bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 228: Curcumin attenuates tumor initiating stem-like property of head and neck cancer through miR145 axis-mediated paracrine signaling.
Authors: Chiou Shih-Hwa , Chiou Guang-Yuh , Lu Kai-Hsi 
Published: August 2014

Abstract
Recent reports have demonstrated that head and neck cancer derived tumor initiating cells (HNC-TICs) presented high tumorigenic, chemo-radioresistant, metastatic properties, and coupled with gain of epithelial-mesenchymal transition (EMT) characteristics. As curcumin, an active component of the spice turmeric, can exert cytotoxic effects on cancer cells without harming normal tissues. The aim of this study was to investigate the chemo-therapeutic effect and regulatory mechanisms of curcumin on HNC-TICs. We first observed that the treatment of curcumin significantly down-regulated the ALDH1 activity, CD44 positivity, self-renewal property, and side population of HNC cells in a dose dependent manner. Using miRNA/mRNA-microarray analysis, curcumin significantly increased expression of tumor suppressive miR-145. Further mechanistic studies showed that the re-expression of PU-PEI-mediated miR145 delivery led to decreased of TICs properties. Blocking of endogenous miR145 can dramatically enhance stemness and tumor-initiating properties in ALDH1-CD44- non-TICs HNC cells. Additionally, the repressive effect of miR-145 on TICs properties was mediated by regulating of EMT. Importantly, in vivo nude mice model showed that cucumin treatment by oral gavage or PU-PEI-mediated miR145 delivery to xenograft tumors reduced tumor growth and metastasis and prolonged the survival times of tumor-bearing mice. From these results, we conclude that the inhibition of tumor aggressiveness in HNC-TIC in by curcumin was in part was mediated by up-regulation of miR-145, suggesting that curcumin would be a valuable therapeutics clinically in treatment modalities for malignant head and neck cancers by elimination of tumor initiating stem-like, and EMT properties.
Citation Format: Shih-Hwa Chiou, Guang-Yuh Chiou, Kai-Hsi Lu. Curcumin attenuates tumor initiating stem-like property of head and neck cancer through miR145 axis-mediated paracrine signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 228. doi:10.1158/1538-7445.AM2013-228
Abstract 2283: Nano-scale proteomic profiles of response to targeted therapy in patients with RCC.
Authors: Fan Alice C. , Leppert John , Liliental Joanna E. , Xu Liwen , Metzner Thomas J. , Shroff Emelyn , Yaghi Alia , Yost Christine , Brooks James D. , Harshman Lauren C. , Sabatti Chiara , Srinivas Sandhya , Felsher Dean W. 
Published: August 2014

Abstract
Novel agents that inhibit targets in the hypoxia and MTOR pathways can achieve response rates of 30-60% in renal cell carcinoma (RCC); however, biomarkers have not yet been identified to measure degree of target inhibition and mechanism of biologic response in individual patients. We developed the use of a high-throughput, nanoscale immunoassay (NIA, Nanopro1000 Instrument, Protein Simple) to profile hypoxia pathways and downstream signaling in serially sampled clinical specimens from patients with RCC. NIA uses charge-based separation to distinguish multiple charged modifications of individual proteins, and measure relative ratios of individual unphosphorylated and phosphorylated isoforms. We first developed and optimized assays to measure therapeutic targets and proteins in hypoxia, proliferation and metabolic pathways (including CaIX, HIF, VEGFR, ERK, AKT, MYC, glutaminase) to analyze frozen surgical specimens, fine needle aspirates (FNA's) and blood PBMC specimens from patients with RCC. Next, we analyzed more than 200 FNA's from solid tumors, comparing RCC with paired adjacent non-tumor tissue and other epithelial malignancies. Basal MAPK signaling across the samples ranged across 3 logs for both normal and tumor tissue, demonstrating the difficulty in setting a threshold predictive of response based on a single pre-treatment measurement. To test whether analysis of serial specimens could detect changes, we prospectively collected and analyzed blood peripheral mononuclear cells from 20 RCC patients before and during treatment with standard targeted therapies including MTOR and tyrosine kinase inhibitors. We report for the first time that targeted inhibitors can preferentially inhibit or activate specific protein phospho-isoforms in patients with RCC. Our studies demonstrate that rapid and quantitative nanoproteomic profiling in very small amounts of serially sampled clinical specimen may accelerate translational studies for predictive proteomic biomarkers of response to targeted therapy.
Citation Format: Alice C. Fan, John Leppert, Joanna E. Liliental, Liwen Xu, Thomas J. Metzner, Emelyn Shroff, Alia Yaghi, Christine Yost, James D. Brooks, Lauren C. Harshman, Chiara Sabatti, Sandhya Srinivas, Dean W. Felsher. Nano-scale proteomic profiles of response to targeted therapy in patients with RCC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2283. doi:10.1158/1538-7445.AM2013-2283
Abstract 231: Conformation-specific monoclonal antibodies against Notch1 target aberrant Notch1 signaling in cancer stem cells.
Authors: Sharma Ankur , Rangarajan Annapoorni , Dighe Rajan R. 
Published: August 2014

