bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4596: Phenethyl isothiocyanate inhibits growth of MIAPaca2 human pancreatic cancer xenograft in vivo in association with apoptosis induction
Authors: Stan Silvia D. , Singh Shivendra V. , Whitcomb David C. , Brand Randall E. 
Published: June 2012

Abstract
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the U.S. with a 5-year survival rate of less than 5%. Low survival rate for patients with pancreatic cancer points towards an increased need for novel chemoprevention, early detection, and therapeutic strategies for this disease. This study was undertaken to determine the efficacy of phenethyl isothiocyanate (PEITC), a naturally occurring isothiocyanate found in cruciferous vegetables, against pancreatic cancer cells in vitro and in vivo. Exposure of human pancreatic cancer cells (MIAPaca2, PL-45, and BxPC3) to PEITC resulted in growth inhibition, which was accompanied by apoptotic cell death regardless of the K-ras status. Apoptotic cell death by PEITC treatment was characterized by an increase in cytoplasmic histone-associated DNA fragmentation and enrichment of sub-diploid fraction. PEITC-induced apoptosis correlated with induction of pro-apoptotic protein Bak, down-regulation of anti-apoptotic proteins Bcl-2 and Bcl-xL, and cleavage of caspase-3 and PARP. Oral administration of 12 µmol PEITC/mouse (five times per week) significantly retarded the growth of MIAPaca2 xenografts in male nude mice without causing weight loss or any other signs of toxicity. PEITC administration significantly reduced proliferation as determined by PCNA and Ki-67 stainings and increased apoptosis in tumors as shown by TUNEL assay. In conclusion, the present study demonstrates, for the first time, that PEITC administration retards the growth of human pancreatic cancer xenografts by inducing apoptotic cell death. The present study provides pre-clinical evidence for development of PEITC as a chemopreventive agent for pancreatic cancer. This investigation was supported in part by the Wayne Fusaro Pancreatic Cancer Research Fund (DCW), the Shirley Hobbs Martin Memorial Fund (REB), and the NCI grants CA101753 and CA113363 (SVS).
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 4596. doi:10.1158/1538-7445.AM2011-4596
Abstract 4617: Bioactive phytochemicals in wheat bran for colon cancer prevention
Authors: Sang Shengmin , Zhu Yingdong 
Published: June 2012

Abstract
Colorectal cancer is a leading cause of cancer deaths in the United States. Many studies have found that dietary cereal fibers protect against colon cancer, however, not all cereal fibers are equally effective. Wheat bran is the only cereal bran that shows consistent protection against colon cancer in laboratory animal models, and corn and oat bran may enhance colon tumorigenesis. We and others have reported that phytochemicals in wheat bran instead of fiber are the major active components for colon cancer prevention. However, the active components are still unknown. Using human colon cancer cells (HCT-116 and HT-29) as the guiding assay, we further purified the active components from wheat bran using column chromatography. In this study, we identified fraction containing 5-n-alkylresorcinols (ARs) had the strongest inhibitory effect on the proliferation of human HCT-116 and HT-29 colon cancer cells. Further purification led to the identification of 5-n-heptadecylresorcinol (C17:0) and 5-n-nonadecylresorcinol (C19:0) as the major active components, whereas 5-n-heneicosenylresorcinol (C21:0) and 5-n-tricosylresorcinol (C23:0) had no inhibitory effects, indicating that the length of the side chain of ARs significantly affects their activities. The effects of other components in wheat bran, such as sphingolipids, will also be discussed. In summary, we identified all the major components in wheat bran and our study indicates that 5-n-alkylresorcinols are the major active colon cancer preventive agents in wheat bran and the length of the alkyl chain significantly affects 5-n-alkylresorcinols’ cancer preventive activities. 5-n-Alkylresorcinols are phenolic lipids present in high amounts in wheat bran and are not found in oat and corn bran. Our finding will help us to further understand why wheat bran inhibits and oat and corn bran (which do not contain ARs) have no effect or enhance colon carcinogenesis.
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 4617. doi:10.1158/1538-7445.AM2011-4617
Abstract 4709: miR-337-3p and its targets STAT3 and RAP1A modulate paclitaxel sensitivity in non-small cell lung cancers (NSCLCs)
Authors: Du Liqin , Subauste Maria C. , Baker Michael , DeSevo Christopher , Borkowski Robert , Zhong Shihua , Schageman Jeoffrey J. , Greer Rachel , Yang Chin-Rang , Girard Luc , Gazdar Adi F. , Wistuba Ignacio I. , Minna John D. , Pertsemlidis Alexander 
Published: June 2012

