bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3603: Zidovudine (AZT)-induced aneuploidy, mediated by Stathmin 1 (STMN1), involves a loss of polymerized β-tubulin.
Authors: Rivera Andrea V. , Sanchez Vanesa C. , Poirier Miriam C. , Olivero Ofelia A. 
Published: August 2014

Abstract
The nucleoside reverse transcriptase inhibitor AZT induces multiple manifestations of genotoxicity, among which aneuploidy, observed as micronuclei containing whole chromosomes, has been reported (Borojerdi et al., Mut Res, 2009). We have seen a loss of β-tubulin polymerization in about 23% of normal human mammary epithelial cells (NHMECs) exposed for 24 hr to 200 μM AZT, and demonstrated down-regulation of hsa-miR-770-5p, a microRNA known to target STMN1, in the same AZT-exposed cells. STMN1 prevents microtubule polymerization, resulting in destabilization of the mitotic spindle and chromosome misalignment. We therefore hypothesized that, if AZT exposure downregulates hsa-miR-770-5p, there should be increased expression of STMN1, which would result in loss of microtubule polymerization leading to aneuploidy. In this study we exposed cells of the human breast line MCF-10A to 100 μM AZT continuously for 1 to 3 passages (P). By Western Blot we showed that total STMN1 was 3.5-fold increased at P1, in AZT-exposed cells, compared to the unexposed controls. Using the same STMN1 antiserum, by immunohistochemistry (IHC), we observed that some cells stained heavily for STMN1, while others had virtually no staining, and that the overall STMN1 fluorescence was increased in AZT-exposed cells, compared to unexposed controls. When tubulin polymerization was evaluated by IHC, using β-tubulin antiserum, 10.1% of AZT-exposed cells showed a loss of tubulin polymerization, while only 0.7% of unexposed cells showed the same effect (p=0.004). The data suggest that AZT induced aneuploidy may be mediated by inhibition of hsa-miR-770-5p, upregulation of STMN1, impaired polymerization of β-tubulin, aberrant mitotic spindle formation and consequent chromosome misalignment resulting in aneuploidy. If confirmed, this will constitute a novel mechanism of AZT-induced genotoxicity that may or may not be related to AZT-DNA incorporation. Ongoing experiments will explore these relationships further by localizing STMN1 and β-tubulin in specific cells, and examining the same cultures for spindle aberrations at mitosis.
Citation Format: Andrea V. Rivera, Vanesa C. Sanchez, Miriam C. Poirier, Ofelia A. Olivero. Zidovudine (AZT)-induced aneuploidy, mediated by Stathmin 1 (STMN1), involves a loss of polymerized β-tubulin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3603. doi:10.1158/1538-7445.AM2013-3603
Abstract 3627: Occupational asbestos exposure is associated with head and neck cancer.
Authors: Langevin Scott M. , O'Sullivan Mattie H. , Valerio Jennifer L. , Applebaum Kate M. , Eliot Melissa , McClean Michael D. , Kelsey Karl T. 
Published: August 2014

Abstract
Asbestos describes a group of naturally occurring silicate mineral fibers that were frequently used in industry during the 20th century due to their desirable flame retardant and tensile properties. Although use has fallen over the last three decades, exposure continues and the burden of disease is considerable. The primary routes of exposure to the fibers include inhalation and ingestion. Asbestos is a known risk factor for several malignant respiratory diseases, including lung cancer and mesothelioma, and has more recently been implicated in pharyngeal and laryngeal cancer. However, studies of asbestos and cancers of the larynx or pharynx with adequate sample-size and control for other risk factors for head and neck squamous cell carcinoma (HNSCC) such as smoking and drinking habit remain somewhat sparse. We report findings from a case-control study consisting of 934 incident HNSCC cases from the greater Boston region and 1180 population-based controls, frequency matched on age (+/- 3 years), sex, and town or neighborhood of residence. Study subjects completed a self-administered questionnaire that provided detailed data on history of asbestos exposure, sociodemographics and personal characteristics, alcohol and tobacco use, personal and family cancer history, and other relevant dietary, occupational, residential and medical exposures. Occupational asbestos exposure was dichotomized as exposed or never exposed based on self reported occupation data. Multivariate unconditional logistic regression was used to assess the association between asbestos exposure and HNSCC, overall and by primary tumor site and smoking history. A total of 217 cases (23.2%) and 226 controls (19.2%) reported an occupational exposure to asbestos. We observed a borderline association of asbestos exposure and laryngopharyngeal cancer (OR = 1.23, 95% CI: 0.95-1.59), adjusted for age, sex, race, smoking, alcohol consumption, and education. After stratifying by smoking history, a significant association was observed between asbestos exposure and laryngopharyngeal cancer among ever-smokers (OR = 1.36, 95% CI: 1.00-1.84). These observations are consistent with the mounting evidence that asbestos is a risk factor for pharyngeal and laryngeal cancer.
