bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3453: Phylogenetic fingerprinting of the fecal microbiota in colorectal cancer patients
Authors: Brim Hassan , Zoetendal Erwin , Lee Edward , Nelson Karen , Torralba Manolito , Smoot Duane , Sears cynthia , Ashktorab Hassan 
Published: February 2011

Abstract
Colonic adenomatous polyps are common tumors occurring in ∼50% of Western populations with ∼10% risk of malignant progression. To date, the environmental exposures proposed to promote the development of colorectal cancer (CRC) have been primarily dietary agents. However, the local environment to which the colonic mucosa is exposed is created by the bacterial microbiota of the colon and their metabolic products that include toxins. A member of the Bacteroidetes division, Bacteroides fragilis is a common human commensal, occupying a mucosal niche in the colon. One molecular class of B. fragilis, enterotoxigenic B. fragilis (ETBF) induces polyp formation in Min (multiple intestinal neopplasia) mice through a STAT3 pathway.
Here we analyzed fecal DNA for gut flora composition in African Americans (n=12) with colon adenoma. A 16S rDNA cloning/sequencing experiment revealed that patients with colon adenomas have a higher rate of Bacteroides bacteria than healthy ones. These data was further confirmed using a HITChip (Human Intestinal Tract Chip) where samples from adenoma patients tended to cluster together pointing to common bacterial profiles.
STAT3 induced in adenoma and tumor by IHC, indicating, signal activation perhaps through ETBF like bacteria.
In conclusion, High throughput and sequencing approaches may help to better detect gut flora components including Bacteroides fragilis that induces colorectal carcinogenesis. In addition, the STAT3 expression results would confirm possible ETBF involvement on colon cancer risk via activating STAT3 downstream factor and molecules that are known to play a key role in the regulation of epithelial proliferation
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 3453.
Abstract 3455: Arsenic trioxide modulates DNA synthesis and apoptosis in lung carcinoma cells
Authors: Walker Alice M. , Stevens Jacqueline J. , Tchounwou Paul B. 
Published: February 2011

Abstract
Arsenic trioxide, the trade name Trisenox, is a drug used to treat acute promyleocytic leukemia (APL). Studies have demonstrated that arsenic trioxide slows the cancer cells growth. Although it has been reported that arsenic acts on cells by influencing numerous signal transduction pathways, cell cycle progression, and/or apoptosis, its apoptotic mechanisms are very complex. The primary objective of this research is to evaluate the effects of arsenic trioxide on DNA synthesis and to determine whether arsenic induced-apoptosis is mediated via caspase activation, p38 mitogen-activated protein kinase (MAPK), and cell cycle arrest. To achieve this goal, the lung cancer (A549) cells were cultured following standard protocol, and exposed to various doses (0, 2, 4, and 6 µg/ml) of arsenic trioxide for 48 h. The effect of arsenic trioxide on DNA synthesis was determined by [3H]thymidine incorporation assay. Apoptosis was determined by caspase-3 fluorescein isothiocyanate (FITC) assay, and immunoblot analysis (p38 MAP kinase activity). The cell cycle analysis was evaluated propidium iodide assay. [3H]Thymidine incorporation assay revealed dose-related cytotoxic response at higher levels of exposure. Our findings revealed that arsenic trioxide modulated caspase 3 activity and induced p38 map kinase activation in lung carcinoma (A549) cells. The data revealed no cell cycle arrest at the sub-G0 in A549 cells when treated with arsenic trioxide.
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 3455.
Abstract 3456: Characterization of dibenzo[a,l]pyrene-trans-11,12-diol glucuronidation by UDP-glucuronosyltransferases
Authors: Olson Kristine C. , Sun Dongxiao , Chen Gang , Sharma Arun K. , Amin Shantu , Ropson Ira J. , Spratt Thomas E. , Lazarus Philip 
Published: February 2011