Abstract
We are addressing the questions of whether microRNAs (miRNAs) play a functional role in modulating drug sensitivity of lung cancer cells, and whether miRNA expression levels can be manipulated to increase drug sensitivity in lung cancer treatment. Using a combination of in silico and in vitro approaches, we identified miR-337-3p as a modulator of paclitaxel sensitivity in NSCLC cell lines where over-expression of miR-337-3p sensitizes NSCLC NCI-H1155 cells to paclitaxel (&gt;2 fold) and docetaxel (&gt;10 fold) by enhancing taxane-induced mitotic arrest. Of several possible targets of miR-337-3p we found that Stat3 and Rap1A are the direct targets responsible for mediating miR-337-3p sensitization to paclitaxel. In studies of multiple NSCLC lines we found that miR-337-3p can, in general, sensitize NSCLC lines to paclitaxel, and that Stat3 expression is significantly correlated with paclitaxel resistance in NSCLC lines, suggesting that tumor Stat3 expression is an intrinsic determinant and biomarker for paclitaxel response. We conclude we have discovered a novel pathway modulating NSCLC paclitaxel sensitivity, which involves the down-regulation of Stat3 and Rap1A expression by miR-337-3p. These findings have prompted: our ongoing studies of patient samples annotated for miR-337-3p, Stat3, and Rap1A expression and response to taxane therapy; preclinical testing of a miR-337-3p mimic as an adjuvant to taxanes for NSCLC therapy; and further tests of this pathway to provide both new therapeutic targets and biomarkers predictive of response for NSCLC taxane based therapy.
This research was supported by NIH R01 CA129632 from the National Cancer Institute and by P50 CA70907 from the UT Southwestern/MD Anderson Cancer Center Lung Specialized Program of Research Excellence.
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 4709. doi:10.1158/1538-7445.AM2011-4709
Abstract 4746: Type I NKT cells mediate anti-tumor immunity through a TNF-α- and NOS-dependent pathway when stimulated with β-ManCer
Authors: O'Konek Jessica J. , Illarinov Petr , Khursigara Deborah Stewart , Ambrosino Elena , Izhak Liat , Castillo Bernard F. , Raju Ravinder , Khalili Maryam , Kim Hee-Yong , Howell Amy , Besra Gurdyal S. , Porcelli Steven A. , Berzofsky Jay A. , Terabe Masaki 
Published: June 2012

Abstract
CD1d-restricted type I NKT cells have been shown to play a critical role in the induction of tumor immunity by producing IFN-γ, which activates effector arms such as NK cells and CD8+ T cells. It has been considered that IFN-γ is necessary for type I NKT cell-induced tumor immunity. In this study, we show that type I NKT cells can induce strong tumor immunity through an IFN-γ-independent pathway when activated with a new type of agonistic antigen, β-mannosylceramide (β-ManCer). The protection induced by β-ManCer treatment was completely abrogated in type I NKT cell deficient Jα18 KO mice. With the observations that in vitro activation of type I NKT cells by β-ManCer was blocked by anti-CD1d blocking monoclonal antibody and that β-ManCer-loaded CD1d dimers bind to type I NKT cells and stimulate type I NKT cell hybridomas in an APC-free system, we concluded that recognition of CD1d presented β-ManCer by a TCR of type I NKT cells is necessary for the protection. Surprisingly β-ManCer-induced protection was not abrogated in IFN-γ deficient mice, which is in contrast with the protection induced by a prototypic agonist α-galactosylceramide (α-GalCer). Instead, β-ManCer-induced protection was dependent on nitric oxide synthase (NOS) and TNF-α since blockade of either completely abrogated the protection while the blockade did not affect protection induced by α-GalCer. The conclusion that NKT cells activated with β-ManCer utilize a different pathway from that used by the cells activated with α-GalCer to enhance tumor immunity was confirmed with the observation that the combination of both antigens synergistically enhanced tumor immunity when suboptimal doses of each were used. These data demonstrate that NKT cells mediate tumor immunity through a TNF-α- and NOS-dependent pathway when stimulated with β-ManCer and that β-ManCer represents a new class of type I NKT cell agonist. Since we observed that human type I NKT cells also can be activated by β-ManCer, β-ManCer may provide a new intervention against 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 4746. doi:10.1158/1538-7445.AM2011-4746
Abstract 4758: Inhibition of checkpoint kinase 1 (Chk1) as a potential therapeutic for pediatric neuroblastoma
Authors: Russell Mike R. , Cole Kristina A. , Maris John M. 
Published: June 2012

