bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5045: The Hh inhibitor IPI-926 inhibits relapse of a non-small cell lung cancer xenograft model following treatment with an EGF-R targeted tyrosine kinase inhibitor
Authors: Mandley Everton , White Kerry , Faia Kerrie , Travaglione Veronica , Read Margaret , McGovern Karen , MacDougall John R.
Published: February 2011

The Hedgehog (Hh) pathway plays a key role in multiple types of cancer, either by mutational activation of the pathway in tumor cells or by ligand-dependent signaling to the tumor cells or paracrine signaling between tumor cells and the tumor microenvironment. We have previously shown in a primary model of SCLC that the Hh pathway inhibitor IPI-926 prevents tumor relapse after regression of the tumor with chemotherapy (Travaglione et al., AACR 2009). To investigate whether tumor regression with a targeted agent could elicit a similar response as that seen with chemotherapy, two NSCLC lines (H1650 and HCC827), with activating mutations in the EGFR were evaluated. NSCLC cell lines bearing mutant EGFR are exquisitely sensitive to EGFR kinase inhibitors. Upon treatment with gefitinib in vitro, HCC827 increased the expression of Indian and Sonic hedgehog ligands 10-fold, as measured by qRT-PCR. When grown in mice as subcutaneous xenografts, H1650 tumors regressed following treatment with the EGFR inhibitor gefitinib (40 mg/kg every day) for 7 days. The gefitinib-treated mice were then administered either vehicle or IPI-926 at 40 mg/kg every other day for three weeks, and in this setting IPI-926 treatment led to a 65% decrease (p=0.0104) in tumor volume compared to vehicle-treated mice. Conversely, tumors that had not been regressed with the EGFR TKI showed no response to the Hh pathway inhibitor, similar to our previous results in SCLC with chemotherapy. Studies are ongoing to define the mechanism of action of IPI-926 in this setting. When grown in mice as subcutaneous xenografts, these tumor cells produce Shh ligand in conjunction with stromal Gli-1 expression in the murine stroma. Stromal Gli-1 expression is inhibited by treatment with IPI-926, indicating that Hh ligand produced by NSCLC tumor cells signals to stroma in a paracrine manner. Together with our previous results in SCLC, these data suggest that therapeutic inhibition of the Hh signaling pathway might be an important strategy to extend progression free survival in patients who initially respond to therapy but later relapse, and that this paradigm is applicable to multiple cancer types and treatment modalities.

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 5045.
Abstract 5181: Forced hemidesmosome assembly blocks pancreatic cancer cell invasiveness
Authors: Laval Séverine , Laklai Hanane , FanJul Marjorie , Pucelle Mélanie , Susini Christiane , Pyronnet Stéphane , Bousquet Corinne
Published: February 2011

Hemidesmosomes (HDs) play a critical role in epithelia integrity by anchoring epithelial cells to the basement membrane (BM). These structures, present at the basal cell surface, link the intracellular intermediate filament network with the extracellular laminins of the BM. Interestingly, HDs are frequently lost in cancer cells, thereby facilitating epithelial tumor cell detachment from the BM.

Surprisingly, we here provide evidence that a strong immunoreactivity for the integrin α6β4 and BP180, two specific hemidesmosomal proteins, is observed in human pancreatic ductal adenocarcinoma cells, where their function served paradoxically to stimulate migration and invasion. Using human pancreatic cancer cells in culture, we described molecular events explaining why these proteins are hijacked from their primary function and, importantly, how to force back the reassembly of HDs, thereby decreasing cancer cell migration and invasion.

This is achieved by introducing in these cells the somatostatin receptor sst2, whose expression is lost in 90% of pancreatic cancers, and which we have shown to have oncosuppressive functions including inhibition of tumor progression and metastasis. Cell treatment with somatostatin forced HDs reassembly by stimulating two separate critical events, as demonstrated in pancreatic cancer cells and in migrating keratinocytes: 1- the dephosphorylation of the α6β4 integrin which drives its relocalization from lamellipodia, where it is delocalised upon its phosphorylation by growth factors in migrating cells, to HDs; 2- the inhibition of the cleavage of BP180 into its pro-migratory BP120 form, which is here shown to account for the strong BP180 immunoreactivity observed in human pancreatic tumor samples as compared to normal pancreas where the full-length BP180 form is mostly expressed. BP180 cleavage into BP120 is here shown to rely at least on the activity of the MMP-9 metalloprotease whose activity is inhibited by sst2. Strikingly, knocking-down BP180 expression (siRNA) impairs somatostatin-induced HDs assembly in sst2-expressing cells. Interestingly, BP180 siRNA partially revert sst2 inhibitory role on in vitro and in vivo cell migration and invasion, as demonstrated using the chick chorioallatoic membrane model whereby tumor progression of pancreatic cancer cell xenografts is monitored. We have identified novel and original mechanisms for somatostatin-activated sst2 to revert cancer cell pro-migratory phenotype by facilitating HD assembly and cancer cell anchorage to the BM.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

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 5181.
Abstract 558: Constitutive activation of p38 MAPK signaling in tumor cells induces osteolytic bone lesions via regulating bone marrow microenvironment
Authors: Yang Jing , Yi Qing
Published: February 2011

