bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C33: Prognostic value of C-myc overexpression in patients with resectable pancreatic cancer.
Authors: Lim Seungtaek , Choi Hye Jin , Lee Jae-hoon , Lee Soohyeon 
Published: August 2014

Abstract
Purpose: Pancreatic cancer is one of the leading causes of cancer-related mortality and it is well known for extremely aggressive tumor growth rate, high incidence of metastasis and high metabolic rate. The aim of this study is to determine the value of metabolic gene expression as prognostic markers in patients with resectable pancreatic cancer. We also investigate the possible association among clinical parameters, 18F-2-fluoro-2-deoxyglucose positron emission tomography (FDG PET) and metabolic markers.
Materials and Methods: We retrospectively reviewed the medical records of 49 pancreatic cancer patients who underwent curative resection. Using formalin fixed paraffin embedded tissues of primary tumors, immunohistochemistry (IHC) was done for GLUT1, hexokinase (HK), p53, IDH, pmTOR, PKM2, CMYC, and AMPK. Kaplan meier analysis and Cox-regression was used for univariate and multivariate analysis to examine the prognostic impact of each marker on survival. Also, Fisher's exact test was performed to examine correlation between metabolic makers and FDG uptake.
Results: Median overall survival (OS) of all patients was 27.3 months (95% CI, 15.9 - 38.6). In univariate analysis, longer overall survival was seen in patients with c-myc overexpression, higher FDG uptake, and poorly differentiated histology. Multivariate analysis revealed that c-myc overexpression was an independent poor prognostic factor after adjustment of higher FDG uptake and tumor differentiation. No association was found between clinical parameters, FGD uptake, and metabolic markers. However, higher FDG uptake was correlated with low AMPK expression (P=0.017).
Conclusions: Our study demonstrated that the c-myc overexpression identified by IHC is an independent prognostic factor in pancreatic cancer patients who underwent curative resection. Future studies are required to explore the underlying mechanism how c-myc overexpression contributes to the progression of pancreatic cancer in consideration with cancer metabolism.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C33.
Citation Format: Seungtaek Lim, Hye Jin Choi, Jae-hoon Lee, Soohyeon Lee. Prognostic value of C-myc overexpression in patients with resectable pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C33.
Abstract C47: Inference of tumor evolution during chemotherapy by computational modeling and single cell analysis of diversity.
Authors: Almendro Vanessa , Cheng Yu-Kang , Gönen Mithat , Itzkovitz Shalev , Marusyk Andriy , Ametller Elisabet , Gonzalez-Farre Xavier , Muñoz Montse , Russnes Hege , Helland Åslaug , Rye Inga , Borresen-Dale Anne Lise , Maruyama Reo , van Oudenaarden Alexander , Dowsett Mitchell , Jones Robin L. , Reis-Filho Jorge , Gascon Pere , Michor Franziska , Polyak Kornelia 
Published: August 2014

Abstract
Cancer therapy exerts a strong selection that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here we report the analysis of single-cell heterogeneity of genetic and phenotypic features and their spatial distribution in breast tumors pre and post neoadjuvant therapy. We found that broad intratumor genetic diversity is tumor subtype specific but does not change significantly during treatment. However, we observed significant alterations in the spatial distribution of cells after chemotherapy whereas adjacent tumor cells were more likely to be genetically divergent yet phenotypically similar. We then developed a stochastic computational model to infer tumor growth patterns and evolutionary dynamics from these topologic features. Lastly, we found that lower pretreatment genetic diversity is associated with a better response, emphasizing the clinical utility of our study. Our results highlight the importance of an integrated analysis of genotype and phenotype of single cells in intact tissue to predict how tumors evolve.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C47.
Citation Format: Vanessa Almendro, Yu-Kang Cheng, Mithat Gönen, Shalev Itzkovitz, Andriy Marusyk, Elisabet Ametller, Xavier Gonzalez-Farre, Montse Muñoz, Hege Russnes, Åslaug Helland, Inga Rye, Anne Lise Borresen-Dale, Reo Maruyama, Alexander van Oudenaarden, Mitchell Dowsett, Robin L. Jones, Jorge Reis-Filho, Pere Gascon, Franziska Michor, Kornelia Polyak. Inference of tumor evolution during chemotherapy by computational modeling and single cell analysis of diversity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C47.
Abstract C54: Aryl-N-(1H-imidazol-2-yl)-acetamides: Nonpeptidic binders of Bir3 cIAP protein.
Authors: Palermo Mark G. , Beckwith Rohan , Straub Christopher S. , Herlihy Kara , Shen Yiping , Zhang Xiaolu , Clapham Matthew , Hurley Brian 
Published: August 2014