Abstract
Neuroblastoma is a cancer derived from cells of the sympathetic nervous system that manifests with significant clinical heterogeneity. Although children diagnosed with low-risk neuroblastoma are very likely to be cured, high-risk patients are frequently resistant to even the most intensive of multi-modal regimens, and at least half of these children suffer relapse that is almost always fatal. To address the unmet need for novel therapeutic targets, our lab conducted an unbiased siRNA screen and determined that the loss of cell cycle checkpoint kinase 1 (Chk1) produced the most robust cytotoxic effect across multiple neuroblastoma cell lines. We subsequently confirmed that many neuroblastoma cell lines express constitutively phosphorylated Chk1 – a discovery that is supported by identical findings in tumors obtained from high-risk patients. Here we present evidence that the combination of a small molecule inhibitor of Chk1 with either irinotecan (SN-38) or cisplatin was synergistic or additive in vitro in cell lines sensitive to single agent Chk1 inhibition. Inhibition of Chk1 signaling as potential therapy in neuroblastoma is further supported by complimentary experiments in which we found that induction of shRNA specific for Chk1 results in marked cytotoxicity. To further understand the chemosensitizing aspect of Chk1 inhibition in neuroblastoma cells, we assayed the ATR/Chk1 pathway for potential biomarkers predictive of response. Candidate signaling partners in this pathway were isolated based upon either pharmacological inhibition or shRNA-induced silencing of Chk1, followed by hybridization to antibody microarrays. This technique has allowed for identification of Chk1-related signaling proteins involved in the DNA damage response pathway. Lastly, we have assessed the efficacy of Chk1 inhibition in an in vivo xenograft mouse model of pediatric neuroblastoma. We found that daily administration of a small molecule Chk1 inhibitor, currently undergoing Phase I clinical testing, was able to significantly impede the growth of NB1643 neuroblastoma xenografts (p=0.001). Efforts are currently underway in our laboratory to investigate a potentially synergistic effect in vivo through co-administration of this inhibitor with irinotecan or cisplatin. Taken together, these results provide a strong rationale for further studies to assess the use of Chk1 inhibition as either a single-agent or combinatorial therapy in pediatric neuroblastoma.
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 4758. doi:10.1158/1538-7445.AM2011-4758
Abstract 4809: Epigenomic profiling of oral cancer
Authors: Yoshiba Sayaka 
Published: June 2012