Bone residing tumor cells cause osteolysis, characterized with severe bone pain, multiple fractures and hypercalcemia in patients. While it has been proposed that tumor cells activate osteoclasts and/or inhibit osteoblasts, leading to bone resorption, the mechanism underlying tumor-induced osteoclastogenesis activation in bone marrow microenvironment, which causes osteolytic bone lesions, is yet to be elucidated. P38 mitogen-activated protein kinase (MAPK) is commonly constitutively activated in malignant osteolytic tumors. We hypothesize that constitutive activity of p38 MAPK in tumor cells might contribute to osteolytic bone lesions via regulating bone marrow microenvironment. For this purpose, we applied of small hairpin RNAs (shRNAs) to disrupt p38 MAPK activity in myeloma ARP-1 and bone metastatic breast cancer MDA-MB-231 cells. To evaluate the role of tumor p38 MAPK in bone lesions, tumor cells with p38 MAPK-shRNAs or control vectors were intravenously injected to SCID mice. Lytic lesions in tibial bones were measured by radiograph and μ-CT, and further confirmed by histological examination. The results showed that lytic bone lesions were found in mice bearing of tumor cells with control vectors. In contrast, no or less bone lesions were found in mice with shRNA-expressing tumor cells. Moreover, decrease of osteoclast amounts covered bone surface, as well as circulating levels of collagen type I (bone resorption marker) and TRAP5b (active osteoclast marker), but increase of osteoblast amounts, and osteocalcin (bone formation marker) and ALP (active osteoblast marker), were found in those mice injected with shRNA-tumor cells. Noticeably, tumor p38 MAPK enhanced osteoclast differentiation and activity, as well as inhibited osteoblast maturation and function in vitro. However, disruption of p38 MAPK activity in tumor cells did not affect tumor growth and tumor cell homing to bone. We further identified that tumor p38 MAPK-derived monocyte chemotactic protein-1 (MCP-1) and dickkopf-1 (DKK-1) induced bone lesions via activation of RANK/RANKL-mediated NFκB, p38 MAPK and ERK1/2 signaling pathways. In conclusion, our results elucidate a novel mechanism that tumor p38 MAPK activity regulates bone marrow microenvironment and contributes to tumor-induced osteolytic bone lesions. Thus, inhibition of p38 MAPK signaling in tumor cells may have an important implication to treat bone lesions in patients with osteolytic tumors.

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 558.
Abstract 5654: Novel changes in colonic epithelial junctional complexes precede onset of colitis in response to Citrobacter rodentium infection
Authors: Ahmed Ishfaq , Chandrakesan Parthasarathy , Umar Shahid
Published: February 2011

Activation of β-catenin is recognized as a critical early factor in tumorigenesis. Citrobacter rodentium (CR) induces transmissible murine colonic hyperplasia (TMCH) and variable degrees of inflammation and necrosis depending upon the genetic background. Utilizing the CR-induced hyperplasia and/or inflammation in C3H/HeNHsd (C3H) inbred mice, we observed a dual phase wherein initially, an increase in proliferation at days 5 and 7 was followed by development of colitis at day 9 of TMCH. When sequential changes in proteins involved in adherens and tight junctions were analyzed in isolated colonic crypts, increasing levels of β-catenin, ZO-1, ZO-2 and claudin-2 were measured in TritonX100-soluble fraction at days 5 and 7 of TMCH, while E-cadherin and claudin-5 were mainly present in TritonX100-insoluble (cytoskeletal) pool. Interestingly, the cytoskeletal pools exhibited extensive degradation of β-catenin/E-cadherin/ZO-1 and ZO-2 but not of claudin-5 at days 5 and 7 of TMCH and preceded active colitis at day 9. Immunohistochemically, almost complete loss of membrane-bound β-catenin/E-cadherin and ZO-2 was recorded between 9 and 11 days post-infection. However, changes in permeability, as measured by increases in serum FITC-dextran levels, increased significantly at days 5 and 7 and peaked between day 9 and 11 post-infection paralleling bacterial dissemination to spleen and liver at these time points. Mechanistically, β-catenin translocated to the nucleus, interacted with increasing levels of T-cell factor-4 and upregulated downstream targets, cyclinD1 and c-myc thereby promoting crypt hyperplasia at days 5 and 7 of TMCH. When CR-infected mice were placed on: 6% pectin (source of colonic butyrate), 4% curcumin and 4% bael extract diets for 9 days starting 2 days post-CR infection, all three dietary interventions: i) reduced the morbidity and mortality of CR-infected C3H mice, ii) restored the junctional labeling of β-catenin/E-cadherin and ZO-2, iii) blocked increases in colonic permeability thereby preventing bacterial dissemination to distant organs and finally, iv) promoted β-catenin-independent increases in colonic crypt proliferation as was revealed by increased Ki-67 labeling. Thus, i) fragmentation of β-catenin/E-cadherin/ZO-1 and ZO-2 precedes loss of barrier function and onset of colitis and, ii) epithelial hyperproliferation in response to dietary interventions may facilitate epithelial recovery following inflammatory insult but may also promote mucosal priming for neoplasia. TMCH model therefore provides an excellent tool to separate the anti-inflammatory effects of dietary ingredients from pro-proliferatory functions in vivo.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5654.
Abstract 5662: RBAC, a modified form of Arabinoxylan from rice bran, impairs prostate cancer cell line proliferation, adhesion, and invasion in vitro
Authors: Brush Thomas P. , Trinh Sandra , Brawner Christopher M. , Ali Karriem H. , Hauke Ralph J. , Elkahwaji Johny E.
Published: February 2011

