changes on 3403 independent genes in this cohort (Phase I). To discriminate somatic changes from germ-line polymorphisms, we developed a second array for a direct analysis of the 9148 nucleotide changes, which was hybridized with genomic DNA from the leukemic blasts as well as with that from CD4-positive T cell fractions (paired controls) from the same cohort (Phase II). Analysis of CD4-positive fractions revealed that most of these nucleotide changes in Phase I were also present in the paired control genome, leaving only 11 somatic, nonsynonymous mutations among 11 genes. One of these somatic changes results in a Met-to-Ile substitution at amino-acid position 511 of Janus kinase 3 (JAK3), and the JAK3(M511I) protein exhibited transforming potential both in vitro and in vivo. Further screening for JAK3 mutations showed novel and known transforming changes in 9 out of 286 cases with leukemia. Our experiments also showed a somatic change responsible for the Arg-to-His substitution at amino-acid position 882 of DNA methyltransferase 3A, which results in a loss of &gt;50% of the catalytic activity. Our data have thus revealed a unique profile of gene mutations in human leukemias. Given that only a small number of sequence alterations were proved to be “somatic” after Phase II selection, it would be important to use appropriate paired control samples in the search for somatic mutations in the cancer genome.
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 4967. doi:10.1158/1538-7445.AM2011-4967
Abstract 4975: Next generation sequencing reveals a connection between KRAS mutation and the NFkB pathway in lung adenocarcinoma samples
Authors: Kalari Krishna R. , Rossell David , Asmann Yan , Nair Asha , Baker Tiffany , Carr Jennifer , Chai High-Seng , Hossain Asif , Sun Zhifu , Li Ying , Middha Sumit , Bot Brian , Passow Jeanette Eckel , Kocher Jean-Pierre , Perez Edith , Fields Alan , Thompson Aubrey 
Published: June 2012

Abstract
Motivation: KRAS is commonly mutated in a variety of cancers including lung cancer. The KRAS gene is frequently mutated at codons 12 and 13 in lung adenocarcinomas in patients with a history of smoking. Tumors harboring an activating KRAS mutation are aggressive and are often resistant to available therapies. In the present study, we set out to identify pathways that are specifically altered in lung cancer patients whose tumors harbor a KRAS mutation using next generation sequencing technology.
Methods: We performed 50nt paired-end RNA-sequencing in 15 lung adenocarcinoma samples (8 and 7 samples with and without KRAS mutation). Reads were aligned to genome and exon junctions using Illumina's alignment tool ELAND_RNA. CASAVA and Genome Studio data analysis software were used to obtain read counts for genes, exons and exon junctions. We applied a variety of computational methods (Casper R package, Bowtie, TopHat) and softwares (Partek, R statistical software, JMP, Ingenuity Pathway Anlaysis, DAVID) to carry out our analyses.
Results: Differential gene expression and splicing analysis were performed between the two groups. We identified 115 genes that were differentially expressed and 112 genes that consist of splicing variants with at least 2 fold changes and p-value &lt; 0.01. We randomly selected 6/15 samples and performed real-time qRT-PCR for 6 differentially expressed genes. Significant correlations were observed ranging from 0.44 to 0.83, when qRT-PCR results were compared with RNA-sequencing expression data. Pathway analysis with 115 differentially expressed genes and 112 splicing variants revealed that the most significant pathway is composed entirely of NFκB focus genes, suggesting that there is a direct connection between oncogenic KRAS and activation of the NFκB signaling pathway.
Conclusions: NFκB has been implicated in KRas-mediated formation of early stage lung adenomas in the LSL-Kas mouse model. Our data indicate that this connection also occurs in human lung cancer and establish NFκB activation as a key manifestation of KRAS mutation in human lung cancer. Hence drugs targeting NFκB and NFκB related genes may potentially be helpful for the treatment of patients with oncogenic KRAS mutations. (Supported in part by grants from the 26.2 with Donna Foundation and the Florida Department of Health Bankhead/Coley program.)