Abstract
Inhibitor of Apoptosis Proteins (IAP) negatively regulate cell death through a caspase-3 and caspase-7 activation. IAP inhibitors (IAPi) were derived from the peptide sequence Alanine-Valine-Proline (AVP) based on Smac-protein binding to the BIR-3 domain of IAP protein. These peptidic compounds are low molecular weight and mimic Smac when binding to the BIR3 domain of XIAP, CIAP1, and CIAP2. However, peptides generally suffer from poor permeability that can potentially influence the amount of drugability largely due to the amide backbone and an alternate chemotype was sought. In an effort to find a replacement for AVP scaffolds, an FBS by NMR identified indole-carboxylic acid 1 as a hit in competitive binding studies. The indole scaffold was further refined through FEPOP, virtual screening, and SAR leading to the benzimidazole scaffold which upon further docking studies resulted in 2-aminobenzimidazole 2. In silico tools were utilized to propose a synthetic pharmacophore which resulted in a phenyl-hetero-imidazole tricyclic series peptidomimetic with only one amide moiety.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C54.
Citation Format: Mark G. Palermo, Rohan Beckwith, Christopher S. Straub, Kara Herlihy, Yiping Shen, Xiaolu Zhang, Matthew Clapham, Brian Hurley. Aryl-N-(1H-imidazol-2-yl)-acetamides: Nonpeptidic binders of Bir3 cIAP protein. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C54.
Abstract C92: MET amplification and overexpression sustain resistance and drive drug dependency to the DN30Fab antibody in MET-addicted cells.
Authors: Martin Valentina , Corso Simona , Petronzelli Fiorella , De Santis Rita , Comoglio Paolo M. , Giordano Silvia 
Published: August 2014

Abstract
The establishment of the oncogenic role of the tyrosine kinase receptor for hepatocyte growth factor, encoded by the MET gene, led to the development of several specific inhibitors, many of which are currently in clinical trials. Clinical experience has shown that the main limit to the efficacy of targeted treatments is represented by resistance. Although the mechanisms underlying resistance to MET-specific Tyrosine Kinase Inhibitors (TKIs) have been already described, nothing is known, up to now, about the emergence of resistance to treatment with MET monoclonal antibodies (mAbs). To predict the mechanisms of acquired resistance, we generated resistant cells by treating a MET-addicted lung cancer cell line (EBC1) with increasing concentrations of the monovalent form of the DN30mAb (DN30Fab), previously developed as a therapeutic tool to block MET activation. The molecular analyses revealed that resistant cells underwent MET amplification and reached such a level of MET overexpression that DN30Fab was no longer able to efficiently downregulate MET and to abrogate its constitutive activation. However, resistant cells remained MET-addicted as they were still sensitive to MET TKIs. Interestingly, resistant cells acquired drug dependence, since removal of DN30Fab led them to death due to excess of signal. Finally, we also show that cells with acquired resistance to MET TKIs are still sensitive to treatment with DN30Fab and that the two drugs have a synergistic effect on tumor cells. Our findings might have important clinical meaning, since they indicate a combined therapy (mAb plus TKI) and a discontinuous treatment as possible strategies to bypass resistance to anti-MET antibodies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C92.
Citation Format: Valentina Martin, Simona Corso, Fiorella Petronzelli, Rita De Santis, Paolo M. Comoglio, Silvia Giordano. MET amplification and overexpression sustain resistance and drive drug dependency to the DN30Fab antibody in MET-addicted cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C92.
Abstract CN05-04: Novel DNA repair targets for anticancer treatments.
Authors: Helleday Thomas 
Published: August 2014