Introduction and objective: Prostate cancer (CaP) remains a major concern of public health in the United States. Standard treatment already in clinical use has a high curability rate in patients diagnosed with localized and androgen-dependent CaP; however, the progression to hormone refractory CaP is associated with disease relapse and poor prognosis. Hence, it is important to discover a novel strategy to prevent progression of disease whilst minimizing toxicity. One such promising approach is the dietary administration of certain natural compounds such as RBAC, a rice bran carbohydrate extract hydrolyzed by Shiitake mushroom enzymes. Several experimental studies have shown that RBAC in vitro increases both susceptibility and sensitivity of many human malignant cells to undergo apoptosis and to respond to chemotherapeutic drugs. Furthermore, RBAC immunomodulates natural killer (NK) cells in vitro and in vivo and enhances plasma cytokine production and anti-tumor activity in an in vivo mouse model. The aim of this study was to investigate the direct anti-tumor activity of RBAC on CaP cell lines and its impact on cell proliferation, adhesion, and invasion.

Methods: A panel of stromal and epithelial cell lines was used [Mesenchymal Stromal Cells (MSC) and CaP epithelial cell lines (PC3 and LNCaP)]. Cell lines were cultured in appropriate media supplemented with 10% FBS in a 5% CO2 incubator. Cells were treated for 24, 48, and 72h with different doses of RBAC (0-1000 µg/ml). The cell proliferation, adhesion, and invasion assays were determined by Trypan blue and AlamarBlue® proliferation assays, Cytotracker™ adhesion assay, and CytoSelect™ invasion assay, respectively.

Results: RBAC significantly decreased the epithelial cell proliferation of MSC, and CaP human malignant cell lines (PC3 and LNCaP) (p<0.05). The inhibition occurred in a dose-dependent manner and was more pronounced at high doses of RBAC (1000 µg/ml). Also, that same dose of RBAC impaired the MSC-PC3 cell adhesion and PC3 cell invasion in vitro.

Conclusions: These data suggest that RBAC exhibits an anti-proliferative and pro-apoptotic effects on CaP cell lines in vitro and might have therapeutic potential in advanced human CaP.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

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 5662.
Abstract 5727: B vitamins and reduced risk of lung cancer among 900 cases and 1800 controls from the EPIC cohort study
Authors: Brennan Paul J. , Johansson Mattias , Relton Caroline , Vollset Stein Emil , Midttun Oivind , Nygard Ottar , Ueland Per Mange , Vineis Paolo ,   on behalf of the EPIC cohort study.
Published: February 2011

Background: B-vitamins including folate help to ensure DNA integrity and the regulation of gene expression and may be associated with subsequent reduced cancer risk. One previous cohort study among smokers identified a substantial protective effect for vitamin B6 on lung cancer.

Methods: The EPIC study population included 385,747 participants from 23 centres in ten countries who completed a dietary questionnaire and provided a blood sample at recruitment between 1992 and 2000. 899 lung cancer cases were identified by 2006, with an average follow-up of 5 years, and matched to 1,770 controls for country, sex, date of birth and time of blood collection. Circulating concentrations were measured for four specific B-vitamins (B2, B6, folate and B12) as well as methionine, homocysteine and cotinine.

Results: After adjusting for matching variables and cotinine, a substantial decreasing risk for lung cancer was seen for increasing levels of B6 (relative risk of 4th vs 1st quartile [RR] = 0·44, with 95% confidence interval [CI] 0·33-0·60; p for trend [ptrend]<0·000001), as well as for methionine (RR=0·52, CI 0·39-0·69; ptrend<0·000001). Similar and consistent decreases in risk were observed for never, former and current smokers, indicating that results were not due to a smoking associated artifact. The magnitude of risk was also constant with increasing length of follow-up, indicating the effects were not explained by pre-clinical disease. A decrease in risk was also seen for folate, (RR=0·68, CI 0·51-0·90; ptrend=0·001), although this was apparent only for former and current smokers. When participants were classified by median levels of both methionine and B6, having above median levels of both resulted in a substantial decrease in lung cancer risk overall (RR=0·41, CI 0·31-0·54), as well as separately among never (RR=0·36, CI 0·18-0·71), former (RR=0·51, CI 0·34-0·76), and current smokers (RR=0·42 CI 0·27-0·65).

Interpretation: Higher serum levels of both vitamin B6 and methionine were associated with a substantial decrease in lung cancer risk on average 5 years later, indicating that they, or strongly related dietary factors, have an important effect on future lung cancer development. Increased knowledge of protective factors for lung cancer over and above tobacco cessation could make a significant contribution to disease prevention, particularly in former and never smokers.

