bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 532: Evaluation of the role of miRNA-4728-3p, a miRNA located in an intron of HER2 gene, in breast cancer stem cells
Authors: Carneiro Juliana Laino do Val , Nunes Diana Noronha , Dias-Neto Emmanuel 
Published: May 2015

Abstract
Background: Cancer stem cells (CSCs) contribute to tumor metastasis, chemotherapy resistance, and are highly tumorigenic when injected into immunodeficient mice. High levels of aldehyde dehydrogenase (ALDH1) are characteristic of stem cells and allow the isolation of subpopulations of CSCs, including those derived from breast cancer. HER2+ tumors, which are more aggressive than tumors with no amplification of this oncogene, are enriched in CSCs, a finding that suggests the participation of this oncogene in the generation and maintenance of CSCs. miR-4728-3p is a poorly investigated miRNA, which is located inside an intron of HER2. Its expression is increased in HER2+ tumors and cell lines, but its role in CSC formation and tumor behavior has not been investigated. Aim: to contribute to the better understanding of the role of miRNA-4728-3p in the biology of CSCs in HER2+ breast cancer cell lines. Methods: miR-4728-3p levels were evaluated in breast cancer cell lines MCF-7, BT-474 and SKBR3 grown in adherent conditions and in conditions that favor the formation of mammospheres for 7, 14, 21 and 28 days. Overexpression of miR-4728-3p was performed using lentiviral transduction with plasmids for the overexpression of this miRNA. Flow cytometry was performed to analyze ALDH1 expression in adherent cells and cells derived from mammospheres and also in cells overexpressing miRNA-4728-3p. Results: Mammospheres in culture for 7 days showed high levels of ALDH1 for all cells lines evaluated. The overexpression of miR-4728-3p induced a significant increment (&gt;10-fold) of ALDH1+ subpopulations in MCF-7 and SKBR3, reinforcing its possible role in the biology of CSCs. Conclusion: HER2-amplification is an event that intrinsically leads to the amplification of miR-4728-3p. The effects of the amplification of this oncogene and this miRNA have to be evaluated together as both may have important consequences for tumor behavior and CSC formation. This increased expression of ALDH1 after miR-4728-3p overexpression suggest the importance of this miRNA in the biology of CSC formation.
Note: This abstract was not presented at the meeting.
Citation Format: Juliana Laino do Val Carneiro, Diana Noronha Nunes, Emmanuel Dias-Neto. Evaluation of the role of miRNA-4728-3p, a miRNA located in an intron of HER2 gene, in breast cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 532. doi:10.1158/1538-7445.AM2014-532
Abstract 5336: Mathematical models for cellular response to radiochemotherapy
Authors: Williams Katherine S. , El-Kareh Ardith W. , Secomb Timothy W. 
Published: May 2015

Abstract
To optimize radiochemotherapy, several clinically adjustable factors must be considered: sequence order (drug administered before, during, or after radiation exposure); time interval between the agents; dose of each agent; and fractionation. Because the combined effects of all these factors are complex, mathematical modeling can provide a useful framework for discerning the role of each individual factor and can be applied to predict response to future experimental protocols. To date, there has been scant effort devoted to mathematical models for cellular response to radiochemotherapy. One widely-used model is based on the assumption that the two modalities act completely independently; the total cell survival fraction is the product of survival fractions for each agent acting alone. However, an examination of a number of dose-response data sets for paclitaxel followed by radiation exposure shows that the independent cell kill model consistently underestimates cell kill. The additive damage model, which is based on the assumption that cell kill depends on a quantity called cellular damage, is constructed as the sum of terms from each agent and is shown to better describe some data sets for ascorbate and paclitaxel. Cellular dose-response data sets for radiochemotherapy have shown complex interactions between therapies, with strong dose-dependent antagonism in some cases, and significant, non-monotonic dependence on the time interval between the modalities in others. We present generalizations of the additive damage model, which include either dose-dependent cell-cycle blocking or transport kinetics, and show that they can describe some of these experimentally-observed complex behaviors. In conclusion, the generalized additive damage model is a promising tool to describe cellular pharmacodynamics of radiochemotherapy and is expected to have application to the optimization of dosage and schedule.
