bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5700: Preparation and evaluation of glycosylated paclitaxel loaded in tastuzumab-immunoliposome
Authors: Murakami Masaharu , Kasai Tomonari , Okada Masashi , Mikuni Katsuhiko , Egashira Naoyoshi , Seno Masaharu , Hamada Hiroki
Published: August 2012

Targeted drug delivery is considered to enhance the therapeutic effects of anti-cancer agents because high amount could be administered with least side effects. However, water-insoluble hydrophobic chemical compounds such as paclitaxel are not suitable for efficient drug delivery. We conferred water-solubility of paclitaxel by coupling glucose at 7-OH to produce 7-alpha-glucosyloxyacetylpaclitaxel (7-GLG-PT). Although the 7-GLG-PT showed lower cytotoxicity than paclitaxel, encapsulation of 7-GLG-PT into liposomes was more efficient than that of paclitaxel. In our experiment, paclitaxel encapsulated liposomes was not detectable. Trastuzumab was then conjugated on the surface of 7-GLG-PT liposomes to prepare immunoliposome (GLG-PT-IL). The GLG-PT-IL exhibited cytotoxicity on SK-BR-3 cells overexpressing HER2. The IC50 values of paclitaxel, 7-GLG-PT, 7-GLG-PT liposome and GLG-PT-IL were 6, 126, 130 and 94 nM, respectively. From this evaluation, the concentration of each formula to suppress the cell growth completely was estimated around 30 to 300 nM. At these concentrations, the time required for each formula to suppress the growth at the half maximal level was evaluated. GLG-PT-IL showed the shortest time of 5 hours, which was one third of the others when compared with paclitaxel, 7-GLG-PT and 7-GLG-PT liposome. The specific targeting potential of the immunoliposome on SK-BR-3 cells was assessed. The accumulation on the cell surface was competitively inhibited by the excess amount of free tastuzumab. The endocytosis of the immunoliposomes was simultaneously confirmed by time-lapse imaging. Thus GLG-PT-IL has been successfully demonstrated to target the HER2-overexpressing cancer cells specifically suppressing their growth. Trastumab itself is considered to induce the antibody dependent cellular cytotoxicity, so that the endocytosis of HER2 may not be always necessary. However, HER2-mediated endocytosis was induced by the immunoliposomes while single trastuzumab did not show the endocytosis in SK-BR-3 cells. In this context together with the results demonstrated in this study, the 7-GLG-PT immunoliposome should be a promising candidate of highly efficient drug delivery system of cancer treatment targeting HER2.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5700. doi:1538-7445.AM2012-5700
Abstract 5714: Combination of glucagon-like-peptide-1 (GLP-1) receptor targeted therapy with anti-angiogenic compounds in a mouse model of neuroendocrine tumors
Authors: Wicki Andreas , Wild Damian , Orleth Annette , Rochlitz Christoph , Mamot Christoph , Christofori Gerhard
Published: August 2012

Neuroendocrine tumors are well vascularized and express specific cell surface markers, such as somatostatin receptors and glucagon-like peptide-1 receptors (GLP-1R). Using the Rip1Tag2 transgenic mouse model of pancreatic neuroendocrine tumors, we have investigated the potential benefit of a combination of anti-angiogenic treatment with targeted internal radiotherapy. To this end, [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4, a radiopeptide that selectively binds to GLP-1R expressed on insulinoma and other neuroendocrine tumor cells, was co-administered with PTK787, an inhibitor of vascular endothelial growth factors (VEGFR). For biodistribution, Rip1Tag2 mice were pre-treated with PTK787 for 0, 3, 5 or 7 days. Subsequently, [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 was administered and the biodistribution assessed after 4 hours. For therapy, mice were injected with 1.1 MBq [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 and treated with PTK787 orally for another 7 days. Tumor volume, tumor cell apoptosis and proliferation, and microvessel density were quantified. Combination of [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 and PTK787 was significantly more effective than single treatments (p<0.05) and reduced the tumor volume by 97% in the absence of organ damage. Pre-treatment of mice with PTK787 led to a reduction in the tumor uptake of [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4, indicating that concomitant administration of PTK787 and the radiopeptide was the best approach. Thus, combination of targeted radionuclide therapy with an anti-angiogenic compound inhibiting VEGF signaling had a synergistic effect on therapy efficacy. The combination of 1.1 MBq of [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 with PTK787 had the same effect on a neuroendocrine tumor as the injection of 28 MBq of the radiopeptide alone, but without any apparent side-effects, such as radiation damage of the kidneys.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5714. doi:1538-7445.AM2012-5714
Abstract 5729: The Wnt transcription factor TCF4 mediates resistance of colorectal cancer cells to (chemo-) radiotherapy in a β-catenin-independent manner
Authors: Grade Marian , Eimer Christine , Emons Georg , Kendziorra Emil , Spitzner Melanie , Gaedcke Jochen , Wolff Hendrik , Beissbarth Tim , Ried Thomas , Pukrop Tobias , Ghadimi Michael
Published: August 2012