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 5727.
Abstract 68: Nampt regulates fatty acid synthesis, ER homeostasis, and survival in prostate cancer
Authors: Ryan Sarah , Kridel Steven
Published: February 2011

Nicotinamide adenine dinucleotide (NAD) is crucial for the survival of living organisms. This coenzyme functions in both redox metabolism and as a substrate for several proteins, notably Sirtuin deacetylases and poly-(ADP ribose) polymerases, which control stress response and apoptosis in cancer. The rate limiting step of NAD biosynthesis is catalyzed by Nicotinamide phosphoribosyl transferase (Nampt). Recent evidence suggests Nampt may play a role in cancer by regulating survival. The Nampt inhibitor FK866 is in phase II clinical trials against a variety of solid malignancies, however no studies have focused on the role of NAD in prostate cancer (PCa). Because tumor cells have a high requirement for NAD and PCa has increased fatty acid synthesis, we hypothesized that Nampt is important for PCa cell survival and metabolism. Our studies demonstrate that Nampt activity is required for the survival of prostate tumor cells (PC-3, LNCaP, and DU145), but not normal prostate epithelial cells, as determined by treatment with FK866. Exogenous NAD rescued cell death, indicating FK866 is a specific inhibitor of Nampt. To test whether PCa cells can rely on de novo NAD synthesis, we treated cell lines with FK866 and added back nicotinic acid, the substrate for the de novo pathway. Only DU145 cell survival was rescued by nicotinic acid demonstrating that NAD biosynthesis pathways are heterogeneous in PCa. Furthermore, expression of Nicotinic acid phosphoribosyl transferase (Naprt1), the rate-limiting step of the de novo pathway, correlated with the rescue by nicotinic acid in DU145 cells. Additionally, Nampt inhibition activated endoplasmic reticulum (ER) stress and autophagy in a pro-survival manner in all cell lines. Interestingly, FK866 also dramatically reduced fatty acid synthesis in PC-3 and DU145 cells, independent of fatty acid synthase levels. However, LNCaP cells showed no decrease in 14C-acetate incorporation. Robust phosphorylation of ACC occured in DU145 and PC-3 cells upon treatment with FK866, and this effect was rescued by adding back NAD. This correlated with reduced ATP levels and activation (phosphorylation) of AMPK at T172. LNCaP cells had a less dramatic depletion of ATP and no changes in AMPK or ACC phosphorylation, indicating a potential mechanism of fatty acid synthesis shutdown. However, lipid synthesis (as measured by incorporation of 14C-choline) was reduced in all 3 cell lines, albeit to a lesser extent in LNCaP cells. Overall, these findings demonstrate a novel role for Nampt in PCa, and highlight the contribution of NAD to ER homeostasis, fatty acid synthesis, and survival. Targeting NAD biosynthesis could be a novel approach to disrupting PCa cell survival and lipid synthesis.

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 68.
Abstract 76: Mitochondrial filamentation
Authors: Gosalvez Mario
Published: February 2011

A number of molecular targets have been scrutinized in cancer research therapeutics. I will call briefly your attention to mitochondrial fillamentation. This is a molecular target important for the development of cancer reversal techniques and the possible use of cancer as a therapeutic agency when all the cancers will be cured for the duration of life.

My group signaled recently that when mitochondria are isolated with low thermal, mechanical, and chemical stress many of them appear with short micro filaments, of 25, 10, and 5 nanometers of diameter radially anchored in the mitochondrial external membrane, with or without cones of anchorage or veils of condensation.

These probably more physiological mitochondria are partially or almost totally uncoupled from oxidative phosphorylation (1). In darkness, anoxia and in the presence of bicarbonate, fillamented mitochondria are able to produce oxygen at a rate superior to their oxygen uptake. Oscillations of the oxygen concentration are observed when recording these mitochondrial preparations for long periods of time. Also these mitochondria seem to be able to compartmentalize some enzymes of the glycolytic pathway. Fillamented mitochondria are abundant at rest and in young animals. In cancer cells, senility, or high activity their number and extent of fillamentation decrease.

My agents for cancer reversal possibly increase mitochondrial fillamentation, while some chemical carcinogens decrease it, even at doses lower than those needed for their mutagenic effects. This is inferred from their effects on oxygen production by fillamented mitochondria (1, 2).

These novel aspects of mitochondria, to which I call your attention, deserve further investigation by the cancer and mitochondria research community (1, 2, 3)

(1) M Gosálvez Gosálvez. Producción de Oxígeno por Mitocondrias Filamentadas. Importancia para el Cáncer y la Neurodegeración. Anales de la Real Nacional Academia de Medicina, CXV, 3°, 747-756, 1998. Madrid. Spain

(2) M Gosálvez Gosálvez. Reversión del Cáncer y Filamentación Mitocondrial. Anales de la Real Nacional Academia de Medicina. CXVII, 4°, 825-834, 2000, Madrid. Spain.

