bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5539: Snail expression is associated with epithelial to mesenchymal transition and a poor prognosis in malignant pleural mesotheliomas
Authors: Kobayashi Masashi , Huang Cheng-long , Sonobe Makoto , Kikuchi Ryutaro , Ishikawa Masashi , Imamura Naoto , Kitamura Jiro , Iwakiri Shotaro , Itoi Kazumi , Yasumizu Ryoji , Date Hiroshi
Published: August 2012

Introduction: Malignant pleural mesotheliomas (MPMs) are aggressive tumors with a poor prognosis. Regarding tumor histology, however, the survival has been reported to be lower in patients with non-epitheloid tumors than in those with epitheloid tumors. Therefore, in order to identify molecular targets for the treatment against MPM patients, we investigated several molecules associated with epithelial to mesenchymal transition, such as Snail, Twist, E-cadherin and N-cadherin. Methods: We studied one hundred and nine patients with MPMs, including 61 epitheloid tumors (55.9%), 21 sarcomatoid tumors (19.2%), 20 biphasic tumors (18.3%) and 7 desmoplastic tumors (6.4%). Immunohistochemical assays were performed to evaluate the intratumoral expressions of Snail, Twist, E-cadherin and N-cadherin. Results: Among 109 MPMs, 41 tumors (37.6%) were Snail-high tumors, 30 tumors (27.5%) were Twist-high tumors, 18 tumors (16.5%) were E-cadherin-positive tumors, and 35 tumors (32.1%) were N-cadherin-positive tumors. Regarding tumor histology, the nuclear expression of Snail expression was significantly higher in non-epithelioid tumors than in epitheloid tumors (P<0.001). Furthermore, the E-cadherin expression was significantly lower in Snail-high tumors than in Snail-low tumors (P=0.046). As a result, the E-cadherin expression was significantly lower in non-epithelioid tumors than in epitheloid tumors (P=0.013). In addition, the Snail expression was significantly higher in Twist-high tumors than in Twist-low tumors (P=0.007). The frequency of N-cadherin-positive tumors was also significantly higher in Twist-high tumors than in Twist-low tumors (P=0.005). Regarding patient survival, the overall survival was significantly lower in patients with Snail-high MPMs than in those with Snail-low MPMs (P=0.002), especially among patients with non-epitheloid tumors (P=0.009). A multivariated analysis also demonstrated that the nuclear expression of Snail was a significantly factor of a poor prognosis in MPM patients (P=0.014). Conclusions: Snail expression is associated with epithelial to mesenchymal transition and a poor prognosis in MPMs. The Snail could be a potential molecular target for the treatment of MPM patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5539. doi:1538-7445.AM2012-5539
Abstract 5694: Targeted photothermal-chemotherapy with doxorubicin-loaded hollow gold nanospheres directed at EphB4 receptors
Authors: You Jian , Xiong Chiyi , Li Chun
Published: August 2012

Photothermal ablation (PTA) is an emerging technique that uses near-infrared (NIR) laser light-generated heat to destroy tumor cells. Doxorubicin (DOX)-loaded hollow gold nanospheres (DOX@HAuNS) mediated simultaneous PTA of cancer cells and local drug release, resulting in enhanced antitumor activity. EphB4, a member of the largest family of receptor tyrosine kinases, is overexpressed in numerous tumors. The purpose of this study was to synthesize DOX@HAuNS conjugated to an EphB4 receptor-binding peptide, and evaluate the pharmacokinetics, biodistribution, and antitumor efficacy of the resulting EphB4-targeting DOX@HAuNS. A cyclic 17-mer peptide [c(TNYL-RAW) with high binding affinity to EphB4 was conjugated to DOX@HAuNS through a PEG linker. The cell uptake of c(TNYL-RAW)-conjugated Dox@HAuNS was examined in human ovarian cancer Hey cells over-expressing EphB4. The biodistribution tumor uptake of c(TNYL-RAW)-Dox@HAuNS was assessed at 24 h after intravenous injection in nude mice bearing Hey and A2789 ovarian cancers, and in nude mice bearing human MDA-MB231 breast tumors. Near-infrared (NIR) light-triggered Dox release in tumor-bearing mice was evaluated using a dual tracer-autoradiography technique. Antitumor effect was evaluated by measuring the tumor grow delay in mice bearing Hey ovarian cancer. In vitro, c(TNYL-RAW)-Dox@HAuNS were selectively taken up by Hey cells. This resulted in increased tumor uptake of targeted nanoparticles in all three EphB4-positive tumor models evaluated. Significantly higher cell killing effect against EphB4(+) A2780 cells was shown with DOX@c(TNYL-RAW)-HAuNS cells than with free DOX or DOX@PEG-HAuNS. In vivo, conjugation of c(TNYL-RAW) onto PEG-HAuNS did not cause significant change on pharmacokinetic properties of the nanoaprticles. DOX@c(TNYL-RAW)-HAuNS and DOX@PEG-HAuNS were almost completely eliminated from the blood at 48 h after injection. Treatment with targeted c(TNYL-RAW)-Dox@HAuNS followed by near-infrared laser irradiation (combined PTA and DOX therapies) resulted in significantly increased tumor growth control as compared to treatments with DOX@PEG-HAuNS-plus-laser (combined PTA and DOX therapies) and with PEG-HAuNS-plus-laser (PTA therapy alone). Mice in all treatment groups did not show lost in body weight, whereas free DOX caused ∼20% body weight loss at the equivalent DOX dose level. Targeted photothermal-chemotherapy exemplified by a single-agent nanoconstruct c(TNYL-RAW)-DOX@HAuNS is a promising approach to effective anticancer therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5694. doi:1538-7445.AM2012-5694
Abstract 5713: Significant systemic therapeutic effects of high-LET immunoradiation by 212Pb-Trastuzumab against prostatic tumors of androgen-independent human prostate cancer in mice
Authors: Tan Zongqing , Chen Pingping , Schneider Nathan , Glover Samuel , Cui Lingling , Torgue Julien , Rixe Oliver , Spitz Henry B. , Dong Zhongyun
Published: August 2012

