bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1669: A quantitative real-time RT-PCR gene signature to detect circulating CD34+ cells as a pharmacodynamic biomarker following anti-EGFL7 treatment in preclinical models of efficacy
Authors: Kadel Edward E. , Huseni Mahrukh , Kan David , Desai Rupal , Yu Shang-Fan , Raja Rajiv , Ye Weilan , Hegde Priti 
Published: February 2011

Abstract
EGFL7 is an extracellular matrix protein that is highly expressed in endothelial cells of angiogenic vessels, including embryonic, tumor and injured vasculatures. Inhibition of EGFL7 activity by anti-EGFL7 monoclonal antibodies results in a reduction of tumor microvascular density (MVD) and tumor growth in genetically engineered models of cancer such as RIP-TβAg. Anti-EGFL7 therapy also leads to a decrease of circulating CD34+ cells in tumor-bearing mice. Utilizing in-silico and murine in-vivo analyses, we have identified a gene signature that can specifically monitor circulating CD34+ cell populations by quantitative real-time PCR using volumes as low as 50μl of mouse whole blood. This PCR-based assay shows a limit of quantification of 0.1 cells/μl of murine whole blood. Experiments comparing CD34+ progenitor cell quantification by flow cytometry to qPCR have shown equivalent performance and good correlation. We propose that using this qPCR based approach to evaluate changes in CD34+ cells in mouse blood in response to anti-angiogenesis therapies, including anti-EGFL7, may be an easy and viable alternative to the current flow cytometry-based assays.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1669.
Abstract 1671: A simple HPLC method to measure plasma mitotane and its two main metabolites in adrenocortical cancer patients
Authors: Garg Madhu B. , Sakoff Jennette A. , Ackland Stephen P. 
Published: February 2011

Abstract
Adrenocortical carcinoma (ACC) is a rare, aggressive tumour which is often detected in advanced stage. Mitotane (o,p’-DDD) is the drug of choice for unresectable, recurrent and metastatic ACC. Intraadrenal metabolic transformation is essential for its therapeutic effects but the metabolite responsible is unknown (o,p’-DDE or o,p’-DDA). Benefit depends on maintenance of adequate plasma drug levels &gt;14μg/ml and toxicity occurs at &gt;20μg/ml. The relationship between dose administered and steady state plasma level is variable, with up to 5-10 fold inter-patient variation. Plasma level monitoring during treatment allows more rapid and consistent attainment of levels between 14-20μg/ml. Measurement of o,p’-DDD and metabolites o,p'-DDE and o,p’-DDA could provide a better understanding of mitotane pharmacokinetics and pharmacodynamics.
We have developed and validated a simple HPLC method to measure plasma mitotane and its two principal metabolites using an internal standard (p,p’-DDD), which involves an isocratic elution and separation through a reversed phase phenyl HPLC column with UV detection (λ 226nm). All these compounds are well separated from each other and from other interfering peaks with a total run time of 21min. The method has been evaluated using 63 plasma samples from 11 patients on mitotane therapy, median age 53 years (range13-73) with start dose of 1-4.5 gm/day. Trough o,p’-DDD levels ranged between 0.9-37.7μg/ml, o,p'-DDE levels 0-4.4μg/ml and o,p’-DDA levels 8.5-90.8μg/ml indicating o,p’-DDA levels in patient plasma are about 1.2-18.1 times higher than the parent compound. 37 samples with o,p’-DDD levels &lt;14μg/ml were recommended to steadily increase dose up to 12 gm/day to achieve target level and then continue at that dose. 10 samples with o,p’-DDD levels &gt;20μg/ml were recommended to decrease dose. Correlation with clinical data would allow us to confirm a relationship between plasma level of o,p’-DDD, o,p'-DDE and o,p’-DDA and clinical outcome, including tumour response or stablisation and toxicity. We aim to establish a therapeutic drug monitoring facility for assessment of plasma mitotane and metabolite levels in patients in the Asia Pacific region. A result and dosing recommendation could be available within 7 days of receipt of sample.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1671.
Abstract 1675: Lung cancer chemotherapy: genetic variations in the transforming growth factor beta pathway as predictors of survival
Authors: Lin Moubin , Hildebrandt Michelle , Stewart David , Lippman Scott M. , Lu Charles , Spitz Margaret R. , Wu Xifeng 
Published: February 2011