Abstract
Despite combined surgery and radiation therapy, long-term survival for oral cancer has not improved over the past several decades. This is primary due to poor clinical prognosis of patients with the lymph nodes metastasis. Therefore, deeper understanding of the molecular basis of highly malignant property and patient stratification along with these characters are needed.
Although, recent genome-wide analyses of DNA methylation have revealed a large number of aberrantly methylated genes in many cancers, and allowed us to identify the molecularly defined subgroups such as CpG island methylation phenotype (CIMP) in certain tumors, the methylation diversity of clinical oral cancers are still unknown. The purpose of this study is to characterize DNA methylation profiles of oral cancer tissues (six normal oral mucosal swab, three non-cancerous mucosal tissues, and fifty-nine oral cancer tisseus) and to identify the specific methylation pattern related to the clinical features. Genome-wide methylation analysis was performed using Infinium HumanMethylation27 BeadArray system, which can analyze methylation status of 27,000 CpG sites semi-quantitatively, using 500ng of genomic DNA.We found 2,762 aberrantly methylated CpG sites in oral cancers against normal mucosa. By unsupervised clustering analysis, oral cancer could be divided into two methylation epigenotypes that are significantyly correlated with high incidence of lymph node metastasis and poor differentiation. We obtained the highly predictive candidates of classifier genes and they were confirmed by MassARRAY analysis. In summary, we identified two methylation epigenotypes related with clinical outcome in oral cancer, and candidate classifier genes would be useful clues of patient stratification for intensive therapy to overcome the tumor recurrence.
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 4809. doi:10.1158/1538-7445.AM2011-4809
Abstract 487: Evidence for tumor initiating stem cells in lung cancer
Authors: Zhang Wen Cai , Yang He , Soh Boon Seng , Sun Li Li , Chin Tan Min , Lim Elaine Hsuen , Lim Bing 
Published: June 2012

Abstract
Despite advances in our knowledge of the genetics of cancer and some progress in cancer treatment over the last few decades, lung cancer remains the leading cause of cancer mortality worldwide. Therefore the identification of new therapeutic targets is necessary and important.
By applying xeno-transplantation of primary cells from lung cancer specimens into immune deficient mice, we have identified a subpopulation of cells that can form tumor in transplanted mice which histologically resemble the primary tumor. This subpopulation can be enriched 200 fold for tumor initiating cells (TICs) by sorting primary tumor cells with a specific cell surface marker. The TIC population can give rise to unique epithelial colonies when seeded on feeders. Primary tumor cells when cultured serum free with EGF and FGF give rise to tumor-spheres that contain TICs at greater than 2% frequency. Microarray analysis of TICs from primary tumor samples, xenografts and tumor spheres are analyzed to derive “gene signature” of lung TICs. Several oncogenes and genes in metabolic pathways are overexpressed. Amongst them, LIN28B appears amongst the top list. Knockdown of LIN28B results in reduced tumor growth and, conversely, overexpression of LIN28B leads to transformation of NIH/3T3 and increases clonogenicity of normal lung fibroblasts.
The isolation of lung TICs should facilitate further investigation of the cellular origin and carcinogenesis of lung cancers.
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 487. doi:10.1158/1538-7445.AM2011-487
Abstract 4904: Mechanisms of cytotoxicity of bifunctional epoxide cross-linking agents
Authors: Ng Christopher , Silvestri Vanesa L. , Lingar Morgan T. , Millard Julie T. 
Published: June 2012

Abstract
The discovery that bifunctional alkylating agents have antitumor activity led to the development of cancer chemotherapy over 50 years ago. While these compounds form a variety of cellular lesions, DNA interstrand cross-links are believed to be the most lethal, impeding both replication and expression of the genetic material. We are characterizing the mechanisms by which diepoxybutane (DEB) and the structurally related compound epichlorohydrin (ECH) exert their cytotoxic effects in cultured cells. Our first goal is to determine the relationship between interstrand cross-linking and cytotoxicity. We are assaying cross-linking ability in cultured cells using Hoechst 33258 to determine the amount of duplex DNA following alkaline denaturation. Only cross-linked DNA reanneals rapidly and interacts with the dye, which is highly fluorescent when bound to duplex DNA. Preliminary results in chicken 6C2 and human HL60 cells suggest a correlation between cross-linking and LD50 values for these compounds. Our second goal is to characterize the pathways by which these compounds induce apoptosis. Reverse-transcriptase real-time PCR analysis of HL-60 cells treated with DEB and ECH under conditions determined to induce apoptosis suggests up-regulation of several key genes involved in the mitochondrial apoptotic pathway, including BAK1, BAX, DIABLO, PUMA and APAF1. Finally, we are identifying the covalent structure of the ECH-cross-linked lesion via electrospray LC/MS. Characterization of the DNA modifications induced by these agents is an important step in understanding how these compounds exert their cytotoxic effects.
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 4904. doi:10.1158/1538-7445.AM2011-4904
Abstract 4960: Circulating miRNAs as noninvasive biomarkers in esophageal adenocarcinoma patients
Authors: Song Jee Hoon , Cheng Yulan , Yang Jian , Wu Wenjing , Mori Yuriko , Olaru Alexandru V. , Bootwalla Moiz , Sharpf Robert , Meltzer Stephen J. 
Published: June 2012

