bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5716: Interference with repair of sub-lethal radiation damage by ABT-888, an inhibitor of poly(ADP-ribose) polymerase (PARP), and theobromine
Authors: Patel Ravi , Chiu Song-mao , Machtay Mitchell , Oleinick Nancy 
Published: August 2012

Abstract
BACKGROUND: Upon DNA damage, PARP-1 and -2 use NAD to build a polymer of ADP-ribose on themselves, histones, and other proteins, altering chromatin and recruiting repair complexes to the damage. Inhibition of PARP activity sensitizes cancer cells or tumor xenografts to radiation therapy (RT) and inhibits DNA repair. RT is usually delivered as fractionated daily doses, allowing sub-lethal damage (SLD) to be repaired between doses. We asked if ABT-888, a specific PARP inhibitor, or theobromine (TB), which radiosensitizes via a PARP-independent mechanism, could inhibit SLD repair. METHODS: Human lung cancer cells A549 and H460 were plated at a range of cell densities, exposed to Cs-137 γ-radiation (0-8 Gy), as single doses or as multiples of 2 Gy/day, with or without drugs, then allowed to form colonies. DNA double-strand breaks (DSB) were estimated as γH2AX foci. RESULTS: In agreement with literature data, 2.5 μM ABT-888 produced a dose enhancement factor (DEF) of 1.4 at 10% survival for single radiation doses, and 10 μM was only modestly better (DEF 1.5). A549 cells showed marked repair of SLD (Table), such that the surviving fraction (SF) after 6 Gy was lower (0.13) than for 3 x 2 Gy (0.52). When ABT-888 or TB was added 1 h before the first irradiation, cells were sensitized to 6 Gy single dose or 3 x 2 Gy. The combination was more effective. ABT-888-sensitized cells responded to 3 x 2 Gy with similar killing as unsensitized cells to a single 6 Gy dose (p = 0.93). The combined effects are reflected in a decrease in mean inactivation dose (MID). Higher levels of γH2AX foci in drug-treated cells indicate inhibition of damage processing. CONCLUSIONS: Radiosensitization of human lung cancer cells by ABT-888 is at least partially via inhibition of SLD repair. Although more ABT-888 produces little additional benefit, addition of TB, which acts through a complementary mechanism, further improves the response.

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 5716. doi:1538-7445.AM2012-5716
Abstract 5723: Inhibition of angiogenesis in the mouse heart by ionizing radiation
Authors: Kanthou Chryso , Gharaei Zahra , Haagen Julia , Lunt Sarah Jane , Reyes-Aldasoro Constantino Reyes-Aldasoro C. , Doerr Wolfgang , Tozer Gillian M. 
Published: August 2012

Abstract
The heart is a critical dose-limiting organ during radiotherapy. In patients treated for breast cancer or Hodgkin's disease, regions of the heart can receive radiation doses in excess of 40 Gy. More recently, epidemiological and clinical studies suggested that even moderate to low radiation doses increase the risk of cardiovascular disease that can present years after the initial exposure. Radiation can cause cardiac microvascular damage but the mechanisms of pathogenesis of radiation-induced heart disease have not been clearly defined. Cardiac injury triggers repair processes in the myocardium requiring neovascularisation. Here, we investigated latent effects of ionizing radiation on angiogenic responses in the mouse heart. We also assessed the effects of radiation on cardiac endothelial responses and angiogenesis in vitro. The hearts of C57BL/6 and ApoE-/- mice were locally irradiated with 0.2 to 16 Gy and animals were sacrificed at 20, 40 and 60 weeks post-irradiation. Formation of angiogenic sprouts was assessed in ventricular heart explants embedded in fibrin gels. The angiogenic capacity of irradiated hearts was also assessed through a novel fibroblast-endothelial “self-assembling assay” we developed. Mouse hearts were enzymatically digested into a single cell suspension and cultured for 10 days. Within 5 to 7 days, endothelial cells began to form capillary-like structures surrounded by fibroblasts and pericytes, modeling the angiogenic process. Cardiac endothelial cells were also irradiated in vitro and effects on migration and capillary-tube formation on a fibroblast bed were established. Radiation caused a dose-dependent inhibition of endothelial sprout formation in explants from both mouse models. Significant changes were observed at 8 and 16 Gy after 20 weeks and at ≥2 Gy after 40 or 60 weeks post irradiation. Irradiation also significantly reduced the adherence and growth of extracted cardiac cells and inhibited the quantity and quality of the capillary-like structures formed in the “self-assembling” model. In vitro, irradiation (≥0.2 Gy) inhibited the migration of cardiac endothelial cells in scratch wound assays and capillary-like formation on a fibroblast bed. Our data show that radiation causes persistent and progressive vascular damage and suppresses angiogenic activity in the heart. Angiogenesis was inhibited at doses likely to be delivered during thoracic radiation in cancer patients. Impairment of the angiogenic response could lead to further ischemia and degeneration in the myocardium and contribute to the development of heart disease.
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 5723. doi:1538-7445.AM2012-5723
Abstract 5731: PET and fluorescence imaging of brain cancer with a dual modality probe based on sarcophagine cage
Authors: Liu Shuanglong , Huang Chiun-Wei , Yap Li-Peng , Park Ryan , Li Zibo , Conti Peter S. 
Published: August 2012