Background: We recently demonstrated that the Wnt transcription factor TCF4 is over-expressed in rectal cancers that were resistant to preoperative chemoradiotherapy. Because the association between Wnt signaling and chemoradioresistance is a novel finding, we aimed to investigate whether this over-expression is functionally relevant. Methods: Three colorectal cancer cell lines were transfected with two shRNA-vectors targeting TCF4. Stable single-cell clone (SCC) populations were established, and selected clones were irradiated at 0, 1, 2, 4, 6 and 8 Gy. γH2AX staining was used to evaluate DNA double strand repair after irradiation, and changes in cell cycle distribution were analyzed before and after radiation. Finally, β-catenin activity was inhibited using both siRNAs and the small molecule inhibitor XAV939. Results: Silencing of TCF4 led to a significant radiosensitization in SW837 and SW480, whereas there was no effect in HT-29. Well-fitting, we observed significantly more γH2AX foci 24 hrs after radiation in SW837 SCCs compared to HT-29 SCCs, pointing to an impaired DNA damage repair in SW837. Furthermore, in SW837 SCCs, but not in HT-29 SCCs, we noticed a change in the cell cycle distribution towards radiosensitive cell cycle phases before radiation, and compromised cell cycle control after radiation. Finally, both siRNA- and small molecule-mediated inhibition of β-catenin activity did not influence the sensitivity to chemoradiotherapy. Conclusion: Our results indicate a novel mechanism through which the Wnt transcription factor TCF4 mediates chemoradioresistance in a β-catenin-independent manner. Moreover, they suggest that TCF4 is a potential molecular target to sensitize resistant tumor cells to (chemo-) radiotherapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5729. doi:1538-7445.AM2012-5729
Abstract 617: Apigenin intake regulates Fox ‘O’ signaling in an autochthonous mouse model of prostate cancer
Authors: Shukla Sanjeev , Bhaskaran Natarajan , MacLennan Gregory T. , Fu Pingfu , Gupta Sanjay
Published: August 2012

Forkhead transcription factors of ‘O’ class (FoxOs) are involved in a paradigm that supports proliferation, survival, longevity during multiple cellular environments, and tumor development. Perturbation of FOXO activity leads to altered cellular response which results in cancer development and progression. We previously showed that FOXO signaling is deregulated in human prostate adenocarcinoma and in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model that mimics progressive forms of human disease. In the present study we aimed to demonstrate the potential role of apigenin, a common dietary flavonoid present in fruits and vegetables, in modulating FoxO signaling and its downstream events to suppress cancer progression using in vivo and in vitro models. Apigenin was fed to TRAMP mice at 20- and 50- μg/mouse/day (gavaged in 0.2 ml vehicle containing 0.5% methyl cellulose and 0.025% Tween 20) for six days in a week for 20 weeks; whereas control animals received vehicle only. Apigenin intake by TRAMP mice from 8-28 weeks of age exhibited marked reduction in tumor growth with no signs of metastasis. Apigenin feeding to TRAMP resulted in a significant dose-dependent reduction in Foxo3a, but not Foxo1a protein observed in the dorso-lateral prostates. Foxo3a protein was redistributed more in nuclear than the cytosolic compartments after apigenin feeding. Simultaneously, decreased Foxo3a phosphorylation (Ser253) was observed in the dorso-lateral prostate, which correlated with decreased cytoplasmic retention of Foxo3a with no significant change in 14-3-3 chaperone protein in the cytosol after apigenin feeding. Conversely, TRAMP mice have higher 14-3-3 expression than non-transgenic mice and this higher level accounted for nuclear retention of Foxo3a. A subsequent decrease in p-Akt (Ser473) was noted after apigenin feeding demonstrating that the decreased nuclear presence of p-Akt (ser473) may be restricting Foxo3a phosphorylation and its retention in the nucleus. Furthermore, an increase in the levels of MnSOD and Cu/ZnSOD was observed in TRAMP mice after apigenin intake. Similar findings were recorded in cell culture studies where apigenin treatment to human prostate cancer LNCaP and PC-3 cells resulted in the restoration of FOXO3a in the nucleus. This increase in Foxo3a protein levels in the nucleus may be a decisive factor resulting in the inhibition of prostate cancer. These finding suggests that apigenin has potential role in regulating the FOXO signaling cascade and may be a major therapeutic target in prostate cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 617. doi:1538-7445.AM2012-617
Abstract 641: Prognosis of breast cancer is associated with one-carbon metabolism related nutrients among Korean women
Authors: lee yunhee , Lee Sang-Ah , Choi Ji-Yeob , Sung Hyuna , Jeon Sujee , Park Sue K. , Yoo Keun-Young , Noh Dong-Young , Ahn Sei-Hyun , Kang Daehee
Published: August 2012

The 5-year survival rate for breast cancer has increased from 78% during 1993 to 1995 to 90% during 2004 to 2008 among Korean women. Despite such improvement, breast cancer remains the leading cause of cancer mortality among women. One-carbon metabolism, which requires adequate supply of methyl group donors and B-vitamins, may affect breast cancer prognosis. This study aimed to investigate the associations of dietary intake of vitamin B2, vitamin B6 and folate before diagnosis and breast cancer prognosis. We assessed dietary intake from Food Frequency Questionnaire in 980 women who were newly diagnosed and histopathologically confirmed first primary breast cancer from hospitals located in Seoul, Korea in 2004 to2007 and followed for an average of 5.3 years. Univariate and multivariate analyses were used to investigate association between dietary intake of B-vitamins and disease free survival. There was no association between dietary intake of B vitamins and breast cancer prognosis. However, we found higher dietary intake of vitamin B6 was associated with improved survival in patients with BMI more than 25kg/m2 (harzard ratio (HR), 0.32; 95% confidence intervals (CI), 0.11-0.94) or positive hormone status in estrogen receptor(ER)/progesterone receptor(PR) (HR, 0.39; 95%CI, 0.16-0.97). Our study suggests that the high intake of vitamin B6 is associated with improved breast cancer survival in patients with higher BMI and positive hormone status in ER/PR.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 641. doi:1538-7445.AM2012-641
Abstract 67: Characterization of the role of KLF9 transcription factor in breast cancer estrogen response
Authors: Pitch Michelle A. , Russell Beth A. , Greene Geoffrey L.
Published: August 2012