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 4975. doi:10.1158/1538-7445.AM2011-4975
Abstract 5014: Analysis of recruitment of patients into clinical trials for colorectal cancer
Authors: Joubert Richard , Thomas Moehler , Raeth Ulrich 
Published: June 2012

Abstract
Background: Correct estimation of patient enrollment is an important success factor for planning clinical studies including studies for metastatic colorectal cancer (CRC). Methods: We performed a systematical review of all published articles on clinical studies in the indication colorectal cancer published in the Journal of Clinical Oncology and Annals of Oncology between 01/2007 and 10/2008 focusing on aspects relevant for patient recruitment.
Results: Of the 43 studies we identified, 37 studies could be integrated in the final analysis. Most clinical studies were performed in the metastatic indication. Overall, a mean enrollment of 0.77 Patient/Site/Month (range 0.10 to 6.50) was observed with highest recruitment efficacy of 3.30 Patients/Site/Month (range 1.81 to 6.50) found in 4 single institution phase II trials. The recruitment rates in Patients/Site/Month were 0.67 for phase I trials, 1.35 for phase II trials and 0.32 phase III trials. The mean recruitment rate for all phase II/III multicenter trials was 0.46 Patients/Site/Month. Highest recruitment rates were recorded for third line studies investigating novel agents either as single agents or in an combination regimen in phase II settings.
Conclusions: Phase II clinical trials on novel agents with high potential to change future treatment standard demonstrate almost a threefold higher-than-mean recruitment rate for multi-center trials (0.46 Patient/Site/Month). Despite some limitations in the interpretation of results, our analysis provides important information to support estimation of patient recruitment in future clinical trials for 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 5014. doi:10.1158/1538-7445.AM2011-5014
Abstract 5020: Potential lifestyle intervention in inner city women with endometrial cancer: A pilot study
Authors: Nevadunsky Nicole S. , Huang Gloria , Rivera Yvy , Moadel Alyson , Kuo Dennis , Harris Kimala , Goldberg Gary 
Published: June 2012

Abstract
Hypothesis: Evidence suggests that modification of diet and exercise practices may prevent cancer recurrence. It may also decrease the risk factors for the leading causes of death in women including heart disease and stroke.
Methods: 100 patients with previously diagnosed endometrial cancer were enrolled in a pilot study to collect data regarding current lifestyle, willingness to change and preferred programs of nutrition and exercise. All enrolled subjects were verbally asked to respond to a questionnaire that included validated and novel instruments.
Results: Mean age was 64 (39-86 years) and mean body mass index was 34 kg/m2 (17-55). 38% of the responders were Black/African American, 33% were Caucasian, and 21% were Hispanic. Of these, 69% were born in the United States of America. 75% described themselves as “overweight”. The most common mode of current exercise was walking (54%). 89% of the patients responded that they would be interested in participating in a diet or exercise program. The most common reason that women stated they would want to participate was to improve overall health (48%). Only 4% stated that they thought it would prevent recurrence of their cancers.
Diabetes mellitus was previously diagnosed in 30% of participants. Eighty three percent of diabetic patients had body mass index over 30 kg/m2 and 30% had body mass index over 40 kg/m2. Eleven patients currently on therapy for diabetes had hemoglobin A1C values greater then 6.5 and are at risk for microvessel damage and end-organ dysfunction including kidney failure and impaired vision
Discussion: These data present the opinions of a racially heterogeneous group of women at risk for cancer recurrence, as well as the morbidity and mortality related to obesity and diabetes. These data suggest that women at our center should participate in a dietary and exercise intervention program and our patients would benefit from the additional health education.