Citation Format: Scott M. Langevin, Mattie H. O'Sullivan, Jennifer L. Valerio, Kate M. Applebaum, Melissa Eliot, Michael D. McClean, Karl T. Kelsey. Occupational asbestos exposure is associated with head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3627. doi:10.1158/1538-7445.AM2013-3627
Abstract 3630: Fat intake interacts with cigarette smoking to alter lung cancer risk.
Authors: Zhang Jianjun , Tanaka Hideo , Ito Hidemi , Matsuo Keitaro 
Published: August 2014

Abstract
Although cigarette smoking is the primary cause of lung cancer, it alone cannot explain large difference in risk of this malignancy worldwide. During the last three decades, age-adjusted male lung cancer mortality rates have been remarkably higher in Hungary than in Japan, but per capita cigarette consumption has remained lower in Hungary than in Japan. A similar pattern of difference has been observed between other Asian and western countries, (e.g., China, South Korea, Poland, and the US). It remains unclear why this lung cancer paradox occurs. Lung cancer incidence is generally high in countries with high intake of saturated fat. In addition, animal studies revealed a synergistic effect of fat and tobacco carcinogens on the development of lung tumors. Therefore, it is possible that different types of fat interact with cigarette smoking to modulate lung cancer risk. We sought to investigate this hypothesis in a hospital-based case-control study conducted from 2000 to 2005 in Nagoya, Japan. Cases (n=500), ages 20-79, were patients pathologically diagnosed with lung cancer at the Aichi Cancer Center. Controls (n=500) were recruited from visitors to the outpatient department of the same institution, and matched to cases by age (within 5 years) and sex. Fat intake was assessed with a validated food frequency questionnaire, and cigarette smoking was evaluated with a pre-tested risk factor questionnaire. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression. After adjustment for age, sex, BMI, energy intake, and alcohol drinking, lung cancer risk among heavy smokers (≥40 pack-years) decreased with increasing intake of monounsaturated fat (MUFA). Compared with never or light smokers (≤20 pack-years), ORs (95% CI) were 8.44 (4.53, 15.7), 4.34 (2.32, 8.13), and 3.63 (1.84, 7.04) for heavy smokers who were in the 1st(lowest), 2nd, and 3rd tertiles of MUFA intake, respectively. A similar pattern of interaction was present for intake of polyunsaturated fat (PUFA) and for moderate smokers (20-39 pack-years). To our knowledge, the present study is among the first to show that intake of unsaturated fat modifies the association between cigarette smoking and lung cancer risk, and thereby sheds new light on the etiology and prevention of this malignancy.
Citation Format: Jianjun Zhang, Hideo Tanaka, Hidemi Ito, Keitaro Matsuo. Fat intake interacts with cigarette smoking to alter lung cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3630. doi:10.1158/1538-7445.AM2013-3630
Abstract 3656: Methodology design for identifications of protein targets of chemopreventive isothiocyanates using click chemistry.