Kruppel-like factor 9 (KLF9) is a member of the KLF family of transcription factors. Previous studies report significant KLF member involvement in breast cancer estrogen response, notably KLF4 [1, 2] and KLF5 [3, 4]. KLF9 has been shown in uterine cancer cells to function as an estrogen-dependent regulator of the estrogen response pathway [5]. We aim to evaluate the role of KLF9 in breast cancer cell estrogen response. We have performed studies demonstrating that KLF9 exhibits an early-activated estrogen response. Five sites have been identified upstream of the KLF9 gene that interact with estrogen receptor alpha (ERα) [6-8]; we observe ERα enrichment at three of these sites that is estradiol-dependent. Though KLF9 has been shown to act as an essential element in estrogen response in the uterus, KLF9 response in breast cancer cells has yet to be characterized. To study the role of KLF9 in estrogen-mediated responses in transcriptional and proliferative activity, we have manipulated the level of KLF9 expression in MCF-7 breast cancer cells. These cells have been shown to exhibit a clear transcriptional response to estradiol in luciferase reporter assays. We have optimized RNAi conditions to achieve significant knockdown of the KLF9 gene in MCF-7 cells. Additionally, we have produced and tested a KLF9 overexpression vector construct that significantly upregulates expression of KLF9 in this cell line. These tools will be used to more extensively characterize the role of KLF9 in MCF7 cell estrogen-stimulated transcription and proliferation. We are measuring transcriptional response to estrogen signaling with luciferase reporter assays and estrogen stimulated cell proliferation with BrdU proliferation assays. Elucidating KLF9 involvement in E2-mediated breast cancer cell signaling and response, therefore, is an important component of understanding of the regulatory mechanisms behind estrogen response in breast cancer. 1. Akaogi K et al. (2009). Oncogene 28(32): 2894. 2. Quintana AM et al. (2011). BMC Cancer 11: 30. 3. Guo P et al. (2010). International Journal of Cancer 126(1): 81. 4. Zhao KW et al. (2011). Biochemical Journal 437(2): 323. 5. Velarde MC et al. (2007). Molecular Endocrinology 21(12): 2988. 6. Carroll JS et al. (2006). Nature Genetics 38(11): 1289. 7. Hua S et al. (2008). Molecular Systems Biology 4:188. 8. Fullwood MJ et al. (2009). Nature 462(7269): 58.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 67. doi:1538-7445.AM2012-67
Abstract 676: Serological levels of folate at birth and risk of childhood acute lymphoblastic leukemia
Authors: Chokkalingam Anand P. , Chun Danielle , Hsu Ling-I , Metayer Catherine , Rabinowitz Daniel J. , Zhang Mindy , Wiemels Joseph L. , Buffler Patricia A.
Published: August 2012

A role for folate in the etiology of childhood acute lymphoblastic leukemia (ALL) has long been suspected due to folate's dual role in control of DNA methylation as well as maintenance of DNA synthesis. Case-control studies examining self-reported maternal folate intake and supplementation during pregnancy have been inconclusive. Furthermore, while studies of children's own folate metabolism and transport genes have identified potential disease loci, the results have been mixed on the whole. A child's exposure to folate in utero is modulated by a number of factors, including maternal intake/supplementation, maternal genes, and child's genes. Therefore, we examined the role of folate in childhood ALL risk more directly by utilizing a quantitative microbiologic assay to measure newborn red blood cell folate levels in archived dried bloodspots collected at birth from 319 incident cases and 413 matched population-based controls who enrolled in the Northern California Childhood Leukemia Study between 1995 and 2002. After adjustment for income, race/ethnicity, gender, and age, we found no difference in newborn folate levels between cases and controls overall (971 vs. 968 nmol/L, p=0.94). In addition, no differences between cases and controls were observed after stratification by birth year to account for the start of folate fortification of grain products in the US (1982-1994: 953 vs. 952 nmol/L, p=0.98; 1995-1998: 1018 vs. 975 nmol/L, p=0.34; and 1999-2002: 878 vs. 990 nmol/L, p=0.23). Children whose mothers reported pre-pregnancy supplement use had somewhat higher newborn folate levels overall, but we observed no case-control differences in folate levels after stratification by supplement use. Our results do not support an association between folate levels at birth and risk of childhood ALL. However, our results do not rule out a role for folate exposures after birth. Future epidemiologic studies of childhood ALL should pay particular attention to post-natal folate exposures.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 676. doi:1538-7445.AM2012-676
Abstract 680: Loss of miR-34a as measured by quantitative in situ hybridization on a tissue microarray is associated with poor outcome in breast cancer
Authors: Agarwal Seema , Hanna Jason A. , Rimm David L.
Published: August 2012

