bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4329: Modulation of metastatic behavior in breast cancers harboring p53 mutations
Authors: Morrison Bethanie L. , Bernal Federico 
Published: August 2012

Abstract
The mutation of p53 generally occurs during the later stages of cancer and leads to the increased metastatic potential of triple negative (ER_/PR_/Her2_) breast cancer. The low survival rates of advanced metastatic cancer make it critical not only to understand the mechanisms underlying the functional implications of p53 mutation, but also to identify ways to regulate its impact in cancer cell physiology. We have previously described the design, synthesis, and evaluation of a stabilized α-helix of p53 (SAH-p53) capable of inhibiting the p53-HDM2 and p53-HDMX interactions in order to restore the functionality of p53. Despite having low expression of both HDM2 and HDMX and mutations in p53, SAH-p53 treatment of the triple negative breast cancer cell lines MDA-MB-231 and HS578T results in a modest decrease in proliferative activity. While mutant p53 is known to promote metastatic behavior of breast cancer cells, the propensity of triple negative breast cancer cells to migrate and invade through Matrigel in the presence of EGF was decreased by treatment with SAH-p53. The anti-proliferative and anti-migratory effects of SAH-p53 treatment are independent of each other, yet both are accompanied by an alteration in cell morphology that includes the loss of cell membrane integrity and actin cytoskeletal organization. The surface level of β1 integrin, which is typically kept constant by mutant p53, is decreased in the presence of SAH-p53, pointing to possible alterations in integrin recycling. SAH-p53 also causes a change in the localization of the adhesion protein and stem cell marker CD44. Moreover, it has been suggested that mutant p53 enhances invasive properties by interacting with and inhibiting isoforms of p63, which have been implicated in the regulation of cell adhesion. Treatment of the triple negative breast cancer cells with a stabilized α-helix of p63 showed a significant decrease in cell viability as well as an enhanced inhibition of migration when treated simultaneously with SAH-p53. Targeted therapy for triple negative breast cancer is currently very limited and patients must rely on standard chemotherapeutic regimens. These data show that the use of SAH-p53 and SAH-p63 peptides provides a novel avenue to study the molecular interactions that drive metastatic behavior originated by p53 gain-of-function mutations.
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 4329. doi:1538-7445.AM2012-4329
Abstract 4330: Transcriptional regulation of gp170 by YY1 and prognostic significance in childhood acute lymphoblastic leukemia (ALL)
Authors: Andres-Antonio Gabriela , Rangel-Santiago Jesus , Tirado-Rodriguez Ana B. , Dorantes-Acosta Elisa , Vega Mario I. , Aquino-Jarquin Guillermo , Lopez Briseida , Jimenez Elba , Pelayo Rosana , Bonavida Benjamin , Medina-Sanson Aurora , Huerta-Yepez Sara 
Published: August 2012

Abstract
Leukemia is the most common cancer among children under the age of 15 years in the United States and many developed countries. In recent years, there has been the emergence of novel therapeutic drugs for this disease. However, the development of drug resistance by the tumor cells remains the most important obstacle in the treatment of leukemia. A widely studied mechanism of tumor resistance to chemotherapeutic drugs is through the expression of the multi-drug resistance (MDR) genes. P-glycoprotein 170 (gp170) is an MDR1 gene product which serves as an ATP-dependent cell membrane transporter; it facilitates the efflux of xenobiotics from the cells to prevent damage for prolonged drug activity, including chemotherapeutics agents. In addition to MDR1, several reports in different cancers have indicated that the transcription factor Yin Yang 1 (YY1) is over-expressed and regulates tumor cell response to chemotherapeutic drugs. TESS analysis demonstrated that the gp170 proximal promoter contains four putative binding sites for the YY-1 protein. We also hypothesized that the YY1 may too be over-expressed in ALL and that its expression may be correlated with the expression of gp170. These hypotheses were examined first by reporter systems analyze, the gp170 protein was cloned and we developed a luciferase reporter assay. Examination of the putative YY1 binding sites that were individually mutated (deleted), showed revealed that mutation at the site –1860 abolished the activity. Mutation at the site –1920 abolished approximately 50% and mutation at –1230 site abolished approximately 25%. Further, CHIP analysis demonstrated that YY1 transcription factor binds directly to the gp170 gene MDR1 promoter. In addition, we examined the expression of YY1 and gp170 in childhood ALL (n= 84). The expression of YY1 and gp170 was determined evaluated by IHC in tumor tissues and the frequency of positive cells was determined. For comparison, normal controls were also analyzed (n=53). The findings demonstrate that were a significant increase in the frequency of positive cells in ALL compared to controls for both YY1 (38% vs. 8%, p=0.001) and for gp170 (42% vs. 12%, p=0.001). There was a good correlation between the expression of YY1 and gp170 (Pearson's test, r=0.4, p=0.001). The findings suggest that YY1 transcriptionally regulates the mdr1 and may be a therapeutic target in MDR positive ALL and its inhibition may reverse resistance to chemotherapeutic drugs.
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 4330. doi:1538-7445.AM2012-4330
Abstract 4331: Analysis of stem cell-like compartments in Embryonal Rhabdomyosarcoma modulated by Sonic Hedgehog signaling
Authors: Satheesha Sampoorna , Walter Dagmar , Bornhauser Beat , Schäfer Beat W. 
Published: August 2012

