bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A106: Efficacy of EGFr inhibitors gefitinib on development of OH-BBN-induced rat bladder tumors: Dose dependency and modulation of biomarkers
Authors: Lu Yian , Lubet Ronald A. , You Ming , Bode Ann , Steele Vernon E. , Townsend Reid , Grubbs Clinton J. 
Published: January 2011

Abstract
The preventive effects of the EGFr inhibitor Iressa on the induction of urinary bladder cancers induced by OH-BBN was determined. Treatment of rats with Iressa (10 mg/kg BW/day) beginning two weeks after the last dose of OH-BBN decreased the incidence of large palpable bladder cancer lesions by 95% at an 8-month observation period. Treatment with lower doses of Iressa (4 and 1.33 mg/kg BW/day) decreased the incidence of large tumors by 80 and 65%, respectively. This preventive efficacy was similarly observed when one examined an incidence curve; i.e., a large increase in tumor latency. At 3 1/2 months after the last OH-BBN dose, 75% of the rats had already developed microscopic cancers. Iressa treatment beginning at this time period also lowered the incidence of large tumors; implying that most of the effects of Iressa were during the latter periods of tumor progression. We also examined potential biomarkers modulated by short-term exposure to Iressa (10 mg/kg BW/day) in urinary bladder cancers. Three approaches were taken to identify biomarkers: (1) Alterations in EGFr related proteins directly associated with the efficacy of Iressa by immunohistochemistry. Levels of various biomarkers (phosphorylated EGFr, phosphorylated AKT, but not phosphorylated ERK levels were significantly decreased in the bladder tumors of treated rats. (2) Alterations in protein expression when comparing control and Iressa treated tumors. Employing two-dimensional gel electrophoresis and tandem mass spectrometry, it was found that proteins associated with the angiogenic effects of VEGF were decreased in tumors from treated animals. These included cytoskletal proteins nucleolin, annexin A1 and the MAP kinase (MAPKK). (3) Alterations in gene expression employing array gene technology. Numerous metabolic and cellular pathways were markedly altered by Iressa treatment, most particularly cell cycle related genes; i.e., there were strong inhibition of expression of CDC20 and both of the aurora kinases. Thus, we have identified biomarkers that might be relevant as pharmacodynamic or efficacy biomarkers in clinical prevention trials of urinary bladder cancer.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A106.
Abstract A21: Global DNA methylation analysis of bronchial epithelia of former smokers with COPD, with and without lung cancer
Authors: Vucic Emily A. , Wilson Ian M. , Chari Raj , Kennett Jennifer Y. , Lonergan Kim M. , Lam Stephen , Lam Wan L. 
Published: January 2011

Abstract
Introduction: Emerging evidence suggests that aberrant epigenetic regulation is involved in the development and progression of malignant and nonmalignant respiratory diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer. Moreover, patients with COPD have an increased risk of developing lung cancer. Besides similar risk factors such as tobacco smoke exposure, little is known about the shared biology between COPD and lung cancer. Smoking causes aberrations in airway and lung parenchyma at both the genomic and epigenomic levels, resulting in global changes to gene expression. In this study, we hypothesize that alterations at the level of DNA methylation in airway epithelia of former smokers (FS) with COPD with and without non-small cell lung cancer (NSCLC) may be used to identify genes involved in the pathogenesis of these respiratory diseases, independent of the effects of active smoking.
Methods: Bronchial epithelial cells were obtained from brushings of small airways (&lt; 2 mm diameter) during bronchoscopy from FS with COPD (n=22), without COPD (n=22) and patients with COPD as well as previous surgical resection of Stage I NSCLC (n=6). Illumina's Infinium Methylation (HM27) assay was used to assess DNA methylation status of 27,578 CpG sites associated with 14,475 genes.
Results: COPD patients are distinguished from non-COPD patients based on airway methylation profiles. Genes differentially methylated in airways between COPD and non-COPD patients include several modulators of aryl hydrocarbon receptor and IL6 signaling, as well as genes previously implicated in COPD, including immune chemotaxis regulators (CXCL11, CCR8) and GABA receptor signaling (GABRA5). Airway epithelial DNA from COPD patients with NSCLC compared to those without NSCLC was differentially methylated at sites encoding multiple key regulators of xenobiotic metabolism, regulators of free radical savaging/detoxification and retinol metabolic pathway components including several alcohol dehydrogenase, glutathione S transferase, and UDP glucoronosyltransferase genes.
Conclusion: Our preliminary results suggest a role for DNA methylation in the deregulation of previously identified COPD-related genes, and specifically highlight differences in airways of COPD patients with/without NSCLC corresponding to well-known smoking-related metabolomic processes. Knowledge of DNA methylation disruption will further our understanding of the etiological role of COPD in the development of lung cancer, and contribute to the development of chemo-prevention strategies targeting the biology of both COPD and NSCLC. Supported by CIHR.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A21.
Abstract A23: Allele specific regulation of esophageal cancer related gene 2 by miR-1322 in esophageal squamous cell carcinoma
Authors: Zhang Tengfei , Zhao Dan , Wang Qiming , Yu Xiying , Guo Liping , Lu Shih Hsin 
Published: January 2011

