bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3681: Vascular endothelial growth factor receptor tyrosine kinase inhibitor inhibited mutated epidermal growth factor receptor-driven tumors ex vivo and in vivo
Authors: Kubo Toshio , Ohashi Kadoaki , Osawa Masahiro , Takeda Hiromasa , Ichihara Eiki , Ninomiya Takashi , Takigawa Nagio , Harita Shingo , Nakata Yasunari , Tanimoto Mitsune , Kiura Katsuyuki 
Published: June 2012

Abstract
We previously established a non-smoking-related lung cancer mouse model employing an epidermal growth factor receptor (EGFR) L858R transgenic mouse using an SP-C promoter. The mice developed pulmonary atypical adenomatous hyperplasia (AAH), multifocal adenocarcinoma, and died due to multiple invasive lung tumors at 4, 7, and approximately 40 weeks of age, respectively. We demonstrated the marked chemopreventive effect of gefitinib, an EGFR tyrosine kinase inhibitor, in a non-smoking-related lung cancer mouse model and presented a novel concept of molecular targeted chemoprevention of lung cancer in non-smokers. In this study, we focused on the expression of vascular endothelial growth factor receptor (VEGFR) -2 and vascular endothelial growth factor (VEGF) in a non-smoking-related lung cancer mouse model.
Surprisingly, we found that VEGFR-2 and EGFR were activated in the transgenic mice at 3 weeks of age by Western blotting, before the histological detection of AAH and adenocarcinoma. And fluorescent immunostaining of lung tissues in transgenic mice showed activation of VEGFR-2 occurred in tumor cells themselves or cells in an initial stage of carcinogenesis, not only in vascular endothelial cells. We also found that VEGFR-2 was activated in the lung cancer cell lines (PC-9, H3255) harboring EGFR mutation, and that EGFR-L858R transfected 293T cells expressed more phosphorylated VEGFR-2 than non-transfected 293T cells. EGFR-L858R-transfected 293T cells were more sensitive than non-transfected 293T cells to cediranib (Recentin), a pan-VEGFR tyrosine kinase inhibitor. In this mouse model, cediranib (5 mg/kg/day, 5 days/week, 12 weeks, p.o.) inhibited surface lung tumors (long axis diameter &gt;1 mm, 0 ± 0.4 versus 4.9 ± 3.2, p &lt; 0.01); however, cediranib could not completely suppress tumor formation microscopically.
If VEGFR-2 is activated during an early phase of carcinogenesis due to EGFR mutations, these data suggest that inactivation of VEGFR-2 may be effective in preventing carcinogenesis of non-smoking-related lung cancer. These findings provide t the new concept of VEGFR-2 role in chemoprevention.
Recentin (cediranib) is a trademark of the AstraZeneca group of companies.
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 3681. doi:10.1158/1538-7445.AM2011-3681
Abstract 3699: Novel combinatorial strategies for cancer chemoprevention using polymethoxyflavones from orange and atorvastatin
Authors: Qiu Peiju , Charoensinphon Noppawat , Zheng Jinkai , Song Mingyue , Dong Ping , Riddle Ryan , Xiao Hang 
Published: June 2012

Abstract
Cancer is a complex disease, and multiple aberrant molecular events are driving forces for cancer progression. It is difficult to control cancer progression by a single agent. We investigated a novel approach to inhibit cancer cell growth by using polymethoxyflavones (PMFs, isolated from aged orange peel) and atorvastatin (Lipitor, a commonly used cholesterol-lowering drug) in combination. The goal is to identify combination regimen that can produce synergy in inhibiting human cancer cell growth. Our results on multiple colon and lung cancer cells demonstrated that permethoxylated PMFs, namely nobiletin and tangeretin, can synergistically interact with atorvastatin and produced much stronger inhibitory effects than either agent alone. On the other hand, the hydroxylated PMFs, namely 5-hydroxy nobiletin (5HN) and 5-hydroxy tangeretin (5HT) showed different interaction profiles with atorvastatin, i.e., 5HN produced strong synergy with atorvastatin while 5HT did not. Further mechanistic study demonstrated that the combination treatment with 5HN and atorvastatin for 24 hr caused extensive cell population