Purpose The purpose of this study was to determine therapeutic effects and systemic toxicity of 212Pb-Trastuzumab in an orthotopic model of human prostate cancer cells in nude mice. Experimental Design TCMC-Trastuzumab was radiolabeled with 212Pb. The activity and integrity of 212Pb-Trastuzumab was confirmed by a competitive binding assay and SDS-PAGE analysis. Therapeutic effects were determined in an orthotopic model of human prostate cancer in nude mice. Body weight, blood cell counts, serum alanine transaminase (ALT), blood urea nitrogen (BUN), and tissue histology were examined to evaluate systemic toxicity of 212Pb-Trastuzumab therapy. Results The 212Pb-Trastuzumab generated from the procedure was intact and had high binding affinity with a dissociation constant (Kd) of 3.9 ± 0.99 nM. PC-3MM2 cells, which expressed relatively a lower level of Her2 both in culture and in tumors, were used in the study. A single injection of 212Pb-Trastuzumab reduced tumor growth by 60-80%, reduced aortic lymph node metastasis, and prolonged the survival of tumor-bearing mice. Treatment with 212Pb-Trastuzumab did not cause significant changes in body weight, serum SGPT and BUN, hematological profiles, and histological morphology of several major organs of tumor-bearing mice. Conclusion The data presented in this report demonstrated that the 212Pb-Trastuzumab therapy did not cause significant systemic toxicity and was very effective in retarding tumor growth and prolonging survival of mice bearing tumors that express very low levels of Her2. These findings suggest that 212Pb-Trastuzumab, used alone or in combination with other means, could be an effective modality for management of advanced human prostate cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5713. doi:1538-7445.AM2012-5713
Abstract 5719: Improvement of radiotherapy for glioblastoma by co-targeting PI3K and HSP90
Authors: Wachsberger Phyllis Rachelle , Lawrence Richard Y. , Liu Yi , Andersen Barbara , Dicker Adam P.
Published: August 2012

Introduction: Glioblastoma (GBM) tumors frequently contain mutations in the tumor suppressor gene, PTEN, leading to loss of PTEN activity. PTEN loss causes overactivation of the PI3K pathway, inducing inhibition of apoptosis and radioresistance. Heat-shock protein 90 (HSP90) is a molecular chaperone that is over-expressed in GBM and that has among its client proteins, PI3K and Akt. It was hypothesized that dual inhibition of Hsp90 and PI3K signaling would additively or synergistically radiosensitize GBM through inhibition of radiation-induced PI3K/Akt signaling, leading to enhanced apoptosis. This study investigated the radiosensitizing effect of the HSP 90 inhibitor, HSP990 in combination with the PI3K inhibitor, BKM-120 in U87 GBM xenografts. Methods: Human U87 (GBM) cells, null for PTEN, were studied. Radiosensitivity was determined by apoptotic assays (Annexin V kit) in vitro and by tumor growth delay studies in vivo. Immunoblots were performed to assess pAkt levels. HSP990 and BKM 120 were provided by Novartis Pharmaceuticals. Results: Apoptotic assays revealed the following percentages of cells undergoing apoptosis 48 hrs after treatments: radiation alone: 57%; HSP990 alone: 75%; HSP990 + radiation (RT): 86%; BKM120 alone: 59%; BKM120+ RT: 42%. The combination of BKM120 + HSP990 induced the highest percentage of apoptosis (89% of cell population). The addition of radiation to the combined drug treatment did not increase the percentage of cells undergoing apoptosis (66% for triple modality treatment vs. 89% for HSP990 + BKM120 treatment). In vivo, each individual treatment (RT, HSP990 or BKM120) slowed the rate of tumor growth compared with the control group and all pairs of treatments performed better than either of the component treatments alone (p<0.0001 for all comparisons). The combination of all three treatments performed significantly better than BKM+RTX and HSP+RTX (p=0.01 for both) but was not significantly better than BKM+HSP (p=0.06). Conclusions: The response of U87 glioblastoma to radiotherapy was enhanced in the presence of BKM120 and HSP990. Enhanced apoptosis contributed to the mechanism of cell death. This work was supported by a grant from Novartis Pharmaceuticals.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5719. doi:1538-7445.AM2012-5719
Abstract 572: Induction of NAD(P)H-Quinone oxidoreductase 1 by antioxidants in female ACI rats is associated with decrease in oxidative DNA damage and inhibition of estrogen-induced breast cancer
Authors: Bhat Hari K. , Singh Bhupendra
Published: August 2012