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 5020. doi:10.1158/1538-7445.AM2011-5020
Abstract 5030: Necitumumab (IMC-11F8), a recombinant human anti EGFR antibody, increases the antitumor effects of cisplatin/paclitaxel in human NSCLC xenograft models
Authors: Tonra James R. , Li Huiling , Deevi Dhanvanthri S. , Bao Channa , Samakoglu Selda 
Published: June 2012

Abstract
Epidermal growth factor receptor (EGFR) targeted antibodies may have a role in the treatment of non-small cell lung cancer (NSCLC), based on preclinical and clinical data. Here we have demonstrated a significant benefit of adding necitumumab, a recombinant human IgG1 antibody targeting EGFR, to cisplatin+paclitaxel administered at its maximum tolerated dose, in subcutaneous xenograft tumor models established in nu/nu athymic mice with A549 or NCI-H1650 NSCLC cell lines.
Necitumumab monotherapy or cisplatin+paclitaxel therapy inhibited xenograft tumor growth with a T/C% of 47 and 63, respectively in A549 tumor model. A similar anti tumor effect was seen in NCI-H1650 xenograft tumors treated with necitumumab monotherapy or cisplatin+paclitaxel therapy with a T/C% of 37 and 50, respectively. Furthermore, the combination of necitumumab with cisplatin+paclitaxel significantly inhibited tumor growth with a magnitude greater than any of the therapies alone in A549 xenograft tumors with a T/C% of 33 and in NCI-H1650 xenograft tumors with a T/C% of 18. Combination treatment resulted in partial regressions (3 out of 9 mice) in A549 and maximum tumor regressions (10 out of 12) in NCI-H1650. Chi-Squared test for all animals in the treatment groups showed p=0.02 in A549 and p=3.0E-08 in NCI-H1650 xenograft tumors.
In vitro analysis on A549 and NCI-H1650 cell lines treated with cisplatin+paclitaxel, with/without necitumumab (5 μg/ml) demonstrated that this combination benefit was associated with the increased apoptotic index in both models. Cell cycle arrest during combination therapy was also observed as an increase in the percentage of cells in G2/M phase in A549 and S or G2/M phase in NCI-H1650 cell lines. We are further utilizing SABiosciences PCR arrays to demonstrate combination benefit related gene function in apoptosis, cell cycle signaling pathways and drug specific biomarkers in both A549 and NCI-H1650 cell lines.
Thus our results demonstrate the potential utility of necitumumab for enhancing the efficacy of cytotoxic chemotherapy in both in A549 and NCI-H1650 cell lines and xenograft tumors models.
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 5030. doi:10.1158/1538-7445.AM2011-5030
Abstract 5037: Sensitivity of ovarian clear cell carcinoma cells to PI3K inhibitors
Authors: Kwan Suet Yan , Fung Anita , Izaguirre Daisy , Zu Zhifei , Tsang-Lee Yvonne , Mok Samuel , Wong Kwong-Kwok 
Published: June 2012

Abstract
Introduction: Ovarian Clear Cell Carcinoma (OCCC) is generally aggressive and chemoresistant, with five year survival rate of approximately 40%. Recent mutation analysis has indicated a high frequency of PIK3CA mutations, the gene encoding for the p110α subunit in PI3K, in OCCC. Aberrant signaling of the PI3K/AKT pathway might be linked to the aggressiveness of OCCC. In this study, we investigated the sensitivity of ovarian clear cell carcinoma cells with different PIK3CA mutations to inhibitors targeting the PI3K signaling pathway.
Experimental design: To elucidate the functional roles of PIK3CA mutations in OCCC, 12 OCCC cell lines carrying PIK3CA wildtype or different PIK3CA mutations were used. By performing WST-1 assay, the IC50 values for cisplatin of the cell lines were compared. Eight stable OCCC cell lines expressing a luciferase reporter fused with a FOXO3a promoter were constructed. FOXO3a is a transcription factor that is exported out of the nucleus by AKT. The difference in the PI3K/AKT pathway activation in these cell lines was then correlated with luciferase activity. PI3K inhibitor LY294002 and dual PI3K/mTOR inhibitor NVP-BEZ235 were used to elucidate the dependency of OCCC cell lines on the PI3K/AKT pathway.