accumulation in G0/G1 phase; whereas at 48 hr or longer, apoptosis was induced significantly. Our results also demonstrated that the combinational effects of 5HN and atorvastatin were associated with increased levels of p21Cip1/Waf1, and p27Kip1; decreased levels of CDK-2, CDK-4,CDK-6,Cyclin D1, Mcl-1 and hyper-phosphorylated Rb(Ser 780); and activation of caspase cascade. More importantly, we investigated the inhibitory effects of PMFs/atorvastatin combinations in an NNK-induced mouse lung tumorigenesis model, and our results demonstrated that dietary administration of nobiletin and 5HN in combination with atorvastatin caused potent inhibition of lung tumor formation in A/J mice. These inhibitory effects were much stronger than those produced by singular nobiletin, 5HN, or atorvastatin treatments at much higher doses. The isobologram-based statistic analysis confirmed that nobiletin, 5HN and atorvastatin produced strong synergy in inhibiting lung tumorigenesis in mice. In conclusion, the present work provided promising leads for future investigation on the novel combination of PMFs and atorvastatin as novel strategy for cancer chemoprevention. (This study was supported in part by NIH-CA139174, AICR-#10A044, CEAR pilot grant, and USDA Special Grant on Bioactive Foods).
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 3699. doi:10.1158/1538-7445.AM2011-3699
Abstract 3701: Dimethylbenzanthracene (DMBA) and DMBA dihydrodiol mutagenicity in rat epithelial and fibroblast cell lines, and its inhibition by combinations of nutraceuticals
Authors: Sacks Peter G. , Zhao Zhong-Lin , Kosinska Wieslawa , He Zhiming , Josephy P. David , Guttenplan Joseph B. 
Published: June 2012

Abstract
7,12-Dimethylbenzanthracene (DMBA) is a potent mammary carcinogen in rats. Combinations of non-toxic nutraceutical agents, administered at or near physiological levels, were investigated for their abilities to inhibit the mutagenicity of DMBA or DMBA-dihydrodiol (DMBAD, a primary metabolite and proximate mutagen of DMBA) in vitro, in rat mammary epithelial and fibroblast cells derived from a lacI (BigBlue) Fischer rat (McDiarmid, H.M., Douglas, G.R., Coomber, B.L., and Josephy, P.D. Epithelial and fibroblast cell lines cultured from the transgenic BigBlue rat: an in vitro mutagenesis assay. Mutat. Res., 497: 39-47, 2001). In the epithelial cells, DMBA was not appreciably mutagenic at concentrations up to 4 µM, but DMBAD, was significantly mutagenic at ten-fold lower concentrations. These results indicate that the epithelial cells can bioactivate the intermediate, DMBAD, but cannot effect the complete biotransformation of DMBA to its ultimate mutagenic metabolite, DMBA-dihydrodiolepoxide. In the fibroblast cell line, in contrast, DMBA was mutagenic at concentrations as low as 20 nM and DMBAD was even more potent than DMBA. Several combinations of nutraceuticals (dietary components providing health benefits) were tested for their abilities to inhibit mutagenesis in these cell lines; the concentrations tested were based on reported serum concentrations and these were used to establish 1x concentrations. The agents and their 1x concentrations were: resveratrol (Res), 2.4 μM; sulforaphane (Sul), 0.06 μM; antioxidant mix (α- and γ-tocopherol, 30 μM, plus vitamin C, 68 μM – VCE); α-lipoic acid (LA), 2 μM; epigallocatechin gallate (EGCG), 0.7 μM; and N-acetylcysteine (NAC), 12 μM. None of the agents or their combinations, tested at 1 – 3 x concentrations, showed any cytotoxicity. In both epithelial and fibroblast cells, Sul and Res alone slightly inhibited mutagenesis at 2x concentrations; no other agents had observable effects. All binary combinations of Res, LA, and Sul, at 2x concentrations, inhibited mutagenesis; the Res + Sul combination was particularly effective (ca. 50% inhibition). These results suggest a role for fibroblast cells in the bioactivation of carcinogens, implicating the microenvironment, and indicate that combinations of nutraceuticals can inhibit mutagenesis by polycyclic aromatic hydrocarbons. Supported by the Susan Komen Foundation grant # KG080836 (JBG) and NSERC Canada (PDJ).