Abstract
The development of a PET/optical imaging system is attractive because of the opportunity to obtain complementary data from two similar contrast mechanisms using one probe. Different from PET/CT or SPECT/CT, a linker is generally needed to efficiently incorporate PET tag, optical tag, and the biomarker together. Previously we developed a dicarboxyl-functionalized chelator (BaBaSar) derivatized from sarcophagine cage (denoted as Sar). BaBaSar has been used for 64Cu radiopharmaceutical development and the great in vivo stability of 64Cu-BaBaSar encouraged us to continue to derivatize the sarcophagine core for versatile conjugation styles with biomarkers. In this study, we synthesized a hetero-functionalized sarcophagine named BaAnSar: carboxyl group at one end of the Sar cage and amino group on the other end. The pendant hetero-arm could be further conjugated to multiple targeting ligands via biologically stable amide bonds. In order to prove the advantage of the this BaAnSar chelator, we chose dimeric c(RGDyK) peptide (denoted as RGD2), a well-known ligand targeting integrin αvβ3, onto the carboxyl side and fluorescent dye Cy5.5 on the amino functional side of the Sar cage. After labeling with 64Cu, a dual-modality probe, 64Cu-BaAnSar-RGD2-Cy5.5 was made and evaluated in U87MG tumor bearing nude mice. Both NIR fluorescence imaging and microPET clearly delineated the U87MG tumor from the surrounded normal tissue at 1, 4, and 20 h post injection of 64Cu-BaAnSar-RGD2-Cy5.5. The microPET quantification of U87MG tumor uptake was determined as 6.41 ± 0.28, 6.51 ± 1.45, and 5.92 ± 1.57 %ID/g at 1, 4, and 20 h post injection, respectively. Good correlation was also observed between the results measured by ex vivo PET and NIRF organ imaging. In conclusion, we have successfully developed a bifunctional chelator for dual PET and NIRF imaging probe construction. The BaAnSar chelator developed herein has the potential to enhance resolution for comprehensive visualization of the probe distribution and provides a rapid and efficient imaging method for basic research and potential clinical applications, especially as a visual guide during surgery.
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 5731. doi:1538-7445.AM2012-5731
Abstract 5733: Detection of M1dG and 6-oxo-M1dG from biological samples in rats
Authors: Shuck Sarah C. , Kingsley Philip J. , Akingbade Dapo , Marnett Lawrence J. 
Published: August 2012