Abstract
A procarcinogen found most notably in tobacco smoke is dibenzo[a,l]pyrene (DB[a,l]P), which can be further metabolized into its epoxide, diol, and carcinogenic diol-epoxide forms. DB[a,l]P metabolites are some of the most potent carcinogens of the polycyclic aromatic hydrocarbon (PAH) family of compounds due to a structural feature called the fjord region. The activated metabolites of DB[a,l]P bind mostly to deoxyadenosine in DNA to form stable adducts, which can potentially lead to DNA damage. UDP-glucuronosyltransferase (UGT) enzymes mediate the attachment of a UDP-glucuronic acid to a wide variety of endogenous and exogenous substrates including several carcinogens, resulting in increases in water solubility and elimination of the carcinogen from the body. The focus of the current study was to examine the detoxification of the carcinogenic diol form (DB[a,l]P-trans-11,12-diol) by glucuronidation. In order to understand the metabolism of this potent PAH by human UGT enzymes, HEK293 cell lines over-expressing individual UGTs were screened for glucuronidation activity toward DB[a,l]P-11,12-diol. Glucuronide products were quantified using an ultra-performance liquid chromatography (UPLC) method. Six UGTs (UGTs 1A1, 1A7, 1A8, 1A9, 1A10 and UGT2B7) were found to be highly active. Three glucuronide conjugates were observed in activity assays with UGT1A1 and 1A10, while only two glucuronides were formed with UGTs 1A7, 1A8, 1A9, and 2B7. Enzyme kinetic analysis indicated that UGT1A9 is the most active isoform among all the UGTs, exhibiting the highest Vmax/Km for the two glucuronide products it formed. These results suggest that multiple UGTs are involved in stereospecific glucuronidation of DB[a,l]P metabolites in humans. In addition to the further characterization of (DB[a,l]P-trans-11,12-diol) glucuronide conjugates, studies examining the role of polymorphisms in active UGTs on cancer risk are currently on-going.
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 3456.
Abstract 3472: Inhaled carcinogen induced lung cancer in mice
Authors: Zou Yiyu , Qiu Xuan , Perez-Soler Roman 
Published: February 2011

Abstract
Inhaled carcinogen-induced lung cancer originates at the bronchial epithelium. Traditional animal models with tumor grafting or intraperitoneal/intravenous injection of tobacco carcinogens either lack the natural stages of tumor initiation and progression, or lack the advantage of modeling the disease through direct exposure of the airway epithelium to the causative agents. To overcome these problems, we used intratracheal inoculation of the major tobacco carcinogens benzo[a]pyrene (BP) and nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to induce lung premalignancy and lung cancer in two different strains of mice. This mouse model of inhaled carcinogen-induced lung cancer consistently mimics the carcinogenesis process in tobacco-induced human lung cancer that progresses through a series of identifiable histopathological stages. In our model the lung carcinogenesis clearly progresses through three different stages: 1. Early transitional stage with no pathological lesions (0-15 weeks after first dose of the carcinogens); 2. Premalignant stage with dysplasia in the lungs in 100% of both A/J and ICR mice at 16 weeks after the first dose of the carcinogens; 3. Malignant stage with tumor nodules developed in the lungs in 100% of A/J and &gt; 60% of ICR mice at 20-24 weeks. We have been using this model in trying to identify key molecular players in each stage that could possibly serve as therapeutic targets for lung cancer treatment. Currently it is one of best available models for studying environmental carcinogen-induced lung cancer and warrants further characterization. Future studies using this model are expected to enhance our understanding of the disease and facilitate our efforts of developing early therapeutic interventions. Supported by NIH grants CA96515 and CA104297.
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 3472.
Abstract 3474: Formation of myosmine under oxidation of nicotine
Authors: Zwickenpflug Wolfgang , Hoegg Christof 
Published: February 2011