Exact mechanisms underlying the initiation and progression of estrogen-related cancers are not clear. Literature evidence and our studies strongly support the role of estrogen metabolism-mediated oxidative stress in estrogen-induced breast carcinogenesis. We have recently demonstrated that antioxidants vitamin C and butylated hydroxyanisole (BHA) or estrogen metabolism inhibitor α-naphthoflavone (ANF) inhibit 17β-estradiol (E2)-induced mammary tumorigenesis in female ACI rats. The objective of the current study was to identify the mechanism of antioxidant-mediated protection against E2-induced DNA damage and mammary tumorigenesis. Female ACI rats were treated with E2 in the presence or absence of vitamin C or BHA or ANF for up to 240 days. Nuclear factor erythroid 2-related factor 2 (NRF2) and NAD(P)H-Quinone oxidoreductase 1 (NQO1) mRNA and protein levels were suppressed in E2-exposed mammary tissue and in mammary tumors after treatment of rats with E2 for 240 days. This suppression was overcome by co-treatment of rats with E2 and vitamin C or BHA. Vitamin C and BHA significantly increased NQO1 levels after 120 days. 8-Hydroxydeoxyguanosine (8-OHdG) levels were higher in E2-exposed mammary tissue and in mammary tumors compared to age-matched controls. Vitamin C or BHA treatment significantly decreased E2-mediated increase in 8-OHdG levels in the mammary tissue. In vitro studies using silencer RNA confirmed the role of NQO1 in prevention of oxidative DNA damage. Our studies further demonstrate that NQO1 upregulation by antioxidants is mediated through NRF2.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 572. doi:1538-7445.AM2012-572
Abstract 5721: Garcinol, a histone acetyltransferase inhibitor, radiosensitizes cancer cells by inhibiting non-homologous end joining
Authors: Oike Takahiro , Ogiwara Hideaki , Nakano Takashi , Yokota Jun , Kohno Takashi
Published: August 2012

Purpose: Non-homologous end joining (NHEJ), a major pathway to repair DNA double-strand breaks (DSBs) generated by ionizing radiation (IR), requires chromatin remodeling at DSB sites through acetylation of histones by histone acetyltransferases (HATs). However, effects of compounds with HAT inhibitory activities on DNA damage response (DDR), including NHEJ and cell cycle checkpoint, as well as on the radiosensitivity of cancer cells remain largely unclear. Here, we investigated whether garcinol, an HAT inhibitor found in the rinds of Garcinia indica fruit (called mangosteens), has effects on DDR and whether it can be used for radiosensitization. Methods and Materials: The ability of garcinol to inhibit DSB repair, including NHEJ, was examined by two assays; the conventional neutral comet assay and a cell-based assay recently developed by us, in which the activity of NHEJ against DSBs on chromosomal DNA was evaluated. The effects on cell cycle checkpoint after IR were assessed by phosphorylation levels of checkpoint kinases CHK1 and CHK2, and histone H3. The radiosensitizing effect was assessed by clonogenic survival assay. The effects on apoptosis and senescence were examined by annexin V and Senescence-associated β-galactosidase (SA-β-Gal) staining, respectively. Results: Garcinol was shown to inhibit DSB repair, including NHEJ, without affecting cell cycle checkpoint. Garcinol radiosensitized A549 lung and HeLa cervical carcinoma cells with a dose enhancement ratio at 10% surviving fraction of 1.6 and 1.5, respectively. Cellular senescence induced by IR was enhanced by garcinol. Conclusion: These results suggest that garcinol is a radiosensitizer that inhibits NHEJ and facilitates senescence, without impairing activation of cell cycle checkpoint.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5721. doi:1538-7445.AM2012-5721
Abstract 5724: HER2-mediated resistance of breast cancer stem cells in HER2-negative/low breast cancer
Authors: Candas Demet , Fan Ming , Duru Nadire , Menaa Cheikh , Wen Yunfei , Xiao Kai , Eldridge Angela , Chromy Brett A. , Li Shiyong , Spitz Douglas R. , Lam Kit S. , Max Max S. , Li Jian Jian
Published: August 2012