Abstract
Reactive oxygen species (ROS) produced from cellular metabolism and exposure to environmental agents pose a significant threat to genomic stability. Direct DNA oxidation by ROS or indirect modification by products of lipid peroxidation results in the formation of mutagenic DNA adducts that are implicated in carcinogenesis. Following oxidation of phospholipid and/or DNA, several reactive aldehydes are formed including base propenal and malondialdehyde (MDA), both of which can react with DNA to form oxopropenyl-adducted bases. The most abundant DNA adduct produced, M1dG, is the product of reaction with deoxyguanosine. This adduct has been extensively characterized and shown to be mutagenic in both mammalian and bacterial systems and repaired by the nucleotide excision repair (NER) pathway. M1dG has also been detected in the genomic DNA of both healthy and disease-bearing individuals, indicating its presence and significance in cellular metabolism. Previous work has demonstrated that M1dG is oxidized in rats to a single metabolite, 6-oxo-M1dG, which can be detected in both urine and feces and has the potential to be used as a biomarker for oxidative stress and disease. We have developed antibodies against M1dG and 6-oxo-M1dG, which are being utilized in a novel assay for the analysis of M1dG and 6-oxo-M1dG in biological samples. Using solid phase extraction and mass spectrometry, we have developed a reliable assay for the analysis of 6-oxo-M1dG in urine and feces from male Sprague-Dawley rats. We have determined the level of excreted 6-oxo-M1dG to be 0.19 pmol/kg/day in urine and 0.92 pmol/kg/day in feces. We are currently expanding our studies to analyze samples from animals with increased oxidative stress in order to determine how excretion and metabolism of M1dG is altered under these conditions.
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 5733. doi:1538-7445.AM2012-5733
Abstract 5735: Synthesis and characterization of PEG-ylated porphyrins for targeting the epidermal growth factor receptor in colorectal cancer detection
Authors: Ledet Russell J. , Fontenot Krystal , Vicente Graça H. 
Published: August 2012

Abstract
ABSTRACT According to the National Cancer Institute, an estimated 102,900 (colon) and 39,670 (rectal) new cases were obtained in 2010. An estimated 51,370 people have died from colon and rectal cancers combined. This makes colorectal cancer (CRC) the second leading cause of cancer-related deaths in the United States. Consequently, the development of an in-vivo imaging agent that is selective for CRC has long been needed. Much of the detection for tumorigenesis relies on the efficacy in detecting small tumors. Current agents are not selective and often stain tissue not associated with the cancer cells making it difficult to delineate between viable and tumorigenic entities. This project introduces a novel macrocycle conjugated to polyethylene glycol linker, which we hypothesize will serve as the template for a selective molecule with high fluorescence yields that greatly increases earlier detection. Our targeted remedy is a porphyrin that is conjugated to a peptide with an affinity for the Epidermal Growth Factor Receptor (EGFR). Porphyrins are characteristically aromatically stable, contain trademark absorption bands in the visible and near-IR range, and have fluorescence quantum yields much above the current fluorophores. This makes the macrocycle optimal for confocal laser endomicroscopy (CLE) agent production. Consequently, we use a polyethylene glycol linker in order to increase water solubility, retain low toxicity, and to achieve high fluorescence quantum yields, as well as high conjugation yields. In this research, we were able to produce both precursors to the porphyrin-peptide conjugate, MesoPOR-(mono)-3PEG and MesoPOR-(di)-3PEG. These molecules were synthesized successfully with the use of peptide conjugation mechanisms. Molecular weights were confirmed using Matrix Assisted Laser Desorption Ionization Mass Spectrometry (MALDI-MS). Characterization was performed using 1H Nuclear Magnetic Resonance (1H-NMR) and Ultraviolet-Visible Spectroscopy (UV-Vis) of the intended molecules. The synthesized molecules, MesoPOR-(mono) 3PEG and MesoPOR-(di) 3PEG, will be useful in peptide conjugation that targets EGFR. These peptide ligands will increase selectivity and detect CRC via CLE.
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 5735. doi:1538-7445.AM2012-5735
Abstract 5741: GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity
Authors: Lin Jieru Egeria , Snook Adam , Li Peng , Schulz Stephanie , Waldman Scott 
Published: August 2012

