bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-4: Mitochondrial localized de2-7EGFR (EGFRvIII) protects glioma cells from metabolic shock
Authors: Johns Terrance G. 
Published: February 2011

Abstract
Thirty percent of glioma patients express an activating mutation of the epidermal growth factor receptor (EGFR) known as the de2-7EGFR (or EGFRvIII). Glioma cells expressing de2-7EGFR contain an intracellular pool of the receptor that predominantly displays high-mannose glycosylation, consistent with delayed processing. We now show in glioma cells that most of the intracellular de2-7EGFR is located in the Golgi apparatus; identifying the Golgi as the organelle where the delay arises. This intracellular analysis also revealed low-levels of the de2-7EGFR within the mitochondria. Transfection of U87MG. 2-7 cells with a constitutive active Src, or activation of the endogenous Src via integrin engagement, enhanced this mitochondrial localization. In contrast, pharmacological inhibition of Src significantly reduced mitochondrial de2-7EGFR. Since de2-7EGFR is phosphorylated by Src at Y845, we generated U87MG glioma cells expressing a de2-7EGFR with a Y845F modification. The de2-7EGFR845F failed to show mitochondrial localization even when co-expressed with constitutive active Src. Given the role of mitochondria in metabolism, the effect of low glucose on de2-7EGFR localization was examined. U87MG.de2-7EGFR glioma cells grown in low glucose displayed significantly increased levels of mitochondrial de2-7EGFR and were able to survive and proliferate in low concentrations of glucose lethal to isogenic parental cells. Finally, the presence of an active and functional pool of de2-7EGFR in the mitochondria, probably explains why this receptor is clinically-resistant to some EGFR-specific therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-4.
Abstract LB-426: Delphinidin suppresses ultraviolet B-induced cyclooxygenases-2 expression through inhibition of MAPKK4 and PI-3 kinase
Authors: Kang Nam Joo , Kwon Jung Yeon , Kim Jong-Eun , Jung Sung-Keun , Hwang Mun Kyung , Lee Hyong Joo , Lee Ki Won , Heo Yong-Seok , Bode Ann M. , Dong Zigang 
Published: February 2011

Abstract
Cyclooxygenase-2 (COX-2), a key mediator of inflammation, and its product, prostaglandin E2 (PGE2), enhance carcinogenesis, particularly in skin. Ultraviolet (UV) B is the most carcinogenic component of solar irradiation, and a crucial role of COX-2 in UVB-mediated skin carcinogenesis has been reported. Here, we investigated the effects of delphinidin, an abundant dietary anthocyanin, on UVB-induced COX-2 upregulation and the underlying molecular mechanism. We found that delphinidin suppressed UVB-induced COX-2 expression in JB6 P+ mouse epidermal cells. COX-2 promoter activity and PGE2 production were also suppressed by delphinidin treatment within non-cytotoxic concentrations. Activator protein-1 and nuclear factor- B, crucial transcription factors involved in COX-2 expression, were activated by UVB and delphinidin abolished this activation. UVB-induced phosphorylation of c-Jun N-terminal kinase, p38 kinase and Akt was inhibited by delphinidin. The activities of mitogenactivated protein kinase kinase (MAPKK) 4 and phosphatidylinositol-3 kinase (PI-3K) were inhibited markedly by delphinidin. A pull-down assay using delphinidin-Sepharose beads revealed that delphinidin binds directly with MAPKK4 or PI-3K in a manner that was competitive with adenosine triphosphate. Moreover, in vivo investigations using mouse skin revealed that the upregulation of COX-2 expression, MAPKK4 activity and PI-3K activity induced by UVB was abolished with delphinidin treatment. Collectively, our results demonstrated that delphinidin targets MAPKK4 and PI-3K directly to suppress COX-2 overexpression, suggesting a potential protective role for delphinidin against UVB-mediated skin carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-426.