Despite a recent trend toward improvement, breast cancer (BC) mortality remains high due to resistance of recurrent tumors. A major cause of recurrence is likely a micro-metastatic seeding of cells that developed resistance by activating intrinsic or acquired survival pathways. In this regard, HER2 expression and cancer stem cells (CSCs) are the major cause for recurrence and targeting HER2 is well considered in therapeutic regiments. However, clinical data showed that anti-HER2 also benifit HER2−/low BC patients, suggesting that tumor cells may acquire HER2 gene activation to survive. We have previously reported that NF-κB mediates radioresistance by controlling HER2 gene. Herein, we identified HER2-expressing BC stem cells (HER2+/CD44+/CD24−/low) in radiation-resistant HER2−/low BC cells, MCF7/C6. Matrigel invasion, tumor sphere formation and radioresistance were enhanced in the HER2 mediating radioresistant cells. About 10% of the CD44+/CD24−/low cells sorted from MCF7/C6 cells or irradiated xenografts showed co-expression of HER2/CD44, ALDH and high tumorigenicity compared to HER2−/CD44+/CD24−/low cells, suggesting that the induction of HER2 expression further increased the BCSC aggressiveness. In fact, clinical data indicates that cells co-expressing HER2/CD44 were increased in recurrent tumors (84.6%) compared to the primary tumors (57.1%). Proteomics analysis identified a unique profile of proteins including DNA repair, mitochondrial function, redox, mTOR pathways that may govern the resistance of HER2+/CD44+/CD24−/low CSCs. These results demonstrate that HER2-mediated BC resistance can develop at the level of BCSC. Thus, HER2-expressing BCSCs may serve as an effective target to treat BC recurrence even from primary HER2−/low tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5724. doi:1538-7445.AM2012-5724
Abstract 5730: Dosimetric properties of a new thermobrachytherapy seed with ferromagnetic core for treatment of solid tumors
Authors: Subramanian R , Parsai Ishmael E. , Bhoj Gautam R. , Shvydka Diana , John Feldmeier J.
Published: August 2012

Studies of the curative effects of hyperthermia and radiation therapy on treatment of cancer show a strong evidence of a synergistic enhancement when both radiation and hyperthermia modalities are applied simultaneously. Varieties of tissue heating approaches developed up to date still fail to overcome such essential limitations as an inadequate temperature control, temperature non-uniformity, and prolonged time delay between hyperthermia and radiation treatments. We propose a new self-regulating Thermobrachytherapy seed, which serves as a source of both radiation and heat for concurrent administration of brachytherapy and hyperthermia. The proposed seed is based on the BEST Seed Model 2301-I125, where tungsten marker core and the air gap are replaced with a ferromagnetic material. The ferromagnetic core produces heat when subjected to alternating electro-magnetic (EM) field and effectively shuts off after reaching the Curie temperature (TC) of the ferromagnetic material thus realizing the temperature self-regulation. We present the Monte Carlo study of dose rate constant and the other TG-43 radiation characteristic factors for the proposed seed. For the thermal characteristics, we studied a model consisting of 16 seeds placed in the central region of a cylindrical water phantom using a finite-element partial differential equation solver package “COMSOL Multiphysics”. The modeling result shows that temperature of the thermoseed surface rises rapidly and stays constant around TC of the ferromagnetic material. The amount of heat produced by the ferromagnetic core is sufficient to raise the temperature of the surrounding volume to the therapeutic range. The volume of the therapeutic temperature range increases with increase of frequency or magnetic field strength. These studies demonstrate that an optimal isothermal distribution can be achieved on a target volume to match with the radiation isodose distribution for the seed configuration by tuning frequency and intensity of the alternating magnetic field. The proposed combination seed model has a high potential for implementation of concurrent brachytherapy and hyperthermia.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5730. doi:1538-7445.AM2012-5730
Abstract 5732: Mercapturic acid excretion and N7-GA-Gua DNA adduct formation after low dose oral application of acrylamide to rats
Authors: Watzek Nico , Böhm Nadine , Feld Julia , Scherbl Denise , Berger Franz , Merz Karl-Heinz , Lampen Alfonso , Reemtsma Thorsten , Tannenbaum Steven R. , Skipper Paul L. , Baum Matthias , Richling Elke , Eisenbrand Gerhard
Published: August 2012

Acrylamide (AA), a genotoxic carcinogen (IARC class 2A), is a food contaminant formed by thermal treatment of food. The margin of exposure (MOE) of AA, representing the distance between the bench mark dose associated with 10% tumor incidence in rats and the estimated average human exposure, is considered to be low and of human health concern. After uptake, AA is partly converted by CYP450 2E1 into the genotoxic epoxide glycidamide (GA). GA forms DNA adducts, primarily at N7 of guanine (N7-GA-Gua). AA and its genotoxic metabolite GA are conjugated to glutathione and excreted via urine as mercapturic acids (MA), namely N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA), and N-acetyl-S-(2-hydroxy-2-carbamoylethyl)-cysteine (GAMA) which are used as biomarkers for exposure. Female Sprague Dawley (SD) rats were kept on an AA free diet. AA was given by gavage in a broad dosage range, covering single doses of 0.1-10,000 µg/kg bw. Formation of urinary MAs and of N7-GA-Gua DNA adducts in liver, kidney and lung was measured 16 h after application. The lowest dosage of 0.1 µg AA/kg bw did not result in significantly enhanced MA excretion, as compared to untreated controls, found to excrete about 0.8 nmol MA. Since the animals may have ingested at best 0.4 nmol AA/d with the diet, this findings suggests a background level of endogenously formed AA. At the lowest dosage (0.1 µg AA/kg bw), N7-GA-Gua adducts above the limit of detection (LOD, 0.2 adducts/10exp8 nucleotides) were not detected in any organ tested. At 1 µg/kg bw, enhanced adduct levels were found in kidney (around 1 adduct/10exp8 nucleotides) and lung (< 1 adduct/10exp8 nucleotides), but not in liver. At 10 and 100 µg/kg bw, adducts were found in all three organs, at levels not significantly different to those found at 1 µg AA/kg bw (about 1-2 adducts/10exp8 nucleotides). Taken together, the results of this in vivo study allow to conclude that exposure to single doses of AA in the range of human dietary exposure leads to N7-GA-Gua adduct levels in tissues of SD rats at the low end of steady state background DNA lesions of various origin in human and rat tissues. This study was supported by ISIC, the Institute for Scientific Information on Coffee.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5732. doi:1538-7445.AM2012-5732
Abstract 5738: Expression profiling of microRNA and mRNA on hepatic inflammation in high-fat induced murine model
Authors: Hur Won Hee , Choi Jung Eun , Kim Sung Woo , Hong Sung Woo , Lee Young Ki , Lyoo KwangSoo , Yoon Seung Kew
Published: August 2012