Abstract
Treatments based on molecular determinants are likely to maximize therapeutic index for chemotherapy in non-small-cell lung cancer (NSCLC). The purpose of this study is to take a pathway-based approach to systematically evaluate the pharmacogenetic effects of transforming growth factor (TGF-β) pathway on lung cancer and identify potential genetic predictors of platinum-based chemotherapy. We genotyped 227 SNPS in 23 TGF-β pathways genes to evaluate their associations with overall survival in 598 late stage NSCLC patients receiving first-line platinum-based chemotherapy with or without radiotherapy. In individual analysis, 22 SNPs were significantly associated with overall survival, of which the strongest associations were found for BMP2:rs235756 (HR=1.45; 95%CI, 1.11-1.90; P=0.006) and SMAD3:rs4776342 (HR=1.25; 95%CI, 1.06-1.47; P=0.009). Cumulative effect analysis showed that individuals with multiple risk genotypes had a significant dose-dependent adverse affect on overall survival (Ptrend=2.44×10−15). Analysis stratified by treatment modality showed that SMAD3 haplotypes exhibited significant associations with outcomes of chemotherapy. Survival tree analysis categorized subgroups of patients with dramatically different survival pattern. The low-risk genetic profile group identified from patients treated with chemoradiation had a median survival time (MST) of 30.4 months. In comparison, the high-risk genetic profile group had a more than four-fold increased risk of death with MST of 6.8 months. The low-risk genetic profile group identified from patients treated with primary chemotherapy without definitive radiotherapy had a MST of 18.03 months, while the high-risk genetic profile group had a MST of 5.9 months and a four-fold increased risk of death. These results suggest that genetic variations in TGF-β pathway are potential predictors for clinical outcome in advanced NSCLC treated with platinum-based chemotherapy. We also found that genetic variations within the TGF-β signaling pathway may be able to identify potential subgroups of patients who will most benefit from platinum-based chemotherapy with or without radiotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1675.
Abstract 1687: Carcinogen induced inflammation and pancreatic cancer
Authors: Kadekar Sandeep , Silins Ilona , Hogberg Johan , Dreij Kristian , Stenius Ulla 
Published: February 2011

Abstract
National Toxicology Program (NTP) performs two-year cancer bioassays. We have analyzed the NTP rat data base and searched for gender differences in susceptibility to carcinogens. We identified 10 chemicals that induced exocrine pancreatic cancer in male rats only, but found no chemical that induced pancreatic cancer in female rats only. Furthermore, males were most affected by three chemicals that induced pancreatic cancer in both sexes. In an effort to understand this sex difference in susceptibility, we used a tool which builds on the technology published in BMC Bioinformatics 2009, 10, 303. This tool was built to assist cancer risk assessors in the analysis of literature data on modes of action (MOA). We used this tool in the analysis of 2041 PubMed abstracts on the 10 male-specific carcinogens. The tool automatically selected 634 abstracts as relevant for cancer and sorted them in taxonomies. The sorting suggested that induction of oxidative stress and inflammation was a common feature among the 10 carcinogens. As chronic pancreatitis is a risk factor for human exocrine pancreatic cancer, we investigated the effects of the 10 carcinogens on Ca2+ signaling and on inflammatory markers in pancreatic cancer cell line Panc-1. It was found that many the 10 male specific carcinogens rapidly increased intracellular [Ca2+] and interfered with extracellular ATP-induced Ca2+ release in Panc-1 cells. The effect on [Ca2+] was followed by activation of calcineurin and phosphorylation of Erk. Some of these effects were blocked by inhibitors of the purinergic P2X7 receptor, a receptor which may rapidly increase intracellular [Ca2+]. We further studied the induction of mRNA levels of inflammatory mediators, and found that IL8 was significantly up-regulated by most of the 10 chemicals. Our data suggest that inflammation is important for chemically induced exocrine pancreatic cancer in the rat and that male rats are more susceptible. Our data may have a bearing on human pancreatic cancer as men, and in particular young men, have a higher incidence of pancreatic cancer than women. Increased levels of the P2X7 receptor has also been detected in chronic pancreatitis in humans.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1687.
Abstract 1692: TRAF2 phosphorylation plays a critical role in cell adaptation to chronic oxidative stress
Authors: Habelhah Hasem , Blackwell Ken , Altaeva Aliya , Zhang Laiqun , Shi Zhaohui 
Published: February 2011