Abstract
Background & Aims. The barrier separating mucosal and systemic compartments is formed by tight junctions annealing epithelial cells together, which limit paracellular exchange that threatens compartmental homeostasis. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Methods. Gucy2c−/− and villinERT2-ROSA-Guca2a mouse models, as well as in vivo ligand supplementation models were examined for tight junction structure by expression profile, electron microscopy, and immunoblot analysis. Barrier integrity was quantified by oral FITC-dextran after barrier disruption with DSS. Systemic genotoxicity and tumorigenesis were examined in mice with and without GUCY2C signaling. The role of AKT in tight junction regulation was examined in Akt+/− mice and in Caco2 cells using shRNA or AKT mutants. Results. Gucy2c−/− mice exhibited disrupted tight junctions, associated with reduced junctional proteins and barrier hyperpermeability. Conversely, ligand activation of GUCY2C in mice increased junctional proteins and reduced barrier permeability. Further, eliminating GUCY2C exacerbated, while activation reduced, DSS-induced barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, oxidative DNA damage and tumorigenesis in lymph nodes, liver and lung. GUCY2C regulated barrier integrity by repressing AKT1 which increased the junction proteins occludin and claudin 4 in mice and Caco2 cells. Conclusions. GUCY2C defends the intestinal barrier, restricting permeability to maintain homeostasis in mucosal and systemic compartments. The pathophysiological significance of GUCY2C-dependent barrier protection is highlighted by its impact on colitis and systemic genotoxicity and tumorigenesis in multiple organs. Its translational potential is underscored by the imminent regulatory approval of oral GUCY2C ligands, which can be used for chemoprophylaxis in inflammatory bowel disease and 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 5741. doi:1538-7445.AM2012-5741
Abstract 576: Novel compounds from Allspice (Pimenta dioica) inhibit breast cancer growth by autophagy induction
Authors: Zhang Lei , Nagarajarao Shamaladevi , Lokeshwar Bal L. 
Published: August 2012

Abstract
Background: Breast Cancer (BrCa) ranks second as cause of cancer death in women, causing 40,000 deaths in 2010. Recent studies have shown that novel plant-derived compounds used as dietary chemopreventive agents prolong survival and reduce breast cancer deaths. Lack of mechanism of action and limited bioavailability are the leading concerns for adopting natural dietary compounds as chemopreventive or adjuvant therapeutic agents against breast and other cancers. We identified several likely anti-cancer compounds from water extract of Allspice, the unripe berries of Pimenta dioica (Jamaican pepper). The compounds limit the growth of breast cancer cells by novel mechanism and may synergize with main-stream cancer therapeutics. Methods: An aqueous extract of Certified-organic Allspice (AAE) was prepared and a solution of suitable strength was tested on several BrCa cell lines (MCF-7, T47D, MDA-MB231, SKBr3) for potential inhibition of proliferation, autophagy and estrogen-receptor inactivation using commonly used analytical techniques. Potential effect on estrogen receptor levels and transcriptional activities were determined using quantitative-real time PCR, promoter luciferase assay and immunoblotting. Results: AAE reduced the viability and clonogenic growth of BrCa cells (IC50α100μg/ml) with limited activity (50% less toxicity in quiescent cells). AAE induced cell-death was only associated with several characteristics of autophagy, including increase in acidic vesicular organelle content, levels of GFP-LC3-positive puncta, and LC3-II protein level. Knockdown of ATG-7 gene expression by siRNA partially prevented AAE-induced cell death by 40%. Autophagy was induced by Endoplasmic reticulum (ER) stress but not changes in ATP levels. Further, AAE caused inhibition of mTOR signaling pathway and enhanced cytotoxicity combined with mTOR inhibitor, rapamycin. Furthermore, AAE reduced Estrogen Receptor-α protein as well mRNA levels in ERα positive-BrCa cell lines MCF-7 and T47D. The decrease in ERα protein level was only partially rescued by proteasome inhibitor MG132, indicating AAE accelerates ERα protein degradation. Activity based purification combined with chemical identification strategies resulted in identification of one compound Ericifolin, and several compounds in a highly enriched fraction exhibiting same properties as that of AAE. Conclusion: We showed the anti-cancer effects of aqueous extract of Allspice on BrCa cells, which includes anti-proliferation by inducting autophagy after AAE treatment and ERα downregulation which has promising clinical application for BrCa treatment. [Grant Support: R01 CA156776-01and Sylvester Cancer Center (BLL)].
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 576. doi:1538-7445.AM2012-576
Abstract 582: Superoxide dismutase 3 is induced by antioxidants, inhibits oxidative DNA damage, and is associated with inhibition of estrogen-induced breast cancer
Authors: Singh Bhupendra , Bhat Hari K. 
Published: August 2012