Abstract
Notch signaling pathway plays a key role in regulating various cell fates including those of stem cells, throughout the mammalian development and adult homeostasis. Here we report characterization of anti-Notch1 monoclonal antibodies (mAb's) with potential therapeutic applications. Antibodies against various domains of human-Notch1 receptor were generated and characterized, mAb's generated against primary ligand-binding domain (EGF like repeats 11-12) and activation domain NRR (Negative Regulatory region) showed most prominent therapeutic potential. The Notch1 specific mAb 602.101 against ligand-binding domain (EGF like repeats 11-12) prevents binding of Jagged and Delta-like ligands and subsequent Notch1 receptor activation in breast cancer stem cells. Further, antibody treatment leads to apoptosis, inhibition of epithelial to mesenchymal transitions as well as irreversible depletion of cancer stem cells. The conformation specific mAb's against Notch1 NRR can specifically distinguish between the mutant and the wild type human Notch1 receptor present on cancer cells. Anti-NRR mAb's 604.107 (mutant specific) and 604.132 (wild type specific) specifically inhibited Notch1 signaling in leukemic and breast cancer stem cells. These mAbs can serve as a potential tool to irreversibly combat therapy resistant cancer stem cell subpopulations and to inhibit the epithelial to mesenchymal transitions in various types of cancers.
Citation Format: Ankur Sharma, Annapoorni Rangarajan, Rajan R. Dighe. Conformation-specific monoclonal antibodies against Notch1 target aberrant Notch1 signaling in cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 231. doi:10.1158/1538-7445.AM2013-231
Abstract 2314: The chromatin structure regulates selective glucocorticoid receptor recruitment to the genome in intact tissue.
Authors: Grontved Lars , John Sam , Baek Songjoon , Liu Ying , Buckley John , Vinson Charles , Aguilera Greti , Hager Gordon L. 
Published: August 2014

Abstract
The dissection of regulatory pathways in physiological and pathophysiological states and during pharmacological intervention necessitates the application of biochemical and genomic approaches in intact target tissues. The hypothalamus-pituitary-adrenal axis is a highly conserved neuroendocrine pathway that results in the synthesis of glucocorticoid hormones from the adrenal gland to control reactions to stress and inflammatory processes. Exploiting a mouse model in which animals have been adrenalectomized to remove endogenous glucocorticoids, we monitor changes of the chromatin landscape in liver, following a single glucocorticoid injection, using ChIP-seq and DNase-seq methodologies.
We observe that GR exclusively occupies accessible chromatin, demonstrating that accessible chromatin can be highly predictive of transcription factor occupancy in tissue. Importantly, changes in RNA polymerase II recruitment to GR regulated genes are associated with proximal regions of induced and repressed chromatin accessibility. Underscoring the highly tissue-specific GR-dependent transcriptional response, GR binding sites in other cell types are occluded in liver through highly positioned nucleosomes and inaccessible chromatin. Remarkably, we demonstrate that sixty two percent of GR binding sites in liver are associated with C/EBPbeta occupancy. At the majority of these sites chromatin is pre-programmed, suggesting a priming function of C/EBPbeta in GR recruitment. However, at a subset of GR binding sites C/EBPbeta loading is assisted by GR recruitment in conjunction with de novo chromatin remodeling.
Disruption of C/EBPbeta binding to chromatin using a dominant negative C/EBP targeted to the liver results in an attenuation of pre-programmed chromatin accessibility, GR recruitment and GR induced chromatin remodeling only at sites occupied by GR and C/EBP. Our results demonstrate a highly cooperative mechanism by which C/EBP regulates selective GR binding to the genome in liver tissue and provides a mechanism for phenotypic similarities described for GR and C/EBP mouse models. We suggest that the selective targeting of GR in other tissues is likely mediated by the combined action of cell-specific priming proteins and chromatin remodelers.
Citation Format: Lars Grontved, Sam John, Songjoon Baek, Ying Liu, John Buckley, Charles Vinson, Greti Aguilera, Gordon L. Hager. The chromatin structure regulates selective glucocorticoid receptor recruitment to the genome in intact tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2314. doi:10.1158/1538-7445.AM2013-2314
Abstract 2343: A novel ERK inhibitor is active in models of acquired resistance to BRAF and MEK inhibitors.
Authors: Samatar Ahmed A. , Morris Erick J. , Jha Sharda , Clifford Restaino R. , Luttrerbach Bart , Pelletier Marc , Philippar Ulrike , Jayaraman Lata , Zawel Leigh , Fawell Steve , Gilliland Gary 
Published: August 2014

