bluuebunny/crossref_metadata_2025 huggingface dataset:
Processing and analysis of cardiac optical mapping data obtained with potentiometric dyes
Authors: Laughner Jacob I. , Ng Fu Siong , Sulkin Matthew S. , Arthur R. Martin , Efimov Igor R.
Published: July 2012

Optical mapping has become an increasingly important tool to study cardiac electrophysiology in the past 20 years. Multiple methods are used to process and analyze cardiac optical mapping data, and no consensus currently exists regarding the optimum methods. The specific methods chosen to process optical mapping data are important because inappropriate data processing can affect the content of the data and thus alter the conclusions of the studies. Details of the different steps in processing optical imaging data, including image segmentation, spatial filtering, temporal filtering, and baseline drift removal, are provided in this review. We also provide descriptions of the common analyses performed on data obtained from cardiac optical imaging, including activation mapping, action potential duration mapping, repolarization mapping, conduction velocity measurements, and optical action potential upstroke analysis. Optical mapping is often used to study complex arrhythmias, and we also discuss dominant frequency analysis and phase mapping techniques used for the analysis of cardiac fibrillation.
The congenital bicuspid aortic valve can experience high-frequency unsteady shear stresses on its leaflet surface
Authors: Yap Choon Hwai , Saikrishnan Neelakantan , Tamilselvan Gowthami , Vasilyev Nikolai , Yoganathan Ajit P.
Published: July 2012

The bicuspid aortic valve (BAV) is a common congenital malformation of the aortic valve (AV) affecting 1% to 2% of the population. The BAV is predisposed to early degenerative calcification of valve leaflets, and BAV patients constitute 50% of AV stenosis patients. Although evidence shows that genetic defects can play a role in calcification of the BAV leaflets, we hypothesize that drastic changes in the mechanical environment of the BAV elicit pathological responses from the valve and might be concurrently responsible for early calcification. An in vitro model of the BAV was constructed by surgically manipulating a native trileaflet porcine AV. The BAV valve model and a trileaflet AV (TAV) model were tested in an in vitro pulsatile flow loop mimicking physiological hemodynamics. Laser Doppler velocimetry was used to make measurements of fluid shear stresses on the leaflet of the valve models using previously established methodologies. Furthermore, particle image velocimetry was used to visualize the flow fields downstream of the valves and in the sinuses. In the BAV model, flow near the leaflets and fluid shear stresses on the leaflets were much more unsteady than for the TAV model, most likely due to the moderate stenosis in the BAV and the skewed forward flow jet that collided with the aorta wall. This additional unsteadiness occurred during mid- to late-systole and was composed of cycle-to-cycle magnitude variability as well as high-frequency fluctuations about the mean shear stress. It has been demonstrated that the BAV geometry can lead to unsteady shear stresses under physiological flow and pressure conditions. Such altered shear stresses could play a role in accelerated calcification in BAVs.
Solvent-Free Synthesis of New Coumarins
Authors: Al-Bayati Redah I. , Radey Mahdi F. , Al-Amiery Ahmed A.
Published: July 2012

A solvent-free synthesis of five series of coumarin derivatives using microwave assistant is presented herein. The synthesized compounds are fully characterized by UV-VIS, FT-IR, and NMR spectroscopy.
Garcinol Regulates EMT and Wnt Signaling PathwaysIn VitroandIn Vivo, Leading to Anticancer Activity against Breast Cancer Cells
Authors: Ahmad Aamir , Sarkar Sanila H. , Bitar Bassam , Ali Shadan , Aboukameel Amro , Sethi Seema , Li Yiwei , Bao Bin , Kong Dejuan , Banerjee Sanjeev , Padhye Subhash B. , Sarkar Fazlul H.
Published: July 2012

Anticancer properties of Garcinia indica–derived garcinol are just beginning to be elucidated. We have earlier reported its cancer cell–specific induction of apoptosis in breast cancer cells, which was mediated through the downregulation of NF-κB signaling pathway. To gain further mechanistic insight, here, we show for the first time that garcinol effectively reverses epithelial-to-mesenchymal transition (EMT), that is, it induces mesenchymal-to-epithelial transition (MET) in aggressive triple-negative MDA-MB-231 and BT-549 breast cancer cells. This was associated with upregulation of epithelial marker E-cadherin and downregulation of mesenchymal markers vimentin, ZEB-1, and ZEB-2. We also found that garcinol upregulates the expression of miR-200 and let-7 family microRNAs (miRNAs), which provides a molecular mechanism for the observed reversal of EMT to MET. Transfection of cells with NF-κB p65 subunit attenuated the effect of garcinol on apoptosis induction through reversal of MET to EMT. Forced transfection of p65 and anti–miR-200s could also reverse the inhibitory effect of garcinol on breast cancer cell invasion. Moreover, treatment with garcinol resulted in increased phosphorylation of β-catenin concomitant with its reduced nuclear localization. The results were also validated in vivo in a xenograft mouse model where garcinol was found to inhibit NF-κB, miRNAs, vimentin, and nuclear β-catenin. These novel findings suggest that the anticancer activity of garcinol against aggressive breast cancer cells is, in part, due to reversal of EMT phenotype, which is mechanistically linked with the deregulation of miR-200s, let-7s, NF-κB, and Wnt signaling pathways. Mol Cancer Ther; 11(10); 2193–201. ©2012 AACR.
Abstract 1739: Reversal of ABCB1- and ABCG2-mediated drug resistance by sildenafil
Authors: Tiwari Amit K. , Shi Zhi , Shukla Suneet , Robey Robert W. , Singh Satyakam , Kim In-Wha , Bates Susan E. , Peng Xing-xiang , Abraham Ioana , Ambudkar Suresh V. , Talele Tanaji T. , Fu Li-wu , Chen Zhe-Sheng
Published: July 2012