Abstract
The tumor microenvironment is characterized by hypoxia, low glucose and oxidative stress. Cancer-cell adaptation to such chronic stress has profound consequences for malignant progression and the response to therapy. Numerous studies have demonstrated that the NF-κB signaling pathway promotes tumor progression and metastasis, whereas its inhibition sensitizes cancer cells to stress-induced apoptosis. TNF receptor associated factor 2 (TRAF2) is an adaptor protein that regulates the activation of the JNK and NF-κB signaling cascades in response to TNFα stimulation. We mapped two phosphorylation sites (Ser-11 and Ser-55) on the N-terminal RING domain of TRAF2, and reported that phosphorylation at these sites increases basal and TNFα-induced NF-κB activation. Recently we found that oxidative stress induces TRAF2 phosphorylation at both Ser-11 and Ser-55, and that this phosphorylation plays a critical role in cell survival in the context of chronic oxidative stress: cells that expressed a TRAF2 mutant in which both Ser-11 and Ser-55 are replaced by Ala (TRAF2-S11/55A) underwent apoptosis even when the cells were subjected to sublethal oxidative stress. Analysis of both JNK and IKK pathways revealed that oxidative stress induces strong and prolonged JNK, but not IKK, activation in cells expressing TRAF2-S11/55A, suggesting that TRAF2 phosphorylation promotes cell survival by inhibiting the prolonged phase of JNK activation. Importantly, TRAF2 was found to be constitutively phosphorylated in some malignant cancer cell lines, as well as in some human tumor tissues. In addition, basal TRAF2 phosphorylation is elevated in H-Ras-V12-transformed cells, and its inhibition significantly sensitized the cells to oxidative stress-induced apoptosis. These results unveil a new layer of mechanism for cancer cell adaptation to oxidative stress modulated by TRAF2 phosphorylation, and suggest that inhibiting TRAF2 phosphorylation could be a new target for anti-cancer drug development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1692.
Abstract 1699: The effects of hypoxia and oxidative stress on transcriptional regulation of carcinogen metabolizing enzymes
Authors: Richardson Amira , Williams Shardae , Kioko Stephen , Kirlin Ward 
Published: February 2011