Abstract
Nicotine and myosmine are alkaloids in tobacco products at which nicotine occurs in 200fold higher concentrations than myosmine. Nicotine is restricted on tobacco mainly, but myosmine is widespread in the biosphere and food materials additionally. Activation of nicotine showed amongst others N-nitrosation conversion to a compound class, the tobacco specific N-nitrosamines (TSNA). N’-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) represent nicotine derived substances. These are assumed to be responsible for tumorigenesis and cancer disease, especially from the lung after activation to highly reactive intermediate species pyridyloxobutanone (POB). POB is known in the context of CYP 450 dependent activation of TSNA and was detected in DNA of tissues from laboratory animals, after TSNA application. The POB-DNA adducts release under hydrolysis 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) which was observed also during myosmine metabolism in rats, under N-nitrosation and under peroxidation procedures of this compound. Partially, nicotine and myosmine seem to be metabolized on similar way and support assumption from employment of identical CYP450 isozymes. Oxidation processes of nicotine and myosmine employing non CYP450 dependent systems undergoe different pathways involving N or N’ ring positions of their pyridine and pyrrole structures. Peroxidation of nicotine is reported under formation of nicotine N-oxides mainly. First results of finding higher myosmine contents in cigarette filter tips from smoked in relation to unburned cigarettes gave rise to deliberation of possible conversion of nicotine to myosmine. Following, (−)-nicotine in concentrations equivalent to amount in cigarettes 4.9-5.5µmol was incubated with hydrogen peroxide at 37°C and analyzed. To simulate the assumed reaction on biological systems, (−)-nicotine was incubated with horse radish peroxidase (HRP) and occurence of the relevant compounds analyzed. The assays were directly measured with high pressure liquid chromatography (HPLC) instrumentation and confirmed by cochromatography with respective standard compounds. Our results showed formation of myosmine under peroxidation from (−)-nicotine. This would mean conversion of nicotine to myosmine releases activated methyl-species, which could undergo protein or DNA methylation. This possible effect would indicate ability of nicotine to become activated not only as nitrosated but also as peroxidated species. Additional experiments are demanded to elucidate possible carcinogenic risk of nicotine conversion to myosmine. Acknowledgement: This work was supported by DFG grant 59/2-2
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 3474.
Abstract 3486: Interaction of flaxseed oil with trastuzumab in HER2 overexpressing human breast tumors (BT-474)
Authors: Mason Julie K. , Chen Jianmin , Thompson Lilian U. 
Published: February 2011

Abstract
BACKGROUND: Trastuzumab (TRAS) is a first line therapy for breast tumors that overexpress the human epidermal growth factor receptor 2 (HER2) but tumors develop resistance within one year of treatment. Flaxseed oil (FO) rich in n-3 fatty acid alpha linolenic acid (ALA) has been shown to reduce HER2 expression and signalling in estrogen receptor positive human breast tumors. Our objective was to determine whether combining dietary FO with TRAS treatment will enhance TRAS effectiveness in reducing tumor growth.
METHODS: Ovariectomized mice with established HER2 overxpressing tumors (BT-474) and estrogen pellet implant were fed the basal diet (BD) (control) or treated with TRAS (1 or 2.5mg/kg body weight) and fed either the BD or BD supplemented with 4% FO for 4 weeks. Palpable tumor area was measured weekly. After animal sacrifice, excised tumors were analyzed using immunohistochemistry for cell proliferation (Ki-67) and apoptosis and using Western blot analysis for HER2, MAPK and Akt.
RESULTS: Tumors in the control, TRAS1, TRAS2.5, and TRAS1+FO, had palpable tumor areas that significantly increased (p&lt;0.05) by 164%, 104%, 60% and 107%, respectively at the end of the study compared to week 0 while tumors in the FO+TRAS2.5 group did not significantly increase in size. FO+TRAS2.5 treated tumors also had significantly lower (p&lt;0.05) palpable tumor area compared to the TRAS2.5 and other treated tumors at week 4. There was no difference in palpable tumor area between TRAS1 and FO+TRAS1 treated tumors. FO+TRAS2.5 caused a 39% greater increase in apoptosis (p&lt;0.05) and a 61% greater reduction in cell proliferation (p&lt;0.05) compared to TRAS2.5 treatment alone. Western blots support these results and indicate enhanced reductions in HER2, MAPK and Akt expression when TRAS2.5 treatment was combined with dietary FO.
CONCLUSIONS: ALA-rich FO enhanced the effectiveness of TRAS at 2.5mg/kg in reducing tumor growth and the mechanisms may involve reduced cell proliferation and increased apoptosis through modulation of HER2 signalling pathways. This is significant as it could lead to a simple, inexpensive complementary treatment for HER2+ patients being treated with TRAS.
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 3486.
Abstract 349: PI3K inhibitor GDC-0941 synergizes with mTOR inhibitors by blocking negative feedback and causes distinct effects on signaling and apoptosis compared to a dual PI3K/mTOR inhibitor
Authors: Vijapurkar Ulka , Robillard Liliane , Friedman Lori S. , Belvin Marcia P. 
Published: February 2011