Results: When compared with PIK3CA wildtype cell lines, cell lines with PIK3CA mutations K111N, E545K and H1047R had higher IC50 values for cisplatin and PI3K inhibitor LY294002. These 3 cell lines also have lower luciferase activity, indicating increased activation of the PI3K/AKT pathway. The IC50 values for NVP-BEZ235 are similar in PIK3CA wildtype or mutated cell lines.
Conclusion: The constitutive activation of the PI3K/AKT pathway in ovarian clear cell carcinoma appears to lead to increased resistance to chemotherapy, possibly by promoting cell survival and inhibiting apoptosis. Inhibition of PI3K/AKT pathway may overcome this resistance. NVP-BEZ235 was shown to be a potent drug in OCCC, it was effective in the nano molar range (IC90 value was reached in all cells lines at drug concentration of 100nM) and was active against PIK3CA mutants.
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 5037. doi:10.1158/1538-7445.AM2011-5037
Abstract 5072: Protein signatures associated with dysplasia of ulcerative colitis
Authors: Pan Sheng , Crispin David , May Damon , Bronner Mary P. , Lai Lisa A. , Hockenbery David M. , McIntosh Martin , Brentnall Teresa A. , Chen Ru 
Published: June 2012

Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease affecting approximately half a million patients in the United States. Patients with extensive UC of more than eight years duration have an increased risk of colorectal cancer, approximating 0.5-1% per year of colitis. There are major challenges with UC cancer surveillance. Unlike sporadic colon cancer, dysplasia or cancer in UC frequently occurs in benign-appearing colonic mucosa of UC patients without evidence of a polyp. Therefore, an objective molecular biomarker of dysplasia would aid the clinical management of cancer risk in UC patients. We apply a novel, highly sensitive quantitative proteomics approach combining with cutting-edge bioinformatics to develop protein signatures for detecting the neoplastic dysplasia presented in the normal-appearing (i.e., non-dysplastic) colon and rectum for prediction of cancer risk of UC patients. A list of dysregulated proteins potentially associated with colon cancer was identified using large-scale quantitative global protein profiling. Functional analysis was performed to explore the mechanisms that may underlie UC neoplastic progression. Mitochondrial proteins, cytoskeletal proteins, RAS superfamily, proteins relating to apoptosis and metabolism are the important protein groups or pathways differentially expressed in the non-dysplastic and dysplastic tissues of UC progressors, suggesting their importance in UC neoplastic progression. The resultant protein candidates have been ranked and are being rigorously validated using complementary methods, including immunohistochemistry and emerging technology of targeted quantitative proteomics. A molecular signature combining multiple proteins has displayed a statistically significant difference in distinguishing patients with dysplasia/cancer from patients without dysplasia/cancer. Protein biomarker candidates identified in this study may potentially be useful in predictive risk assessment and/or early diagnosis of inflammatory bowel disease associated 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 5072. doi:10.1158/1538-7445.AM2011-5072
Abstract 509: The CTGF antibody FG-3019 blocks CTGF-stimulated migration in ovarian cancer cells
Authors: Samimi Goli , Wong Carol , Spong Suzanne M. , Birrer Michael J. 