Abstract LB-429: Synergistic effects of low-fat diet combined with IGF-I receptor blockade on 22RV1 prostate cancer xenografts
Authors: Konijeti Ramdev , Galet Colette , Liu Bingrong , Gray Ashley , Barnard R. James , Said Jonathan , Castor Brandon , Koyama Satomi , Hwang David , Beltran Pedro , Calzone Franck , Cohen Pinchas , Aronson William J. 
Published: February 2011

Abstract
Introduction: IGF-I receptor (IGF-1R) blockade has previously been shown to slow prostate cancer xenograft growth. Dietary fat reduction also inhibits xenograft growth, possibly by modulation of the IGF axis. We hypothesized that a low-fat (LF) diet combined with IGF-I receptor blockade would cause additive retardation of prostate cancer growth and offset the possible untoward metabolic effects of IGF-1R antibody therapy.
Methods: Fifty severe combined immunodeficient mice were injected subcutaneously with 22RV1 cells (suppressible with IGF-1R blockade in vitro) and were randomized to four groups: 1) high-fat (HF) diet with intraperitoneal saline, 2) high-fat diet with intraperitoneal IGF-I receptor blocking antibody from Amgen: AMG479, (HFAb), 3) low-fat diet with intraperitoneal saline (LF), 4) low-fat diet with intraperitoneal AMG479, (LFAb). Treatment with either antibody or saline was initiated 10 days after tumor injection and given twice weekly, tumors were measured serially. The animals were euthanized at 19 days of treatment. Tumors were then weighed and stained for Ki67, TUNEL, and CD31. Serum levels of insulin, resistin, murine IGF-I, murine IGFBP-3, and TNF-alpha were measured.
Results: Mean tumor weights were significantly lower (by ∼ 40%) in the HFAb and LFAb group relative to the HF group. There was no difference in mean tumor weight between the HFAb and LFAb groups. Ki67 expression (% positive cells) was significantly decreased in the LFAb group compared to the HFAb group (62 + 29 vs. 94 + 4.3, p&lt;0.001). IGF-1R antibody caused a significant increase in serum insulin levels compared to the LF and HF group, but combining the LF diet with the IGF-1R antibody significantly reduced serum insulin levels by 40% relative to the HFAb group. Likewise, combining a LF diet with the IGF-1R antibody also reduced serum TNF-alpha levels relative to the HF group.
Conclusion: IGF-1R antibody therapy inhibited xenograft growth in mice on HF and LF diets. Whereas combining a LF diet with IGF-1R antibody did not have additive growth inhibitory effects on tumor size, there was evidence of decreased tumor cell proliferation, reduced serum insulin levels and reduced pro-inflammatory cytokine levels. Further pre-clinical and clinical trials are warranted to evaluate the role of dietary interventions to enhance anti-tumor effects and offset the metabolic consequences of IGF-1R antibody therapy.
Aknowledgements: This work was supported by the NCI grant # P50CA92131 and “The Ruby Family Foundation”.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-429.
Abstract LB-432: Validation studies for Korean breast cancer prediction model
Authors: Park Boyoung , Lee Ji Young , Chang Myung-Chul , Noh Dong-Young , Ahn Sei-Hyun , Kang Daehee , Yoo Keun-Young , Park Sue K. 
Published: February 2011

Abstract
Background: A model for predicting breast cancer risk has been developed in Korea. Associated risk factors included in the model were 1st degree relatives with breast cancer, age at menarche, menopausal status, number of children, age at first fullterm pregnancy, mammography, and exercise for patients less than 50 years of age and 1st degree relatives with breast cancer, age at menarche, age at menopause, number of children, BMI, mammography, and exercise for patients greater than 50 years of age. The area under the curve among over 50 year olds was 0.655 and 0.611 among under 50 year old.
Objectives: The objective of the study was validation of an absolute risk prediction model for breast cancer in Korea by using a large, population cohort and patient registry.