Abstract
Mutations in DNA repair are sometimes found in cancer, such as mutations in mismatch repair or BRCA1 or BRCA2 genes. We previously demonstrated that PARP inhibitors can selectively kill BRCA2 defective tumours through synthetic lethality.
Here, I describe efforts into translating the synthetic lethal approach into treatment of cancer in the clinic and the challenges. The overall conclusion is that the synthetic lethal approach offers significant advantages, but no real cancer cures and suffer from similar resistance problems as many other targeted therapies.
I exemplify how DNA repair inhibitors to a novel DNA repair target, MTH1, can be used in a different context, to overload the high level of DNA damage that is present in cancer. The MTH1 protein sanitises oxidized dNTP pools, converting 8-oxo-dGTP to 8-oxo-dGMP, to prevent incorporation of damaged bases during DNA replication. Here we show that cancer cells are dependent on MTH1 activity for survival, due to the effects of MTH1 in preventing incorporation of oxidized dNTPs into DNA to avoid ATM and p53 mediated apoptosis. We validate MTH1 as an anticancer target in vivo and describe small molecules that potently and selectively inhibit MTH1. Protein co-crystal structures demonstrate that the compounds bind as inhibitors in the enzymatic pocket of MTH1. These first-in-class inhibitors of the Nudix hydrolase family cause increased incorporation of oxidized dNTPs in cells subject to high ROS levels, causing DNA damage and cytotoxicity to cancer cells. This study exemplifies a new general therapeutic approach by using enzyme inhibitors to increased overall DNA damage load in cancer. This strategy may offer a treatment for a broad spectrum of cancers, regardless of cancer genotype.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN05-04.
Citation Format: Thomas Helleday. Novel DNA repair targets for anticancer treatments. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN05-04.
Abstract CN08-02: Therapeutic biomarker discovery in cancer cells.
Authors: Garnett Mathew 
Published: August 2014

Abstract
There is compelling evidence that alterations in cancer genomes strongly influence clinical responses to anticancer therapies. Indeed, there are now several examples where genomic changes are used as molecular biomarkers to stratify patients most likely to benefit from a treatment (e.g. BRAF in melanoma). Despite these successes, the majority of cancer drugs have not been linked to specific molecular features that could be used to direct their clinical use to maximize patient benefit. We are using pharmacogenomic profiling in a panel of &gt;1,000 cancer cell lines as a biomarker discovery platform by systematically linking pharmacological data with extensive genomic information. I will present results from our most current large-scale analysis of drug screening results as well highlight some the new approaches we have developed to harness clinical sequencing data to guide our analyses.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN08-02.
Citation Format: Mathew Garnett. Therapeutic biomarker discovery in cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN08-02.
Abstract PL06-04: Molecular characterization of circulating tumor cells.
Authors: Haber Daniel A. , Maheswaran Shyamala , Sequist Lecia , Yu Min , Ozkumur Emre , Ting David , Miyamoto David , Lee Richard , Shah Ajay , Bardia Aditya , Stott Shannon , Toner Mehmet 
Published: August 2014