Citation Format: Katherine S. Williams, Ardith W. El-Kareh, Timothy W. Secomb. Mathematical models for cellular response to radiochemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5336. doi:10.1158/1538-7445.AM2014-5336
Abstract 5337: Molecular dynamics study on keap1 point mutations in lung cancer
Authors: Yang Chia-Ning 
Published: May 2015

Abstract
Keap1 is a BTB-Kelch substrate adaptor protein that regulates steady-state levels of Nrf2, a bZIP transcription factor, in response to oxidative stress. In basal condition, Nrf2 is negatively regulated through ubiquitination by Keap1. However, upon exposure to oxidative stress, ubiquitination of Nrf2 is inhibited, resulting increased steady-state level of Nrf2 and increased transcription of cytoprotective ARE (antioxidant response elements)-dependent genes. Reported in 2006, the structure of Keap1 Kelch domain in complex with a 16-mer peptide derived from Nrf2 has been solved by X-ray crystallography to a resolution of 1.85Å. Accordingly, it grants us a chance to evaluate the interaction between Keap1 and Nrf2 and further interpret numerous experimental findings on unbinding due to modifications on Keap1. Herein we apply molecular dynamics simulations to study the binding behaviors of Keap1 and Nrf2 based on the solved structure to investigate how single point mutations G364C and G430C on Keap1 affect Keap1-Nrf2 binding and further cause lung cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Chia-Ning Yang. Molecular dynamics study on keap1 point mutations in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5337. doi:10.1158/1538-7445.AM2014-5337
Abstract 534: MicroRNA-143 is a putative predictive biomarker for 5-FU-based chemotherapy in patients with metastatic colorectal cancer
Authors: Simmer Femke , Dijkstra Jeroen , Venderbosch Sabine , Faber Claudius , Mekenkamp Leonie , Koopman Miriam , Haan Ton de , Punt Cornelis , Nagtegaal Iris 
Published: May 2015

Abstract
Background: Approximately half of the colorectal cancer (CRC) patients develop metastatic disease, either at diagnosis or during follow-up. 5-FU-based chemotherapy forms the backbone of treatment in these patients. However, the response to this therapy varies between individuals. Therefore, an important challenge in CRC research is to identify biomarkers that are predictive of this response.
MicroRNAs are short RNAs that post-transcriptionally regulate the gene expression of many genes. MicroRNA levels are frequently altered in cancer, and can affect expression of genes that modulate tumorigenesis.
Objective: In this study, we explore the potential of microRNAs, and the microRNA producing protein Dicer, as biomarkers that can predict chemo-sensitivity in patients with metastatic colorectal cancer.
Methods: We analyzed the levels of a selected panel of 22 miRNAs and the Dicer protein in primary CRC tumors from patients enrolled in the CAIRO study (a phase III study of the Dutch Colorectal Cancer Group). MiRNA levels were determined with Taqman microRNA assays and Dicer level with immunohistochemistry. Correlation between the expression status of microRNAs or Dicer in primary tumors and the progression free survival (PFS) were investigated. In addition, we evaluated correlations between Dicer and miRNA levels.
Results: Variable Dicer intensities were observed among the analyzed samples, but there was no significant association between Dicer levels and PFS. In addition, no clear correlation between Dicer and miRNA levels could be identified. We especially detected higher expression of miR-31 and miR-21 in tumors compared to matched normal tissue, whereas miR-137 and miR-215 were lower expressed. Interestingly, miR-143 expression was reduced in a subset of the primary CRC tumors, and this differential expression showed a relationship with PFS. The group with reduced miR-143 expression showed higher PFS. The median PFS for patients with reduced, neutral and increased miR-143 expression was 261, 167 and 142 days, respectively (p-value log-rank test=0.018).
Conclusion: The expression level of miR-143 may have clinical utility as a biomarker for response to 5-FU-based chemotherapy. These findings warrant further studies to investigate the relationship between miR-143 expression and 5-FU.
Citation Format: Femke Simmer, Jeroen Dijkstra, Sabine Venderbosch, Claudius Faber, Leonie Mekenkamp, Miriam Koopman, Ton de Haan, Cornelis Punt, Iris Nagtegaal. MicroRNA-143 is a putative predictive biomarker for 5-FU-based chemotherapy in patients with metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 534. doi:10.1158/1538-7445.AM2014-534
Abstract 5344: Rapid induction and progression of PhIP+DSS-induced colon carcinogenesis in CYP1A-humanized mice
Authors: Chen Jayson X. , Wang Hong , Li Guangxun , Liu Anna , Yang Chung S. 