Method: The Korean Multi-center Cancer Cohort (KMCC) and registry data of breast cancer patients constructed by the Korean Breast Cancer Society were used to validate the model. 12221 women more than 30 years of age at baseline answered questions about demographic characteristics, reproductive factors, lifestyle, family history since 1993 and we identified 11 and 5 incident breast cancer patient more than 50 and less than 50 years of age, respectively. Age, resident area, and included year were matched to select controls; women aged less than 50 were matched 1:20 while women aged greater than 50 were matched 1:10. In the breast cancer registry, clinical, demographic characteristics and reproductive factors of breast cancer patients were collected since 1980. We selected 2727 patients under 50 years old and 2000 patients over 50 years old matched by age and diagnostic year and calculated their 10, 20, 30, and 40 year absolute risk.
Result: In the KMCC data, 10 year absolute risk was 0.39 (95% CI 0.36-0.42) among cases and 0.36 (95% CI 0.35-0.37) among controls under 50 years old and 0.16 (95% CI 0.10-0.22) among cases and 0.08 (0.07-0.09) among controls over 50 years old and it was significantly different in the median test (P-value: 0.02 in both groups). Among breast cancer patient group over 50 years old, 10, 20, 30 and 40 year absolute risk were 0.22 (95% CI 0.21-0.23), 0.35 (95% CI 0.34-0.36), 0.43 (95% CI 0.42-0.45), 0.46 (95% CI 0.44-0.48) respectively and 0.56 (95% CI 0.55-0.57), 1.18 (95% CI 1.15-1.21), 1.53 (95% CI 1.50-1.57), 1.74 (95% CI 1.70-1.78).
Conclusion: Due to the short follow up time and small number of cancer incidence in the KMCC cohort, although absolute risk was small, a significant difference was confirmed. Future validation study with a large number and enough follow up cohort time is needed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-432.
Abstract LB-48: Non-invasive imaging of response to MEK Inhibition with AZD6244 (ARRY-142886) in a human melanoma xenograft monitored by diffusion-weighted MRI
Authors: Beloueche-Babari Mounia , Jamin Yann , Arunan Vaitha , Walker-Samuel Simon , Smith Paul D. , Waterton John C. , Halliday Jane , Workman Paul , Leach Martin O. , Robinson Simon P. 
Published: February 2011

Abstract
Background: Non-invasive imaging biomarkers are key to the development and evaluation of novel targeted anti-cancer drugs. The MEK inhibitor, AZD6244 (ARRY-142886), is one such agent that is now undergoing clinical testing. This drug causes inhibition of growth and induction of apoptosis in a range of pre-clinical tumor models. We therefore reasoned that such effects could translate to changes in tumor tissue cellular density that may be detectable by diffusion-weighted magnetic resonance imaging (DW-MRI). Here we test this hypothesis in a human melanoma xenograft model.
Methodology: Female nude mice bearing V600E BRAF WM266.4 melanoma sub-cutaneous xenografts (∼550 mm3 volume) were treated twice daily for 3 days by gavage with vehicle (n=9) or 75mg/kg AZD6244 (n=9). DW-MRI data were acquired pre- and 3h post the last dose, and correlated with phosphorylated (P-) ERK1/2 and the necrotic tumor fraction by histological analysis of excised tumors.
Results: Our results show that AZD6244-treated tumors were not significantly different in size compared to day 0 (100±6%) while the vehicle treated-tumors had grown by ∼ 1.4-fold (p=0.001). Relative to day 0, the mean values of the apparent diffusion coefficient (ADC), a parameter that is inversely related to tissue cellularity, were not changed in the control group (109±12%, p=0.45) but increased significantly to 160±20% (p=0.01) in the AZD6244-treated group. This effect correlated with substantially reduced P-ERK1/2 levels and increased tumor necrosis from 10± 10% in the vehicle group to 60±9% in the drug-treated group (p=0.036).
Conclusions: This study highlights changes in ADC that follow treatment with a MEK signaling inhibitor, and which precede tumor shrinkage. Our data support the use of ADC as a non-invasive pharmacodynamic biomarker for early assessment of response to AZD6244 and other therapies targeted at MEK-ERK1/2 signaling during clinical trials.