Abstract
The high frequency of activating BRAFV600E mutations in melanoma (40-70%), thyroid (50%) and colorectal cancer (10%), or KRAS/NRAS mutations in melanoma (20%), pancreatic (90%), colorectal (50%) and non-small cell lung cancer (30%), provides strong rationale for targeting the MAPK pathway as a therapeutic strategy 1-6. Vemurafenib (PLX4032) and dabrafenib (GSK2118436), selective BRAF inhibitors, and trametinib (GSK1120212), an allosteric MEK inhibitor, have shown robust clinical efficacy in melanoma patients 7-10. However, the majority of responses are transient and cellular resistance is often associated with pathway reactivation involving the downstream extracellular-signal-regulated kinases 1 and 2 (ERK1/2) (reviewed in 11). We hypothesized that pathway blockade at ERK, the last signaling node prior to MAPK transcriptional programming, would not only be efficacious in MAPK-activated tumors but would also have utility in BRAF or MEK inhibitor resistant settings. We therefore sought to identify small molecule inhibitors of ERK. This report describes the identification and characterization of SCH772984, a potent and selective ATP competitive inhibitor of ERK1/2 which displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency on tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor resistant models as well as in the context of BRAF/MEK combination resistance. Together these data support the clinical development of ERK inhibitors, not only in patients with MAPK activated tumors, but also in patients who have developed acquired resistance to BRAF or MEK inhibitors or resistance to the recently described combination of these agents.
Citation Format: Ahmed A. Samatar, Erick J. Morris, Sharda Jha, Restaino R. Clifford, Bart Luttrerbach, Marc Pelletier, Ulrike Philippar, Lata Jayaraman, Leigh Zawel, Steve Fawell, Gary Gilliland. A novel ERK inhibitor is active in models of acquired resistance to BRAF and MEK inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2343. doi:10.1158/1538-7445.AM2013-2343
Abstract 2354: An E2F signature predicts benefit of adjuvant chemotherapy in early-stage non-small cell lung cancer.
Authors: Kurtyka Courtney A. , Chen Dung-Tsa , Chen Lu , Brazelle William , Welsh Eric A. , Berglund Anders E. , Eschrich Steven A. , Schabath Matthew B. , Haura Eric B. , Cress W. Douglas 
Published: August 2014

Abstract
Early-stage non-small cell lung cancer (NSCLC) is primarily treated by surgical resection. Unfortunately, after resection, one-third to one-half of early-stage patients will die of metastatic recurrence. Adjuvant chemotherapy (ACT) improves the survival of patients with early-stage disease and has become the standard treatment for patients with resected stage II-III NSCLC. However, the five-year survival advantage of ACT is only 4%-15% suggesting that many patients do not benefit. Given the morbidity associated with ACT, it is imperative to develop new prognostic tools to identify those patients with a high probability of relapse. Toward this end, we have used small inhibitory RNAs targeting multiple E2F pathway components to derive an E2F gene expression signature in vitro. This signature was refined by filtering for its components that were altered in non-small cell lung cancers compared to normal tissue. Principle component analysis was then used to represent the signature which was tested for correlation to overall survival in two large cohorts. The first of the two cohorts was the Molecular Classification of Lung Adenocarcinoma (MCLA) from the Director's Challenge Consortium and the second was a novel database on 444 lung adenocarcinomas treated as a part of Moffitt's Total Cancer Care Network. The E2F signature is strongly prognostic in both cohorts with P values &lt;0.0001. Additionally, using data in the JBR.10 trial (GSE14814) for patients who either did or did not receive ACT we were able to determine that patients having a high E2F signature benefit from ACT (have increased overall survival), whereas patients with a low E2F signature do not. Overall, these results suggest that this approach could be optimized in the clinical setting to distinguish patients likely to benefit from ACT from those who will not.
Citation Format: Courtney A. Kurtyka, Dung-Tsa Chen, Lu Chen, William Brazelle, Eric A. Welsh, Anders E. Berglund, Steven A. Eschrich, Matthew B. Schabath, Eric B. Haura, W. Douglas Cress. An E2F signature predicts benefit of adjuvant chemotherapy in early-stage non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2354. doi:10.1158/1538-7445.AM2013-2354
Abstract 2365: Comparison of epidermal growth factor receptor mutation tests in patients with recurred non-small cell lung cancer after surgery.
Authors: Oh In-Jae , Kim Woo-Jin , Kang Hyunwook , Kim Kyu-Sik , Kim Young-Chul , Song Sang-Yun , Choi Yoo-Duk , Hwang Jun-Eul , Yang Sei Hoon 
Published: August 2014