(3) Mario Gosálvez y Gosálvez. “The Zipper Mechanism”. Madrid. 1982.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

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 76.
Abstract 964: Chlormethiazole, an inhibitor of CYP2E1, prevented chemical carcinogen-initiated and alcohol-promoted hepatic carcinongenesis in rats.
Authors: Ye Qinyuan , Chavez Pollyanna R.G. , Lian Fuzhi , Wang Yan , Hu Kang-Quan , Ling Wenhua , Seitz Helmut K. , Wang Xiang-Dong
Published: February 2011

Chronic and excessive alcohol ingestion, a known risk factor of liver cancer, has been shown to upregulate hepatic cytochrome P450 2E1 (CYP2E1), which is associated with the production of reactive oxygen species and carcinogenic acetaldehyde, the activation of procarcinogens as well as the enhanced catabolism of retinoid. Further, treatment with the CYP2E1 inhibitors, including chlormethiazole (CMZ), have been shown to protect against alcohol-induced liver injury. In order to determine whether treatment with CYP2E1 inhibitor protects against diethylnitrosamine (DEN)-initiated, alcohol-promoted carcinogenesis in the liver, we fed rats (n=6) with either an ethanol liquid diet (Lieber-DeCarli diet) or a non-ethanol liquid diet with isocaloric maltodextrin, with or without CMZ (100 mg/kg BW), for a short-term (1 month) and a long-term (10 months). DEN was given as an initiator for hepatic carcinogenesis by i.p. injection of 20 mg DEN/kg BW. Hepatocarcinogenesis was assessed by examining the placental glutathione-s-transferase (p-GST) immunostaining of altered hepatic foci (AHF) and hepatic tumors lesions. Hepatocyte proliferation was assessed by immunohistochemistry for proliferating cellular nuclear antigen and Ki67, as well as cyclin D1. Hepatic expression of TNF-α and activation of NF-κB and CYP2E1 were assessed by either RT-PCR or Western blotting analysis. Hepatic retinol and retinoic acid were analyzed by reverse-phase HPLC. Results showed that CMZ treatment significantly inhibited ethanol-induced AHF formation, CYP2E1 expression and activity, TNF-α mRNA expression, NF-κB activation and hepatocyte proliferation after a 1-month period. After 10-months of treatment, hepatic nodular regenerative hyperplasia, and hepatocellular adenoma and carcinoma were detected in the ethanol-fed rats, but not in the rest of rat groups with the same dose of DEN treatment, including non-ethanol fed rats and ethanol-fed rats with CMZ treatment. In addition, the CMZ treatment prevented alcohol-reduced retinol and retinoic acid in the livers of rats after 1- and 10-months of treatment. These data demonstrate that CYP2E1 inhibitor can counter the tumor-promoting action of ethanol by restoring normal hepatic levels of retinoic acid. In considering the efficacy and complex biological functions of retinoids in human cancer prevention, intervention using CYP2E1 inhibitors that target alcohol-induced CYP2E1, could provide complementary or synergistic protective effects against alcohol-related cancer risk.

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 964.
Abstract 978: Secondhand tobacco smoke in bars and restaurants in Guatemala: Before and after indoor smoking ban evaluation
Authors: Arvizu Mariel , Hernandez Juan Carlos , Barnoya Joaquin , Navas-Acien Ana
Published: February 2011

Since February 2009 Guatemala has implemented a smoke-free law that includes bars and restaurants. In this study, we sought to assess air nicotine levels in bars and restaurants 6 months after the implementation of the law (post-law) and to compare them with levels found in 2007 (pre-law). Exposure was estimated by passive sampling of vapor-phase nicotine using a filter badge. Filters were placed for 7 working days in 10 bars and 11 restaurants randomly selected in Guatemala City. In total, 50 monitors were placed (for quality control, 10% were duplicate and blank). Filters were checked once to verify the correct placement, count the number of persons and smokers if there were any. Nicotine was measured by gas-chromatography and the time weighted average concentration in µg/m3 was estimated. Median (interquantile range, IQR) air nicotine levels are presented and compared using Mann-Whitney rank test. In addition, 32 employees answered a survey about air quality and opinions about secondhand smoke. The survey results were also compared with pre-law survey results using a chi-square statistic. Before the law, detectable levels of nicotine were found in all bars and restaurants. Median nicotine levels were 4.57 (IQR 1.71-6.44) μg/m3 in bars and 0.58 (IQR 0.43-0.7) μg/m3 in restaurants. After the law, nicotine was detected in all bars and most (76%) restaurants. Median nicotine levels were 0.59 (IQR 0.17-0.80) μg/m3 in bars and 0.06 (IQR 0.01-0.09) μg/m3 in restaurants. These levels were significantly lower compared to those found before the law (p=0.003 and p=0.05; respectively). The nicotine reduction was similar in bars (87%) and restaurants (89%). Employees’ support for a smoke-free workplace rose significantly after the law was implemented (from 32% to 81%, p<0.001). In conclusion, six months after the law went into effect, nicotine levels were significantly decreased in bars and restaurants and workers support for the law was high. Given that no other tobacco control law has been implemented in Guatemala, our results can be attributed to the smoke-free law. However, in order to be effective in reducing lung cancer incidence a smoke-free law should be strictly enforced. Our data should prove useful to exert pressure upon the Guatemalan government to more strictly enforce the law.