Abstract
Epidemiological data and studies in rodent models strongly support the role of estrogens in the development of breast cancers. Oxidant stress has been implicated in this carcinogenic process. We have recently demonstrated that antioxidants vitamin C or butylated hydroxyanisole (BHA) severely inhibit 17β-estradiol (E2)-induced breast tumor development in female ACI rats. The objective of the present study was to characterize the mechanism of antioxidant-mediated prevention of breast cancer. Female ACI rats were treated with E2; vitamin C; vitamin C + E2; BHA; and BHA + E2 for up to 8 months. mRNA and protein levels of superoxide dismutase 3 (SOD3) were suppressed in E2-exposed mammary tissues and in mammary tumors of rats treated with E2. This suppression was overcome by co-treatment of rats with E2 and vitamin C or BHA. 8-Hydroxydeoxyguanosine (8-OHdG) levels determined as a marker of oxidative DNA damage were higher in E2-exposed mammary tissues and in mammary tumors compared to age-matched controls. Vitamin C or BHA treatment significantly decreased E2-mediated increase in 8-OHdG levels in the mammary tissues and in MCF-10A cells. Increased nuclear translocation of SOD3 was demonstrated in vitamin C-treated mammary tissues and in MCF-10A cells. Increased DNA damage was detected after silencing SOD3. Our studies suggest that SOD3 provides protection against nuclear DNA damage. Our studies further demonstrate that SOD3 but not SOD2 and SOD1 is induced by antioxidants and is regulated through NRF2. SOD3 may thus be an important gene in defense against oxidant stress and in the prevention of estrogen-mediated breast 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 582. doi:1538-7445.AM2012-582
Abstract 584: Vitamin D suppresses pro-inflammatory cytokines and microRNAs in 3D prostatic co-cultures
Authors: Giangreco Angeline Antonio , Nonn Larisa 
Published: August 2012

Abstract
MiRNAs are involved in the progression and regulation of inflammation and the immune response in cancer. Understanding the interplay between miRNAs and inflammation in the prostate may be beneficial for the treatment or prevention of prostate cancer (PCa) with anti-inflammatory agents such as vitamin D. We previously found that vitamin D effectively blocked inflammatory cytokine signaling and secretion in primary cultures of normal prostatic epithelial cells. Because inflammatory signaling relies on the crosstalk between epithelial, stromal, and immune cells, our new studies use a human prostate 3-dimensional co-culture model of primary human prostatic epithelial (PrE) cells and stromal (PrS) cells. Single PrE cells seeded in matrigel were grown into spheroid structures termed prostaspheres (PS). Simulating an inflammatory trigger from immune cells with TNF-α and IL-1α (T+I), we found a prolonged inflammatory response in our co-cultures that persisted beyond 24 hours as compared to the transient response in monolayer cultures. IL-6 expression increased and persisted beyond 24 hours after T+I exposure in both the PrS and PS-PrE cells. However, only in the PS-PrE cells did vitamin D blocked IL-6 expression. Cytokine array profiling revealed that vitamin D decreased expression of many T+I-induced cytokine genes, including TNF, IL-1A, IL-8, CCL7. CCL5, and CXCL10. MicroRNAs are also mediators of inflammation. A miRNA microarray demonstrated that miR-146a, -155, and -223, and other miRNAs were altered by cytokine stimulation in co-culture. MiR-146a is a known mediator of inflammation and vitamin D significantly reduced T+I-stimulated miR-146a expression in both PS-PrE and PrS cells. These data demonstrate that vitamin D is involved in the regulation of inflammation at both the mRNA and the miRNA level in a novel 3D prostasphere co-culture model. As miR-146a is found to be down-regulated in PCa, further studies will determine the role of T+I and/or vitamin D in co-cultures of PS-PrE (normal) and PS-PrECa (Cancer) on miR-146a to further understand vitamin D's inflammatory role in cancer. Our model provides a more in vivo-like method to study inflammation in PCa. We will fully validate these in vitro results in laser-capture-microdissected patient tissue from a vitamin D clinical trial, in which patients were supplemented with 400-40,000 IU/day of vitamin D3 prior to radical prostatectomy. Our results should shed light on the complex inflammatory signaling pathways in the prostate and provide further evidence for anti-inflammatory benefits of vitamin D supplementation.
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 584. doi:1538-7445.AM2012-584