The inflammation has been identified as a risk factor for cancer and even as a means to prognose/diagnoses cancer at the inception of the inflammatory process. Therefore, it is necessary to discover novel molecules that might play a critical role in the regulation of inflammation, which can be the target of anti-inflammation. Recent reports indicate that microRNAs (miRNAs) have a significant role in the mechanism of inflammation in chronic inflammatory diseases. The goal of this study was to identify and characterize of miRNA in the regulation of inflammatory responses of high-fat induced inflammation mouse model. In this study, we established a mouse model of high-fat-diet-induced inflammation to gain understanding on the biological functions deregulated by aberrant gene expression based on miRNA and mRNA expression profiling analysis. And then we looked for direct miRNA targets by performing pair-wise correlation coefficient analysis on expression levels of mRNAs and by comparing these results with predicted miRNA targets from TargetScan5.1. We used quantitative PCR technology to evaluate the expression of miRNAs and mRNA on liver tissue. Inflammatory foci were observed over 6 months after high-fat induced inflammation mouse. In cDNA microarray analysis, total 2287 genes were differentially expressed between high-fat induced inflammatory group and normal group. Among those genes, the genes related-metabolic pathway were up-regulated at 3 months while those related inflammatory response were up-regulated at late stage of over 6 months in high-fat induced inflammation mouse model. Furthermore, we identified 15 new miRNAs in high-fat induced inflammation model by bioinformatics analysis and further confirmed their expression by stem-loop RT-PCR. GO analysis indicated that many of the identified miRNA targets may function in high-fat induced inflammation model. For three miRNAs (miR-34a, miR-21 and miR-1224), correlated genes were concordant with predicted targets. A gene set enrichment analysis on these genes demonstrated significant enrichment in biological processes related to lipid and glucose metabolism and inflammation. This study represents, to the best of our knowledge, the first integrated analysis of miRNA and mRNA expression in high-fat induced inflammation model. We identified a distinct profile of miRNAs of which expression differed between inflammation and normal, making these miRNAs candidate markers. Supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0014620).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5738. doi:1538-7445.AM2012-5738
Abstract 5739: Characterization of the metabolism and DNA adduct formation of 2-amino-9H-pyrido[2,3-b]indole in human hepatocytes
Authors: Nauwelaërs Gwendoline C. , Tang Yijin , Gu Dan , Fessard Valérie , Turesky Robert J. , Langouët Sophie A.
Published: August 2012

2-Amino-9H-pyrido[2-3-b]indole (AαC) is a heterocyclic aromatic amine (HAA) and considered to be a possible human carcinogen by the International Agency for Research on Cancer (IARC). Like other HAAs, AαC is metabolized in the liver and can undergo bioactivation to produce highly electrophilic derivatives that can form DNA adducts by covalent binding to DNA. Among the HAAs, AαC is of particular interest because it is present at high levels in tobacco smoke and ubiquitous in the environment. AαC was shown to form high levels of DNA adducts in primary cultured human hepatocytes. The adduct levels were higher than those formed by other HAAs such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and comparable to those derived from 4-aminobiphenyl (4-ABP), a known human carcinogen. An understanding of the metabolism of AαC and its potential to form DNA adducts would provide a better assessment of the human health risk posed by AαC. Indeed, the metabolism pathways of MeIQx, PhIP and AαC are different. These differences in metabolic processing of HAAs can lead to variable levels of DNA adducts formed in humans and impact the interindividual susceptibility towards these procarcinogens. Knowledge about the metabolism of AαC in humans is unknown. We have analyzed the role of human cytochromes P450, especially CYP1A2, in the metabolism of AαC and DNA adduct formation. The ring-oxidized 3-HO-AαC and 6-HO-AαC sulfate and glucuronide conjugates, AαC-N2-Gl, N2-acetyl-AαC and the glucuronide conjugates of 2-hydroxyamino-9H-pyrido[2,-3-b]indole (HONH-AαC) and the deoxyguanosine DNA adduct, dG-C8-AαC, were identified and quantified by liquid chromatography coupled with multistage mass spectrometry in human hepatocytes in primary culture. The levels of DNA adducts formed after a 24hr-treatment with AαC were (2 folds) lower when cells were pre-treated with furafylline, a specific CYP1A2 inhibitor; however, the levels of most of the metabolites formed were not significanly affected by furafylline. Our data suggests that CYPs other than CYP1A2 may be involved in AαC metabolism, while CYP1A2 is the main enzyme involved in the production of reactive metabolites leading to the formation of DNA adducts. The identification of CYPs and Phase II enzymes involved in AαC metabolism in human hepatocytes are under study to fully understand the health risk of AαC to humans.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5739. doi:1538-7445.AM2012-5739
Abstract 579: 3, 3′-diindolylmethane enhances the effectiveness of Herceptin by upregulation of miR-200 through down-regulation of FoxM1 in breast cancer cells
Authors: Ahmad Aamir , Ali Shadan , Sakr Wael , Rahman KM
Published: August 2012