Sildenafil is a selective inhibitor of type 5 cGMP-specific phosphodiesterase and is clinically used to treat erectile dysfunction and pulmonary arterial hypertension. Overexpression of ABC transporters such as ABCB1, ABCC1 and ABCG2 is one of the main causes of the development of resistance in cancer cells to chemotherapeutic drugs. However, the effect of sildenafil on these ABC transporters is still unknown. In the present study, we found that sildenafil had differential effects on these transporters. In ABCB1-overexpressing cells, non-toxic doses of sildenafil were found to inhibit resistance to ABCB1 substrate anticancer drugs, as well as significantly increase intracellular accumulation of [3H]-paclitaxel. Similarly, in ABCG2-overexpressing cells, sildenafil partially reversed resistance to ABCG2 substrate anticancer drugs and increased intracellular accumulation of [3H]-mitoxantrone as well as the fluorescent compound BODIPY-prazosin. Sildenafil also moderately inhibited the transport of [3H]-E217βG and [3H]-methotrexate by ABCG2. Sildenafil significantly stimulated ABCB1 ATPase activity but it only slightly stimulated ABCG2 ATPase activity. However, it inhibited photolabeling of both ABCB1 and ABCG2 with [125I]-IAAP. Additionally, sildenafil did not alter the sensitivity of parental, ABCB1- or ABCG2-overexpressing cells to non-ABCB1 and non-ABCG2 substrate drug and had no effect on the function of ABCC1. We also modeled the binding of sildenafil within the large cavity of the transmembrane region of homology model of ABCB1 based on the mouse Abcb1a structure. Overall, we conclude that sildenafil can inhibit the function of ABCB1 and ABCG2, with a stronger effect on ABCB1. These findings suggest that it may be possible to develop potent MDR reversal agents from clinically approved drugs with known side effects and drug interactions.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1739. doi:10.1158/1538-7445.AM2011-1739
Abstract 174: MicroRNA signatures of castration resistant human prostate cancer
Authors: Sun Tong , Yang Ming , Chen Shaoyong , Balk Steven , Pomerantz Mark , Brown Myles , Kantoff Philip W. , Lee Gwo-Shu Mary
Published: July 2012

Androgen-dependent (AD) prostate cancer (CaP) typically progresses to castration resistant prostate cancer (CRPC) after after some duration of androgen deprivation therapy (ADT). The mechanisms of this transition are at the beginning to be understood. MicroRNAs (miRs) are non-coding small RNAs (19-25nt) that play an important role in the regulation of gene expression. So far, only a few studies have looked at prostate cancer-specific miRNA signatures relevant to the development and progression of CaP. By performing genome-wide expression profiling of miRs, we found 7 miRs (miR-221, miR-222, miR-15a, miR-16-1, miR-203, miR-23b and miR-27b) differentially expressed in the AD prostate cancer LNCaP cell line and the LNCaP derived CRPC cell line- LNCaP-Abl. In particular miR-221 and miR-222, were most dramatically increased in the CRPC cell lines. Over-expression of miR-221 or -222 in LNCaP or another AD cell line, LAPC-4 significantly reduced the level of the dihydrotestosterone (DHT) induced up-regulation of PSA expression and increased androgen independent (AI) growth of LNCaP cells. Knocking down the expression level of miR-221 and -222 with antagonist miRs in the LNCaP-Abl cell line restored the response to DHT induction of PSA transcription and also increased the growth response of LNCaP-Abl cells to androgen. To determine the clinical relevance of the differential expression patterns of these miRs, we compared the expression levels of these 7 miRs in 86 normal prostate tissues, 34 localized hormone naïve primary tumors and 17 bone metastatic CRPC samples. Despite of the anticipated heterogeneity of CRPCs within each individual or among patients, surprisingly ∼90% of analyzed CRPC tumors can be characterized by significant up-regulation of miR-221/-222 and down-regulation of miR-23b/-27b. This finding suggests that the signature of altered miR-221/-222 and miR-23b/-27b expression is associated with the development of CRPC in human tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 174. doi:10.1158/1538-7445.AM2011-174
Abstract 1742: Suppression of Akt activity selectively induced apoptosis of Ara-C resistant AML cells
Authors: Lee Chansu , Oh Jeong In , Kwon Jung Hye , Kim Byoung Kook , Ahn Kwang-Sung , Yoon Sung-Soo
Published: July 2012