Published: May 2015

Abstract
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant heterocyclic amine generated from high temperature cooking of meat and fish, is metabolically activated by human cytochrome P450 (CYP)1A2 to a proximate carcinogen. Using CYP1A-humanized (hCYP1A) mice, previous study in our lab demonstrated that a single i.g. administration of PhIP (200mg/kg b.w.), followed by 1.5% Dextran Sodium Sulfate (DSS) in drinking water for 7 days, can rapidly induce tumors in the colon with 100% incidence. Multiple adenocarcinomas were observed with elevation of β-catenin, a key protein in the Wnt signaling pathway, as well as iNOS, COX-2, cyclin D1 and c-Myc. In the present study, we investigated the early stage colon carcinogenesis in the hCYP1A mice treated with PhIP (2x 100mg/kg b.w.) and DSS (4 days). After 4 days of DSS treatment, clinical manifestation such as weight loss, diarrhea, and bloody stools were observed. At day 1 after DSS cessation, we found severe damages to the colon epithelium with expansive crypt degeneration, ulcerations and inflammation. At days 3 and 7, we detected epithelial hyperplasia and dysplasia in addition to extensive ulcerations and inflammation. At days 11 and 17, we identified early adenoma and adenocarcinoma, respectively. Similar adenomatous lesions were not observed in hCYP1A mice treated with only DSS. Using immunohistochemistry, we detected strong nuclear staining of β-catenin, specifically within the early adenomas and adenocarcinomas. Further examination using Ki67 marker revealed strong nuclear staining in the adenomas and adenocarcinomas as well as areas of hyperplasia and dysplasia, indicating their high level of proliferation and generation. DNA sequencing revealed 96% of the PhIP+DSS induced colon tumors at week 10 carried a β-catenin mutation, particularly in the codon 32, 33, and 34. Altogether, we demonstrate the rapid induction and progression of colon tumorigenesis in hCYP1A mice, initiated by PhIP-induced Wnt dysregulation and promoted by DSS-induced colitis. (Supported by NIH grants F31CA168333, RO1CA120915 and RO1CA133021 as well as shared facilities funded by CA72720 and ES05022)
Citation Format: Jayson X. Chen, Hong Wang, Guangxun Li, Anna Liu, Chung S. Yang. Rapid induction and progression of PhIP+DSS-induced colon carcinogenesis in CYP1A-humanized mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5344. doi:10.1158/1538-7445.AM2014-5344
Abstract 5353: Leptin regulates cell differentiation and protumorigenic responses in pancreatic stellate cells
Authors: Gong Jun , Gong Raymond , Waldron Richard T. , Lugea Aurelia , Pandol Stephen J. 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked desmoplasia orchestrated by pancreatic stellate cells (PaSCs). Epidemiological studies indicate that obesity and chronic pancreatitis (from alcoholism) increase the risk of PDAC. We recently showed that a diet high in fats and calories increases blood leptin levels and accelerates the development of desmoplasia and early pancreatic neoplasia in the conditional KrasG12D mouse model of pancreatic carcinogenesis. We hypothesize that environmental risk factors such as obesity and alcohol abuse facilitate PDAC progression by regulating PaSC tumorigenic responses. Here we measured leptin and ethanol effects on cell differentiation into the myofibroblast phenotype, cell proliferation and fibrogenic responses in primary mouse PaSC and mouse and human PaSC lines. Inhibitors of mTOR signaling were used to delineate the role of mTOR on leptin-mediated PaSC responses. We found that leptin receptors are expressed in cultured-activated primary mouse PaSCs and in immortalized mouse and human PaSCs. In quiescent PaSCs isolated from the mouse pancreas, leptin alone or in combination with ethanol markedly accelerated PaSC activation and promoted extracellular matrix (ECM) protein production (collagen and fibronectin) via ERK and Akt/mTORC1 signaling pathways, suggesting that these pathways interact to modulate the activated PaSC phenotype. In activated PaSCs, leptin induced activation of JAK/STAT and mTORC1 signaling pathways, and the mTORC1 inhibitor rapamycin blocked leptin-induced mTORC1 activation and markedly reduced fibronectin production and cell proliferation. Other factors known to regulate cell proliferation and inflammation in obesity and alcohol abuse, such as IGF-1, TNFα, and LPS also transiently activated Akt/mTORC1 signaling in PaSCs. Further, we found that pancreatic intraepithelial neoplasia (PanIN) cells isolated from the KrasG12D mice interact with PaSCs to promote their proliferation and ECM production. Our data support a key role for leptin-induced Akt/mTOR signaling in regulating PaSC pro-tumorigenic responses and indicate that leptin and other inflammatory factors provide the mechanistic underpinnings of environmental risk factor promotion in PDAC.