Many patients with high levels of HER2/neu experience disease progression even when treated with Herceptin as a single agent. Current Herceptin-based combination therapies involving conventional chemotherapeutic drugs have been shown to increase survival rate in only a portion of patients with high levels of HER2/neu. Furthermore, these treatments are associated with several toxicities. Thus, there is a strong need for developing new tumor selective agents that can be co-administered with Herceptin successfully, and with minimal toxicity, to treat breast cancer patients whose tumors express high levels of HER2/neu. 3,3′-diindolylmethane (DIM), a cruciferous plant-derived and non-toxic chemopreventive agent, has been reported to selectively kill breast cancer cells without affecting normal cells and sensitizes breast cancer cells to chemotherapeutic agents. In this study, we evaluated the effects of Herceptin alone and in combination with DIM on cell viability, apoptosis and clonogenic assays in SKBR3 (HER2/neu overexpressing) and MDA-MB-468 (HER2/neu-negative) breast cancer cell lines. We found that DIM could sensitize breast cancer cells to Herceptin by significantly reducing cell viability, which was associated with the induction of apoptosis and significant inhibition of colony formation when compared with single agent treatment. These results were also consistent with the down-regulation of Akt and NF-κB. Mechanistic investigations revealed a significant upregulation of miR-200, which resulted in the reduction of FoxM1 expression in DIM plus Herceptin-treated breast cancer cells. These results provide experimental evidence, for the first time, that DIM plus Herceptin therapy could be translated to the clinic as a therapeutic modality to improve treatment outcome of patients whose tumors express high levels of HER2/neu.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 579. doi:1538-7445.AM2012-579
Abstract 59: Effects of Cdc42 overexpression on the developing mammary gland
Authors: Bray Kristi M. , Hwang Melissa , Brakebusch Cord , Vargo-Gogola Tracy Vargo-Gogola
Published: August 2012

The Rho GTPase Cdc42 is overexpressed and hyperactivated in human breast cancer; however, its precise role during normal mammary gland (MG) development and the stochastic process of mammary tumor formation in vivo remains unknown. We, therefore, investigated the effects of Cdc42 knockout and overexpression during mammary morphogenesis using conditional mouse models. Previously, we demonstrated that loss of Cdc42 prevents primary mammary acinus formation in a three-dimensional (3D) in vitro culture system. Defects in proliferation, survival, and polarity contributed to the aberrant phenotype. Furthermore, preliminary studies using MMTV-cre mice to conditionally delete Cdc42 in ∼30% of mammary epithelial cells (MECs) in the developing MG suggest that Cdc42 knockout MECs are outcompeted by wildtype MECs in vivo. To investigate the effects of Cdc42 overexpression on MG development, and ultimately tumorigenesis, we generated tetracycline-regulatable Cdc42 overexpressing mice. Interestingly, Cdc42 overexpression results in aberrant terminal end bud (TEB) morphogenesis, increased ductal branching, and ductal dilation, suggesting that Cdc42 overexpression increases MEC proliferation and invasion and may cause defects in cell adhesion and tight junctions. Consistent with these data, Cdc42 overexpressing MECs give rise to dysmorphic, invasive acini in 3D culture assays. Taken together, these data demonstrate that Cdc42 is a key regulator of proliferation and tissue architecture in the developing MG and suggest that Cdc42 overexpression may contribute to tumor formation by disrupting these processes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 59. doi:1538-7445.AM2012-59
Abstract 596: Combination of SAHA with dietary energy restriction for breast cancer prevention
Authors: Zhu Zongjian , Jiang Weiqin , McGinely John N. , Neil Angie , Steiner Danna , Thompson Henry J.
Published: August 2012