Treatment outcome of acute myeloid leukemia (AML), intensive Ara-C chemotherapy, remains unsatisfactory. It has been shown that the frequency of relapse is high and only 20 to 30% rate of the overall five year survival. Ara-C resistance could be one of major factors in decreasing the efficacy of intensive Ara-C chemotherapy. In this study, we established in vitro Ara-C resistant AML cell lines (KG1 and ML-1) and examined to ascertain the cause of Ara-C resistance. The expression levels of CDA in Ara-C resistant cell lines were higher than in parental cell line. However, the expression of other genes was not significantly different. Besides, PI3K/AKT was persistantly activated in Ara-C resistant cell lines. Also, mTOR, downstream of AKT, was highly expressed in AML resistant cell lines. MTT assay showed that PI3K specific inhbitor, LY29002, and mTOR inhibitor, rapamycin, inhibited the growth of AML cells and there was no different among AML cells. A synergic effect of Ara-C induced apoptosis was not detected in AML cells co-treated with rapamycin. Nevertheless, LY29002 and rapamycin was more effective to induce apoptosis in Ara-C resistant AML cell lines. Our data indicated that persistent activation of Akt in AML cells contributed to becoming resistant to Arc-C treatments. Inhibition of Akt activation would be a potential target to overcome Ara-C resistance in AML.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1742. doi:10.1158/1538-7445.AM2011-1742
Abstract 1747: Biochanin A overcomes gemcitabine resistance in pancreatic cancer cells
Authors: Bhardwaj Vikas , Lai James C.K. , Bhushan Alok
Published: July 2012

Drug resistance is one of the major reasons for failure of chemotherapy and high mortality rate in pancreatic cancer. Gemcitabine (GEM) and 5-fluorouracil are two drugs which have shown to improve the survival of pancreatic cancer patients but intrinsic or acquired characteristics make this cancer resistant to these drugs. Previously, we have observed that biochanin A (bioA) effectively reduces the survival, signaling and progression of pancreatic cancer cells. In this study, we aim at determining the effect of bioA on drug resistant pancreatic cancer cells. To test our hypothesis, first we compared three pancreatic cancer cells line: Panc1, MiaPaCa2 and AsPC1 for their sensitivity to gemcitabine and protein expressions. We found that Panc1 cells are highly resistant to GEM with IC50 of 75µM while the same for MiaPaCa2 and AsPC1 cells was 0.04µM. Our western blot data show that the levels of NFkappaB, EGFR and CD133 were higher in Panc1 cells compared to other two cell lines suggesting the role of these factors in imparting drug resistant characteristics to pancreatic cancer cells. Our cell survival studies show that bioA is more effective in reducing the survival of Panc1 cells compared to the other two cell lines. Next, we selected GEM resistant cells (AsPC/G) by continuously exposing AsPC1 cells with increasing concentration of GEM. We generated a GEM resistant cell line that was 20-fold resistant to GEM compared to the parent cell line. AsPC/G cells had higher colony formation ability and in vivo tumorigenicity compared to the parent cells. Also, the expression of p-EGFR, NFκB, p-Akt and EMT markers were upregulated in AsPC/G cell compared to AsPC1 cells. We found that bioA was more cytotoxic to AsPC/G cells compared to AsPC1 cells suggesting that bioA affects the molecular mechanisms which impart drug resistant characteristics. To further understand this phenomenon, we analyzed the molecular mechanisms affected by bioA. We observed that bioA reduces the levels of p-EGFR, p-Akt and NFκB in AsPC1 cells. Upregulation of these proteins is known to impart drug resistant characteristics to pancreatic cancer cells; therefore, by inhibiting them, bioA reduces the survival of GEM resistant pancreatic cancer cells. Our study concludes that bioA reduces the survival of GEM resistant pancreatic cancer cells and a treatment regimen with bioA may improve the outcome of chemotherapy in pancreatic cancer patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1747. doi:10.1158/1538-7445.AM2011-1747
Abstract 1748: Metformin overcomes cisplatin-resistance in triple negative breast cancer
Authors: Lau Ying Ka Ingar , Shaw Jacquelyn M. , Campbell Julie L. , Maurer Matthew A.
Published: July 2012

Background: Triple negative breast cancers (TNBC) account for approximately 15% of breast cancer but 30% of deaths. The majority of TNBC are basal breast cancers that have higher rate of relapses as compared with other breast cancer subtypes, indicating there exists a sub-population of tumor cells that are highly resistant to chemotherapies. Platinum-based agents and PARP inhibitors have shown efficacy in basal breast cancers with BRCA1/2 mutation background. In this study, we expand the analysis to basal breast cancer lines without BRCA1/2 mutations.