Abstract
Circulating tumor cells (CTCs) are present at extraordinarily low levels in the blood of patients with non-hematological cancers, but they provide a non-invasive source of cancer cells for potential diagnostic applications, as well as for understanding the process of blood-borne metastasis. We have developed and tested three generations of microfluidic devices for the isolation of CTCs, each with further improvements in automation, processing throughput, and downstream analytical capabilities. The CTC-iChip allows high throughput and high efficiency depletion of normal leukocytes through a microfluidic magnetophoresis device, revealing untagged CTCs. The unbiased isolation of CTCs irrespective of tumor epitopes, together with their presentation in a format where they can be readily manipulated, provides unique opportunities for their detailed molecular characterization. We have previously shown that rising or declining numbers of CTCs are well correlated with tumor progression or therapeutic response; that they can be used to monitor the prevalence of known clinically-relevant mutations; and that changes in their composition can be followed longitudinally during the course of targeted cancer therapies. Epithelial-to-mesenchymal transition (EMT) is evident among CTCs and evolves dynamically during the course of response or progression following cancer therapy. The heterogeneity of CTC populations is evident in single cell imaging analyses and sequencing studies, with implications for understanding the complexity of metastatic progression and therapeutic responses. Taken together, the application of novel bioengineering technologies to the isolation and analysis of CTCs across multiple different cancer types offers a unique window into the properties of cancer cells that invade into the bloodstream and give rise to metastases.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL06-04.
Citation Format: Daniel A. Haber, Shyamala Maheswaran, Lecia Sequist, Min Yu, Emre Ozkumur, David Ting, David Miyamoto, Richard Lee, Ajay Shah, Aditya Bardia, Shannon Stott, Mehmet Toner. Molecular characterization of circulating tumor cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL06-04.
Abstract PL07-01: Immune checkpoint blockade in cancer therapy: New insights and opportunities.
Authors: Allison James P. 
Published: August 2014

Abstract
The existence of multiple non-redundant l inhibitory pathways that limit T cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits T cell proliferation by interfering with the interaction of the costimulatory molecule CD28 with its ligands B7-1 and B7-2 on the surface of antigen presenting cells. Antibodies to CTLA-4 have proven effective against multiple tumor types in both pre-clinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long term (&gt;4.5 years) survival benefit in about 23% of patients in a randomized, placebo-controlled trial in late stage melanoma. In 2011 it was approved by the FDA for treatment of late stage melanoma and is now a standard of care for that disease. The mechanism(s) of action of anti-CTLA-4 are still being elucidated. We and others have shown that CLTA-4 limits T cell proliferation by a cell intrinsic mechanism. However, there is also evidence that anti-CTLA-4 has to engage the target on both effector (Teff) and regulatory (Treg) T cells. We have recently uncovered a mechanism whereby anti-CTLA-4 antibodies expand Treg in lymph nodes but cause their depletion in the tumor microenvironment. Thus anti-CTLA-4 exerts its anti-tumor effects by multiple mechanisms. PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T cell antigen receptor mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25%. A recent Phase II trial of a combination of anti-PD-1 and anti-CTLA-4 in melanoma showed objective responses in about 50% of late stage melanoma patients. These studies and their implications for cancer therapy will be discussed.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL07-01.
Citation Format: James P. Allison. Immune checkpoint blockade in cancer therapy: New insights and opportunities. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL07-01.
Abstract 1854: Effects of supplemental antioxidant micronutrients on oxidative DNA damage marker in normal colorectal mucosa: A randomized clinical trial
Authors: Lakkur Sindhu , Ahearn Thomas , Bostick Roberd 
Published: August 2014