Published: June 2012

Abstract
Ovarian tumors generally arise from the surface epithelium of the ovary, and require interactions with host stroma to promote tumor cell proliferation and expansion. The signaling mechanisms between tumor-associated stroma and adjacent ovarian epithelial tumor cells remain unclear. We have previously analyzed gene expression profiles of laser-capture microdissected stromal cells from normal ovary and ovarian tumors and have demonstrated that normal ovarian stroma undergoes significant gene expression changes in response to the epithelial tumor microenvironment. Connective Tissue Growth Factor (CTGF), a TGF-β-regulated gene, was identified as specifically up-regulated in tumor-associated versus normal stroma. CTGF is a component of the tumor microenvironment with a demonstrated role in tumor progression and metastasis. FG-3019, a fully human monoclonal antibody against CTGF, is currently under clinical investigation in pancreatic cancer. The aim of this current study was to further elucidate the role of CTGF in ovarian cancer and examine its potential as a therapeutic target. We demonstrate that normal ovarian fibroblasts and ovarian cancer-associated fibroblasts treated with TGF-β secreted high levels of CTGF, whereas ovarian cancer epithelial cells secreted significantly lower levels. We next assessed the paracrine effect of CTGF on three different ovarian cancer cell lines, A224, OVCAR3, and SKOV3. Expression of endogenous CTGF is low in these cells which is consistent with the level found in primary ovarian tumor cells. Addition of recombinant CTGF for 6-hr stimulated migration of A224 (443 ± 20.5 vs. 85 ± 24.4 cells), OVCAR3 (104 ± 11.7 vs. 68 ± 30.1 cells) and SKOV3 (334 ± 45.6 vs. 82 ± 16.6 cells) in a transwell migration assay. Addition of the CTGF-blocking antibody FG-3019 significantly inhibited transwell migration in the presence of recombinant CTGF in all three cell lines (from 443 ± 20.5 to 197 ± 65.4 cells in A224, 334 ± 45.6 to 119 ± 29.0 cells in SKOV3 and 104 ± 11.7 to 36 ± 2.5 cells in OVCAR3). However, recombinant CTGF did not promote proliferation of these cell lines. We demonstrate that CTGF may contribute to ovarian tumor biology and that its function can be blocked by FG-3019, thus determining CTGF as a potential therapeutic target in ovarian 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 509. doi:10.1158/1538-7445.AM2011-509
Abstract 5090: Targeted inhibition of MEK and AKT pathways in combination with radiation as a novel treatment paradigm in pancreatic cancer
Authors: Williams Terence M. , Flecha Athena , Ram Ashwin N. , Keller Paul R. , Galban Stefanie , Galban Craig , Ross Brian D. , Rehemtulla Alnawaz , Sebolt-Leopold Judith S. 
Published: June 2012

Abstract
There is an urgent need for the development of novel therapies to treat pancreatic cancer, which is among the most lethal of all cancers. KRAS activating mutations, which are found in &gt;90% of pancreatic adenocarcinomas, drive tumor dependency on the RAS/MAPK and AKT signaling pathways. Radiation is currently being explored in both the post-operative and inoperable settings as a component of the standard treatment regimen for pancreatic cancer. The purpose of this study was to test the hypothesis that MEK inhibitors will offer clear therapeutic benefit when integrated into radiotherapy treatment regimens for treatment of this disease. We explored the activation of the MAPK and AKT pathways in response to radiation in multiple pancreatic tumor cell lines. Small molecule inhibitors of MEK (PD0325901) and AKT (API-2) were subsequently evaluated for their radiosensitizing potential alone and in combination. In vivo efficacy was tested in subcutaneous MiaPaCa2 xenografts and diffusion MRI (dMRI) was explored as a surrogate biomarker of response. Phosphorylated levels of ERK and AKT were found to increase in response to radiation treatment in our pancreatic tumor cell line panel. MEK inhibitor-induced radiosensitization was observed in vitro as well as in vivo, where changes in dMRI strongly correlated with changes in tumor burden. The further addition of an AKT inhibitor to the MEK inhibitor/radiation regimen resulted in enhanced therapeutic gain as measured by radiosensitization and tumor cell death. In conclusion, MEK inhibition results in growth arrest, apoptosis, and radiosensitization of multiple preclinical pancreatic tumor models and the effects can be enhanced by combination with an AKT inhibitor. These results provide rationale for further testing of a treatment regimen in pancreatic cancer that combines MEK inhibition with radiation, optimally in conjunction with AKT inhibition.
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 5090. doi:10.1158/1538-7445.AM2011-5090