Abstract
Enzymes are essential to every biochemical process; it is through the action of enzymes that the many metabolic pathways of the body can synchronize with one another to coordinate the processes needed to maintain life. Enzymes are also involved in the metabolism of xenobiotics including dietary chemicals, drugs and environmental chemicals. In this capacity they are very involved in chemical carcinogenesis. Cytochrome P450 1A1 (CYP1A1) and NAD(P)H: quinone oxidoreductase (NQO1) are two enzymes that play a vital role in the process of chemical carcinogenesis. The aryl hydrocarbon receptor (AhR), located in the cytoplasm, mediates various biological responses to environmental pollutants via the adaptive pathway. The binding of a xenobiotic to the AhR triggers transcriptional activation of xenobiotic metabolizing enzymes such as CYP1A1 and NQO1. Our current research investigates the contrast between oxidative stress and hypoxia on the transcriptional activation of CYP1A1 and NQO1 enzyme expression. Hypoxia is a frequent characteristic of tumors as a result of low vascualrization. The transcription factor HIF1alpha can serve as a marker of hypoxia, and aids as a key regulator of the hypoxic response. Previous research in our lab has shown that oxidative stress results in an increase in CYP1A1 and NQO1. We hypothesize that under hypoxic conditions the expression of NQO1 and CYP1A1 are altered which could indicate that hypoxia may possibly play a role in carcinogen metabolism. Two human cancerous cell lines, HEPG2 and HT29, were used to test this hypothesis. Both cells lines were treated with 500 µM of the hypoxic mimetic agent cobalt chloride and harvested at one, two and four hour increments. Hypoxic conditions were then confirmed via HIF1 alpha staining in immunocytochemistry. We then observed mRNA, protein and enzyme expression via RTPCR, Western Blots and enzyme assays, respectively. Altered levels of NQO1 and CYP1A1 suggest that these enzymes respond to hypoxia in a similar manner as they do to oxidative stress. This may provide preliminary evidence into one of the potential mechanisms by which hypoxia is chemopreventive. (Support: NIH MBRS/GM028248; RCMI RR033032).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1699.
Abstract 171: Cell memory of a genotoxic insult is mediated by methyltransferases
Authors: Rugo Rebecca E. , Mutamba James T. , Mohan K. Naga , Yee Tiffany , Chaillet J. Richard , Greenberger Joel S. , Engelward Bevin P. 
Published: February 2011

Abstract
Characterization of the direct effects of DNA damaging agents shows how DNA lesions lead to specific mutations. Yet, serum from Hiroshima survivors, Chernobyl liquidators, and radiotherapy patients can induce a clastogenic effect on naive cells, showing indirect induction of genomic instability that persists years after exposure. Such indirect effects are not restricted to ionizing radiation, as a chemical genotoxin induces a heritable and transmissible genomic instability phenotype. While such indirect induction of genomic instability is well described, the underlying mechanism has remained enigmatic. Here, we show that mouse embryonic stem (ES) cells exposed to γ-radiation remember the insult for weeks. Specifically, conditioned media from progeny of exposed cells can induce DNA damage and homologous recombination in naive cells. Notably, cells exposed to conditioned media also elicit a genome destabilizing effect on their neighbours, thus demonstrating transmission of genomic instability. Moreover, we show that the underlying basis for the memory of an insult is completely dependent on two of the major DNA cytosine methyltransferases (MTases), Dnmt1 and Dnmt3a. Targeted disruption of these genes completely eliminates transmission of genomic instability. Furthermore, transient inactivation of Dnmt1, using a tet-suppressible allele, clears the memory of the insult, thus protecting neighbouring cells from indirect induction of genomic instability. We have therefore shown that a single exposure can lead to long-term genome destabilizing effects that spread from cell to cell, and we provide a specific molecular mechanism for these persistent bystander effects. Collectively, our results impact current understanding of risks from toxin exposures and suggest specific mechanisms for suppressing genomic instability in people exposed to carcinogenic genotoxins.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 171.
Abstract 1715: Leptin regulates the IL-1 system in breast cancer
Authors: Zhou Weiqiang , Gonzalez-Perez Ruben R. 
Published: February 2011