Results and Methods: We treated a panel of basal breast cancer lines (HCC70, MDA-MB-468, BT549, HCC1143) with cisplatin and observed that 6 µM of cisplatin were able to kill >99% of a confluent plate of these cell lines. The cisplatin-resistant population, however, behaved very differently in these lines. Cisplatin-resistant MDA-MB-468 cells had similar phenotype as cisplatin-sensitive cells and they repopulated the whole plate in a short time. Cisplatin-resistant cells in the other 3 TNBC lines had a different phenotype than the cisplatin-sensitive cells and remained quiescent for 2-3 weeks before proliferating in a vertical fashion. The vertical string of cells eventually detached from the plate and kept expanding as clusters of cells in suspension. Screening through various drugs, we observed that 2 mM of metformin as a combined treatment with cisplatin was able to irradicate these cisplatin-resistant cells in both MDA-MB-468 and BT549 cell lines. Additionally, we demonstrated that using aminoimidazole carboxamide ribonucleotide (AICAR), an AMP kinase (AMPK) activator, and Rapamycin, an mTORC1 inhibitor had the same effect as metformin indicating the AMPK-mTOR axis might be important for the survival of cisplatin-resistant cells.

Conclusions: TNBC without BRCA1/2 mutation are sensitive to cisplatin treatment but possess a sub-population of resistant cells. We demonstrated that cisplatin-resistant cells in TNBC lines behaved differently after cisplatin treatment and that combined treatment of metformin and cisplatin may be able to overcome this resistance. Future experiments include comparing this combination with the combined treatment of cisplatin and PARP inhibitor, which might have effect in cisplatin-sensitive cells but not in cisplatin-resistant cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1748. doi:10.1158/1538-7445.AM2011-1748
Abstract 1882: Short- and long-term risk of adenoma recurrence with cigarette smoking: An analysis of the Polyp Prevention Trial and Continued Follow-Up Study
Authors: Laiyemo Adeyinka O. , Doubeni Chyke , Williams Carla D. , McDonald-Pinkett Shelly , Schoen Robert E. , Marcus Pamela M. , Lanza Elaine , Schatzkin Arthur , Smoot Duane T. , Cross Amanda J.
Published: July 2012

Background: Prospective studies have evaluated the association between cigarette smoking and colorectal adenoma recurrence within 4 years of follow-up, a relatively short duration. We sought to examine short- and long-term risk of adenoma recurrence in association with cigarette smoking among participants in the Polyp Prevention Trial (PPT), a multicenter, randomized controlled trial that evaluated the effect of a low fat, high fiber, fruits and vegetable diet on the risk of colorectal adenoma recurrence.

Methods: A cohort of 774 participants with colorectal adenoma completed a baseline questionnaire including tobacco use and completed the 4-year trial during which they underwent colonoscopy at 1 year and 4 years after enrollment. After the trial was completed, these participants consented to passive follow-up in the Continued Follow-up Study (CFS) during which the colonoscopy reports subsequent to the trial were collected and analyzed. We defined adenoma recurrence as any adenoma detected after the baseline colonoscopy. We used Poisson regression models to evaluate risk of adenoma recurrence up to 4 years (short-term) and up to 12 years of follow-up (long-term).

Results: At baseline, 461 (59.6%) participants had a history of smoking: 379 (49.0%) former smokers and 82 (10.6%) current smokers. Mean age of the patients was 59.6 years and 66.2% were males. The mean total duration of follow-up was 8.4 years (range 4.9 – 12.4 years). When compared with never smokers, there was no association between cigarette smoking and adenoma recurrence with either short- or long-term follow-up (Table).

Conclusions: Cigarette smoking is not associated with adenoma recurrence in the short- or the long-term.

Table: Relative Risk (RR) and 95% confidence interval (CI) for adenoma recurrence during short-term and long-term follow-up according to baseline smoking status

Models were adjusted for age, sex, NSAIDs use, BMI and family history of colorectal cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1882. doi:10.1158/1538-7445.AM2011-1882
Abstract 1884: Serological testing along with epidemiological data establishes a trend of pylori's association with colon polyps
Authors: Brim Hassan , Lee Edward L. , Razjouan Hadi , Smoot Duane T. , Hassanzadeh Hassan , Ashktorab Hassan
Published: July 2012

Background: It has become common wisdom that Helicobacter pylori (HP) infection is linked to gastric cancer. However, its involvement in colorectal cancer (CRC) is still under investigation. The trophic effects of induced hypergastrinemea on colon homeostasis as well as HP direct effects on the colon mucosa might play a role in CRC.

Methods: We previously reported that epidemiological data in African American patients (n=1262, >40 years old) who underwent bidirectional gastrointestinal endoscopy show an HP association with colon polyps formation. To substantiate this linkage, we used serological testing on healthy (n=94) and colon polyp (n=95) patients for anti-HP and anti-CagA antibodies to further confirm our epidemiological findings. Microarray used to detect the Gut flora including HP using 16rDNA from stool (n=12) of healthy and colon adenomas.

Results: The healthy individuals had an average age of 63.7 (SD=9.80) while the polyp patients had an average age of 62.8 (SD=9.7). The gender distribution was 42/52 and 41/54 in the two groups for males and females, respectively. As such, the two groups were age and sex matched. In the polyp patients, 55.6% was HP-positive while there was only 48.8% positive in the control group (p=0.30 for this difference). Cag A positive samples were 73.3% in polyp patients and 67.5% in healthy individuals (p = 0.5).

Gut flora analysis using a 16S rDNA microarray from stool (n=12) samples revealed the presence of HP signals in healthy and colon adenomas analyzed samples.