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 978.
Abstract 989: Reliability of a modified version of the Health Belief Model Scale-C for cervical cancer screening behaviors in lesbians
Authors: Tracy Kathleen , Dawson Rebecca S. , Tang Ying
Published: February 2011

Background: Cervical cancer incidence and mortality rates have decreased significantly during the last 60 years as a result of wide spread cervical cancer screening, yet certain subgroups of women continue to be at elevated risk due to lack of screening; lesbians are one such group. To better understand the association between health beliefs and cervical cancer screening behaviors in lesbians, we adapted the Champion Health Belief Model Scale from its original focus on breast cancer screening to a focus on cervical cancer and screening via Papanicolaou (Pap) test.

Purpose: The purpose of this pilot study was to assess the reliability and validity of our adapted version of the Health Belief Model Scale (HBMS) using an internet-based survey. Analysis included descriptive statistics of demographic data and internal consistency reliability estimates using Cronbach's alpha coefficients.

Methods: HBMS items for perceived susceptibility, perceived seriousness, perceived benefits, and perceived barriers subscales were modified from their original form to reference cervical cancer (rather than breast cancer) and Pap testing (rather than mammography). In addition, we constructed a knowledge scale based on a series of true/false questions regarding risk factors for cervical cancer and recommendations for cervical cancer screening.

Results: Complete data were available for 218 self-identified lesbian volunteers ranging in age from 18 to 68. Cronbach's internal consistency reliability coefficients were calculated for each subscale from our adaptation of the HBMS. Coefficients ranged from .75 to .91. Coefficients were similar to those reported previously.

Conclusion: Our adaptation of the HMBS for assessing health beliefs regarding cervical cancer screening was determined to be reliable and valid. The HBMS-C has the potential to be a useful tool in ongoing studies of the associations between health beliefs and cervical cancer screening behaviors.Reliability coefficients for HBMS-CSubscaleAlphaSusceptibility.91Seriousness.88Benefits.79Barriers.81Knowledge.75

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 989.
Abstract 998: KLF4 interacts with β-catenin/TCF4 and blocks p300/CBP recruitment by β-catenin
Authors: Chen Xi , Evans Paul M. , Zhang Wen , Liu Chunming
Published: February 2011

Wnt signaling is crucial in the organization and maintenance of the human intestinal epithelium, and somatic mutations that result in deregulated Wnt signaling are an early event in the development of colorectal cancer. The Wnt ligand ultimately results in the stabilization of cytoplasmic β-catenin, which is then free to enter the nucleus and activate transcription through its interaction with the transcription factor TCF4. Our laboratory recently found that KLF4, a transcription factor highly expressed in the adult intestine and critical for intestinal differentiation, interacts with β-catenin and inhibits Wnt signaling. In this study, we characterize the molecular mechanisms of KLF4-mediated inhibition of Wnt/β-catenin signaling. We find that the KLF4 directly interacts with the C-terminal transactivation domain of β-catenin and inhibits p300/CBP recruitment by β-catenin. KLF4 inhibits p300/CBP-mediated β-catenin acetylation as well as histone acetylation on Wnt target genes. In addition, we observe that KLF4 directly interacts with TCF4 independently of β-catenin, and that KLF4 and TCF4 are expressed in similar patterns within the large intestine, with greatest staining near the epithelial surface. These results provide a deeper understanding of the regulation of β-catenin in the intestine, and will have important implications in cancer and stem cell research.

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 998.
Abstract LB-100: Optimal modulation of DNA repair in CLL therapy
Authors: Amrein Lilian , Davidson David , Shawi May , Petruccelli Luca , Miller Wilson , Aloyz Raquel , Panasci Lawrence
Published: February 2011

Resistance to chlorambucil (CLB) in chronic lymphocytic leukemia (CLL) can occur as a consequence of increased DNA repair including c-abl stimulated Rad-51 related homologous recombinational repair (HRR) and DNA-PK related nonhomologous endjoining (NHEJ).

Recent reports suggest that the nonreceptor tyrosine kinase c-abl plays an important role in CLL. In particular, we have previously demonstrated that imatinib inhibition of c-abl or NU7026 inhibition of DNA-PK in CLL lymphocytes results in sensitization to CLB in most samples. Here we report that nilotinib, a superpotent (20-30 fold greater than niltinib) inhibitor of c-abl is more efficacious than imatinib in sensitizing CLL lymphocytes to CLB in the majority of the CLL lymphocyte samples associated with a greater nilotinib related inhibition of c-abl autophosporylation, increased apoptosis and decreased repair of CLB-induced DNA damage (increased activated H2AX).

Furthermore, in CLL samples in which c-abl was inhibited by either inhibitor, there was an increased activation of DNA-PK. Utilizing NU7026, a specific inhibitor of DNA-PK, with nilotinib or imatinib resulted in further sensitization to CLB but there was a greater sensitization to CLB with nilotinib than imatinib. These results suggest: (1) a more potent inhibition of c-abl is more efficacious in sensitizing CLL lymphocytes to CLB, (2) inhibition of c-abl results in a compensatory increase in DNA-PK and (3) inhibiting both DNA repair systems optimally sensitizes CLL lymphocytes to CLB, an effect which is most pronounced with the more potent c-abl inhibitor, nilotinib.