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 3701. doi:10.1158/1538-7445.AM2011-3701
Abstract 3704: Diindolylmethane induces ER stress mediated autophagy in ovarian cancer cells
Authors: Kandala Prabodh K. , Srivastava Sanjay K. 
Published: June 2012

Abstract
Endoplasmic reticulum (ER) is responsible for biosynthesis, folding assembly and modification of various soluble and membrane proteins. ER stress is the imbalance in protein folding resulting in the accumulation of misfolded proteins in ER lumen. In our study, we observed that Diindolylmethane (DIM), a compound present in cruciferous vegetables induces ER stress in ovarian cancer cells. Treatment of SKOV-3, OVCAR-3 and TOV-21G ovarian cancer cells with varying concentrations of DIM for 24hours resulted in the upregulation of Bip, a molecular chaperone. Bip or Grp78 binds to IRE1α, ATF6 and PERK under normal condition, however, during ER stress, Bip dissociates and releases all the three proteins. DIM treatment also significantly increased the expression of IRE1α, ER oxidase (ERO1) and CHOP. CHOP translocate to nucleus and initiate apoptotic stimuli in cells undergoing ER stress. Moreover, DIM induced ER stress also lead to the activation of eIF2α by phosphorylation. Activation of eIF2α inhibits protein translation to avoid further protein accumulation in ER. The release of calcium by DIM treatment in ovarian cancer cells was evaluated by Accuri C6 flowcytometer. The advantage with Accuri C6 is that calcium levels can be monitored without interruption. DIM treatment increased the cytosolic calcium levels in SKOV3 cells. Increase in cytosolic calcium is known to cause ER stress. In addition, our flowcytometry results indicate that DIM induces autophagy in all the ovarian cancer cells in a concentration dependent manner. Exposure of SKOV-3, OVCAR-3 and TOV-21G cells to DIM upregulated the expression of LC3B, a potent indicator of autophagy. DIM induced autophagy was blocked by bafilomycin, an autophagy inhibitor. Treatment of cells with mithramycin (ER stress inhibitor) blocked ER stress proteins activated by DIM. Interestingly, we also observed that blocking DIM-induced ER stress by mithramycin blocked autophagy in ovarian cancer cells. Taken together these results suggest that induction of autophagy in ovarian cancer cells was associated with ER stress caused by DIM. Further mechanistic studies are in progress. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by 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 3704. doi:10.1158/1538-7445.AM2011-3704
Abstract 3717: Evaluation and comparison of breast cancer risk prediction models for Hispanic and non-Hispanic white women in the Women's Health Initiative
Authors: Banegas Matthew P. , Gail Mitchell H. , LaCroix Andrea , Thompson Beti , Martinez M. Elena , Wactawski-Wende Jean , John Esther M. , Hubbell F. Allan , Yasmeen Shagufta , Katki Hormuzd A. 
Published: June 2012

Abstract
Introduction: The National Cancer Institute (NCI) Breast Cancer Risk Assessment Tool (BCRAT) has not been previously validated for use in Hispanic women. We evaluated and compared BCRAT risk projections for Hispanic and non-Hispanic White (NHW) participants in the Women's Health Initiative (WHI).
Methods: We used data on 6,248 Hispanic and 127,426 NHW post-menopausal WHI participants aged 50 years and older. Absolute risks of developing invasive breast cancer over the WHI main and extension studies were calculated using the BCRAT and an updated BCRAT using 1993-2007 SEER breast cancer incidence rates. We assessed model calibration by the ratio of observed to expected number of breast cancers (O/E ratio) and discriminatory accuracy with the concordance statistic (c-statistic).