Authors: Fu Ying , Mi Lixin , Aggarwal Monika , Appella Daniel M. , Chung Fung-Lung 
Published: August 2014

Abstract
Isothiocyanates (ITCs) derived from cruciferous vegetables are inhibitors of carcinogenesis in animal models and can induce cell cycle arrest and apoptosis in a variety of cancer cell lines. It is known that ITCs can conjugate with glutathione (GSH) and induce cellular oxidative stress; ITCs can also bind to intracellular proteins (e.g. tubulin) which may constitute a mechanism underlying their cancer preventive effects. To fully understand the cellular responses to ITCs, it is crucial to develop an unbiased method that can rapidly identify their protein targets. In this study, the direct protein targets of phenethyl isothiocyanate (PEITC) were investigated by using click chemistry. An alkyne-tagged ITC was used as an analog of PEITC, a known cancer prevention agent. The tagged ITC (N-(2-(4-methoxyalkyne)phenethyl)isothiocyanate (NPPEITC) was designed and synthesized with a moiety for copper-catalyzed Huisgen 1,3 dipolar cycloaddition reaction (click chemistry), the tagged ITC, NPPEITC, was also found to show similar biological activities to PEITC; The click-chemistry reaction conditions of copper-catalyzed azide-alkyne cycloaddtion (CuAAC) for NPPEITC and N-(2-(4-methoxyalkyne)phenylethyl)acetamide (NPA, a negative control) with biotin azide were optimized and the reaction product was isolated and analyzed by mass spectrometry. A model click reaction between NPPEITC and tubulin was employed to validate this method. The western-blot showed that the tubulin protein is modified by biotin after NPPEITC treatment then followed by click reaction with biotin azide. In contrast, no biotin was found on NPA treated tubulin. Secondly, cancer cells exposed to the tagged ITC (NPPEITC or NPA) was lysed and exposed to click chemistry reagents to conjugate ITC-adducted proteins with biotin for subsequent affinity purification; the ITC conjugated proteins were identified and quantified using proteomic analysis by LC/MS/MS.(Supported by NCI grant CA100853)
Citation Format: Ying Fu, Lixin Mi, Monika Aggarwal, Daniel M. Appella, Fung-Lung Chung. Methodology design for identifications of protein targets of chemopreventive isothiocyanates using click chemistry. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3656. doi:10.1158/1538-7445.AM2013-3656
Abstract 3659: Next generation sulindac.
Authors: Li Nan , Xi Yaguang , Tinsley Heather N. , Gurpinar Evrim , Gary Bernard D. , Zhu Bing , Li Yonghe , Keeton Adam B. , Grizzle William E. , Piazza Gary A. 
Published: August 2014

Abstract
Sulindac displays promising antineoplastic activity, but toxicity from cyclooxygenase (COX) inhibition limits its long-term use for chemoprevention. Previous studies have concluded that the tumor cell growth inhibitory activity of sulindac is COX-independent and suggest that safer and more efficacious drugs can be developed by targeting the underlying mechanism. Here we report that sulindac sulfide (SS) inhibits cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) activity, increases intracellular cGMP levels and activates protein kinase G at concentrations that suppress proliferation and induce apoptosis of colon tumor cells. Normal colonocytes were refractory to the anti-proliferative and pro-apoptotic effects of SS as well as its ability to induce cGMP signaling. PDE5-specific inhibitors such as tadalafil also inhibited the growth of colon tumor cells that expressed high levels of the cGMP-specific PDE5 isozyme compared with colonocytes. RNAi knockdown of PDE5 selectively inhibited proliferation and induced apoptosis of colon tumor cells as did SS. SS, 8-bromo-cGMP, and PDE5 siRNA reduced β-catenin levels, as well as the expression of cyclin D and survivin that are regulated by β-catenin-dependent TCF transcriptional activity by a mechanism involving the transcriptional repression of β-catenin. The significance of these findings are highlighted by studies in the FCCC Min mouse model of intestinal tumorigenesis showing that a novel non-COX inhibitory derivative of SS can strongly inhibit colon tumor formation by a mechanism that appears to involve cGMP PDE inhibition. These observations suggest that safer and more efficacious drugs can be developed for colorectal cancer chemoprevention by targeting PDE5 and possibly other cGMP degrading isozymes.