Abstract
Rhabdomyosarcoma (RMS) is a heterogeneous group of malignancies with features of impaired skeletal muscle differentiation and represents the majority of the soft tissue cancers in the pediatric age group. Current treatment regimens offer some clinical respite but at a significant risk of averse side effects and secondary tumors later in life. Identifying and targeting sub-populations with higher tumorigenic potential and self renewal capacity not only decreases tumor burden but also lowers the probability of relapse. Using the sphere formation assay we could select for self-renewing cells from the heterogeneous monolayer cultures of embryonal RMS cell lines, RD and Rh36, which had multipotent differentiation ability in vitro and greater tumorigenic potential in vivo. Preliminary results suggest that the self renewing ability of RMS cells could be modulated by Hedgehog signaling, a developmental pathway important in RMS biology. Microarray analysis of the sphere cultures revealed Prominin 1 (CD133) as one of the surface markers with significantly higher expression. The CD133-positive cellular sub-population was more resistant to DNA damaging agents and had a greater capacity for tumor formation in an orthotopic xenotransplantation model. Embryonal RMS patients with higher expression of CD133 had a significantly lower overall survival. Ongoing work seeks to validate the importance of Hedgehog signaling in the embryonal RMS stem cell-like compartment.
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 4331. doi:1538-7445.AM2012-4331
Abstract 4333: Difference in the synergistic effect of cytotoxicity in pediatric brain stem gliomas and adult glioblastomas to combination treatment with temozolomide and molecular target-specific agents
Authors: Kim Dong Ok , Shin Hong Kyung , Ra Yoon Hwan , Park Jun Bum , Ra Young Shin 
Published: August 2012

Abstract
Brain stem glioma (BSG) in children is comparable to adult glioblastoma (GBM) with regard to poor survival and resistance to chemo-radiation therapy. Temozolomide (TMZ) is an alkylating agent and rapidly penetrates the central nervous system (CNS), making it a standard chemotherapeutic agent for adults with malignant glioma. Despite some improvement of survival, radiation with TMZ monotherapy rarely provides long-term control. This study aimed to determine combination effect of conventional anticancer agent, TMZ and molecular target-specific agents such as Sunitinib, Tandutinib, Cediranib and Rapamycin in BSG and GBM. The drug combination effects were tested by cell proliferation inhibition in glioma cells from six children with BSG and five established GBM cell lines. The half-maximal inhibitory concentration (IC50) of each agent was estimated 48hr after treatment of agents by cell proliferation assay. The values of IC50 in brain stem gliomas were higher as much as 1.5 to 4 times than those of GBM cell lines in all of agents, suggesting that brain stem gliomas are more resistant to not only TMZ, but also to various molecular target specific agents. O6-methylguanine methyltransferase (MGMT) promoter methylation status was determined by methylation-specific PCR after bisulfite treatment. As a result, MGMT promoter methylation was detected in all of GBM cell lines, whereas incomplete methylated or unmethylated MGMT was shown in six brain stem gliomas from pediatric patients. For combination therapy, IC10 of each agent plus IC10 of TMZ was treated in each cell for 48hr to assess cytotoxicity. TMZ+Cediranib, +Rapamycin, +Sunitinib showed some tumor proliferation inhibition in 60%, 40%, 20% of 5 GBM cell line respectively. In BSGs, however TMZ-Sunitinib and TMZ-Cediranib presented considerable tumor growth inhibition in 2 (33%), 1 (16%) among 6 BSGs although most BSGs were unmethylated in MGMT promoter. BSGs in children showed different chemotherapeutic effect and MGMT promoter methylation status compared to GBM in adult. The combination therapy of TMZ and molecular target-specific agents showed more synergistic effects in cytotoxicity for BSG and GBM than TMZ only. Also children with BSG can be more effectively treated with TMZ with multiple molecular targeted agents such as Sunitinib than adult GBM. These results can be translated clinically to develop new chemotherapeutic trials for children with BSG.
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 4333. doi:1538-7445.AM2012-4333
Abstract 4343: Ionizing radiation reduces VLA4 mediated adhesion of macrophage via generation of ROS
Authors: Yuan Ye , Wu Shiyong 
Published: August 2012