Results: In the WHI main study, the BCRAT underestimated the number of breast cancers in Hispanics (O/E ratio=1.18, 95% CI = 0.99, 1.40) and NHWs (O/E ratio=1.18, 95% CI = 1.14, 1.21). The updated BCRAT was well calibrated for Hispanics (O/E ratio=1.08, 95% CI = 0.91, 1.28) and NHWs (O/E ratio=0.98, 95% CI = 0.96, 1.01). The c-statistic was 0.629 (95% CI = 0.582, 0.676) for Hispanics and 0.575 (95%CI = 0.566, 0.583] for NHWs. In the WHI extension study, where women reported being screened less frequently, BCRAT overestimated risk in both Hispanics and NHWs.
Conclusion: Underestimation of breast cancer risk by the BCRAT in Hispanic and NHW women was corrected by using updated SEER breast cancer incidence rates. Recalibrating the BCRAT with current SEER incidence rates and racial/ethnic specific relative risk estimates may improve the predictive accuracy for Hispanic women.
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 3717. doi:10.1158/1538-7445.AM2011-3717
Abstract 3723: Predicting breast cancer risk to age 80: A clinical tool
Authors: Colditz Graham A. , Rosner Bernard 
Published: June 2012

Abstract
While numerous models of breast cancer risk have been developed, few are used in routine clinical care. Thus women are not advised of potential strategies to reduce their future risk of breast cancer; either SERMS for high risk women or weight control and physical activity, reduction in alcohol or other approaches for moderate risk women. Furthermore, few models incorporate the full range of known risk factors and provide easy access for clinical use. The Rosner-Colditz log incidence model of breast cancer was developed and validated on independent data sets within Nurses’ Health Study cohort 1. The model includes a full range of reproductive and lifestyle risk factors for breast cancer. We now have developed a tool for batch or individual data input that provides 5-year risk, and risk to age 80. Input variables include current age, weigh at age 18, current weight, height, current alcohol intake and at age 18, age at menarche, age at menopause and type of menopause, family history of breast cancer and history of benign breast disease, hormone use (current, past, never) and type of hormone used, duration of postmenopausal hormone use, and age at each birth. Parameter estimates are drawn from Nurses’ Health Study data where we have shown the model performs with higher predictability (area under the ROC curve was 0.623) significantly better than the Gail model (area under the ROC 0.578) (p&lt;0.001). For the total cohort, Incidence of invasive breast cancer in the NHS is consistent with SEER data (O/E = 1.0; 95%CI 0.98-1.03). For clinical use, risk estimates are adjusted for US mortality to provide incidence estimates to age 80 that account for competing risks. Clinical application requires assumptions regarding future weight change, duration of continued use of hormone therapy, and for premenopausal women, future age at menopause.
1. Colditz G, Rosner B. Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses’ Health Study. Am J Epidemiol. 2000;152(10):950-964.
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 3723. doi:10.1158/1538-7445.AM2011-3723
Abstract 3727: Telangiectasias in the skin of patients: Indicator of angiogenic status of tumors?
Authors: Ellberg Carolina , Jernström Helena , Olsson Håkan 
Published: June 2012

Abstract
Background: The angiogenic status of a tumor is related to the prognosis of the patient, and to the possibility of treatment with angiogenesis inhibitors. Patients who express telangiectasias (spiders) in the skin have an increased ability to form vessels, due to, for example, hormonal influences. We hypothesized that tumor tissue to some extent resembles the normal tissue in a patient, which could mean that is if a patient is prone to form spiders in the skin, the same would be true in their tumors. Spiders are associated with hormonal influence, and therefore telangiectasias in patients could be a reflection of hormonal influence and angiogenic status of their tumor.