Studies of human populations and experimental models indicate that dietary energy restriction (DER) inhibits the development of breast cancer. Of the several candidate mechanisms that DER is known to affect, one that is the widely observed is the induction of class III histone deacetylase sirtuin 1 (SIRT1). Evidence is controversial as to whether induction of SIRT1 is essential for DER's cancer preventive activity or if it limits DER's effectiveness. Therefore an experiment was designed to determine if suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, would diminish or enhance the cancer preventive activity of DER. Female Sprague Dawley rats (n=30/group) were injected with 1-methyl-1-nitrosourea (50 mg/kg) at 21 days of age and 7 days thereafter were randomized to groups and fed either control diet (AIN-93G) or that diet formulation supplemented with 0.1% SAHA (w/w). Other treatment groups were 40% DER, or 0.1% SAHA+40% DER; diets were a modification of AIN93-G that assured that the only variables among groups were DER and/or SAHA. Rats were fed respective diets for 8 weeks. An additional group, 0.1% SAHA+40%DER-release, was fed 0.1% SAHA+40%DER diet for 5 weeks and released to control diet for the final 3 weeks of the experiment. Both 40%DER or 0.1%SAHA+40%DER significantly reduced mammary cancer incidence, the number of mammary adenocarcinomas per rat, and cancer burden, as well as prolonging cancer latency (p<0.01). After releasing rats from SAHA+DER, the number of mammary adenocarcinomas per rat was significantly lower and the cancer latency was still significantly longer than the control gp (p<0.05). The mechanisms of the cancer inhibition include effects on circulating factors, IGF1/IGFBP3, insulin, adiponectin, leptin, and C-reactive protein. Thus it does not appear that SIRT1 induction is not requisite for the cancer preventive activity of DER. Rather inhibition of cancer was associated with cellular AMPK activation and Akt-mTOR down regulation by SAHA+DER with additional effects being mediated via FOXO3a. Supported by PHS grant CA52626 from the National Cancer Institute.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 596. doi:1538-7445.AM2012-596
Abstract 653: Passive smoking facilitate the risk of CIN1 in high risk HPV-positive women: Korean HPV Cohort Study
Authors: Kim Mi Kyung , Lee Binna , Mishra Siddhartha Kumar , Lee Jae Kwan
Published: August 2012

Cervical cancer is the second most common malignancy and the second most common cause of cancer-related death worldwide. Recently, the International Agency for Research on Cancer (IARC) of the World Health Organization in France completed reviewing all published studies related to cigarette smoke and cancer. Among several risk factors, tobacco smoking has been less explored despite it being a well-established risk factor for cervical precancer and cancer. The epidemiologic and biological studies suggest the association of passive smoking on the risk of cervical cancer; however, the evidence has been suggestive rather than sufficient to implicate the role of passive smoking in the etiology of cervical cancer among lifetime nonsmoking women. We investigated the associations between passive smoking and risk of cervical intraepithelial neoplasia (CIN), and cervical cancer in high risk HPV-positive women in the Korean HPV cohort study (KHPV). The KHPV recruited 1,306 women, aged 18-65, including HPV-positive women with normal cytology (n=577), CIN1 (n=419), CIN2/3 (n=165), and cervical cancer (n=145) from March 2006 to December 2009. Detailed information on passive smoking and other lifestyle factors were collected by questionnaires. Multinomial logistic analysis was performed to estimate multivariate-adjusted odds ratios. Ex- and current smoker had an increased risk of CIN1 (OR = 1.81; 95% CI: 1.26 ∼ 2.60) as compared to nonsmokers. The risk of CIN1 increased with increasing exposure time of passive smoking regardless of smoking after adjusting for potential confounder (OR = 2.09; 95% CI: 1.33 ∼ 3.28, p for trend = 0.0023). In non-smoker, the subject with passive smoking had an increased of CIN1 (OR = 1.48; 94% CI: 1.04-2.10, p for trend = 0.0276) after adjusting for potential confounder. In smoker, the effects of passive smoking were not statistically significant. Both of exposure time separated by two hours per day (p for trend = 0.0003), and 1 hour and 2 hours per day (p for trend = 0.0006) of passive smoking demonstrated significant associations with development of CIN1. This is the first study to demonstrate that passive smoking is an independent and combined risk factor of CIN1. HPV viral load and alcohol synergize to increase the risk of CIN1 among high-risk HPV-positive women.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 653. doi:1538-7445.AM2012-653
Abstract 672: Diabetes mellitus as a risk factor for prostate cancer progression after radical prostatectomy in an Hispanic population
Authors: Guerrios Lourdes , Perez Cynthia , Irizarry-Ramirez Margarita , Freedland Stephen
Published: August 2012

Abstract: Introduction and Objective: Prostate Cancer (PC) mortality is higher in Puerto Rico (PR) versus either US Hispanics or Caucasians, despite lower incidence. Also, PR has the highest self- reported prevalence of diabetes mellitus type 2 (DM) among all states and territories. Data on the association between DM and PC is mixed, but a prior study by our group suggested it may affect PC differentially by White vs. Black race. This has not been studied in Hispanic men. Methods: We conducted a retrospective analysis of men treated with RP between 2000-2010 at the San Juan, PR VA Hospital. Data collection is ongoing with 99 men identified to date treated between 2000 and 2003. The association between DM and PSA recurrence was tested using a Cox proportional hazards model. Results: Of the 99 abstracted to date, 21 had DM (21%). There were no differences in pre-operative features between men with and without DM (all p>0.14). Similarly, pathological features were similar between men with and without DM at surgery (all p>0.13). On unadjusted analyses, DM was significantly associated with increased risk of PSA recurrence (HR 2.81, 95% CI 1.31-6.07, p=0.008). These results did not vary significantly after adjusting for age, BMI, Gleason score, and PSA (HR 2.61, 95% CI 1.16-5.89, p=0.021). Updated data will be presented. Conclusion: In a radical prostatectomy cohort of Hispanic men from PR, our preliminary data showed that men with DM at the time of surgery had significantly higher rates of PSA recurrence. As this is the first study of DM and RP outcomes in Hispanic men, these results require validation both in our full cohort and in other datasets. If confirmed, further research is needed to better understand why DM is linked with aggressive PC in Hispanics and whether this information can be used to identify better prevention and treatment strategies for PC, especially for Hispanic men.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 672. doi:1538-7445.AM2012-672
Abstract 69: Genomic deletions clustered on chromosomes 8 and 9 are associated with pancreatic cancer progression
Authors: Sinha Arkadeep , Lenkiewicz Elizabeth , Barrett Michael , Haab Brian B.
Published: August 2012