Abstract
Adhesion molecules have direct connection with radiation-associated atherosclerosis which is an adverse effect observed after radiation therapy, but the mechanism is still not fully understood. Considerable interest has been focused on the effect of radiation on endothelial cells. Previous work has demonstrated that adhesion molecules of endothelium are up-regulated after exposure to ionizing radiation, which facilitates adhesion of leukocytes and lymphocytes. However, as the initiator in the atherosclerosis development, not enough attention was paid to macrophages which are exposed to the same radiation. In this study, we report that the adhesion between very late Antigen-4 (VLA-4) and its ligand vascular cell adhesion molecule-1 (VCAM-1), the most important adhesion molecules for atherosclerotic lesion formation, was reduced after a clinical dose of radiation (5 Gy). All the adhesion evaluations were tested under flow conditions by using a parallel plate flow chamber to mimick physiological shear stress. We found that the adhesion decreased after irradiation despite macrophage surface expression of VLA-4 was up-regulated in a time dependent manner. Total level of alpha-4 integrin increased whereas beta-1 had no change. Pretreatment with free radical scavenger N-acetylcysteine (NAC) did not change integrin expression but eliminated the adhesion difference following irradiation. Taken together, we hypothesize high levels of ROS generated by ionizing radiation inhibits the affinity of VLA-4 to VCAM-1, in which integrin expression is not the dominant factor.
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 4343. doi:1538-7445.AM2012-4343
Abstract 435: Targeted exome sequencing to understand tumor progression and identify targeted therapies
Authors: Greenawalt Danielle , Hardwick James , Zhang Theresa , Ferguson Mark , Lewis Patrick , Hunstman Shane , O'Brien Shawn , Tu Zhidong , Lezhnin Sergey , Loboda Andrey , Kerzner Cathy , Yeatman Timothy J. , Dalton William , Dai Hongyue 
Published: August 2012

Abstract
There is a large effort in the public domain to systematically perform DNA and RNA sequencing on large numbers of tumor samples. These efforts will bring us to a greater understanding of tumor biology and lead to identification of new tumor drivers. However, these efforts may fall short in allowing us to understand the progression of tumor resistance, relapse and metastasis, factors which make tumors difficult to treat and increase mortality rates. We are currently performing targeted DNA sequencing on 4000 tumor samples. We have selected 1321 genes, 5 GB of the genome to sequence. Genes were selected through a thorough review of the literature, mutation databases and key pathways in tumorigenesis such as growth factor signaling, DNA damage, p53 signaling, cell cycle and apoptosis. Our effort not only includes a diverse panel of breast, colon, ovarian, and kidney tumors but we have also sequenced pancreatic, liver, esophageal, cervix, endometrial, melanoma, CLL, DLBCL and carcinoid tumors. Our dataset also includes approximately 300 matched tumor-metastatic pairs and an additional 550 metastatic samples. Clinical phenotypes, treatment information, gene expression profiling and copy number variation data is available for all samples. To achieve the next level of care for cancer patients we must understand the biology of the tumors we are trying to treat, which are often metastatic and standard of care resistant. We believe that increasing our efforts in targeted DNA sequencing of key tumor and metastatic samples will allow us to achieve these goals.
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 435. doi:1538-7445.AM2012-435
Abstract 4350: Normal stem cells exhibit hypersensitivity and cell death in response to ionizing radiation
Authors: Misri Sandeep , Jacobs Keith , Hallahan Dennis E. , Sharma Girdhar G. 
Published: August 2012

Abstract
Radiotherapy is an efficient method of treating cancer. Several decades of clinical observation in patients treated with radiation/ radiomimetic drugs has, however, revealed undesirable consequences to the normal tissue. Ionizing radiation induced normal tissue injury manifests through symptoms such as hair loss, skin regeneration defects, erosion of intestinal epithelium, hematopoietic anomalies, diminished sperm counts, infertility, neuro-cognitive impairments etc. The phenomenon of “stem cell drop-out” can be attributed as the underlying cause for these side effects. However, insufficient research has been conducted for investigating the relative radiosensitivity of undifferentiated stem/ progenitor cells compared to their differentiated progenies and the underlying molecular mechanisms of this differential radiation response (DNA damage response and IR induced apoptotic response). We demonstrate stem cell specific apoptosis and hypersensitivity to low dose IR in various stem cell niches in vivo. Further, this stem cell hypersensitivity observed in the mouse tissue niches, is recapitulated in multiple primary cell culture models of undifferentiated stem cells and isogenic differentiated cells grown in appropriate stem cell culture/ differentiation conditions. Cell cycle parameters, checkpoint response and radiosensitive phases of these cells have been studied. Towards characterizing the novel associations between cellular differentiation, DNA damage response and apoptotic response, we have studied alterations in transcription profiles of stem and isogenic differentiated cells with and without radiation. Our investigation has uncovered transcriptional induction and suppression of genes that are unique to differentiation states. Results of our studies will be presented.
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 4350. doi:1538-7445.AM2012-4350
Abstract 4351: Exposure to ionizing radiation causes long-term increase in serum estradiol and activation of PI3K-Akt signaling pathway in mouse mammary gland
Authors: Suman Shubhankar , Johnson Michael D. , Fornace Albert J. , Datta Kamal 
Published: August 2012