Abstract
Background: Epidermal growth factor receptor (EGFR) mutations are predictive marker of EGFR-tyrosine kinase inhibitor (TKI) therapy in non-small cell lung cancer (NSCLC). We compared the agreements between three EGFR mutation tests with surgical specimens of recurred NSCLC.
Methods: We retrospectively analyzed paraffin-embedded tissues, which were obtained from 111 (76 adenocarcinoma, 17 squamous cell carcinoma, 18 others) cases of 108 patients treated by EGFR-TKIs after surgery between 2003 and 2011 in Chonnam National University Hwasun Hospital. EGFR mutations in exons 18-21 were analyzed by three different methods- Cobas® EGFR mutation test (Roche), PNA Clamp™ EGFR mutation test (Panagene) and direct sequencing- and compared with radiologic response to EGFR-TKIs. The degree of agreement was evaluated by Cohen's kappa value.
Results: The mean treatment duration of total 111 (64 gefitinib, 47 erlotinib) cases was 188.5±198.7 days. The response rate was 18.9%, and disease control rate was 63.1%. EGFR mutation rates were 38.7% in PNA clamping, 34.2% in Cobas test, and 31.5% in direct sequencing. The agreement of Cobas test and PNA clamping was 93.7% (k=0.864, p&lt;0.001), that of Cobas test and sequencing was 84.7% (k=0.653, p&lt;0.001), and that of PNA and sequencing was 78.4% (k=0.528, p&lt;0.001). The prediction rates of EGFR-TKIs response were 39.5% of Cobas test, 37.2% of PNA clamping, and 34.3% of sequencing. The degree of agreement between mutation and clinical response was better in Cobas test (k=0.350, p&lt;0.001) and PNA clamping (k=0.330, p&lt;0.001) than sequencing (k=0.252, p=0.008).
Conclusion: The strength of agreement of Cobas test was very good with PNA clamping and good with direct sequencing. So Cobas test can be useful test for EGFR-TKI therapy in recurred NSCLC after surgery.
Citation Format: In-Jae Oh, Woo-Jin Kim, Hyunwook Kang, Kyu-Sik Kim, Young-Chul Kim, Sang-Yun Song, Yoo-Duk Choi, Jun-Eul Hwang, Sei Hoon Yang. Comparison of epidermal growth factor receptor mutation tests in patients with recurred non-small cell lung cancer after surgery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2365. doi:10.1158/1538-7445.AM2013-2365
Abstract 2368: An online tool for the validation of survival-predicting biomarkers in non small-cell lung cancer using microarray data of 1,329 patients.
Authors: Gyorffy Balazs , Lanczky Andras 
Published: August 2014