Abstract
Esophageal adenocarcinoma (EAC) is one of the most rapidly increasing cancers in the United States and throughout the developed world. The current primary screening method for EAC is gastrointestinal endoscopy (EGD), and this method is unsuitable and impractical for population-based screening or detection of asymptomatic EAC. Moreover, thus far, only a few reports have described altered miR expression in EAC, none of which were carried out in serum or plasma. We discovered a panel of noninvasive circulating microRNA (miR) biomarkers to promote earlier detection of EAC. We extracted total RNA from serum of each subject and hybridized it to fixed-probe miR microarrays in 12 sera each from EAC patients, subjects with normal EGDs, and 12 matched EAC tissues and normal esophageal tissues from EAC patients. Data was extracted and normalized using Feature Extraction Software 9.3 and GeneSpring software (Agilent) and subsequently analyzed by classification trees, multiple leave-one-out cross-validation, and relative influence plots. We selected the most influential miRs for validation by quantitative RT-PCR assays. Our preliminary miR findings indicate that several miRs show dramatic and significant differences in serum levels between EAC and normal control subjects. An ROC curve assembled based on aggregate data yielded an area under the curve (AUC) = 0.885, with sensitivity = 92% and specificity = 83%. We conclude that a panel consisting of several miRs is likely to discriminate asymptomatic EAC patients from normal subjects, leading to earlier diagnosis and improved prognosis.
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 4960. doi:10.1158/1538-7445.AM2011-4960
Abstract 5036: Activating MEK1(F129L) mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation
Authors: Niu Huifeng , Wang Huisheng , Daouti Sherif , Li Wen-Hui , Wen Yang , Rizzo Christine , Higgins Brian , Packman Kathryn , Rosen Neal , Boylan John F. , Heimbrook David 
Published: June 2012

Abstract
Targeting the Ras/Raf/MEK pathway represents a promising anticancer strategy. The clinical development of MEK inhibitors, similar to other highly selective targeted agents, is expected to have limited durable clinical response due to the emergence of drug acquired resistance. To identify potential mechanisms underlying such resistance, we established MEK inhibitor-resistant clones (HT-29R) from a human colorectal cancer cell line HT-29 harboring the B-Raf V600E mutation. HT-29R are resistant to MEK inhibition under both in vitro and in vivo growth conditions. Drug-induced feedback activation of MEK/ERK and downstream targets were found primarily accountable for the resistance. Moreover, we identified the MEK1(F129L) mutation as a molecular mechanism responsible for pathway activation. In an isogenic cell system and extending into other cancer cell lines, the MEK1(F129L) mutant exhibits higher intrinsic kinase activity than wild type (WT) MEK1, leading to a significant activation of ERK and downstream targets confering resistance to MEK inhibition. The MEK1(F129L) mutation showed stronger binding to c-Raf which suggests an underlying mechanism of the higher kinase activity of the MEK1(F129L). Importantly, the combination of Raf and MEK inhibitors overcame resistance and exhibited greater synergy in HT-29R as compared to HT-29S. This study suggests MEK1 mutation could be a potential mechanism of drug acquired resistance emerging in MEK inhibitor-treated cancer patients and should be monitored in the clinic. Combined inhibition of Raf and MEK represents a potential therapeutic strategy to overcome the resistance.
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 5036. doi:10.1158/1538-7445.AM2011-5036