Conclusion: HP seems to be associated with an increased risk of colon adenoma. However, whether HP is a colon inhabitant and participant in colon carcinogenesis or just a gastric wash-out is under investigation in normal and tumor colon biopsies’ gut flora studies. Large sample size is needed to confirm the above observed trend of a possible association of HP with CRC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1884. doi:10.1158/1538-7445.AM2011-1884
Abstract 1885: Malignancies associated with immune thrombocytopenic purpura
Authors: Arnaout Karim , Khalife Mustapha , Hanbali Amr
Published: July 2012

Background: Cancer and Immune thrombocytopenic purpura (ITP) are two common disorders. However, the relationship between these two diseases has rarely been reported in the literature. The purpose of this retrospective study was to determine the association between cancer and ITP.

Methods: We retrospectively reviewed the charts of 307 patients diagnosed with ITP in our institution between 2005 and 2009. The diagnosis of ITP was defined by a platelet count less than 140.109/l with normal or increased number of megakaryocytes on bone marrow aspirate, after exclusion of thrombocytopenia-induced medications or disorders, and absence of splenomegaly.

Results: 32 patients (10.4 percent) were found to have cancer. Of these 32 patients, breast cancer accounted for 28.1 percent, prostate cancer for 18.8 percent, skin cancer for 15.6 percent, gastrointestinal cancer and multiple cancer history for 12.5 percent each, bladder cancer and lymphoma for 6.25 percent each. 12 patients (37.5 percent) had ITP before cancer diagnosis, and 16 patients (50 percent) after cancer diagnosis. Both diseases were concomitant in 4 patients (12.5 percent).

Conclusion: 10.4 percent of patients with ITP have cancer. Breast cancer accounted for most of the cases followed by prostate cancer. Our data suggest an association between cancer and autoimmune platelet destruction, and further investigation is warranted to understand the exact mechanism.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1885. doi:10.1158/1538-7445.AM2011-1885
Abstract 189: Kaempferol induces apoptosis in ovarian cancer cells through intrinsic pathway
Authors: Luo Haitao , Rankin Gary , DePriest Laura , Chen Yi C.
Published: July 2012

The purpose of this study is to investigate whether and how kaempferol, a dietary flavonoid, induces apoptosis in human ovarian cancer cells.

Ovarian cancer cell lines, OVCAR-3, A2780/CP70, and A2780/wt, were treated with kaempferol for 24 hours and analyzed for cell proliferation and cytotoxicity by genomic DNA staining and LDH assay, respectively. Apoptosis of cells were detected with Caspase-Glo 3/7 Assay. Intrinsic apoptotic pathway was further confirmed by pre-treating cancer cells with caspase-9 inhibitor, and tested for caspase 3/7 levels after kaempferol treatment. Protein levels of pro-apoptosis genes including p53, Bad, and Bax, and anti-apoptosis gene, Bcl-XL, were analyzed by western blots.

Our data demonstrate that kaempferol inhibits cell proliferation but causes no necrosis in all 3 ovarian cancer cell lines. For apoptosis, caspase 3/7 levels were escalated by kaempferol treatment concentration-dependently and significantly. This effect can be diminished by pre-treatment with caspase-9 inhibitor, indicating an intrinsic apoptosis pathway involved in kaempferol-induced apoptosis in ovarian cancer cells. Western blot analysis revealed that protein levels of anti-apoptosis gene, Bcl-xL were decreased in ovarian cancer cells, while pro-apoptotic genes, p53, Bad, and Bax, were up-regulated by kaempferol treatment.

In conclusion, kaempferol induces apoptosis in ovarian cancer cells through regulating expression of both pro-apoptotic and anti-apoptotic genes within the intrinsic apoptosis pathway. As a natural flavonoid wildly distributed in fruits and vegetables, kaempferol is a good candidate for chemoprevention of ovarian cancers in humans. Further studies in animal models and clinical trials are warranted.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 189. doi:10.1158/1538-7445.AM2011-189
Abstract 1890: Human papillomavirus serology and the risk of lung cancer
Authors: Anantharaman Devasena , Pawlita Michael , Waterboer Tim , Zaridze David , Mukeria Anush , Mates Dana , Szeszenia-Dabrowska Neonila , Rudnai Peter , Lissowska Jolanta , Bencko Vladimir , Scelo Ghislaine , Boffetta Paolo , Brennan Paul
Published: July 2012

A role for HPV in lung cancer has been suggested by several case series. We examined further the role of HPV and lung cancer in a case-control study involving 1633 lung cancer cases and 2729 matched controls from six central European countries. HPV infection status was ascertained for several low-risk and high-risk HPV types by bead-based multiplex serology. Unconditional logistic regression models were used to examine the risk of lung cancer associated with specific HPV types. Overall, low prevalence (<5%) of antibodies for early proteins (E6 and E7) of all HPV types were observed among controls. Seropositivity for both E6 and E7 proteins (for any HPV type) was very rare (<0.3%). We observed a significantly increased risk of lung cancer in the presence of antibodies to HPV6L1, HPV11L1, HPV16L1, HPV18L1, HPV11E6, HPV11E7, HPV16E7 and HPV18E7 after adjustment for potential confounders including age, gender and smoking (Table 1). Similar effects were observed for never, former and current smokers. These results indicate that HPV antibodies are substantially increased in lung cancer cases compared to controls. Whether this indicates a causal relationship is yet to be determined.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1890. doi:10.1158/1538-7445.AM2011-1890
Abstract 1898: The Liverpool Lung Project risk model: An independent validation and clinical utility in primary care
Authors: Field John K. , Raji Olaide Y. , Cassidy Adrian , Duffy Stephen W. , Baker Stuart G. , Christiani David C.
Published: July 2012