Abstract
Background: The PI3K/Akt/mTOR pathway is deregulated in many cancers. and activation of Akt leads to the stimulation of cell survival and proliferation pathways. Akt activation also regulates mTOR to control cell growth in response to growth factors and nutrients. The PI3K pathway is therefore an attractive target for cancer therapy. Multiple targeted inhibitors of PI3K, mTOR and PI3K/mTOR are currently in clinical trials, whileTORC1 inhibitors including rapamycin and analogs are approved. In this study we assessed the consequence of the combination of a PI3K inhibitor, GDC-0941, plus a TORC1 or TORC1/2 inhibitor compared to dual PI3K/mTOR inhibitor, in cancer cell lines with different genetic backgrounds. Method: We analyzed the effects of PI3K, TORC1 or TORC1/2 inhibition alone or in combination on the viability, cell cycle profile and apoptosis of cancer cell lines with varying PI3K, PTEN, K-ras, and LKB status. Effects on signaling were analyzed by measuring the phosphorylation of signaling proteins by reverse phase protein array and other techniques. Effects on viability and apoptosis were assessed, along with a calculation of synergy for combinations. Results: Inhibition of PI3K with GDC-0941 or a dual PI3K/mTOR inhibitor inhibited proliferation of cancer cell lines and in certain tumor lines induced apoptosis. Treatment also resulted in the inactivation of downstream markers including pAKT, pPRAS40 and pS6. TORC1/2 inhibition resulted in a potent inhibition of pS6, however it had differential effects on phospho-AKT and survival proteins pBad and pGSK3b, likely due to the release of the negative feedback regulation. The signaling effects demonstrated by TORC1/2 inhibition also differed from TORC1 inhibition by rapamycin. Inhibition of mTOR resulted in a cytostatic response in all lines tested. Combination of PI3K and mTOR inhibitors (either TORC1 or TORC1/2) caused a significant decrease in cell viability, enhanced apoptosis and caused a greater, sustained knockdown of the signaling pathway. However, treatment with a dual PI3K/mTOR inhibitor led to slight but consistently lower levels of apoptosis than the combination of the separate agents. There were also differences in phosphoprotein status of some of the pathway components. Conclusion: Inhibiting multiple nodes within the same signaling pathway is synergistic and can be an effective strategy to enhance potency in cancer cells. However, combinations of selective targeted agents do not necessarily cause identical effects as a single molecule that inhibit multiple targets simultaneously.
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 349.
Abstract 3490: Selective estrogen receptor modulators enhance efficacy of small molecule CDK inhibitors on human breast cancer cells differing in the expression of ER
Authors: Wesierska-Gadek Jozefa , Zulehner Nora , Komina Oxana , Maurer Margarita 
Published: February 2011