Abstract
Background: Basic science and animal studies suggests that oxidative stress plays a role in colorectal oncogenesis. Smokers are reported to have increased oxidative DNA lesions in transformed colorectal epithelial cells and increased colorectal cancer risk; however, the majority of observational and clinical studies report weak or null associations between oxidative stress and risk of colorectal neoplasia. To address this we conducted, a pilot, randomized, double blinded, placebo controlled clinical trial to test the effects of an antioxidant micronutrient combination on a marker of oxidative DNA damage, 8-hydroxy-2’-deoxyguanosine (8-OH-dG), in the normal colorectal mucosa.
Methods: Forty-seven patients diagnosed with at least one pathology confirmed sporadic colorectal adenoma were given a daily antioxidant micronutrient combination (800mg dl-alpha-tocopherol acetate, 24 mg beta carotene, 1.0 g vitamin C, 200µg l-selenomethionine, 7.2 mg riboflavin, 80 mg niacin, 60 mg zinc, 5 mg manganese) or placebo for 4 months. A subset of patients (n=33) for whom tissue was available pre- and post supplementation was used in this analysis. 8-OH-dG was detected in biopsies of normal-appearing colorectal mucosa using standardized automated immunohistochemistry. Overall labeling and distribution of 8-OH-dG within the colon crypts were quantified by novel image analysis methods. Treatment effects were assessed using a MIXED effects model as implemented in SAS v9.2.
Results: Relative to the placebo group, in the antioxidant group 8-OH-dG labeling decreased 13% (p=0.87) along the full length of crypts, 27% (p=0.49) in the upper third of crypts, 27 % (p=0.53) in the middle third of crypts, and 8% (p=0.92) in the bottom third of crypts. Among smokers (n=14), relative to the placebo group, in the antioxidant group 8-OH-dG labeling increased 6% (p=0.82) in the upper third of crypts, 28% (p=0.65) in the middle third of crypts, and 51% (p=0.50) in the bottom third of crypts. In non-smokers (n=18), relative to the placebo group, in the antioxidant group 8-OH-dG expression decreased 23% (p=0.55) in the upper third of crypts, 34% (p=0.44) in the middle third of crypts, and 24% (p=0.57) in the bottom third of crypts.
Discussion: These preliminary findings, while not statistically significant 1) suggest that antioxidants may modulate oxidative DNA damage in the normal-appearing human colorectal epithelium – potentially modified by smoking status; 2) provide support for the use of 8-OH-dG as a potential treatable biomarker of risk for colorectal neoplasms; and 3) provide support for extending this investigation in a larger, more definitive trial.
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 1854. doi:10.1158/1538-7445.AM2011-1854
Abstract 1934: Molecular mechanism of abnormal localization of nucelolin on cell-surface of gastric cancer cells, with regard to Ras signaling pathway
Authors: Watanabe Tatsuro , Hirano Kazuya , Beppu Masatoshi , Yamaguchi Kensei , Takahashi Atsushi , Fujiki Hirota , Suganuma Masami 
Published: August 2014

Abstract
Our intensive study of TNF-α inducing protein (Tipα), a carcinogenic factor secreted from H. pylori, revealed that nucleolin acts as a receptor of Tipα in a mouse gastric cancer cell line (MGT-40). Although nucleolin is a major nucleolar protein, nucleolin was found in the cell membrane by cell fractionation and on the cell-surface by flow cytometrical analysis. We further found that nucleolin shuttles Tipα from cell surface to the cytosol, resulting in expression of TNF-α gene, an endogenous tumor promoter. Moreover, a large amount of nucleolin was found in the membrane fraction of MGT-40 cells, but not in that of mouse normal glandular stomach. These results suggest that abnormal localization of nucleolin occures in gastric cancer, as an associated process of carcinogenesis. In the light of this evidence, we think that the abnormal localization of nucleolin on cell surface produces the optimal carcinogenic environment for Tipα binding in gastric cancer development by H. pylori infection. Experimentally we found that large amounts of nucleolin were expressed on the surface of four human gastric cancer cell lines (MKN-45, MKN-74, AGS, and KATOIII), with smaller amounts on that of another cell line (MKN-1), although the total amounts of nucleolin were almost the same among these five cell lines. It is important to note that the amounts of cell-surface nucleolin are correlated well with those of Ras-GTP form, the active form of Ras protein in these cell lines, and we confirmed that MKN-1 cells had the lowest amounts of Ras-GTP form among the five lines. Moreover, the treatment of AGS cells with okadaic acid, a tumor promoter and inhibitor of protein phosphatases 1 and 2A, reduced the amount of nucleolin localized on cell-surface, indicating that abnormal localization of nucleolin on cell surface can be induced by Ras signaling pathway and post-translational modifications. Thus, we discuss the relationship between the abnormal localization of nucleolin and the disorder in the Ras signaling pathway in gastric cancer development.
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 1934. doi:10.1158/1538-7445.AM2011-1934