Abstract
Background and Aim: TCA3/TCA4 Short Tandem Repeat (STR) polymorphism in 3’ untranslated regions of esophageal cancer related gene 2 (ECRG2) was reported to be associated with esophageal squamous cell carcinoma (ESCC) incidences and the prognosis of ESCC patients. This study is to explore the mechanisms of TCA3 allele as a risk factor and poor prognosis indicator rather than TCA4 allele mainly in the functional relevant of microRNAs regulation in ESCC.
Methods: Two genotypes of luciferase reporter plasmids containing ECRG2 3’UTR (TCA3 allele and TCA4 allele respectively) were constructed and expression were compared between the two alleles in three esophageal cancer cell lines: EC9706, EC109 and KYSE150. Bioinformatics predictions of microRNAs binding were performed by software TargetScan5.1, MicroInspector, RNA22 and RNAcofold. Dual-Luciferase reporter assay with or without microRNAs mimics or inhibitors were conducted to verify the effects of predicted microRNAs on expression of different alleles. The different expression of identified microRNAs in cancer tissues and the adjacent normal esophageal tissues from 44 ESCC patients were determined by Real-Time PCR.
Results: Dual luciferase reporter assays indicated that expression level of TCA4 allele is 2-4 folds higher than TCA3 allele in all the three esophageal cancer cell lines. Bioinformatics analysis by software TargetScan5.1, MicroInspector, RNA22 and RNAcofold showed 4 potential microRNAs (miR-580, miR-1182, miR-1272 and miR-1322) binding at the TCA polymorphism site of the 3’UTR of ECRG2. Dual luciferase reporter assays indicated that miR-1182 and miR-1272 is not able to regulate either TCA3 or TCA4 allele in all three cell lines, however, miR-1322 and miR-580 dramatically down-regulated TCA3 allele expression (P &lt;0.01) whereas slightly regulated TCA4 allele (P&gt;0.05). The expression of miR-580 were under the detection threshold of real-time PCR analysis in most of the 44 paired tissue samples but the expression of miR-1322 were detectable, and 28 cases (63.6%) had at least 2-fold up regulation in their cancer tissues. No statistical differences were found between metastasis and non-metastasis and in different stage of disease.
Conclusions: The differential regulation of TCA3 and TCA4 allele by miR-1322 might explain the difference in cancer risk and prognosis for different genotype carriers. MiR-1322 has an important role in human ESCC by regulating tumor suppressor gene ECRG2 and miR-1322 was up regulated in esophageal cancer, which itself might severs as a tumor promoter and potential marker and therapeutic target for esophageal squamous cell carcinoma.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A23.
Abstract A29: EYA4 is a risk- and survival-associated TSG that is deleted and hypermethylated in the earliest stages of NSCLC
Authors: Enfield Katey , Wilson Ian M. , Vucic Emily A. , Chari Raj , Zhang Yu-An , You Ming , MacAulay Calum , Gazdar Adi F. , Lam Stephen , Lam Wan L. 
Published: January 2011