Introduction: MicroRNAs (miRNAs) have emerged as key regulators in the pathogenesis of cancers as either oncogenes or tumor suppressors. It has been shown that the loss of miR-34a leads to tumor progression and metastasis using cell lines and a limited number of patient samples by RT-PCR. Lack of a robust, reproducible and quantitative method has limited large scale analysis and assessment of miR-34a as tumor suppressor marker in cancer. Herein, we have developed and validated a method for the quantitative analysis of miRNA expression by in situ hybridization (qISH) allowing for the direct assessment of tumor epithelial expression of miR34a in breast cancer. Method: Expression level of miR-34a was measured in a retrospective breast cancer (n=461) cohort with 20 year follow-up using quantitative immunofluorescence (AQUA) technology for ISH in a tissue microarray (TMA) format. The assay was performed in two-fold redundancy with a 40 case index TMA for reproducibility and standardization. Averaged AQUA scores for miR34a were correlated with clinical and pathological characteristics and 10 year disease-free survival in this cohort. Results: Since miR-34a is a tumor suppressor, we determined the threshold at which no specific hybridization was seen (AQUA score =16.89). Reproducibility between two different builds (cores) of the TMA was R*2 = 0.59. Using overall survival as an endpoint in Kaplan Meier analysis with the threshold of expression as the cutpoint, the group with loss of miR-34a had significantly worse survival (log rank p = 0.0264). Cox univariate analysis for miR-34a showed hazard ratio of 1.53 (95% CI: 1.05-2.22, p=0.0276). Cox multivariate analysis including age, nuclear grade, nodal status, ER, PR and Her2 showed miR34a is not an independent marker (p=0.0908). An independent breast cancer cohort will be used to validate this result. Conclusions: The microRNA miR-34a has been proposed to be a tumor suppressor using mechanistic and functional data. This result, showing loss of miR-34a is associated with worse outcome in a large breast cancer cohort provides clinical evidence of the tumor suppressor function of miR-34a.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 680. doi:1538-7445.AM2012-680
Abstract 682: Increased stearoyl-CoA desaturase 1 expression is associated with shorter survival in breast cancer patients
Authors: Holder Ashley M. , Gonzalez-Angulo Ana M. , Chen Huiqin , Akcakanat Argun , Anh-Do Kim , Symmans Fraser , Pusztai Lajos , Hortobagyi Gabriel , Mills Gordon B. , Meric-Bernstam Funda
Published: August 2012

Stearoyl-CoA desaturase 1 (SCD1) is an essential regulator of fatty acid synthesis that affects cell membrane composition and may play a role in cancer cell metabolism. We have previously shown that SCD1 expression is increased by mTOR signaling and that SCD1 increases breast cancer cell growth in vitro. The purpose of this study was to determine protein levels of SCD1 in breast cancer and to determine whether there is an association between SCD1 levels and survival. Fine needle aspirates were collected from the primary breast cancers of 253 patients with Stage I-III breast cancer and protein lysates were prepared. SCD1 expression was analyzed using reverse phase proteomic array. Patient demographic and clinical characteristics including age, ethnicity, menopausal status, clinical stage, tumor grade, and tumor subtype were reviewed. Samples were divided into high or low SCD1 levels based on a cut-off determined from martingale residual plots and regression tree analysis. SCD1 levels were significantly higher in older patients and lower in triple negative (estrogen, progesterone, and HER2 negative) cancers, After adjusting for tumor subtype, tumor grade, age, and clinical stage, patients who had high SCD1 levels had significantly shorter relapse-free survival (RFS) (p=0.013) and overall survival (OS) (p=0.038). SCD1 level varies by breast cancer subtype and predicts significantly shorter RFS and OS. Future studies are needed to define the role of SCD1 in breast cancer and evaluate its potential as a therapeutic target.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 682. doi:1538-7445.AM2012-682
Abstract 704: Expression of FOXO1 is associated with GATA3 and Annexin-1 and predicts disease-free survival in breast cancer
Authors: Wu Yan Yuan , Elshimali Yayha , Sarkissyan Marianna , Mohamed Hezla , Clayton Sheila , Vadgama Jay
Published: August 2012

Purpose: To determine the prognostic value of FOXO1, GATA3 and Annexin-1 expression in breast cancer. Methods: Tissue microarray and individual paraffin tissue slides from 131 patients were used for the study. The association of FOXO1, GATA3 and Annexin-1 expression with clinicopathological features of breast cancer and disease outcome was examined in retrospective samples. Kaplan-Meier survival curves and Cox regression with multivariate analysis were used for assessing the relative risk (RR) and disease-free survival (DFS). The expression of FOXO1, GATA3 and Annexin-1 were determined by immunohistochemistry and the association among the three proteins was analyzed by Logistic regression analysis. Results: The nuclear expression of FOXO1 was observed in most of the normal breast tissues and 51.3% of the malignant breast tissues. GATA3 and Annexin-1 were expressed at 73% and 24.6% respectively in breast cancer tissues. The expression of FOXO1, GATA3 and Annexin-1 were all inversely correlated with lymph node-positive tumors. Both FOXO1 and Annexin-1 expression were also inversely associated with HER2-overexpressing tumors. FOXO1 expression was significantly associated with both GATA3 and Annexin-1 expression. In addition, Multivariate analyses confirm that only FOXO1 levels independently predict DFS. Conclusion: FOXO1 expression in breast cancer is regulated by the PI3K/Akt pathway. The expression of FOXO1 is also associated with GATA3 and/or Annexin-1. Restoring or targeting FOXO1 to the cell nucleus in breast cancer tissues may improve response to therapy and disease outcome. Further clinical studies are warranted to test this hypothesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 704. doi:1538-7445.AM2012-704
Abstract 726: Copy number amplification of the PIK3CA gene is associated with poor prognosis in early-stage head and neck squamous cell carcinoma
Authors: Suda Toshihito , Hama Takanori , Urashima Mitsuyoshi , Kato Takakuni , Moriyama Hiroshi
Published: August 2012