Citation Format: Nan Li, Yaguang Xi, Heather N. Tinsley, Evrim Gurpinar, Bernard D. Gary, Bing Zhu, Yonghe Li, Adam B. Keeton, William E. Grizzle, Gary A. Piazza. Next generation sulindac. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3659. doi:10.1158/1538-7445.AM2013-3659
Abstract 3670: The role of reactive oxygen species in anticancer effects of diallyl trisulfide, a bioactive component of garlic.
Authors: Arlotti Julie A. , Chandra-Kuntal Kumar , Singh Shivendra V. 
Published: August 2014

Abstract
Diallyl trisulfide (DATS) is a bioactive component of processed garlic with in vivo activity against chemically-induced as well as oncogene-driven cancer in rodent models. However, the mechanisms underlying anticancer effects of DATS (eg, growth inhibition, apoptosis induction, and suppression of migration in cancer cells) are not fully understood. The present study reveals a critical role for reactive oxygen species (ROS) in cellular anticancer responses to DATS. Exposure of human breast cancer cells (MDA-MB-231 and MCF-7) as well as a cell line derived from spontaneously developing mammary tumor of a MMTV-neu transgenic mouse (BRI-JM04) to DATS resulted in dose-dependent inhibition of cell viability and apoptosis induction. Interestingly, a non-tumorigenic normal human mammary cell line (MCF-10A) was resistant to growth inhibition and apoptosis induction by DATS. The DATS-induced apoptosis in MDA-MB-231, MCF-7, and BRI-JM04 cells was associated with ROS production as evidenced by fluorescence microscopy and flow cytometry using a chemical probe (MitoSOX Red). Ectopic expression of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) as well as Mn-SOD conferred significant protection against DATS-induced ROS production and apoptotic cell death. The DATS treatment caused activation of Bax and Bak, and activation of Bak was nearly fully abolished by overexpression of Mn-SOD. Likewise, inhibition of MDA-MB-231 and MCF-7 cell migration resulting from DATS treatment was partially but statistically significantly attenuated by stable overexpression of Cu,Zn-SOD and Mn-SOD. This protection against inhibition of cell migration was attributable to abrogation of DATS-mediated induction of E-cadherin and suppression of vimentin. These results indicate that ROS play an important role in anticancer effects of DATS at least in human breast cancer cells. This study was supported by grant CA113363-07 awarded by the National Cancer Institute.
Citation Format: Julie A. Arlotti, Kumar Chandra-Kuntal, Shivendra V. Singh. The role of reactive oxygen species in anticancer effects of diallyl trisulfide, a bioactive component of garlic. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3670. doi:10.1158/1538-7445.AM2013-3670
Abstract 3671: The role of FOXQ1 in benzyl isothiocyanate-mediated inhibition of epithelial-mesenchymal transition in human breast cancer cells.
Authors: Sehrawat Anuradha , Kim Su-Hyeong , Vogt Andreas , Singh Shivendra V. 