Abstract
Background: Previous familial linkage studies have identified a tumor suppressor locus at 6q23-25 in lung cancer (LC). However, no single gene has yet been implicated within this 30 Mb region. The identification of two-hit targets — genes disrupted by two mechanisms at the DNA level, such as copy number loss and hypermethylation — involved in LC risk and development will lead to better methods for risk assessment, early detection and treatment.
Methods: EYA4 was identified as a two-hit target using multidimensional genome-wide analysis combining gene dosage, DNA methylation, and gene expression data in non-small cell lung cancer (NSCLC) and early pre-malignant lesions with matched adjacent non-malignant tissue. The association of allelic variants with LC risk was assessed in data collected by the Genetic Epidemiology of Lung Cancer Consortium (GELCC), and the association of gene expression with prognosis was investigated in public data using statistical analyses. Bronchial epithelial cells of LC patients and high risk individuals were examined for early hypermethylation of EYA4. The role of EYA4 in apoptosis, and the association of EYA4 with the DNA repair genes GADD45a and γ-H2AX was assayed using stable EYA4 mRNA knock-downs in lymphoblast cell lines. Cells were either serum-starved for 12 and 24 hours followed by Annexin5/propidium iodide staining and GADD45a qRT-PCR, or irradiated, and levels of γ-H2AX protein were measured over time.
Results: Integration of NSCLC gene dosage, DNA methylation and mRNA expression showed EYA4 to be frequently affected by two-hits and significantly down-regulated. Numerous EYA4 variants were associated with familial LC, and low EYA4 expression was significantly associated with poor prognosis in multiple independent data sets. Congruent with EYA family member function, in vitro assays revealed that EYA4 knock-down cells displayed a decrease in the number of apoptotic cells following serum starvation. Further investigations led to the discovery of EYA4 hypermethylation not only in the bronchial epithelial brushings of NSCLC patients, but also in the brushings of individuals at a high risk of LC development. EYA4 knock-down led to attenuation of the GADD45a DNA damage repair response, as well as increased levels of γ-H2AX following DNA damage repair.
Conclusions: EYA4 is a gene disrupted early and frequently that maps to a locus previously associated with cancer risk. It is implicated in somatic as well as familial cancers, and is likely a tumor suppressor gene with apoptotic and DNA repair functions. The direct association of EYA4 with risk and survival as well as its early disruption underscores its relevance on a clinical level.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A29.
Abstract A42: Doses of selective estrogen receptor modulations (SERMS) required for prevention and therapy of chemically induced mammary cancers
Authors: Heckman-Stoddard Brandy , Grubbs Clinton , Johnson Karen A. , Lubet Ronald 
Published: January 2011

Abstract
Selective estrogen receptor modulators (SERMs) interfere with the activation of the estrogen receptor. SERMs have been shown to be effective for both treatment and prevention of breast cancer. Here we examine the ability of tamoxifen and arzoxifene, a more easily absorbed form of raloxifene, to prevent mammary tumors at a significantly lower dosage than those used for treatment. For prevention studies, female Sprague-Dawley rats (50 days of age) were injected with a single i.v. dose of MNU resulting in the development of multiple ER-positive mammary tumors beginning 7 weeks after carcinogen treatment. Rats were administered the preventive agent beginning five days after carcinogen administration. When the agents were tested at does varying between 0.15-3.3 ppm in the diet, both agents caused a dose dependent increase in preventive activity. The highest doses of tamoxifen (3.3 ppm) and arzoxifene (3.0 ppm) both decreased tumor multiplicity greater than 90%. Both of these doses are less than one-fifth the human equivalent dose (HED) based on standard FDA scaling factors. Both doses also resulted in substantial decreases in mammary gland development. These dosages were then used in a therapy setting to compare the efficacy. For these studies, MNU treated rats were allowed to develop their first palpable mammary tumor (70-150 mm2) before initiating treatment. Tumor growth or regression was followed by caliper measurements. Neither of the preventive doses of these SERMs exhibited therapeutic activity although substantially higher doses of tamoxifen (33 or 100 ppm) were relatively effective. These results are in contrast to our prior findings with other classes of agents (RXR agonists, EGFR inhibitors, and aromatase inhibitors) in which highly effective preventive doses were as effective as therapeutic doses in this model. These results demonstrate the unique dose differential regarding prevention and therapy with SERMs. Microarray analysis of tumors treated for 5 days with tamoxifen at doses of 3.3ppm or 100ppm reveals overlapping significant gene changes of similar magnitude in comparison to control treated tumors although there were significant gene changes seen at the therapeutic dose which were not observed at the lower dose. These studies raise two questions: 1) whether this class of agents might be used at significantly lower doses in a pure prevention setting as contrasted with a therapeutic setting where they were initially defined; 2) are there gene expression changes which might be used to help identify this differential dosing for prevention vs. therapy.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A42.
Abstract A50: Plantago major inhibits azoxymethane-induced aberrant crypt foci in C57BL/6 mice and modulates apoptosis in mice and human colon cancer cells
Authors: Han Peter S. , Frey Robert J. , Nishino Yuki , Kang Jonathan H. , Yeo Anthony H. , Vassantachart Janna M. , Kim Han Y. , Hausted Randy P. , Wong Brian Y. Y. 
Published: January 2011