Background: Deregulation of the EGFR signaling pathway is one of the most frequently observed genetic abnormalities that drive cancer development. Mutations in downstream components of the EGFR signaling pathway, including KRAS, BRAF and PIK3CA, have been reported in numerous cancers. However, extensive mutation analysis of these genes in clinical samples has not been performed for head and neck squamous cell carcinoma (HNSCC). Patient and methods: We examined mutations and copy number alterations of KRAS, BRAF and PIK3CA in 115 clinical specimens of HNSCC obtained from surgically treated patients. Results: We identified three mutations in K-RAS and two mutations in PIK3CA. Copy number amplification was found in 42 cases (36.4%) for PIK3CA, 12 cases (10.4%) for K-RAS and nine cases (7.8%) for BRAF. Tumor recurrence and death occurred in 49 (42.6%) and in 22 (19.3 %) patients during the median follow-up of 723 days, respectively. Kaplan-Meier survival analysis revealed that in patients with early-stage carcinoma (Stages I-III), copy-number amplification of PIK3CA was drastically associated with cancer relapse. Conclusion: Copy number amplification of the PIK3CA is associated with poor prognosis in early-stage HNSCC. The PIK3CA copy number status will serve as a marker of poor prognosis in patients with HNSCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 726. doi:1538-7445.AM2012-726
Abstract LB-175: β-Escin inhibits NNK-induced lung adenocarcinoma formation in A/J mice by suppressing ALDH1A1 positive cells; and RhoA/Rock induced invasion of human lung cancer cell growth.
Authors: Patlolla Jagan Mohan R. , Qian Li , Barton Laura , Zhang Yuting , Desai Dhimant , Amin Shantu , Lightfoot Stan , Rao Chinthalapally
Published: August 2012

Lung cancer is the leading causes of cancer deaths. β-Escin a triterpene saponin isolated from horse chestnut (Aesculus hippocastanum) seeds, had tested on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma formation in female A/J mice and its possible mode of action was evaluated using human lung cancer cell lines (H460 and H2126). For bioassay, at 6 weeks of age, mice were randomized and fed control AIN-76A modified diet. At 7 weeks of age (25 mice/group) intended for carcinogen treatment received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after the NNK treatment, groups of mice fed either control or experimental diets containing 500 ppm β-Escin. Mice were continued on the respective diets and killed at 20 weeks (10 mice/group) and/or 36 weeks (15 mice/group) after NNK-treatment for lung tumor evaluation by histopathological methods. Administration of 500 ppm β-Escin significantly suppressed lung tumor (adenoma+adenocarcinoma) formation by >40% (p<0.0015), at 20 weeks and 53.3% (p<0.0001), at 36 weeks. Importantly, β-Escin showed NNK-induced lung adenocarcinoma inhibition by 65% (p<0.001), at 20 weeks and by 53% (p<0.0001) at 36 weeks. These results suggest that β-Escin inhibits the NNK-induced lung tumor and more so by suppressing adenocarcinoma formation. Immunohistochemistry analysis revealed that lung tumor harvesting from mice exposed to β-Escin showed significantly reduced ALDH1A1 expression when compared to control lung tumors. Since ALDH1A1 is a putative lung cancer stem cell marker and associated with therapeutic resistance. Furthermore, in Aldefluor assay using FACS analysis of lung cancer cell lines treated with different concentrations of β-Escin (0-40 µM) revealed that the subpopulation of cells with elevated ALDH activity has significantly inhibited by ∼60-85%. Also, β-Escin induced p21 levels and suppressed Rho A and Rock protein expression in H460 and H2126 cell lines and NNK-induced lung tumors. Our findings for the first time suggest that β-escin inhibits tobacco carcinogen-induced lung tumor formation by modulating ALDH1A1 positive cells and RhoA/Rock pathway singling. {Supported by Kerley-Cade Endowment for Cancer Research}

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-175. doi:1538-7445.AM2012-LB-175
Abstract LB-181: Piperlongumine inhibits growth and survival of human Burkitt lymphoma by downregulating NF-κB, c-Myc and LMP1
Authors: Han Seong-Su , Son Dong-Ju , Yun Hwakyung , Janz Siegfried
Published: August 2012