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 LB-100.
Abstract LB-105: Single nucleotide polymorphisms (SNPs) in the CYP19A1 gene are strongly associated with CYP1A2 expression: First evidence for epistasis in the CYP superfamily
Authors: Zhang Xuemei , Kadlubar Susan , Mercer Kelly , Yu Xinfeng , Dhakal Ishwori , Beggs Marjorie , Caldwell David , Edavana Vineetha Koroth , Williams Suzanne , Kadlubar Fred F.
Published: February 2011

CYP1A2 is a member of the cytochromes P450 enzymes responsible for the oxidative metabolism of a wide array of endo- and xenobiotics, and has been demonstrated to be the major isoform responsible for oxidation of estrone and estradiol. To date, SNPs identified in this gene do not adequately explain the 60-80-fold variation in activity observed in Caucasians. We hypothesized that CYP1A2 could be a target of epistatic regulation (i.e., gene-gene interactions where SNPs in one gene influence the expression of another). CYP1A2 and CYP19A1 both lie on chromosome 15, and since CYP19A1 (aromatase) is responsible for the production of estrogens, and CYP1A2 is the primary catabolic P450, we hypothesized that these genes could be coordinately regulated, and SNPs influencing levels of CYP19A1 could also be related to expression levels of CYP1A2. Two TagSNPs (rs749292 A<G and rs727479 A<C) in CYP19A1 were genotyped using Beckman Single Base Extension Kit and TaqMan MGB probe, respectively. Levels of CYP1A2 protein in human liver microsomes from 100 donors were assessed by Western blotting and correlations between CYP19A1 SNPs and CYP1A2 protein amounts were determined. CYP1A2 expression was significantly higher in specimens with CYP19A1 (rs727479) AA homozygous compared with CC genotype (P<0.001), a SNP associated with increased CYP19A1 activity. CYP1A2 expression also is related CYP19A1 (rs749292) polymorphism and AA genotype carriers have higher CYP1A2 expression compared with GG genotype carriers. Moreover, in silico analyses shows the presence of over 300 putative estrogen-responsive elements upstream of the CYP1A2 transcription start sit. SNPs in CYP19A1 are significantly associated with CYP1A2 protein expression. This is the first evidence of epistasis in the P450 enzymes and suggests a role of estrogens in the regulation of CYP1A2.

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 LB-105.
Abstract LB-130: The NCI-Nature Pathway Interaction Database: A cell signaling resource
Authors: Schaefer Carl F. , Anthony Kira , Skinner Mhairi A. , Buchoff Jeffrey R. , Day Matthew , Buetow Kenneth H.
Published: February 2011

The NCI-Nature Pathway Interaction Database (PID, http://pid.nci.nih.gov) is a freely available collection of professionally curated and expert-reviewed signaling and regulatory pathways composed of human molecular interactions, signaling events and cellular processes extracted from primary literature. Pathways selected for curation are based on potential drug targets, suggestions made by our users and reviewers, and other prominent cell signaling molecules. As of February 2010, the database contains 106 pathways encompassing 6696 interactions, 3231 proteins, 142 small molecules, 2622 complexes and 4843 peer-reviewed publications, and includes recent additions to both the p53 and EGFR pathways. Created in a collaboration between the U.S. National Cancer Institute and Nature Publishing Group, the PID is aimed at researchers interested in cell signaling pathways, such as molecular cell biologists, and bioinformaticians. The database offers a range of tools to facilitate pathway exploration. Users can browse the pre-defined set of pathways and create network maps centered on a single molecule or biological process of interest. The Batch query tool allows users to upload molecule lists, such as those derived from microarray data, and visualize the resulting molecular connectivity map. In addition, users can download lists of proteins, references used to create the pathway and complete database content in extensible markup language (XML) or Biological Pathways Exchange (BioPAX) format. The database is updated every month and supplemented by a concise editorial section that provides synopses of recent noteworthy papers in cell signaling and specially commissioned articles on the practical uses of other relevant Bioinformatics tools. Users can sign up for email alerts or RSS feeds to receive database updates.

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 LB-130.
Abstract LB-138: In vivo imaging of DNA damage and repair
Authors: Wang Yanming , Liu Lili , Wu Chunying , Bulgar Alina , Zhu Wenxia , Somoza Eduardo , Gerson Stanton
Published: February 2011

Objectives: To directly quantify abasic sites induced by DNA-targeted chemotherapeutic agents for in vivo studies of base excision repair pathway.

Background: Current cancer treatments rely heavily on chemotherapeutic agents to induce cytotoxic DNA damages and programmed cell death in ancer cells. However, the efficacy of DNA-targeted agents such as temozolomide is often compromised by intrinsic cellular responses such as DNA base excision repair (BER). Previous studies have shown that BER pathway results in formation of abasic or apurinic/apyrimidinic (AP) sites and inhibition of AP sites leads to significant reduction of drug resistance and enhancement of drug sensitivity. Thus, AP-site formation has been identified as an important biomarker in DNA-targeted chemotherapies.