Pancreatic cancer cells that have mesenchymal traits can be particularly migratory and resistant to chemotherapeutics. These cells are presumed to represent a more advanced and deadly population of cells relative to cancer cells with more differentiated, epithelial traits. The factors leading to the acquisition of a mesenchymal phenotype in pancreatic cancer are not well characterized. In this study, we tested the hypothesis that the development of a mesenchymal phenotype occurs selectively in tumor cells that harbor specific enabling genomic alterations. As a model system, we used pancreatic cancer cell lines that had either an epithelial-like or a mesenchymal-like phenotype when cultured in vitro, as defined by morphology and key molecular indicators. We used whole-genome comparative genomic hybridization to compare the genomic amplifications and deletions between 17 epithelial-like cell lines and 9 mesenchymal-like cell lines. An unbiased search revealed that 18 genes (each comprising at least three contiguous probes in a coding region) had alterations in a significantly greater percentage of the mesenchymal-like cells than the epithelial-like cells, whereas no genes had more frequent alterations in the epithelial-like cells. Sixteen of the 18 alterations were deletions, and 14 of the deletions were clustered in specific regions on chromosomes 8 and 9, suggesting the importance of those regions for suppressing de-differentiation. Some of the 18 genes were previously identified in studies of pancreatic cancer, such as SGCZ, KIAA1797 and SMAD4, while others were not. Certain genes showed a good correlation between DNA copy number and mRNA expression, providing evidence for the functional importance of those alterations. The known functions of the 18 genes include cell cycle control, cell membrane homeostasis, immune system regulation, and TGF-β pathway transduction, the deletion of which might provide improved survival advantage and cell structure modification required for metastasis. These findings support the concept that mesenchymal-like cancer cells are genetically more progressed than their epithelial-like counterparts and provide leads on the genomic hits that enable such progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 69. doi:1538-7445.AM2012-69
Abstract 7: Knockdown of EGFR to investigate its therapeutic potential for treatment of non-small cell lung cancers
Authors: Soh Junichi , Shien Kazuhiko , Ueno Tsuyoshi , Tsukuda Kazunori , Suda Kenichi , Kubo Takafumi , Furukawa Masashi , Muraoka Takayuki , Maki Yuho , Tanaka Norimitsu , Yamamoto Hiromasa , Kiura Katsuyuki , Mitsudomi Tetsuya , Toyooka Shinichi , Miyoshi Shinichiro
Published: August 2012

Background: Epidermal growth factor receptor (EGFR) is a transmembrane protein consisting of an extracellular ligand-binding domain, and its activation leads to a multitude of effects including cell proliferation, cell differentiation, angiogenesis, metastasis, and antiapoptosis. EGFR can be a partner of heterodimer of other EGFR family such as HER2 and HER3. EGFR is often overexpressed in non-small cell lung cancer (NSCLC). Anti-EGFR agents including EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have considered to be effective for NSCLC when drug sensitive EGFR mutation is present. However, inherent and acquired resistances are major problems of EGFR targeting therapies. In this study, we knock-downed EGFR using small interfering RNAs (siRNAs) in NSCLC cell lines to examine the significance of targeting EGFR for NSCLC therapy. Materials and methods: We treated 14 NSCLC cell lines including nine EGFR mutant and five EGFR wild-type cell lines by geftinib or siRNAs for EGFR knock-down (siR-EGFR). Three cell line, PC-9-GR-N1, RPC-9, and HCC827-Met, were experimentally established as acquired resistant cells to gefitinib. The anti-tumor effect was determined by MTS or colony formation assay. The protein expression was evaluated using Western blotting. Results: All cell lines showed the expression of EGFR protein and siR-EGFR treatment down-regulated EGFR protein in all 14 cell lines. siR-EGFR suppressed cell viability in 7 of 9 EGFR mutant cells ranged from 8.0% to 73%. PC-9-GR-N1 and RPC-9 also showed inhibition. NCI-H1670 and HCC827-Met harboured EGFR mutation but were not inhibited. Of note, PTEN was deleted in NCI-H1670 and c-MET was amplified in HCC827-Met. Cell viability of all EGFR wild-type cells was not inhibited except NCI-H411. Conclusion: Our results indicated that EGFR can be the therapeutic target of NSCLC with EGFR activation. By contrast, targeting EGFR is not appropriate strategy for tumor of which EGFR is not activated even though EGFR is expressed.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 7. doi:1538-7445.AM2012-7