Abstract
Purpose: Exposure to ionizing radiation is an established risk factor for breast cancer. Radiation exposure during infancy, childhood and adolescence confer the highest risk. Although radiation is a proven mammary carcinogen, it remains unclear where it acts in the complex multi-stage process of breast cancer development. In this study, we investigated the long-term pathophysiological effects of ionizing radiation at a dose (2Gy) relevant to fractionated radiotherapy. Methods and Materials: Adolescent (6 to 8 weeks old; n=10) female C57BL/6J mice were exposed to 2 Gy of total body ≤ radiation and the mammary glands were harvested and serum and urine samples were collected 2 and 12 months post-exposure. Molecular pathways involving estrogen receptor alpha (ERalpha) and phosphatidylinositol-3-OH kinase (PI3K)-Akt signaling were investigated by immunohistochemistry and western blot. Results: Serum estrogen and urinary levels of the oncogenic estrogen metabolite (16alphaOHE1) were significantly increased in irradiated animals. Immunostaining for the cellular proliferative marker Ki-67 and cyclin-D1 showed increased nuclear accumulation in sections of mammary glands from irradiated versus control mice. Marked increase in p85alpha, a regulatory sub-unit of the PI3K was associated with increase in Akt, phospho-Akt, phospho-BAD, phospho-mTOR, and c-Myc in irradiated samples. Persistent increase in nuclear ERalpha in mammary tissues at 2- and 12-month after radiation exposure was also observed. Conclusions: Taken together our data not only supports epidemiological observations associating radiation and breast cancer but it also for the first time specifies molecular events that could be involved in radiation-induced 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 4351. doi:1538-7445.AM2012-4351
Abstract 4352: Radiotherapy-induced plasma cytokine changes and skin toxicity in breast cancer patients
Authors: Liu Zhi , Thomas Venetta , Wright Jean L. , Takita Cristiane , Poitevien Martine , Abreu-Molnar Diana , Zhao Wei , Reis Isildinha , Hu Jennifer 
Published: August 2012

Abstract
Breast cancer is the most common neoplasm and the second leading cause of cancer death in American women. Radiotherapy (RT) is an effective adjuvant treatment after breast-conserving surgery for early-stage breast cancer. However, the majority of breast cancer patients undergoing RT develop acute skin reactions. We pilot tested the effects of RT on immune system and inflammatory cytokines in 12 breast cancer patients (6 with high and 6 with low skin toxicity). Using the Human Cytokine ELISA Plate Array I (Signosis Inc., Sunnyvale, CA), we evaluated 31 plasma cytokines in RT-related skin toxicity. The National Cancer Institute Common Terminology Criteria for Adverse Effects (version 3.0) was used to evaluate skin toxicity grade. Our data showed that RT induced epidermal growth factor (EGF); at baseline EFG was not detectable while post RT-treatment significant levels of EFG was observed (mean+SD: 395±620.4, p=0.0496). Interleukin (IL)-2 was significantly elevated by RT (6.5x106±1.01x106 vs. 4.85x106±1.44x106, p=0.0004). Adiponectin was significantly higher at post RT (3.09x106±1.31x106) than pre RT (1.77x106±1.52x106, p=0.0002). RT-related changes of IL-4 was significantly associated with skin toxicity at week 3 (p=0.018); IL-4 was decreased in patients without toxicity (-668.3±1691.5) and increased in patients with grade 2 toxicity (1830.0±1365.4). IL-12 showed similar trend but with marginal significance (p=0.076). RT-related changes of EGF was significantly associated with skin toxicity at week 6 (p=0.045); EGF was not changed in patients with no or low toxicity (grade 0/1) and increased in patients with grade 2/3 toxicity (592.5±686.4). In summary, our pilot data suggest that RT induces EGF, IL-2, and adiponectin. RT-related changes of IL-4 and EGF were associated with skin toxicity. Our ongoing study with a targeted sample size of 1,000 may shed light on the molecular mechanisms of cytokines in RT-related skin toxicity of breast cancer patients.
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 4352. doi:1538-7445.AM2012-4352