Citation Format: Jun Gong, Raymond Gong, Richard T. Waldron, Aurelia Lugea, Stephen J. Pandol. Leptin regulates cell differentiation and protumorigenic responses in pancreatic stellate cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5353. doi:10.1158/1538-7445.AM2014-5353
Abstract 5361: Development of targeted inhibitors against RecQ1 helicase
Authors: Zuo Mingxin , Maxwell David , Prasad Basvoju A. Bhanu , Peng Zhenghong , Bornmann William , Javle Milind M. 
Published: May 2015

Abstract
Background: RecQ helicases are a ubiquitous family of DNA unwinding enzymes involved in the maintenance of chromosome stability. RecQ1 helicase genomic variations have an important prognostic role and represents a therapeutic target in pancreatic cancer [JCO 2006; 24 (11) 1720-1728]. Pubchem data indicated potential RecQ1 activity &gt;600 compounds using a qHTS RecQ1 assay (NIH Chemical Genomics Center).
Methods: We applied a set of filters including molecular weight, potency and Hill curve fitting and also removed those interfering with biological assay to identify sixteen compounds for studying RecQ1 inhibition. Two compounds showed strong inhibition of RecQ1 helicase activity at 50 µM and at IC50 &lt; 5 µM, respectively. From a large library of compounds, eight potential inhibitors were synthesized in three simple steps. First, sulfonylation of various amines with 3-Nitrobenzenesulfonyl chloride was performed followed by reduction of the nitro group into an amine. Finally, acylation with variety of acid chlorides resulted in the final library of RecQ1 analogs. These agents were studied for RecQ1 helicase activity assay with the radiolabeled partial duplex substrate in vitro. The RecQ1 inhibitor candidate compounds were investigated in pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, PANC-1, and Mia-Paca2) for anti-tumor efficacy using cell proliferation assay with CellTiter-Glo® luminescence. Combination studies with test compounds and poly (ADP ribose) polymerase (PARP) inhibitor olaparib and topoisomerase Inhibitor SN38 were performed. Results: Though none of the compounds showed the same level of activity of the parent compounds, we were able to demonstrate a modest level of helicase activity with several. Two compounds displayed strong inhibition of pancreatic cancer cell proliferation. Two other compounds displayed synergistic inhibition with SN38 or olaparib of pancreatic cancer cell proliferation and induced DNA damage.
Conclusions: Synthesis of RecQ1 inhibitors is feasible and shows potential for anti-tumor efficacy.
Note: This abstract was not presented at the meeting.
Citation Format: Mingxin Zuo, David Maxwell, Basvoju A. Bhanu Prasad, Zhenghong Peng, William Bornmann, Milind M. Javle. Development of targeted inhibitors against RecQ1 helicase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5361. doi:10.1158/1538-7445.AM2014-5361
Abstract 5362: Deficiencies in mismatch repair proteins induce elevated levels of acrolein-derived 1,N2-propanodeoxyguanosine and apoptosis in human colon cancer cells treated with acrolein
Authors: Pan Jishen , Xuan Zhuoli , Dyba Marcin , Zhang Yongwei , Fu Ying , Roy Rabindra , Weiner Louis M. , Chung Fung-Lung 
Published: May 2015

Abstract
Acrolein-derived 1,N2-propanodeoxyguanosine (Acr-dG) is a ubiquitous DNA modification in vivo that may play a role in carcinogenesis. It can be formed when DNA reacts with acrolein in environmental pollutants, such as cigarette smoking and oil combustion, and from endogenous source through oxidation of polyunsaturated fatty acids (PUFAs). We have previously demonstrated that the formation of Acr-dG at a threshold level is linked to apoptosis in cells treated with PUFAs under oxidative condition, suggesting a potential role of Acr-dG in the apoptosis induced by PUFAs, especially ω-3 PUFAs. Acr-dG can be repaired by the nucleotide excision repair (NER) pathway. To examine whether mismatch repair (MMR) pathway is also involved in the repair of Acr-dG, we treated MLH1-deficient HCT116 cell and its isogenic MLH1-proficient HCT116+ch3 cell with acrolein. The Acr-dG levels and apoptosis both were higher