Abstract
Inactivation of cyclin-dependent kinases (CDKs) by pharmacological inhibitors is a very effective weapon against malignant cells. Roscovitine (ROSC), a selective CDK inhibitor primarily affecting CDK2, CDK1, and CDK7, reduces the number of human cancer cells in a concentration-dependent manner. At lower doses ROSC arrests cell cycle progression and at higher doses it induces apoptosis. ROSC inhibits efficiently proliferation of human ER+-ve MCF-7 breast cancer cells by induction of cell cycle arrest at the G2/M transition [1] and concomitantly initiates apoptosis by a p53-dependent pathway [2]. However, the effect of ROSC was much weaker in MCF-7 cells maintained in the presence of estrogen-mimicking compounds [3]. Therefore, we decided to examine the action of selective CDK inhibitors on other breast cancer cell lines differing in the status of p53 and ER and to prove the impact of selective estrogen receptor modulators (SERMs) on the efficacy of ROSC and olomoucine II (OLO II), a new pharmacological CDK inhibitor. ROSC and OLO II were effective on all tested breast cancer cell lines. They arrested MCF-7 and BT-20 cells at G2/M transition and SKBR3 cells in G1 phase and additionally induced apoptosis. The effect of the inhibition of CDKs on distinct cell cycle regulators and pro-survival factors was studied. Interestingly, SERM strongly affected all tested cell lines irrespective of their ER status. Its combination with CDK inhibitors had a different impact. It enhanced G1 or G2 arrest. Our results provide evidence that both CDK inhibitors exert a strong anti-proliferative and pro-apoptotic effect and that their mode of action depends on the cellular context. Moreover, our findings demonstrate that pharmacological CDK inhibitors can be combined with anti-estrogen therapy. The strong effect of anti-estrogens on ER-negative cancer cells indicates that SERMs crosstalk with other steroid hormone receptors.
[1] Wojciechowski J. et al. 2003. Rapid onset of nucleolar disintegration preceding cell cycle arrest in roscovitine-induced apoptosis of human MCF-7 breast cancer cells. Int J Cancer 106: 486-95.
[2] Wesierska-Gadek J. et al. 2005. Roscovitine-induced up-regulation of p53AIP1 protein precedes the onset of apoptosis in human breast cancer cells. Mol Cancer Ther 4: 113-124.
[3] Wesierska-Gadek J. et al. 2006. Phenol red reduces ROSC mediated cell cycle arrest and apoptosis in human MCF-7 cells. J Cell Biochem. 98: 1369-1379.
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 3490.
Abstract 351: Mutations of genes in the c-Kit receptor tyrosine kinase signaling pathway are inactive in adenoid cystic carcinoma of the salivary glands: Implications for c-Kit targeted therapy
Authors: Tetsu Osamu , Phuchareon Janyaporn , Chou Annie , Cox Darren P. , Eisele David W. , Jordan Richard CK 
Published: February 2011

Abstract
Adenoid cystic carcinoma (ACC) is a malignant salivary gland tumor well-known for spreading in wide local area and invasion of vital structures of the head and neck. Unfortunately, conventional therapies have not improved longer-term survival, resulting in significant morbidity and a very low overall survival rate. Improved systemic therapies are clearly needed for this population. ACC tumors overexpress the receptor tyrosine kinase c-Kit, which is thought to be a therapeutic target. However, the role of c-Kit in the pathogenesis of ACC is not currently understood. We addressed this question through a functional genomic study with 17 sporadic ACC tumor specimens. We found heterogeneous missense mutations in three genes in the c-Kit signaling pathway, although mutations were identified at a low frequency. Two ACC tumors had distinct missense mutations in the gene KIT, resulting in G664R and R796G amino acid substitutions in the c-Kit kinase domain. Furthermore, two ACC tumors without KIT mutations had missense mutations in either KRAS or BRAF, causing S17N K-Ras and V590I B-Raf mutants. KRAS and BRAF are downstream effectors of c-Kit. We explored the functional consequences of these amino acid substitutions and found that all of c-Kit, K-Ras and B-Raf mutations in our ACC samples were inactive. These observations suggest that the c-Kit signaling pathway must be dispensable for maintaining established ACC. As a result, we believe that selective c-Kit inhibition is not a suitable treatment for the patients.
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 351.