Piperlongumine (PL), a natural product constituent of the fruit of the Long pepper, Piper longum, has well documented anti-inflammatory and cancer inhibiting properties. The latter include evidence that PL selectively kills solid tumor cells, but spares their normal counterparts. Because it has not been established whether PL can also inhibit hematological malignancies of the B-lymphocyte lineage, we here decided to evaluate the efficacy with which PL suppresses growth and survival of human non-Hodgkin's Burkitt lymphoma (BL) cells in vitro. We found that PL curbed cell growth (IC50 values of PL for 24h treatment: DG-75; 8.5uM, Daudi; 2.84uM, Raji; 7.7uM and Ramos; 4.5uM) and caused Caspase-3-dependent apoptosis of BL cells in a concentration- and time-dependent manner. PL strongly suppressed constitutive NF-κB signaling by inhibition of IκBα degradation and subsequent nuclear translocation of p65 as well as interruption of NF-κB binding to its consensus DNA sequence. PL also disrupted the expression of NF-κB target genes such as E2F1, c-Myb and GADD45B. c-Myc, transcription factor important for BL development and survival, was remarkably reduced after treatment with PL. In EBV-positive BL cell lines that express high level of LMP1 (e.g., Daudi, Raji), PL efficiently repressed LMP1, a known activator of NF-κB. Considering that NF-κB, c-Myc and LMP1 play important roles in the development and in vivo maintenance of B-lineage and other types of blood cells neoplasms, our findings strongly suggest that PL may afford new approaches to the chemoprevention and treatment of blood cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-181. doi:1538-7445.AM2012-LB-181
Abstract LB-328: Plasma antibodies to oral pathogen and commensals and risk of pancreatic cancer in a large European prospective cohort study
Authors: Michaud Dominique S. , Izard Jacques , Wilhelm-Benartzi Charlotte , Riboli Elio , Bueno-de-Mesquita Bas ,   for the EPIC team.
Published: August 2012

Background: A positive relationship between periodontal disease and pancreatic cancer risk has been observed in previous epidemiological studies. In a cohort study of health professional men, never smokers reporting a positive history of periodontal disease had a 2-fold higher risk of pancreatic cancer compared with those reporting no periodontal disease (RR = 2.09, 95% CI = 1.18-3.71). These findings suggest that oral bacteria may be able to disseminate to the pancreas or may be associated with risk indirectly. We examined the relationship between the presence of antibodies to 25 diverse strains of oral bacteria and pancreatic cancer risk in a prospective study. Methods: Antibodies to oral bacteria were measured in prediagnostic blood samples of 405 pancreatic cancer cases and 416 matched controls nested within the European Prospective Investigation on Cancer (EPIC), a large cohort study. Analyses were conducted using conditional logistic regression and additionally adjusted for smoking status and body mass index. Results: Individuals with high antibody levels to Porphyromonas gingivalis ATTC 53978 (>200 ng/ml), a pathogenic periodontal bacteria, had a two-fold higher risk of pancreatic cancer (OR = 2.14, 95% CI =1.05-4.36) compared with individuals with low levels of antibody (<200ng/ml). To explore the association with common oral bacteria, we performed a cluster analysis and obtained two clusters that aggregated individuals according to their antibody profiles. A substantially lower risk of pancreatic cancer was observed in the cluster with consistently elevated levels of antibodies, compared to a second cluster with overall lower levels (OR = 0.55, 95% CI = 0.36-0.83). Conclusions: In this study using prediagnostic bloods, we find support for a positive association between periodontal disease and pancreatic cancer. Additionally, our results further suggest that certain oral bacteria or an enhanced immune surveillance may provide some protection against pancreatic cancer. Our findings are consistent with dental research on periodontal disease etiology and treatment. Whether periodontal disease is causally related to pancreatic cancer or simply a marker of underlying immune response needs to be further elucidated.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-328. doi:1538-7445.AM2012-LB-328
Abstract LB-87: Methylated-mediated repression of ZNF154 in ovarian cancer is associated with poor overall survival
Authors: Okamoto Takako , Yamaguchi Ken , Huang Zhiqing , Whitaker Regina , Konishi Ikuo , Berchuck Andrew , Murphy Susan K.
Published: August 2012

Objectives: Epigenetic gene regulation plays an important role in the development of cancer. We previously found that Zinc Finger Protein 154 (ZNF154), a Krüppel family zinc finger protein, is ubiquitously methylated in a large panel of ovarian cancer cell lines but is unmethylated in normal cells. The objectives of this study were to determine the relevance of ZNF154 methylation to mRNA expression and relationship to clinical outcome in primary epithelial ovarian cancers. Methods: Genomic DNA from 85 ovarian cancers (53 serous, 13 clear cell, 11 endometrioid and 8 mucinous) along with 4 fallopian tube and 4 ovarian surface epithelium specimens was bisulfite modified (Zymo EZ DNA Methylation kit) followed by generation of Illumina Infinium 450k Methylation Beadchip data for >485,000 CpG sites, given as β-values (scale, 0-1, where 1 is completely methylated). Bisulfite pyrosequencing was used to validate array results. ZNF154 mRNA expression was quantified using real time RT-PCR following treatment of 5 ovarian cancer cell lines and 2 immortalized OSE controls with 5µM 5-aza-2′ deoxycytidine (DAC) for 72h. Mann-Whitney U tests were used for group comparisons, Pearson correlation for continuous variables and the Kaplan-Meier method for overall survival. Results: Methylation of ZNF154 was significantly higher in cancers versus normal tissues (average β=0.51 versus β=0.09, respectively; p<0.0001). Methylation values obtained by pyrosequencing strongly correlated with array β-values (R=0.94; p=1.31e-40). ZNF154 mRNA expression was lower in ovarian cancer versus normal cells (p=0.015). Following DAC treatment, ZNF154 expression increased an average 8.01-fold (p=0.0499) while methylation levels decreased up to 20% (p=0.028) compared to mock treated controls. Stage III-IV serous cancers with higher (N=25) versus lower (N=22) ZNF154 methylation had 66 months decreased median overall survival (p=0.032). Conclusions: ZNF154 is ubiquitously methylated in primary ovarian cancers but not in normal cells and expression of ZNF154 is at least partially regulated by DNA methylation. In addition, increased methylation of ZNF154 is associated with poor clinical outcome for advanced stage serous cancers. Our results suggest that ZNF154 methylation status may have utility as a biomarker and also as a tool for prognostic prediction.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-87. doi:1538-7445.AM2012-LB-87
Population-Based Estimates of Neuroendovascular Procedures: Results of a State-Wide Study
Authors: Qureshi Adnan I. , Chaudhry Saqib A. , Majidi Shahram , Grigoryan Mikayel , Rodriguez Gustavo J. , Suri M. Fareed K.
Published: August 2012