Abstract
Plantago major (PM), commonly known as common plantain, is a temperate perennial herb. Traditionally, its seeds and leaves have been ingested or applied externally to treat inflammation and infection. Studies showed PM possesses inhibitory effects towards a variety of tumors and cancer cell lines, including mice Ehrlich ascites carcinoma and breast adenocarcinoma, gastric, leukaemia, ovary, melanoma, and renal human cell lines. While PM has been shown to exhibit selective cytotoxic activity against cancer cells, its quantitative potential as a chemopreventive agent on colon cancer has yet to be elucidated. In this study, C57BL/6 mice (N = 30) of 9 wk old were randomized into three groups (N = 10). Positive and experimental mice groups were injected with Azoxymethane (AOM; 5 mg/kg body weight) at the onset and second wk of the 8-wk duration of the in vivo study while the negative group received no injection. The mice in the experimental group were given daily oral feedings of 20 mg/ml of PM from the onset of the study while the negative and positive control groups were given a sterilized water placebo. All groups were sacrificed after 8 wks and 25 mm cuts of the proximal colon were analyzed for aberrant crypt foci (ACF). PM feeding significantly reduced the number of AOM-induced ACF in the proximal colon compared to the water-fed positive control AOM-induced group (7.02 ± 2.61 &lt; 32.1 ± 9.86; P &lt; 0.0003). The negative control, water placebo group had minimal ACF (2.0 ± 1.56) compared to the experimental and positive control groups. The potency index of the herb was calculated as 4.57. Percent inhibition of AOM-induced ACF formation of 78.1% was obtained with the PM treatment. On average, all three groups gained weight (calculated as % increase) through the course of the experiment (experimental, 6.93 &lt; negative control 15.6 &lt; positive control 39.4). Histological (H&E) slides of the proximal colon displayed a significantly higher apoptotic index than the positive control (AOM only) (2.0 &gt; 0.6) and a lower mitotic index (MI) than control (1.5 &lt; 2.8). Caspase 3 induction was identified in human colon cancer cells (COLO-205) treated with PM (5mg/ml) in chamber slides, using a specific carboxyfluorecein (FAM) labeled peptide fluoromethyl ketone (FMK) caspase inhibitor (FAM-Peptide-FMK). Caspase 3 activation was also observed in immunofluorescent slides of PM treated proximal colon tissues. Through inhibition of AOM-induced ACF via apoptosis, our data suggests PM to be a prospective chemopreventive and potential therapeutic agent for colon cancer.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A50.
Abstract A54: Orthosiphon stamineus leaf extract can prevent the development of colorectal and breast cancer in vivo
Authors: Ahmad Khadeer , Ismail Zhari , Aisheh Abdelrahim A. , Shah Amin Malik , Majid Abdul 
Published: January 2011

Abstract
Java tea also scientifically known as Orthosiphon stamineus (O.S) is used widely in the Southeast Asian region to treat variety of illness including kidney stones and rheumatism. Recently leaf extract of the plant species has been shown to have strong antioxidant and antiangiogenic activity causing significant inhibition in VEGF expression. Two xenograft tumor models transplanted with human breast cancer cells (MCF7) and colon cancer cells (HTC116) were administered orally 200mg/kg solvent extract of O.S. Both groups failed to show any sign of tumor growth compared to the control where almost all transplanted neoplastic tissues developed into full grown tumor. This suggests that O.S can be useful to prevent the onset of neoplasm.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A54.
Abstract A6: Nicotine stimulates lung and pancreatic cancers xenografts by systemic increase in stress neurotransmitters and suppression of the inhibitory neurotransmitter γ-aminobutyric acid
Authors: Al-Wadei Hussein A. , Al-Wadei Mohammed H. , Schuller Hildegard M. 
Published: January 2011