Background: The results from a recent CT screening trial for lung cancer showed evidence of mortality reduction in the screened arm of the study. The long term success of future National Screening Programme as an early diagnosis tool may be dependent upon identifying populations at sufficient risk of developing the disease such that the benefit:harm ratio of the intervention can be maximised. Risk prediction models can play an important role in risk stratification by providing an estimate of individual's risk of developing a disease at a future time, but require validation in independent populations before they can be successfully generalised. Within the Liverpool Lung Project (LLP), we have developed a risk prediction model for estimating individual's 5-year absolute risk of lung cancer. The model was based on five epidemiological risk factors namely smoking duration, prior diagnosis of pneumonia, family history of lung cancer, occupational exposure to asbestos and prior diagnosis of other cancer. We present here an independent validation and clinical utility of the model using data from two case-control studies and a cohort population from Europe and North America.

Method: The 5-year absolute risk of lung cancer was estimated for subjects in the Harvard and European Early Lung Cancer (EUELC) case-control and LLP prospective cohort studies. The model's performance was assessed through its predictive accuracy (discrimination and calibration) and clinical utility. The area under the receiver-operator characteristic curve (AUC) measures the model's discriminatory power while calibration was assessed by comparing the observed and the expected lung cancer cases in the cohort population. The clinical relevance of the model was examined using the decision and relative utility curves.

Results: There was an evidence of good discriminations in Harvard (AUC = 0.76) and LLP cohort (c-index = 0.77, 0.82) with no significant difference in discrimination by age, gender and smoking status. In general, the model calibration indicated an underestimation of absolute risk; this showed improvement with high absolute risks. The application of the model was associated with reasonably good clinical utility across the three datasets as demonstrated by its superior ‘net benefit’ against any other alternative strategy.

Conclusion: The LLP risk model demonstrates good performance and evidence of clinical usefulness in three independent settings and can serve as an adjunct tool for clinicians or used in primary care for referring patients for early detection and prevention intervention.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1898. doi:10.1158/1538-7445.AM2011-1898
Abstract 1899: Validation of the Spitz lung cancer risk prediction model with the Dutch-Belgian randomized lung cancer screening trial (NELSON) cohort
Authors: D'Amelio Anthony M. , Baecke Eleonora , Spitz Margaret R. , de Koning Harry J. , van Klaveren Rob J. , Etzel Carol J.
Published: July 2012

Background: Risk modeling has been shown to be important in detection and prevention of disease, and this is especially true for cancer research. One prominent lung cancer risk model is the Spitz Lung Cancer Risk Model, which was constructed from case-control data and incorporates clinical and epidemiologic variables (smoking status, family history and select co-morbidities). Although the Spitz model is validated using case-control data, the model has not been calibrated.

Methods: We used data from 109 lung cancer patients and 4622 controls that were a subset of a large longitudinal cohort study, the Dutch-Belgian randomized lung cancer trial (NELSON). We estimated absolute lung cancer risks from the Spitz risk model to evaluate the model's calibration, discriminatory power and clinical utility.

Results: With the 10 year absolute risk calculations, the Spitz model was well calibrated with NELSON data, with slightly weaker calibration for five year absolute risk calculations. The overall discriminatory power was 0.69 (95% CI = 0.64-0.74), with current smokers having higher discriminatory power (0.73, 95% CI = 0.67-0.79) compared to former smokers (0.61, 95% CI = 0.51-0.70). When examining clinical utility, it peaked at four lung cancer patients correctly identified by the model for every control incorrectly identified as a lung cancer patient.

Conclusions: This is the first time the Spitz model has been evaluated for calibration, with very good results except for the lowest and highest risk individuals. The calibration results also confirmed the notion by Dr. Peter Bach's group that 10 year absolute risk models are better indicators of cancer risk than five year models. The clinical utility results are very similar to those calculated by the Spitz model with Harvard data that was published in the British Journal of Cancer recently. The Spitz model showed moderate discriminatory power, especially among current smokers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1899. doi:10.1158/1538-7445.AM2011-1899
Abstract 19: Structural insight for the role of Fas binding to FADD and oligomerization degree of Fas/FADD complex in death inducing signaling complex formation
Authors: Yan Qi , McDonald Jay M. , Song Yuhua
Published: July 2012