Methods: Design, synthesis, and evaluation of PET imaging agents that bind to AP sites with high affinity and specificity. We date, we have developed positron-emitting [11C]methoxyamine for positron emission tomography (PET) that allows for quantification of AP sites in vivo.

Results: [11C]methoxyamine has been synthesized with high radiochemical yield and purity. Following radiolabelling, microPET studies have been conducted to evaluate their pharmacokinetic profiles in melanoma and glioma xenograft tumor mouse models that are pre-treated with temozolomide to induce AP-site formation. Subsequent quantitative analysis showed that the radioactivity concentration were elevated in proportion to the AP sites induced in tumor regions pre-treated with temozolomide relative to tumor regions without any treatment. In vivo blocking studies based on microPET also showed that the agents bound to AP sites with high specificity.

Conclusion: our studies demonstrated that PET imaging can be used to monitor BER pathway and evaluate efficacy of DNA-targeted therapeutic treatments in cancer.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

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 LB-138.
Abstract LB-146: Identification of copy number alterations in small cell lung cancer
Authors: Dooley Alison L. , Winslow Monte M. , Chiang Derek , Banerji Shantanu , Whittaker Charles , Bronson Roderick , Crowley Denise , Meyerson Matthew , Jacks Tyler
Published: February 2011

Small cell lung cancer (SCLC) comprises 20% of all lung cancer cases and is a particularly malignant disease. The identification of genomic alterations in small cell tumors and metastases and characterization of the genes within those regions will aid in our understanding of SCLC development and progression. DNA copy number gains and losses in human and mouse tumors frequently highlight genes of functional importance. Mouse tumors are often less genomically complex than their human counterparts and several recent studies have highlighted the power of comparative genomic studies of mouse models to identify genes relevant to human tumor progression. In a mouse model, inactivation of p53 and Rb following Cre-mediated recombination results in the development of lung tumors that resemble human SCLC histopathologically. Using this model of malignant SCLC, we have identified DNA copy number alterations in tumors and metastases using Illumina's Solexa massively parallel DNA sequencing technology. While the majority of the genome is unaltered, we observed several focal deletions and high-level amplifications. We detected an amplification of a region including the gene L-myc, a gene previously identified to be amplified in SCLC, and a region including Nuclear Factor 1/B (Nfib). Additionally, several cell lines derived from these lung tumors and metastases have high-level amplifications of Nfib. The DNA copy number data will be probed for conserved changes in tumors and metastases isolated from different animals and functionally validated using in vitro and in vivo assays.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-146.
Abstract LB-147: Characterization of a Kaiso overexpressing transgenic mouse model
Authors: Chaudhary Roopali , Nanan Kyster K. , Daniel Juliet M.
Published: February 2011

Introduction: The WNT signaling pathway plays critical roles during embryogenesis and maintaining homeostasis of adult tissues. However constitutive WNT signaling leads to tumorigenesis. Upon activation of the WNT pathway, the main downstream effector of the WNT pathway, ß-catenin, stabilizes and translocates to the nucleus where it activates transcription of WNT target genes. Recently, our lab along with others identified the novel transcription factor Kaiso as a negative regulator of WNT target genes in mammalian cell lines and Xenopus models. However a study using a Kaiso depleted mouse model implicated Kaiso as a positive regulator of WNT signaling. Kaiso is a member of the BTB/POZ (broad-complex, tramtrack and bric-à-brac/poxvirus and zinc finger) protein family. The goal of this study is to elucidate the role of Kaiso in WNT signaling using the ApcMin/+ mouse model of intestinal cancer.

Methodology: To assess the role of Kaiso in colon cancer in vivo, Kaiso overexpressing transgenic mice were created (KaisoTg). Targeted overexpression of Kaiso in KaisoTg mice was obtained by pronuclear injection of Kaiso cDNA under the control of the intestine-specific villin promoter. Reverse transcription PCR (RT-PCR) and Western Blot analyses were used to determine tissue specific Kaiso overexpression in KaisoTg mice. Immunohistochemisty (IHC) was performed on mouse intestinal tissues to examine the subcellular localization of Kaiso and assess developmental defects. KaisoTg mice were then mated with APCMin/+ mice models of intestinal cancer that develop polyps in the small intestine due to constitutively active -catenin. KaisoTg-APCMin/+ mice were examined for gross morphological phenotypes and IHC was performed on mouse intestinal tissues for Kaiso and other WNT target genes (e.g. cyclin D1) to elucidate the effects of Kaiso on the WNT pathway.

Results: Western Blot analysis revealed high, moderate and low levels of Kaiso overexpression in three founder lines of the KaisoTg mice. RT-PCR analysis showed Kaiso overexpression limited to villin positive tissues including kidney, small and large intestines. IHC analysis of KaisoTg tissues showed no gross morphological differences compared to non-transgenic mice. However KaisoTg-APCMin/+ displayed decreased body size and weight, and had decreased life span when compared to the parentals (i.e. KaisoTg and APCmin/+). IHC analysis of KaisoTg-APCMin/+ mouse intestines revealed increased polyp numbers with Kaiso staining concentrated near the basal surface of the polyps. These data support Kaiso's potential role as an oncogene in mouse intestinal tissues.

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 LB-147.