Acknowledgements: This work was funded by Cancer Research UK [CUK] project grant C1060/A6916, AstraZeneca and The Royal Society. We acknowledge the support received from the CRUK and EPSRC Cancer Imaging Centre in association with the MRC and Department of Health (England) grant C1060/A10334, also NHS funding to the NIHR Biomedical Research Centre.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-48.
Abstract LB-59: Amrubicin, a third-generation synthetic anthracycline, is active in anthracycline-resistant tumors
Authors: Mamidipudi Vidya , Brady Helen , Richard Normand , Surapaneni Sekhar , Aukerman Lea S. , Heise Carla , Sung Victoria 
Published: February 2011

Abstract
Amrubicin, a third generation synthetic anthracycline and a potent topoisomerase (topo) II inhibitor, is approved in Japan for the treatment of lung cancer (both small-cell and non-small cell) and is being evaluated in a phase III trial in the North America and Europe for the second line treatment of SCLC. The aim of these studies was to evaluate the cross-resistance of amrubicin with other anthracyclines (doxorubicin, epirubicin) and the topo-II inhibitor etoposide, and to identify potential mechanisms of resistance to amrubicin. The doxorubicin-resistant cell lines H69-AR, MES-SA-DX5 & NCI-ADR/RES were confirmed to be resistant to doxorubicin (∼25-fold relative resistance), however, their resistance to amrubicin was low or absent (∼2-fold relative resistance). Additionally, a number of primary human ovarian and breast tumor explants that were resistant to doxorubicin and/or etoposide retained sensitivity to amrubicin. Unlike doxorubicin, amrubicin induced DNA damage, G2M cell cycle arrest and apoptosis in both doxorubicin-sensitive and -resistant lines at or below clinically relevant plasma concentrations (∼10 uM). Furthermore, in contrast to doxorubicin, fluorescence time-lapse imaging demonstrated relatively small differences in amrubicin uptake and accumulation kinetics in doxorubicin-sensitive and resistant cell lines. Using gene expression profiling studies, we showed that a greater number of genes were regulated by amrubicin than by doxorubicin in both OVCAR8 and NCI-ADR/RES lines. Amrubicin is a moderate P-glycoprotein (Pgp) substrate; however, we demonstrated that the inhibitory effect and accumulation of amrubicin is not solely modulated by Pgp in cell lines over-expressing efflux pumps including Pgp. We postulate that the high intracellular accumulation and retention of amrubicin is a result of rapid influx due to the high intrinsic permeability and lipophilic properties of amrubicin. This may explain why amrubicin overcomes pleiotropic drug resistance. In summary, we demonstrated that amrubicin has a distinct mode of action compared with other anthracyclines, is less susceptible to typical anthracycline resistance mechanisms and therefore, may be useful in the treatment of anthracycline-resistant tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-59.
Abstract LB-63: Expression of α+β+ splice variant of human telomerase reverse transcriptase (hTERT) in cytokeratin 19 (CK-19) positive circulating tumor cells (CTCs) of breast cancer patients
Authors: Parisi Kleo , Strati Areti , Malamos Nikolaos , Georgoulias Vassilis , Lianidou Evi 
Published: February 2011

Abstract
Introduction: Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase. The α+β+ splice variant is the functional variant of hTERT. Circulating tumor cells (CTCs) have already been established as strong predictors of prognosis in patients with metastatic breast cancer. Our group has previously shown the prognostic significance of cytokeratin 19 (CK-19) mRNA-positive CTCs in early breast cancer. The aim of our study was to study the expression of hTERT α+β+ splice variant in CK-19 positive CTCs in breast cancer samples by qRT-PCR.