Fas death receptor-activated signaling pathways regulate apoptosis in a variety of cells, including cholangiocarcinoma and other cancer cells. Fas binding to Fas-associated death domain (FADD) activates FADD-caspase-8 binding to form the death-inducing signaling complex (DISC) to trigger apoptosis (Nature reviews 9:231-241, 2008, Cell 81:505-512, 1995). The Fas-Fas association exists primary as a dimer in the Fas-FADD complex and the Fas-FADD tetramer complex has the tendency to form higher oligomers (Nature 457:1019-1022, 2009). The importance of the oligomerized Fas-FADD complex in DISC formation has been confirmed (Nat Struct Mol Biol. 2010 Oct 10). This study sought to provide structural insight for the role of Fas binding to FADD and the oligomerization of Fas/FADD complex in activating FADD-procaspase-8 binding. In this study, we determined the conformational and motion changes of FADD by binding to Fas for the Fas-FADD complex in either dimer or tetramer behavior with molecular dynamics (MD) simulations. The conformational and motion changes in FADD by binding to Fas could directly affect FADD binding to procaspase-8. Results show Fas binding to FADD stabilized FADD conformation, including the increased stability of the critical residues in FADD death effector domain (DED) for FADD-procaspase-8 binding. Fas binding to FADD resulted in the decreased degree of both correlated and anti-correlated motion of the residues in FADD and caused the reversed correlated motion between FADD DED and FADD death domain. The exposure of procaspase-8 binding residues in FADD that allows FADD to interact with procaspase-8 was observed with Fas binding to FADD. We also observed the different degree of the conformational and motion changes of FADD in the Fas-FADD complex with the different degree of oligomerization. The increased conformational stability and the decreased degree of the correlated motion of the residues in FADD in Fas-FADD tetramer complex were observed compared to those in Fas-FADD dimer complex. This study provided structural evidence for the role of Fas binding to FADD and the oligomerization degree of Fas/FADD complex in DISC formation to signal apoptosis. The structural information should facilitate the identification of novel strategies and targets that regulate DISC formation and, thereby, modulate apoptosis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 19. doi:10.1158/1538-7445.AM2011-19
Abstract 1902: Aspirin, nonsteroidal antiinflammatory drugs (NSAIDs) acetaminophen and risk of pancreatic cancer
Authors: Tan Xiang-Lin , Reid Lombardo Kaye M. , Bamlet William R. , Robinson Dennis P. , Anderson Kristin , Petersen Gloria M.
Published: July 2012

Background: Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) show indisputable promise as cancer chemoprevention agents. While aspirin and NSAID use have been suggested to lower risk of developing pancreatic cancer, the results of several epidemiological studies are not in consensus. Methods: Using a case-control design, we examined the association between aspirin, NSAID and acetaminophen use and the risk of pancreatic cancer. We enrolled 904 histological or clinically documented pancreatic ductal adenocarcinoma cases, and 1,223 age and gender matched healthy clinic-based controls evaluated at Mayo Clinic from April 2004 and September 2010. All subjects were ≥ 55 years old and self-reported by questionnaire their use of aspirin, NSAIDs, and acetaminophen at ages 41-60, along with extensive epidemiologic and demographic information. Multivariate logistic regression analysis was used to estimate risk of pancreatic cancer after adjusting for potential confounders. Results: The use of aspirin was associated with a decreased risk of pancreatic cancer. The unadjusted odds ratio (OR) associated with aspirin use ≥ 1 day/month, compared with never or < 1 day/month, was 0.79 [95% confidence interval (CI) 0.65. 0.96, p = 0.015]. This effect remained significant [OR 0.71, 95% CI 0.58,0.87, p = 0.0008], after adjusting for the potential confounders of body mass index and smoking status (never, former, current). The inverse relationship was stronger among former smokers (OR 0.61, 95% CI 0.46, 0.82, p =0.0008) than never and current smokers, although there was not a statistically significant interaction (Pintereaction = 0.333). NSAID and acetaminophen use was not associated with the risk of pancreatic cancer. Conclusions: Results from this large case-control study suggest that aspirin use, but not non-aspirin NSAID use, was associated with lower risk of developing pancreatic cancer and was more pronounced among former smokers than never and current smokers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1902. doi:10.1158/1538-7445.AM2011-1902
Abstract 1915: Specialty supplements and prostate cancer risk in the vitamins and lifestyle (VITAL) cohort
Authors: Brasky Theodore M. , Kristal Alan R. , Navarro Sandi L. , Lampe Johanna W. , Patterson Ruth E. , Peters Ulrike , White Emily
Published: July 2012

Although there is evidence from studies of prostate cancer cell lines and rodent models that several supplements may have anti-inflammatory, anti-oxidant, or other anti-cancer properties, few epidemiologic studies have examined the association between non-vitamin, non-mineral, specialty supplement use and prostate cancer risk. Participants, 50-76 years, were 35,239 male members of the VITamins And Lifestyle (VITAL) cohort who were residents of western Washington State, and who completed an extensive baseline questionnaire in 2000-2002. Participants responded about their frequency (days/week) and duration (years) of specialty supplement uses. 1,602 incident invasive prostate cancers were obtained from the Surveillance, Epidemiology, and End Results registry. Multivariate-adjusted hazards ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazards models. Any use of grapeseed supplements was associated with a 41% (HR 0.59, 95% CI: 0.40-0.86) reduced risk of total prostate cancer. Although not statistically different, the association was somewhat stronger for low-grade (HR 0.58, 95% CI: 0.33-1.03) than high-grade tumors (HR 0.82, 95% CI: 0.34-2.00). There were no associations for use of chondroitin, co-enzyme Q10, fish oil, garlic, ginkgo biloba, ginseng, glucosamine, or saw palmetto. Grapeseed may be a potential chemopreventive agent, however as current evidence is limited, it should not yet be promoted for prevention of prostate cancer.