Background: The Brain Attack Coalition identified the availability of neuroendovascular procedures as an essential component of a comprehensive stroke center. Objective: To provide population-based estimates of neuroendovascular procedures. Methods: State-wide estimates of cervicocerebral angiograms, endovascular ischemic stroke treatments, carotid angioplasty and stent placements, intracranial angioplasty and stent placements, endovascular treatment of intracranial aneurysms, and endovascular treatment of intracranial arteriovenous malformations (AVMs) were obtained. We calculated the annual incidence rates of various neuroendovascular and neurosurgical procedures (per 100,000 persons). For the denominator, total persons in each year were categorized in 10-year age intervals. Results: The incidence of carotid endarterectomy (387.6 per 100,000 persons) and carotid stent placement (34.7 per 100,000 persons) peaked at 75–84 years. The incidence of aneurysm embolization also peaked in that population bracket (67.9 per 100,000 persons), yet there was a dramatic reduction in the incidence of surgical aneurysm treatment (3.6 per 100,000 persons) in those aged 75–84 years. There was a prominent reduction in the incidence of all procedures in the population aged ≥85 years, except for intravenous/intra-arterial thrombolytic use in ischemic stroke. The incidence of ischemic stroke increased almost by 50% in the population aged ≥85 years compared to those aged 75–84 years. However, the incidence of endovascular procedures for acute ischemic stroke decreased from 22.8 per 100,000 persons in the population aged 75–84 years to 13.2 per 100,000 persons in the population aged ≥85 years. Conclusions: A marked disproportion of neuroendovascular procedures performed and disease prevalence was noted in persons aged ≥85 years, an increasing segment of the population according to recent Census.
Prulifloxacin versus Levofloxacin in the Treatment of Respiratory and Urinary Tract Infections: A Multicentre, Double-Blind, Randomized Controlled Clinical Trial
Authors: Chen Yongchuan , Yang Heping , Lu Gensheng , Wu Xiongfei , Huang Wenxiang , Wu Yamei , Lv Xiaoju , Wu Guoming , Zhang Genfu , Li Qiang , Sun Yinghao
Published: August 2012

Background: Prulifloxacin is a promising fluoroquinolone antibiotic. A multicentre, double-blind, randomized clinical study was designed to evaluate its efficacy and safety compared to that of levofloxacin for the treatment of respiratory and urinary infections of Chinese patients. Methods: A total of 267 patients were enrolled and each was randomly assigned to either the treatment or the control group. Prulifloxacin 264.2 mg (equivalent to ulifloxacin 200 mg) b.i.d. or levofloxacin hydrochloride 200 mg b.i.d. was administered orally for 5–14 days according to a patient’s condition. The clinical response, bacterial eradication and incidence of adverse events were evaluated. Results: Two hundred and forty-three patients completed the study. For the modified intention-to-treat population, the cure and effective rates were 45.53 and 82.93% in the prulifloxacin group and 49.18 and 83.61% in the levofloxacin group. For the per-protocol analysis population, the cure and effective rates were 45.90 and 83.61% in the prulifloxacin group and 49.59 and 83.47% in the levofloxacin group. The bacterial eradication rates were 96.59 and 95.35%, and the drug-related adverse event rates were 7.87 and 5.51% in the prulifloxacin and levofloxacin group, respectively. The cure rate and efficacy rate of respiratory and urinary tract infections of the levofloxacin group were better than those of the prulifloxacin group. However, the difference between the 2 groups was not statistically significant (p > 0.05). Conclusion: Prulifloxacin is as effective and well tolerated as levofloxacin in the treatment of respiratory and urinary tract infections.
Urethral Reconstruction Using Buccal Mucosa or Penile Skin Grafts: Systematic Review and Meta-Analysis
Authors: Lumen N. , Oosterlinck W. , Hoebeke P.
Published: August 2012