Abstract
Human lung adenocarcinoma (AC) and pancreatic ductal adenocarcinoma (PDAC) are among the most common types of human cancer and have a poor prognosis in all populations investigated. Smoking is a risk factor for both malignancies. Nicotine addiction is characterized by changes of nicotinic acetylcholine receptors (nAChRs) in the brain to increase the production of excitatory neurotransmitters while reducing inhibitory neurotransmitters. The current study has tested the hypothesis that chronic nicotine stimulates the growth of PAC and PDAC xenografts in nude mice via similar mechanisms. Groups of nude mice carrying xenografts of AC cell line NCI-H322 or PDAC cell line Panc-1 remained untreated, were given nicotine in the drinking water for 30 days in the presence and absence of daily injections with GABA or were treated with GABA alone. The diameters of xenografts were measured. Levels of noradrenaline and adrenaline, the stress hormone cortisol, the neurotransmitter γ-aminobutyric acid (GABA) in serum and xenograft tissues and levels of cAMP in the cellular fraction of blood and in xenograft tissue were assessed by immunoassays. The levels of GAD65, GAD67, nAChRs and signaling proteins downstream of β-ARs in the tumor tissue were determined by Western blotting. Our data show a significant stimulation of xenografts from both cell lines by chronic nicotine that was reversed by treatment with GABA.
Nicotine also significantly increased the systemic levels of adrenaline, noradrenaline and cAMP while decreasing GABA. The protein levels of nicotinic acetylcholine receptors α4 and α7, p-CREB and p-ERK1/2 in the tumor tissue was significantly increased by nicotine and reversed by GABA. Nicotine additionally reduced the protein levels of both GAD isozymes in tumor tissue.
In summary, our findings suggest that nicotine-induced predominance of stimulatory noradrenaline and deficiency in inhibitory GABA similar to nicotine-addiction in the brain may contribute to the development of lung adenocarcinoma in smokers and that GABA may be useful for marker-guided prevention and adjuvant therapy for PAC and PDAC.
Supported by R01 CA042829 and R01 CA130888 with National Institutes of Health.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A6.
Abstract A78: Modifiers of serum vitamin D and prostate cancer risk in African Americans
Authors: Williams Erica H. , Agurs-Collins Tanya , Dodd Kevin W. , Kittles Rick A. 
Published: January 2011

Abstract
Background/Objective: Prostate cancer (PCa) is the most commonly diagnosed cancer among males in the United States. Compared to European American males, African American (AA) males are at increased risk for PCa and tend to have a more aggressive form of the disease. Recent laboratory studies have suggested deficiencies in vitamin D to be related with PCa risk. Serum levels of 25-hydroxyvitamin D [25(OH)D] are considered the best indicators of an individual's overall vitamin D status. However, vitamin D metabolism and physiology are modified by genetic and environmental factors such as ultraviolet radiation (UVR), skin color, diet, body mass index (BMI) and genes involved in vitamin D synthesis. The goal of this project is to study modifiers of serum 25(OH)D levels in order to improve our understanding of the role vitamin D plays on prostate cancer susceptibility in African Americans.
Methods: This case-control study consisted of AA men (N=250) accrued from a university hospital in Washington, DC. Serum levels of 25(OH)D and prostate specific antigen (PSA) levels were assessed. BMI was calculated as weight/height2 (kg/m2). Study participants completed UVR exposure and food frequency questionnaires. Skin color was measured using a reflectance meter. Logistic regression models were used to test for associations between 25(OH)D levels and PCa risk, adjusting for ancestry, age, skin pigmentation, dietary vitamin D, supplemental vitamin D, sun exposure, and other lifestyle factors. In addition, we used linear regression models to explore determinants of serum 25(OH)D levels, including dietary vitamin D intake, ancestry, skin pigmentation and UVR exposure.
Results: There were no significant baseline differences between cases and controls for serum 25(OH)D levels, dietary vitamin D and daily servings of dairy products. Baseline differences were found for age (p&lt;.001), alcohol intake (p&lt;.001) and supplemental vitamin D (p=.004). Multiple logistic regression analysis found no association with serum 25(OH)D levels and PCa risk. Preliminary analysis revealed that supplemental vitamin D (p=.004) and UVR exposure (p=0.03) were determinants of serum 25(OH)D level. Also, there were potential interactions between skin color, dietary vitamin D, serum 25(OH)D levels and risk for PCa.
Conclusion: Supplemental vitamin D and UVR exposure were modifiers of serum 25(OH)D levels. However, we did not observe any significant difference in serum 25(OH)D levels between AA PCa cases and controls. This is likely due to factors such as diet, skin color, BMI and UVR exposure which strongly could influence vitamin D levels and function. Understanding the role of vitamin D in PCa risk may help to explain the higher incidence of PCa among AA males.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A78.