Published: August 2014

Abstract
We have shown previously that breast cancer chemoprevention by benzyl isothiocyanate (BITC) in mouse mammary tumor virus-neu transgenic mice is associated with induction of E-cadherin protein expression. Loss of E-cadherin expression concomitant with induction of mesenchymal markers (eg, vimentin and fibronectin) is a biochemical hallmark of epithelial-to-mesenchymal transition (EMT). EMT is a developmental process but implicated in progression of cancer to aggressive state. We have also shown previously that BITC treatment inhibits EMT in cultured MDA-MB-231 human breast cancer cells. The present study extends these observations and investigates the mechanism by which BITC inhibits EMT. Initially, we designed experiments using another triple-negative human breast cancer cell line (SUM159) to determine generality of the BITC-mediated inhibition of EMT. Exposure of SUM159 cells to pharmacologically-relevant concentrations of BITC (2.5 and 5 μM) resulted in induction of E-cadherin protein expression, which was accompanied by suppression of vimentin protein level especially at the 5 μM dose. Protein levels of slug and snail, which are transcriptional repressors of E-cadherin, were also decreased markedly after treatment of SUM159 cells with BITC, but this effect was relatively more pronounced on slug protein level compared with snail. Similar to MDA-MB-231 cells, the BITC-mediated induction of E-cadherin protein expression in SUM159 cells was accompanied by its transcriptional upregulation as revealed by E-cadherin luciferase reporter assay. Immunofluorescence microscopy confirmed induction of E-cadherin protein and suppression of vimentin protein expression in BITC-treated SUM159 cells. BITC treatment resulted in downregulation of Forkhead Box Q1 transcription factor (FOXQ1) protein and FOXQ1 mRNA in MDA-MB-231, SUM159, and MDA-MB-468 cells. The BITC-mediated inhibition of MDA-MB-231 xenograft growth in vivo was associated with suppression of FOXQ1 protein level. Ectopic expression of FOXQ1 in a mammary epithelial cell line conferred marked protection against BITC-mediated inhibition of EMT as well as cell migration. In conclusion, the present study implicates FOXQ1 suppression in BITC-mediated inhibition of EMT in human breast cancer cells. This study was supported by the grant CA129347-06 awarded by the National Cancer Institute.
Citation Format: Anuradha Sehrawat, Su-Hyeong Kim, Andreas Vogt, Shivendra V. Singh. The role of FOXQ1 in benzyl isothiocyanate-mediated inhibition of epithelial-mesenchymal transition in human breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3671. doi:10.1158/1538-7445.AM2013-3671
Abstract 3673: AMPK-SIRT1 axis: a potential therapeutic target for prostate cancer management.
Authors: Li Guiming , Rivas Paul , Bedolla Roble , Reddick Robert L. , Ghosh Rita , Kumar Addanki P. 
Published: August 2014

Abstract
Recently we have shown that resveratrol (RES) intervention prevents development of high-grade prostatic intraepithelial neoplastic (HGPIN) lesions in prostate-specific PTEN knockout mouse model targeting SIRT1/mTORC1 axis. It is known that insufficient nutrient supply combined with high proliferation keeps solid tumors including prostate under hypoxic and metabolic stress. Tumor cells adapt to survive under such conditions through activation of AMP-activated kinase (AMPK). AMPK has been reported to be activated in prostate tumors. Therefore targeting AMPK and associated signaling pathways will be a promising approach for prostate cancer management. Accordingly we investigated the role of AMPK in RES-induced growth inhibitory effects using multiple human prostate cancer cell lines and preclinical animal model. These data show that RES treatment (50 μM, 24 h) results in activation of SIRT1, significant inhibition of AMPK phosphorylation and cell survival in human prostate cancer cells (RWPE-1, LNCaP, C42B and DU145). The observed molecular changes were associated with induction of apoptosis and autophagy following treatment with RES. Further dietary administration of RES (0.1 and 2%) to 4-5 week old prostate-specific PTEN knockout mice for 11 and 14 weeks showed prevention of HGPIN development. Interestingly intervention for 7 weeks showed prevention of HGPIN development at lower dose but not at high dose. On the other hand, 28-week intervention had no significant effect on the development of HGPIN lesions. Immunohistochemical evaluation showed modulation of AMPK, pS6K and SIRT1 in the prostate. Overall these data provide novel insights into RES-induced prevention of HGPIN development via AMPK/SIRT1/mTORC1 axis. Supported in part by NIH (CA 137518 and 135451 APK).
Citation Format: Guiming Li, Paul Rivas, Roble Bedolla, Robert L. Reddick, Rita Ghosh, Addanki P. Kumar. AMPK-SIRT1 axis: a potential therapeutic target for prostate cancer management. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3673. doi:10.1158/1538-7445.AM2013-3673