Materials and Methods: Peripheral blood (20 ml in EDTA) was obtained from 25 patients with early breast cancer before the administration of adjuvant chemotherapy, 14 patients with verified metastasis who were all tested positive for CK-19 expression by real time PCR (Stathopoulou et al, Int J Cancer 2006), and 17 female healthy volunteers. CTCs were isolated after ficoll density gradient centrifugation, following enrichment with immunomagnetic Ber-EP4 coated capture beads, mRNA was isolated using oligo (dT)25 coated magnetic beads, followed by cDNA synthesis. The expression of hTERT α+β+ splice variant was tested in both CTCs and PBMCs fractions by quantitative real-time PCR in the LightCycler, (Mavroyiannou et al, Clin Chem, 2007).
Results: hTERT α+β+ splice variant was expressed in 4/14 (29%) of CK-19 mRNA positive CTCs samples from patients with metastasis and in 5/24 (21%) of CK-19 mRNA positive CTCs samples from patients with early breast cancer. None of the 17 female healthy volunteers CTCs fraction was tested positive for hTERT α+β+ splice variant, while the corresponding PBMCs fraction was positive in all cases.
Conclusions: To our knowledge this is the first report on the expression of hTERT α+β+ splice variant in CTCs of patients with early breast cancer and verified metastasis. Further studies are needed to evaluate and confirm our findings in a larger number of patients.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-63.
Abstract LB-74: A high-throughput RNAi sensitization screen of rapamycin identifies targets for rational drug combination strategies
Authors: Ou Lihui , Gehlhaus Kristen , Patel Jyoti , Chen Jinqiu , Goldsmith Paul , Mock Beverly , Caplen Natasha 
Published: February 2011

Abstract
RNAi screening affords an unbiased and rapid method to identify genes involved in particular cellular processes and is thus a powerful tool for drug target identification and validation. Rapamycin is a well defined inhibitor of mTOR, a protein being actively pursued as an anti-tumor target. In breast cancer patients, however, treatment with mTOR inhibitors has shown only modest activity suggesting that a combined approach may be required to maximize the clinical application of mTOR inhibitors in these patients. In this study, we performed a high-throughput synthetic siRNA-based RNAi screen of the human kinome plus 350 additional genes (4 siRNAs per gene) in combination with rapamycin, to identify candidate genes whose silencing potentiate the inhibitory effects of rapamycin. Screens were conducted in the ER+ breast cancer cell line MCF-7 and the triple negative breast cancer cell line MDA-MB-468. For the RNAi screen rapamycin (10 nM) or vehicle only (0.1% DMSO) was added 48 hours post siRNA transfection and cell viability was measured after a further 24 hours of incubation. By comparing the normalized effect on cell viability for each siRNA (Z-score) in the control and rapamycin screens we identified 36 candidate genes whose silencing sensitized MCF-7 cells to rapamycin and 56 that sensitized MDA-MB-468 cells. The silencing of six candidate genes sensitized both cell lines to rapamycin, AKT1, ASPA, CDKN2A, MAP3K7IP1, MAPK12 and PCTK3. The sensitization of rapamycin by silencing of AKT1 was confirmed. Rapamycin treatment increased AKT phosphorylation in the cell lines. HDAC inhibitors have been shown to facilitate the dephosphorylation of AKT; therefore, we tested the combination of rapamycin with the HDAC inhibitor MS-275. MS-275 completely blocks rapamycin-induced AKT phosphorylation, and combining it with rapamycin synergistically inhibited the growth of the MCF-7, MDA-MB-468, MDA-MB-435 and MDA-MB-231 breast cancer cell lines. We investigated if other pathways are affected by combining rapamycin with MS-275. De-regulation of the RAF-MEK-ERK pathway is frequently detected in human cancers but the high level of ERK phosphorylation is significantly reduced in cells treated with the rapamycin/MS-275 combination. To profile the unphosphorylated, mono and dual-phosphorylated isoforms of ERK1 and ERK2 we used a capillary isoelectric focusing immunoassay to show that the di-phosphorylated isoform of ERK2 was decreased. Our results highlight the potential of high-throughput siRNA screens to identify rational drug combination strategies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-74.