Abstract
Leptin and IL-1 are inflammatory cytokines promoting breast cancer angiogenesis that are often linked to worse prognosis. We hypothesize the leptin angiogenic effects in mammary tumor (MT) may be linked to, or regulated, in part by IL-1 signaling, therefore, leptin and IL-1 may have synergistic functions in MT progression. To test this hypothesis leptin-dose (0-6.2 nM) and time-course (0-48h) effects on levels of IL-1 system components (IL-1α, IL-1β, IL-1Ra and IL-1R tI) were investigated in mouse MT-4T1 cells. To determine the contribution of specific leptin-activated signaling pathways on IL-1 regulation several kinase inhibitors AG490 (JAK2/STAT3), PD98059 (MEK/MAPK/ERK1/2), Wortmannin (PI-3K/AKT1), Rapamycin (mToR), Go6976 (PKC-Ca dependent), SB203580 (p38 MAP kinase) and SP600125 (JNK) were used and IL-1 system component levels were determined by ELISA and Western blot. To determine if leptin could regulate its own receptor (long isoform, OB-Rb and all isoforms) flow cytometry was used. Our results show that basal levels of IL-1α were 14 fold higher than IL-1β. Remarkably, leptin up-regulates all IL-1 system components and all OB-R isoforms showing the highest effects at 1.2nM/24h. JAK2/STAT3 and MAPK/ERK 1/2 were essential for leptin upregulation of IL-1 system. In contrast, PI-3K/AKT1, PKC and p38 kinases were mainly linked to leptin regulation of IL-1 receptor-related proteins (IL-1R tI and IL-1Ra). JNK and mTOR were related to leptin-mediated induction of IL-1R tI but were not involved on IL-1α or IL-1Ra regulation. Interestingly, leptin-mediated activation of mTOR appears to be a negative regulator of IL-1α but acts as an inductor of IL-1Ra. In conclusion, leptin is an important regulator of IL-1 system in MT. In turn, IL-1 signaling can promote VEGF expression and tumor macrophage recruitment that could indirectly enhance leptin-mediated angiogenic effects and MT growth. This work was supported in part by NIH/NCI 1SC1CA138658-02; NIH/UAB Breast SPORE Career Development Award; BC 504370 Susan G. Komen Foundation for the Cure and the Georgia Cancer Coalition Distinguished Cancer Scholar Award (to RRGP).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1715.
Abstract 1720: Activating peroxisome proliferator-activated receptor γ mutant promotes tumor growth in vivo by enhancing angiogenesis
Authors: Zhou Jie , Tian Lifeng , Casimiro Mathew C. , Pestell Richard G. , Wang Chenguang 
Published: February 2011

Abstract
PPARγ, originally cloned as a transcription factor involved in fat cell differentiation, is activated by endogenous ligands, such as fatty acids produced by sterol response element binding protein 1 (SREBP1) and fatty acids synthase (FASN) pathways and synthetic ligands including the thiazolidinediones (TZD). PPARγ is expressed in a variety of cancer cells. Independent lines of evidence support a role for PPARγ to either inhibit or promote tumorigenesis. Human breast cancer is associated with ErbB2 amplification or overexpression in &gt;30% of patients. Although PPARγ is reduced in ErbB2 induced tumor, the role of PPARγ in growth control of ErbB2-induced tumorigenesis is poorly understood. The addition of ligand activates the receptor by inducing a conformational change in the receptor, which can be recapitulated by mutation. To investigate the role of activated PPARγ signaling in breast cancer, we compared the function of a constitutively active PPARγ (PγCA) mutant with the wild-type PPARγ in ErbB2-induced mammary tumorigenesis in vivo. Tumor cells transduced with either PPARγ or PγCA were implanted into immune competent FVB mice. Enhanced tumor growth was observed in PγCA-transduced cells, which was associated with increased angiogenesis and endothelial stem cells as evidenced by increased number of cells stained with von Willebrand factor (vWF), c-Kit, CD133 and CD31. Genome-wide expression profiling identified a group of genes within the angiogenesis pathway, including Angptl4, as targets of activated PPARγ. PγCA also induced Angptl4 protein secretion in ErbB2-transformed mammary epithelial cells. Angptl4 promoted vascular endothelial cell migration and conversely immuno-depletion of Angptl4 reduced PγCA-mediated cellular migration. Collectively, these studies suggest that activated PPARγ induces Angptl4 to promote tumor growth through enhanced angiogenesis in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1720.