Introduction: Different types of grafts have been described in urethral reconstruction (UR), with penile skin graft (PSG) and buccal mucosa graft (BMG) as the most frequently used ones. It still remains unclear whether one graft is superior in terms of success when compared to the other. Material and Methods: A systematic review of the literature was performed searching the MEDLINE database with the following search strategy: ‘urethroplasty’ AND ‘penile skin’/ ‘urethroplasty’ AND ‘buccal mucosa’. 266 and 144 records were retrieved for urethroplasty with PSG and BMG, respectively. These records were reviewed to identify papers where PSG and BMG were used in UR and where individualized data on success were available within the same series. Results: 18 papers were found eligible for further analysis. In total, 428 and 483 patients were respectively treated with PSG or BMG. If available, follow-up duration was 64.1 versus 42.1 months (p < 0.0001) and stricture length 6.2 versus 4.6 cm (p < 0.0001) for PSG and BMG, respectively. Success of UR with PSG was 81.8 versus 85.9% with BMG (p = 0.01). Conclusions: Success of UR using BMG is significantly better compared to PSG. Results might be seriously biased by a longer follow-up duration and stricture length for PSG compared to BMG.
Myocardial Systolic and Diastolic Performance Derived by 2-Dimensional Speckle Tracking Echocardiography in Heart Failure With Normal Left Ventricular Ejection Fraction
Authors: Morris Daniel A. , Boldt Leif-Hendrik , Eichstädt Hermann , Özcelik Cemil , Haverkamp Wilhelm
Published: August 2012

Background—

The aim of this study was to investigate the myocardial systolic and diastolic performance of the left ventricle (LV) in patients with heart failure with normal LV ejection fraction (HFNEF) through novel LV myocardial indices, which assess the systolic and diastolic function of the whole myocardium of the LV.

Methods and Results—

LV myocardial systolic and diastolic performance were assessed as the average value of peak systolic strain and peak early-diastolic strain rate, respectively, in longitudinal, circumferential, and radial directions from all LV segments using 2-dimensional speckle-tracking echocardiography. We studied patients with HFNEF and a control group consisting of asymptomatic subjects with LV diastolic dysfunction of similar age, sex, and LV ejection fraction. A total of 322 patients were included (92 with HFNEF and 230 with asymptomatic LV diastolic dysfunction). Myocardial systolic and diastolic LV performance were significantly lower in HFNEF (20.13±6.02% and 1.14±0.27 s
−1
) than in patients with asymptomatic LV diastolic dysfunction (25.33±6.06% and 1.37±0.33 s
−1
, respectively; all
P
<0.0001). In addition, patients with HFNEF with low systolic and diastolic LV myocardial performance had significantly higher LV filling pressures (17.1±6.6 and 17.6±6.3 versus 12.0±5.1 and 11.7±4.7, respectively; all
P
<0.001) and lower cardiac output (4.8±1.0 L/min and 4.9±1.1 L/min versus 5.7±1.2 L/min and 5.8±1.1 L/min, respectively; all
P
<0.001) than patients with normal LV myocardial performance. In relation to these findings, the symptomatic status (ie, New York Heart Association functional class) was significantly altered in those patients with low systolic and diastolic LV myocardial performance.

Conclusions—

In patients with HFNEF, both systolic and diastolic LV myocardial performance are impaired, which is associated with increased LV filling pressures, decreased cardiac output, and worse New York Heart Association functional class. Therefore, the measurement of these myocardial parameters could be of great importance in HFNEF because these echocardiographic indices assess the multidirectional function of the whole myocardium of the LV, thereby allowing detection of an alteration of the global function of the LV which is associated with a worse symptomatic status in these patients.
Missed Opportunities
Authors: Subherwal Sumeet , Patel Manesh R. , Kober Lars , Peterson Eric D. , Jones William S. , Gislason Gunnar H. , Berger Jeffrey , Torp-Pedersen Christian , Fosbol Emil L.
Published: August 2012

Background—

Patients with peripheral artery disease (PAD) are at high risk of cardiovascular events and benefit from aggressive secondary prevention; however, changes in the use of cardioprotective medications after incident diagnosis of PAD have not been well described.

Methods and Results—

We used Danish nationwide administrative registries (2000–2007) to identify 2 groups with incident PAD: PAD alone (n=34 160) and PAD with history of coronary artery disease (CAD) (n=9570). With the use of a comparator with incident CAD alone (n=154 183), we assessed temporal trends and comparative use of cardioprotective medications. Relative differences in medication use were examined by using multivariable logistic regression. Use of medications improved temporally among both groups: for PAD alone, any antiplatelet use increased from 29% to 59% from 2000 to 2007 (
P
<0.0001), whereas statin use increased 6-fold (9%–56%;
P
<0.0001). However, use of these therapies by 18 months after incident diagnosis for both PAD groups remained modest and lower in comparison with CAD alone (any antiplatelet, 53% versus 66%; statins, 40% versus 52%; angiotensin-converting enzyme inhibitors, 20% versus 29%). Relative to CAD alone, patients with PAD alone were less likely to use any antiplatelet (adjusted odds ratio, 0.50; 95% confidence interval, 0.49–0.52), statins (adjusted odds ratio, 0.50; 95% confidence interval, 0.48–0.52), or angiotensin-converting enzyme inhibitors (adjusted odds ratio, 0.51; 95% confidence interval, 0.49–0.53) by 18 months.

Conclusions—

Despite improvement in the use of cardioprotective medications over time, patients with PAD alone remain less likely than those with CAD alone to use these agents.
“Savages” in the Service of Empire: Native American Soldiers in Gorham's Rangers, 1744–1762
Authors: Carroll Brian D.
Published: August 2012

Gorham's Rangers, initially an all-Indian ranger company, was instrumental in Britain's conquest of Nova Scotia (Acadia) during the eighteenth century. In the process of uncovering that story, the essay assesses New England Indians’ role in shaping colonial frontier warfare as well as the impact of military service on Native American communities.