in HCT116 cells compared to HCT116+ch3 cells. To further study the role of MMR proteins in the repair of Acr-dG, either MLH1 or MSH2 was knocked down in HCT116+ch3 cells. The results showed that the levels of Acr-dG and apoptosis induction were both significantly higher in the knockdown cells than the cells transfected with control siRNA. The levels of p-ATM and γ-H2AX were also increased to a greater extent in HCT116 cells than HCT116+ch3 cells, and in the MLH1 and MSH2 knockdown cells than the control cells when treated with acrolein at the doses that induce higher levels of Acr-dG. This study shows that MMR proteins, MLH1 and MSH2, are involved in the repair of Acr-dG. The results also suggest that Acr-dG may cause double-strand breaks which lead to apoptosis. Whether MMR acts as an independent repair pathway for Acr-dG or MMR proteins cross-talk and interact with other DNA repair pathways, such as NER, is under investigation. (Supported by NCI grant CA43159)
Citation Format: Jishen Pan, Zhuoli Xuan, Marcin Dyba, Yongwei Zhang, Ying Fu, Rabindra Roy, Louis M. Weiner, Fung-Lung Chung. Deficiencies in mismatch repair proteins induce elevated levels of acrolein-derived 1,N2-propanodeoxyguanosine and apoptosis in human colon cancer cells treated with acrolein. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5362. doi:10.1158/1538-7445.AM2014-5362
Abstract 5363: Genotoxicity of trace level of hexavalent chromium existing in city water
Authors: Tian Xu , Patel Keyur , Ridpath John R. , Swenberg James A. , Nakamura Jun 
Published: May 2015

Abstract
Tens of millions of Americans consume trace amounts of potentially toxic hexavalent chromium (Cr(VI)) through drinking city water every day. According to the studies conducted by the Environmental Working
Group, 89% of the water samples from U.S. cities are contaminated with Cr(VI) at levels ranging from 0.03 to 12.9 μg/L. While trivalent chromium (Cr(III)) is among the essential trace elements for normal carbohydrate, lipid, and protein metabolism in humans, Cr(VI) has been extensively studied as a toxic heavy metal ion. Cr(VI) is a well-known human carcinogen by inhalation; in contrast, it is a rodent carcinogen by ingestion of extremely high doses (57,300 μg/L or higher) in drinking water. The United States Environmental Protection Agency (USEPA) and other regulatory agencies in the world have set the maximum contaminant levels (MCL) for total Cr or Cr(VI) in human drinking water at 50 or 100 μg/L, although the USEPA is currently re-evaluating these regulations. The mechanism by which Cr(VI) causes genotoxicity is well-characterized at concentrations equivalent to current regulatory levels or higher. The genotoxic mode of action of Cr(VI) appears to be due to the intracellular reduction of Cr(VI) to Cr(III) leading to the formation of a ternary complex between DNA, Cr(III), and intracellular reducing molecules. However, little information is available regarding the biological effects of Cr(VI) at doses lower than 100 μg/L. In this study, we investigated the effects of Cr(VI) at nanomolar ranges (1 μg/L or higher) on the DNA damage response in isogenic cultured cells deficient in various DNA repair genes. Here we show that the DNA damage response is observed after a three-day incubation with Cr(VI) at 2-5 μg/L (ppb), which is lower than the Cr(VI) concentrations detected in some of city water in the US. Strikingly, the genotoxicity of Cr(VI) decreased ∼3000 times depending on its incubation time, ranging from three days to ten minutes. Our dose- and time-dependent Cr(VI) genotoxicity results, combined with the estimated transit time of Cr(VI) in the digestive tracts of humans, strongly suggest that trace amounts of Cr(VI) in drinking water at levels 12.9 μg/L or lower are unlikely to cause a significant impact on inducing carcinogenicity in the oral cavity and small intestine.
Citation Format: Xu Tian, Keyur Patel, John R. Ridpath, James A. Swenberg, Jun Nakamura. Genotoxicity of trace level of hexavalent chromium existing in city water. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5363. doi:10.1158/1538-7445.AM2014-5363