This work is supported by NCI grants R25-CA94880, R01-CA142545, and K05-CA154337

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1915. doi:10.1158/1538-7445.AM2011-1915
Abstract 1916: Divergent trends for gastric cancer incidence by anatomic subsite in U.S. adults
Authors: Camargo M. Constanza , Anderson William F. , King Jessica B. , Correa Pelayo , Thomas Cheryll C. , Rosenberg Philip S. , Eheman Christie R. , Rabkin Charles S.
Published: July 2012

Background and aims: Age-specific analyses for noncardia gastric cancer reveal divergent trends among United States (U.S.) whites: rates are declining in older adults (over age 40) but rising in younger persons. To further investigate this heterogeneity, we evaluated incidence trends by anatomic subsite, age, and race/ethnicity.

Methods: Gastric cancer incidence data for 1976-2007 were obtained from the U.S. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program and the Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR). Incidence rates and estimated annual percentage change (EAPC) were obtained by gastric subsite, age group (25-39, 40-59, and 60-84 years), and race/ethnicity.

Results: Based on data from the nine oldest SEER registries (covering about 10% of the U.S. population), long term age-specific incidence rates for corpus cancer increased between 1976 and 2007 with EAPCs of 1.0%/yr (95% CI, 0.1-1.9) for whites and 3.5%/yr (95% CI, 1.8-5.2) for blacks. All other subsite-specific rates decreased in whites and blacks, whereas all noncardia subsites including corpus cancer declined among other races. In the shorter term, age-specific analyses using combined data from NPCR and SEER registries (covering 89.4% of the U.S. population), corpus cancer significantly increased among younger and middle-aged whites from 1999 to 2007; in ethnic-specific analyses, the increase was significant among non-Hispanic whites aged 40-59 years. Age-specific rates for all subsites declined or were stable in this period among blacks and other races.

Conclusions: Long- and short-term incidence trends for noncardia gastric cancers indicate a shifting distribution by anatomic subsite, age and race/ethnicity, consistent with changing risk factor exposures and warranting further investigation.

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention and the National Cancer Institute.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1916. doi:10.1158/1538-7445.AM2011-1916
Abstract 2004: Effect of epigenetic drugs on melanocytes and melanoma cell lines phenotype and aggressiveness
Authors: Molognoni Fernanda , Monteiro Ana Carolina , Morais Alice Santana , Souza Camila Ferreira , Cruz Adriana Taveira , Melisso Fabiana Marcelino , Liang Gangning , Jones Peter Anthony , Jasiulionis Miriam Galvonas
Published: July 2012

Melanoma is the most aggressive skin cancer because of its high resistance to currently available therapy. Like other types of cancer, melanoma is influenced by many factors, including genetic and epigenetic alterations. There are few available models that mimic different steps of melanoma progression. In this way, our laboratory developed a mouse model to study melanoma genesis. Different melanoma cell lines (i.e. 4C11- and 4C11+) were obtained as result of sequential anchorage blockade cycles of a non-tumorigenic melanocyte lineage, melan-a. Melan-a submitted to 2, 3 and 4 deadhesion cycles were also established (2C, 3C and 4C), are not tumorigenic and represent distinct phases of tumor progression. Melan-a, 4C, 4C11- and 4C11+ cells present differences in epigenetic profile, including global and gene specifc DNA methylation, posttranslational histone modifications as well DNA methyltransferases expression. Therefore, we have been interested in determining the separate and combined effects of 5-Aza-2’-deoxycytidine (5-Aza-CdR, inhibitor of DNA methylation) and Trichostatin A (TSA, inhibitor of histone deacetylases) treatment on cell phenotype and tumor characteristics. Our group already showed that TSA or 5-Aza-2’-deoxycytidine treatment causes changes in melanoma cells (4C11- and 4C11+) morphology and in in vivo tumor growth. Interestingly, TSA treatment was more efficient in diminishing 4C11- (non-metastatic melanoma) tumor growth in vivo than 5-Aza-CdR. On the other hand, 5-Aza-CdR treatment was more efficient to decrease 4C11+ (metastatic melanoma) tumor growth in vivo. Moreover, when treated with 5-Aza-CdR and TSA, 4C11- cells (a non-metastatic melanoma) give rise to hemorrhagic invasive tumors in vivo. This kind of treatment might lead to over expression of genes related to invasiveness and metastasis. We already have some candidate genes to investigate as γ-synuclein. Taken together these findings could contribute to a better understanding of epigenetic drugs treatment on melanoma and may have important clinical applications.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2004. doi:10.1158/1538-7445.AM2011-2004