Materials and methods: A clinical series of 1682 consecutive breast cancer patients diagnosed between 1980 and June 2009 were studied. One physician scored the presence/absence of spiders on the upper part of the body at the time of breast cancer diagnosis. The aim was to further study the association between telangiectasias and classical histopathologic subtypes of breast cancer, HRT-ever use, life time number of menstrual cycles and ever use of oral contraceptive pills (OCP). All analyses were performed using multivariate logistic regression, a confidence interval (CI) of 95% was used.
Results: The occurrence of telangiectasias of the upper thorax, neck and face was positively associated with HRT-ever use (OR = 3.24 (CI 2.02 – 5.19)), OCP-ever use (OR = 2.08 (CI 1.30 – 3.32)) and high number of menstrual cycles, above 550 – the upper quartile OR = 4.57 (CI 1.49-13.95). Weight was also associated with spiders, p = 0.006. Contrary to the other histopathologic subtypes no telangiectasias in the skin were observed in patients with comedo carcinoma, p = 0.0002 (Fisher's exact test). No significant difference in spiders was seen between the other patients with the other subtypes. The results above were adjusted for age at diagnosis and for each studied variable simultaneously.
Conclusion: The occurrence of spiders was associated with several hormonal factors indicating the importance of hormones in the induction of telangiectasias. Our theory that the tendency to form vessels is similar in normal tissue as well as in tumor tissue could explain the necrotic core in comedo carcinoma. It has been hypothesized that the necrotic core is due to the high growth rate of the tumor, but it might be due to a lesser ability to form vessels. Are comedo carcinoma patients a group who benefit less from anti-angiogenic therapy while patients with strong endogenous or exogenous hormonal exposures would benefit more from anti-angiogenic therapy?
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 3727. doi:10.1158/1538-7445.AM2011-3727
Abstract 3728: Night work and breast cancer risk: CECILE study
Authors: Menegaux Florence , Truong Thérèse , Anger Antoinette , Kerbrat Pierre , Arveux Patrick , Lamkarkarch Farida , Guénel Pascal 
Published: June 2012

Abstract
Objectives: Epidemiological studies have suggested that night shift work increases the risk for breast cancer. Disruption of the normal circadian rhythm may explain this association. We investigated the role of night work in the occurrence of breast cancer in a population-based case-control study in France.
Methods: The CECILE study was conducted in two French départements (Côte d'Or, Ille-et-Vilaine) between 2005 and 2008. All female residents in these areas aged 25-75 years who were diagnosed with a breast cancer were eligible to the study. Population controls were frequency-matched by 5-year age group to the cases. A total of 1232 incident breast cancer cases and 1317 controls were included. An in-person interview was conducted using a standardized questionnaire to obtain information on recognized or suspected risk factors for breast cancer, as well as on lifetime occupational history. For each job held for more than 6 months, information on night shift work was elicited. Any work shift where the woman had to work for at least one hour between 11 pm and 5 am was defined as night work. Duration (in years) and frequency (times per week) of night shifts were also obtained. Analyses were conducted using unconditional logistic regression adjusting for age and recognized risk factors for breast cancer.
Results: Thirteen percent of the cases and eleven percent of the controls had ever worked at night (OR=1.29 [1.00-1.64]). The association was more pronounced for women who had overnight shifts (full-time shift work between 11 pm and 5 am: OR=1.37 [1.03-1.83]) than for women who had late evening shifts (ending after 11 pm: OR=1.29 [0.78-2.15]) or early morning shifts (starting before 5 am: OR=1.19 [0.43-3.31]). Women who worked in overnight shifts for 3 or more years had an OR of 1.49 [1.05-1.89], but no further increase of the OR was observed for longer durations. Overnight shift work of 3 nights or less per week during overnight periods, implying frequent changes between night and day schedules, was associated with an OR of 1.59 [1.08-2.33]).
Conclusion: Our results support the hypothesis of a role of overnight work in the occurrence of breast 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 3728. doi:10.1158/1538-7445.AM2011-3728