Abstract
To decipher the molecular basis of lung cancer and to improve treatment strategies we have to identify genes correlated to therapy response and to survival. Here, we present the development of a new, freely available online tool suitable for the real-time meta-analysis of published lung cancer microarray datasets to validate expression based survival related biomarker candidates.
First we have searched the caBIG, GEO and TCGA repositories to identify datasets with published gene expression data and survival information. In this, three GEO platforms (GPL96, GPL570 and GPL3921) were considered as these possess 22,277 common probes, which were used for constructing the database. All together 1,329 NSCLC samples in 9 independent datasets were identified, 85% have overall survival and 45% progression free survival info, one-third adenocarcinomas and one-third squamous cell carcinomas, 57% male and the average overall survival is 45 months. Kaplan-Meier survival plot, and the hazard ratio with 95% confidence intervals and logrank P value are calculated and plotted in R using Bioconductor packages. To assess the prognostic value of a gene, each percentile (of expression) between the lower and upper quartiles are computed and the best performing threshold is used as the final cutoff in a Cox regression analysis. The complete meta-analysis tool can be accessed online at: www.kmplot.com/lung.
We demonstrate the application of this integrative analysis pipeline by validating 22 previously published survival associated biomarkers including VEGF, ADAM28, ANXA3, CADM1, CD24, CD82, CDK1, CEA, cyclin E, ERCC1, EZH2, HER2, IFNAR2, MMP9, OPN, P16, p53R2, RAD51, S100A4, survivin, XAF1 and XIAP. Of these, high significances (p&lt;1E-16) were achieved by ANXA3 (HR=0.63), CADM1 (HR=1.7), IFNAR2 (HR=0.54), RAD51 (HR=1.9) and XAF1 (HR=0.58). Five additional genes were significant: S100A4 (HR=1.46, p=3.6E-4), CD82 (HR=1.34, p=0.018), OPN (HR=1.33, p=0.02), HER2 (HR=1.3, p=0.02) and CD24 (HR=0.75, p=0.3). The remaining genes did not achieved statistical significance.
In summary, we developed an online available meta-analysis tool for the validation of genes associated with survival in NSCLC.
Citation Format: Balazs Gyorffy, Andras Lanczky. An online tool for the validation of survival-predicting biomarkers in non small-cell lung cancer using microarray data of 1,329 patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2368. doi:10.1158/1538-7445.AM2013-2368
Abstract 2378: Upregulation of the ATR/CHK1 pathway and decreased therapeutic sensitivity in upper aerodigestive cancer cell lines with distal 11q loss.
Authors: Sankunny Madhav , Parikh Rahul A. , Gollin Susanne M. 
Published: August 2014

Abstract
Gemcitabine, a pyrimidine analog/antimetabolite, is commonly used to treat breast, lung, head and neck, pancreatic, ovarian, biliary, urinary bladder, and cervical carcinomas. Gemcitabine inhibits DNA synthesis by direct inhibition of ribonucleotide reductase by its metabolite, gemcitabine diphosphate, and the incorporation of its active form, gemcitabine triphosphate into the elongating DNA strand, resulting in chain termination. Gemcitabine-induced DNA damage leads to activation of the ATR/CHK1 pathway and S-phase cell cycle arrest. Our previous studies showed that carcinoma cells with our biomarker (distal 11q loss) overexpress ATR and CHK1, resulting in decreased sensitivity to ionizing radiation in biomarker-positive head and neck squamous cell carcinoma (HNSCC) and non-small cell lung carcinoma (NSCLC) cell lines. Several studies in the literature have shown that inhibition of CHK1 increases the sensitivity of tumor cell lines to replication inhibitors, including gemcitabine. In pancreatic cancer cell lines, small molecule inhibitor (SMI)-mediated disruption of CHK1 signaling has been reported to potentiate the cytotoxic effect of gemcitabine. Based on the literature and our previous findings, we now report that biomarker-positive HNSCC and NSCLC cell lines also show ATR/CHK1 upregulation and decreased sensitivity to gemcitabine, Further, we observed that siRNA knockdown of the ATR/CHK1 pathway and SMI inhibition of CHK1 signaling in HNSCC and NSCLC cell lines increase their sensitivity to treatment with gemcitabine. Our previous results showed increased efficacy of ionizing radiation combined with CHK1 inhibition in biomarker-positive cell lines; our new results show increased efficacy of gemcitabine combined with CHK1 inhibition in biomarker-positive HNSCC and NSCLC cell lines. These results provide further support for combining CHK1-targeted therapy with standard therapy in conjunction with an appropriate companion diagnostic biomarker, like distal 11q loss. As is the case with other targeted therapies, biomarker-based selection of the right drug for the right patient appears to increase therapeutic efficacy.
Citation Format: Madhav Sankunny, Rahul A. Parikh, Susanne M. Gollin. Upregulation of the ATR/CHK1 pathway and decreased therapeutic sensitivity in upper aerodigestive cancer cell lines with distal 11q loss. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2378. doi:10.1158/1538-7445.AM2013-2378